The Association between Insulin Dose and …dnp.musites.org/wp-content/uploads/2019/05/Noemi... · Web viewIn a retrospective and cross-sectional approach in 2012 and 2017 respectively

Running head: ASSOCIATION BETWEEN INSULIN DOSE AND HEMOGLOBIN A1C 1

The Association Between Insulin Dose and Hemoglobin A1C in Adult Patients with Type II

Diabetes

Noemi Pamaran Capistrano

Maryville University

ASSOCIATION BETWEEN INSULIN DOSE AND HEMOGLOBIN A1C 2

Abstract

This scholarly project investigated adult patients with type II diabetes utilizing three

nonphysiologic insulin (NPI) regimens used in primary care clinics and examined if these

regimens had an association with the hemoglobin A1c (HbA1c). Nonphysiologic insulin

regimens do not mimic normal insulin secretion; overestimating the basal and underestimating

the bolus of the total daily insulin dose. These NPI regimens were: (a) basal insulin monotherapy

of greater than 0.5 units per kilogram per day, (b) neutral protamine Hagedorn (NPH) and short-

acting or premixed insulin given in equal doses (+10%) twice a day, and (c) basal-bolus insulin

therapy in which the basal dose is greater than 55%, and the bolus dose is less than 45% of the

total daily dose. All other insulin (AOI) regimens comprised the control group of insulin

regimens outside the three NPI definition. This project analyzed the mean HbA1c difference

between the NPI and AOI groups. A retrospective chart review using the pharmacy database and

the electronic health record guided this study. SPSS calculated the mean HbA1c difference

between the NPI and AOI group using an Independent and Paired Samples t-Test. The three NPI

regimens was associated with HbA1c inertia. Reduction in the HbA1c is higher in the AOI

group. A significant statistical difference exists between the change in the mean HbA1c for the

NPI and AOI groups (p=0.009). The findings in this study supported the proposal that NPI delay

improvement in the HbA1c of adult patients with type II diabetes. Increasing the awareness of

primary care providers, advanced practice registered nurses (APRN) and registered nurses (RN)

of the minimal reduction in the HbA1c of NPI regimens and to proactively adjust insulin

replacement therapy following physiologic principles may counter HbA1c inertia.

Key Words: type II diabetes, primary care, basal-bolus and nonphysiologic insulin

regimen.


Acknowledgments

For every enormous goal in any research journey, there are people behind who stands by

to assure that the study reaches the finish line and hopefully obtain a measurable outcome with a

scientific basis. My first acknowledgment goes to my chair Dr. LaDonna Whitten, Dr. Michael

Landry, the university statistician and Dr. Mariea Snell for their continued support and guidance

in helping me complete my DNP scholarly project. Thank you, Dr. Whitten, for facilitating the

application of the IRB amendment to increase the study sample size and adding a comparison

group. With your proficiency in the university’s educational system, I was able to acquire an IRB

amendment approval within 48 hours. Thank you, Dr. Landry, for your help in the statistical

analysis of this research.

Next, I would like to thank Dr. Eli Ipp, my physician mentor who supervised this

research study to allow it to reach its most rigorous state. He framed a robust foundation possible

for this analysis and guided the way to build knowledge on existing data and analyze it with a

trained eye that only vast years of academic and clinical experience could see. He pushed and

encouraged me to settle for nothing less and reminded me that everything that is worthwhile

requires hard work. To Dr. Rachelle Bross, thank you for your thought-provoking questions. And

to Pauline Genter MS, RD, thank you for pointing out often that these too will pass.

Lastly, to my husband who always believed in me, and not once doubted that I could

accomplish my quest in getting my DNP. He remained unmoved when everything else was

uncertain. His faith in God never wavered. To my precious daughter whose everyday mantra

became “You can do it, mommy.” You are a little glimpse of heaven here on earth. And, to my

sister for her endless support, I could not have done it without you.


Table of Contents

CHAPTER I: Introductio

n.......................................................................................................................................................7

Background............................................................................................................................8

Problem Statement...............................................................................................................11

Purpose................................................................................................................................11

Research Question...............................................................................................................12

Significance.........................................................................................................................12

Nursing.........................................................................................................................12

Healthcare...................................................................................................................13

Advanced Practice Nursing.........................................................................................14

Practice Support for Project................................................................................................15

Benefit of Project to Practice..............................................................................................15

Conclusion..........................................................................................................................15

CHAPTER II: Review of Literature..............................................................................................18

Search History.....................................................................................................................18

Glucose Optimization and Hypoglycemia Prevention.........................................................20

Insulin...................................................................................................................................21

Primary Care Barriers..........................................................................................................29

Disease Management...........................................................................................................31


Literature Critique...............................................................................................................31

Strengths...............................................................................................................................31

Weaknesses...........................................................................................................................32

Gaps......................................................................................................................................33

Limitations...........................................................................................................................34

Concepts and Definitions......................................................................................................35

Theoretical Frameworks......................................................................................................36

Conclusion...........................................................................................................................38

CHAPTER III: Methodology........................................................................................................41

Needs Assessment...............................................................................................................41

Research Design..................................................................................................................42

Sample.................................................................................................................................42

Setting..................................................................................................................................43

Data Collection Instrument..................................................................................................44

Data Collection Procedure...................................................................................................44

Data Analysis Plan...............................................................................................................46

Resources.............................................................................................................................47

Budget..................................................................................................................................47

Timeline...............................................................................................................................48

Protection of Human Subjects.............................................................................................48


Conclusion...........................................................................................................................49

CHAPTER 1V: Results.................................................................................................................51

Statistical Tests and Rationale.............................................................................................51

Patient Characteristics........................................................................................................51

Insulin Usage and HbA1c..................................................................................................55

CHAPTER V: Discussion..............................................................................................................64

Hemoglobin A1c Inertia......................................................................................................64

Insulin Adjustment..............................................................................................................66

Bolus Insulin Phobia...........................................................................................................67

Implications of Findings and Study Duration......................................................................67

Physiologic Insulin Replacement........................................................................................67

Clinical Significance............................................................................................................68

Limitations and Strengths...................................................................................................69

Conclusion and Recommendations.....................................................................................70

References......................................................................................................................................72

Appendix A....................................................................................................................................83

Appendix B....................................................................................................................................84

Appendix C....................................................................................................................................86

Appendix D....................................................................................................................................87

Appendix E....................................................................................................................................88


Chapter 1

Introduction

The Centers for Disease Control and Prevention (CDC) estimated in 2017 that 9.4% or

30.3 million of the United States population have diabetes. Diagnosed diabetes accounts for 23.1

million people, and undiagnosed diabetes burden 7.2 million individuals (CDC, 2017). An

estimated 87% to 91% of patients with diabetes have type II diabetes, and 7% to 12% have type I

diabetes (Ogurtsova et al., 2017). One in three Americans will have diabetes by 2050 which

constitutes an alarming prediction (Boyle, Thompson, Gregg, Barker, & Williamson, 2010).

Diabetes continues to be the seventh leading cause of mortality in the U.S and accounts for

200,000 deaths annually (CDC, 2017; Roumie et al., 2014). This chronic disease condition costs

the U.S economy an estimated 266 billion dollars annually which is causing a strain on an

already burdened healthcare system (Gallup News, 2017).

The Los Angeles Department of Health Services (LADHS) is the second largest

metropolitan health system in the U.S and cares for an estimated 600,000 patients (LADHS,

2017). Diabetes has risen to an epidemic proportion nationwide, but not as rapid as the

progression in Los Angeles County. According to the LA County Department of Public Health

(LADPH) in 2012, the age-adjusted rate of diabetes in the county of Los Angeles has gone up by

50% in the last ten years. The estimated medical cost is approximately 6.4 billion annually.

About 685,000 adults who reside in this urban city have diabetes, a rise from 6.6% to 9.9% from

1997 to 2011. The rate for diabetes in Los Angeles is 22% higher than the national average

(Huckfeldt et al., 2012; LADPH, 2012). A study initiative centered on physiologic insulin

management in primary care clinics may help to halt the diabetes progression in LA county.


Background

Insulin replacement therapy is critical in diabetes management. Studies estimated that

50% of patients with type II diabetes would require insulin therapy within six years from

diagnosis (Brunton, Kruger, & Funnell, 2016; Home et al., 2014; Muharrem, Sucakli, Canbal, &

Kosar, 2015). Approximately 90% of patients with type II diabetes access care from their

primary care physicians; however, insulin replacement therapy in the outpatient clinic continues

to challenge providers and most defer the treatment (Home et al., 2014). The number of patients

receiving insulin replacement therapy remains below the standard expectation (Muharrem et al.,

2015) and less than 50% of patients with type II diabetes reach a hemoglobin A1c of 7%

(Giugliano, Maiorino, Bellastella, Chiodini, & Esposito, 2011).

A possible reason for the high rate of patients with uncontrolled type II diabetes on

insulin therapy in primary care may be due to infrequently using physiologic principles in insulin

replacement therapy. These physiologic insulin regimens mimic the normal pancreatic insulin

secretion (DeWitt & Hirsch, 2003) and is the recommended approach in insulin management

(Bellido et al., 2015; Giugliano, Chiodini, Maiorino, Bellastella, & Esposito, 2016; Giugliano et

al., 2011; Riddle et al., 2014; Owens, 2013).

In this research, the author introduced the concept of nonphysiologic insulin (NPI)

regimens. These insulin regimens are problematic in insulin management due to the possible

increased risks of hypoglycemia and delayed improvement in the HbA1c of patients with type II

diabetes. DeWitt and Hirsch (2003) suggested that nonphysiologic insulin replacement therapy

are insulin regimens that does not mimic normal pancreatic insulin secretion. In other recent

studies, the authors reported that insulin ratios that overestimate the total basal dose and


underestimate the total bolus dose were related to uncontrolled HbA1C in patients with type I and

type II diabetes (Dailey, Aurand, Stewart, Ameer, & Zhou, 2014; Kuroda et al., 2011; Porcellati,

Lin, Lucidi, Bolli, & Fanelli, 2017). The author of this research study added this definition to the

NPI concept. Hence, NPI regimens are insulin practices that overestimate the basal and

underestimate the bolus insulin doses which does not mimic normal insulin secretion.

Anecdotal reports of NPI utilization in primary care may prevent improvement in a

patient’s glucose control. Due to the scarcity of diabetes specialists, providers in the primary care

setting are encouraged to enhance and master the skills of initiating and adjusting insulin

regimens appropriately (Brunton et al., 2016). The awareness of a possible association between

NPI and uncontrolled HbA1c is a significant element in the proficiency of insulin management.

One of the primary goals in insulin management includes prevention of hypoglycemia

(ADA, 2017). Increased risk of hypoglycemia events are possible outcomes of NPI regimens. A

study of medicare patients in 2014 reported that hospital admission rates for hypoglycemia have

surpassed that of hyperglycemia in older adults (Lipska et al., 2014). Providers must learn to

balance euglycemia and hypoglycemia prevention by using physiologic concept in insulin

therapy. Ensuring the use of a physiologic insulin approach can be the means to maintain this

balance. Most certified diabetes educators (CDE) have mastered physiologic principles in insulin

therapy. This expertise can be transferred to registered nurses (RNs) including advanced practice

registered nurses (APRN) and providers in the outpatient primary care clinics to assist in

achieving euglycemia promptly.

The American Diabetes Association (ADA) position statement regarding the standards of

medical care in diabetes does not explicitly state a physiologic approach in insulin replacement

therapy (ADA, 2017). Neither does the European Association for the Study of Diabetes [EASD]


(Inzucchi et al., 2012). A study by Mao et al. (1997) in patients with type II diabetes suggested

an insulin ratio of 40% basal and 60% bolus was appropriate in getting the glucose

concentrations to target following these physiologic principles in insulin therapy. A recent study

by Yamada et al. (2017) supported an insulin ratio of 30% basal to 70% bolus of the total daily

dose which achieved an HbA1c of less than 7.5% in patients with type I diabetes. This research

study will investigate the most common nonphysiologic insulin dose trends in the outpatient care

setting and its impact on the HbA1c.

Promoting early insulin initiation is crucial to diabetes management due to the delay in

implementing appropriate insulin therapy may cause macrovascular and microvascular

complications (Brunton et al., 2016). Macrovascular complications affect the coronary and

peripheral large blood vessels resulting in strokes and amputations while microvascular

complications affect the kidneys, the nerves, and the eyes. Gamble et al. (2017) gave support to

the overall safety of the use of insulin for treating type II diabetes. This report must reassure

providers on the safety of insulin therapy in the management of diabetes. Efforts directed

towards improving the HbA1c of patients on insulin therapy may reduce dangerous diabetes

complications

Hemoglobin A1c (HbA1c) is a blood test that measures a person’s average blood sugar

over the past two to three months and indicates glucose management (American Diabetes

Association [ADA], 2014). A normal HbA1c is less than 7% equivalent to a blood sugar average

of about 150 milligrams per deciliter (ADA, 2017). The United Kingdom Prospective Diabetes

Study (UKPDS) demonstrated that as little as a 1% decrease in the HbA1c level correlated to a

37% reduction in small vessel diseases and a 21% decline in the death risk for patients with type

II diabetes (UKPDS, 2014). It is a worthwhile task to reduce the HbA1c of patients with


uncontrolled diabetes at any level to decrease their diabetes-related death risks and promote

health.

Examining the impact of NPI on the HbA1c is essential in improving diabetes

management in primary care because it can change clinical practice by promoting appropriate

insulin ratios in insulin replacement therapy. It is vital to collaborate with the different primary

care medical homes (PCMH) to prevent delay in insulin therapy. This teamwork, in turn, can aid

in accomplishing the perfect aim of diabetes management of preventing long-term complications

(Home et al., 2014; Inzucchi et al., 2012) and improving the health of the patient and the

community.

Problem Statement

There are three nonphysiologic insulin regimens identified by the investigator in the

outpatient primary care clinics in the Western region of the U.S that may hinder improvement in

the HbA1c and may cause hypoglycemia of patients with type II diabetes. These three NPI

regimens are: (a) a basal insulin monotherapy of greater than 0.5 units per kilogram per day, (b)

neutral protamine Hagedorn (NPH) and short-acting or premixed insulin given in equal doses

(+10%) twice a day, and (c) basal-bolus insulin therapy in which the basal dose is greater than

55% and the bolus dose is less than 45% of the total daily dose. Addressing the impact of these

three NPI regimens on the HbA1c may assist in ameliorating the diabetes complications and

prevent hypoglycemia events of patients with type II diabetes in the primary care outpatient

clinics at Harbor UCLA Medical Center in Los Angeles.

Purpose

The purpose of this research is to study the association of three nonphysiologic insulin

regimens with HbA1c levels. The overall goal is to investigate patients utilizing three NPI


regimens used in the primary care outpatient clinics and to examine if these insulin practices

have a relationship with the HbA1c. A significant benefit of this study is the potential for

improving patient safety by reducing hypoglycemia events and possible improvement of the

HbA1c levels.

Research Question

The research inquiry this project explored was: In adults with type II diabetes, does

nonphysiologic insulin replacement therapy based on three identified insulin regimens affect the

HbA1c levels? The target population was adult patients with type II diabetes, the experimental

group was patients on NPI regimens, the comparison group was patients on all other insulin

(AOI) regimens, and the outcome variable was the HbA1c levels.

Significance

Nursing

In a 2010 study, a nurse-managed diabetes intervention program decreased the HbA1c of

132 patients from 11.1% to 7.3% in a 9 to 12-month period. This approach employed a self-

mixed/split insulin regimen adjusted by an RN using a structured insulin protocol which was

successful in achieving the target HbA1c of patients with type II diabetes (Davidson, Blanco-

Castellanos, & Duran, 2010). Registered nurses are great resources to activate in promoting

physiologic insulin management in primary care (Pettitt, Okada Wollitzer, Jovanovic, He, & Ipp,

2005).

The Los Angeles Department of Health Services (LADHS) have RNs who are diabetes

specialist including a cadre of certified diabetes educators (CDE) who are experts in adjusting

insulin regimens under standardized protocol in a diabetes specialty clinic. This expertise which

include using physiologic principles in insulin replacement therapy can be translated into the


primary care clinic to help with the insulin therapy challenges that primary care providers

encounter daily. Extending this specialty following physiologic insulin adjustments may provide

the necessary assistance to improve insulin management in primary care and may help in

decreasing the diabetes rate in Los Angeles county. This approach promotes collaboration and

encourages cohesiveness.

Studies show that greater than 50% of patients on multiple insulin injections per day

continue to have persistent hyperglycemia (Giugliano et al., 2016; Jia et al., 2015; Malek et al.,

2014). This research may target this affected population by identifying the impact of

nonphysiologic insulin regimens on the HbA1c and recommend for the clinical staff to optimize

treatment by utilizing appropriate insulin replacement therapy preventing persistent

hyperglycemia.

Healthcare

Although, there is an advancement in technology, the artificial pancreas or insulin pumps,

continuous glucose monitors, availability of newer insulin analogs and modern oral

hyperglycemic agents, diabetes mellitus has gone pandemic (Ogurtsova et al., 2017). The

expense for diabetes care continues to accelerate and the ramification of this chronic disorder has

become a worldwide concern. The healthcare industry must optimize efforts in reversing this

diabetes projection.

Team management may be another way to improve diabetes care. Brunton et al. (2016)

described the beneficial effect of a team approach to managing type II diabetes. Huckfeldt et al.

(2012) explained how diabetes disease management made an influence in the reduction of the

HbA1c level of patients with type II diabetes by including other healthcare professionals, social

workers, nutritionists, and registered nurses in the care of the patient. The HbA1c reduction was


2% to 4.5% from starting the intervention until achieving the goal of less than 8% (Huckfeldt et

al., 2012).

The expeditious glycemic control of patients with type II diabetes in the primary care

setting with effective insulin therapy may significantly impact health care cost. This research

project may lessen medical expenses by decreasing emergency room visits and hospitalizations.

According to the ADA (2013), diabetes complications cost the U.S an estimated 245 billion

dollars annually, which escalated to 266 billion dollars in 2017 (Gallup News, 2017). This study

can potentially reverse the rise in the cost of diabetes in the outpatient primary care clinics across

Los Angeles Department of Health Services by promoting physiologic insulin regimens which

may bring down the HbA1c faster preventing complications.

Advanced Practice Nursing

In the clinical setting advanced practice registered nurses (APRN) are on the front-line

with patient care. The Doctor of Nursing Practice (DNP) prepared nurses hold the proficiency in

recognizing prevailing customs in the clinic system, understanding the practice process and

possessing the qualifications to improve population management in their fields of expertise. In

the realms of informatics, the DNPs received training on information system and technology to

analyze health care performance, patient management outcomes, and care operations. Their

educational exposures include training in organizational leadership and policy change (Terry,

2015). These characteristics deemed the APRN in a DNP position to be the most qualified

professional to bring knowledge to the clinical environment. APRNs can be the key for clinical

practice change in insulin management to promote safety and achieve target glucose levels.


Practice Support for Project

Multiple research staff in the outpatient clinical setting supported this project. The chief

medical officer from the department of Diabetes and Metabolism for the public hospital system

advocated and encouraged the proposal for this research project (see Appendix A). He

supervised the undertaking of this retrospective chart review. A research coordinator who has

more than a decade of research experience including database management participated in

weekly meetings to contribute in reviewing the research progress. A clinical pharmacist from the

same site supported the undertaking by making available excel files with the pharmacy data of

patients on insulin replacement therapy.

Benefit of Project to Practice

Allowing prompt management of diabetes control can prevent complications such as

myocardial infarctions, strokes, diabetic retinopathies, and amputations to name a few

consequences. Promoting patient safety by preventing and decreasing hypoglycemia events is

another advantage. Increasing the awareness of RNs, APRNs and providers of the negative

impact of nonphysiologic insulin regimens on the HbA1c may improve diabetes management in

the clinical setting.

Conclusion

The acceleration in the prevalence of diabetes in the United States demands attention

from all facets of the healthcare system. Los Angeles County seemed to be one of the most

affected urban city with a diabetes rate that is 22% higher than the national average. Majority of

patients with type II diabetes obtain medical management from primary care providers, but more

than half have uncontrolled glucose levels. Most of these patients will require insulin to achieve


a target HbA1c level, but providers in primary care continue to struggle with insulin replacement

therapy.

Anecdotal reports from diabetes specialists have emerged regarding nonphysiologic

insulin regimens utilized in primary care clinics. The literature described nonphysiologic insulin

(NPI) regimens as insulin doses that exagerate the basal and minimizes the bolus insulin

coverage which may contribute to a delay in the improvement of the hemoglobin A1c (Dailey et

al. 2014; Kuroda et al., 2011; Porcellati et al., 2017). Identifying the prevalence of NPI in

primary care may be an initial step to halt the diabetes progression in Los Angeles County.

Hemoglobin A1c (HbA1c) is the average blood glucose of about three months disclosing

a patient’s glucose management. The United Kingdom Prospective Diabetes Study (UKPDS)

reported that a 1% decrease in the HbA1c levels was linked to a 21% reduction in diabetes-

related deaths. It is important to better understand the impact of nonphysiologic insulin regimens

on the HbA1c to prevent complications and reduce the number of uncontrolled diabetics in

primary care. To date, there is no study found about the association between nonphysiologic

insulin regimens and the HbA1c although NPI descriptions exist in some literature. It is a

worthwhile goal to aid in decreasing the HbA1c of patients with type II diabetes by

accommodating physiologic approaches to insulin management.

Physiologic doses are insulin regimens that attempt to follow the body’s normal function.

A study by Mao et al. (1997) operationalized physiologic insulin as 40% basal and 60% bolus of

the total daily dose. A recent report by Yamada et al. (2017) suggested an insulin ratio of 30%

basal and 70% bolus dose achieved the target HbA1c of patients with type I diabetes. These

insulin regimens mimic normal pancreatic secretions as it provides more coverage for the bolus

(meal-time) and less for the basal (background) dose. In contrast, various studies suggested


insulin regimens that overestimated the basal and underestimated the bolus resulted to

uncontrolled glucose in both type I and type II diabetes (Dailey et al., 2014; Kuroda et al., 2011;

Porcellati et al., 2017). Avoiding NPI regimens in primary care may prevent glucose elevation.

A group of diabetes specialist in the diabetes clinic include certified diabetes educators (CDE)

who are RNs that have mastered insulin replacement therapy using physiologic concepts due to

a daily practice focused on diabetes case management. This skill needs to be translated to the

patient-centered medical homes (PCMH) since the largest number of patients with diabetes

obtain care from these clinics.

For this research project the purpose was investigating the impact of nonphysiologic

insulin regimens on the HbA1c levels. Identifying the prevalence of the three most common

nonphysiologic insulin regimens may reveal avenues for improving insulin management of

patients with type II diabetes in primary care. Ensuring the expeditious glycemic control for

patients with type II diabetes may impact healthcare cost by decreasing emergency room

encounters and hospitalizations. The DNP prepared nurse may be the catalyst to moving

evidence-based research to the clinical setting. The ultimate goal of this research project is to

prevent complications and assist in reversing and delaying diabetes whereby improving the

health of patients with type II diabetes and the community.


Chapter 2

Review of Literature

The purpose of this chapter was to review relevant literature to understand the

relationship between NPI and the HbA1c with the intention of promoting safety by preventing

hypoglycemia events and potentially improving diabetes management. The epidemic of type II

diabetes mellitus in the Western region of the United States has risen to an alarming proportion

(LADPH, 2012); nevertheless, insulin replacement therapy continues to be a delayed and

challenging intervention in the primary care clinical setting (Brunton et al., 2016). The various

insulin regimens used in the primary care setting are a starting point in the identification of

challenges faced by providers and nursing staff in insulin replacement therapy.

This research project is significant to healthcare, to patients and nursing due to the

potential of promoting patient safety by preventing hypoglycemia events and possibly improving

the HbA1c. This scholarly endeavor can promote the collaboration between the patient-centered

medical homes (PCMH) and the diabetes team to encourage a holistic patient care approach to

insulin management. Another significance of this project is to increase the awareness of

registered nurses who are conducting nurse-directed clinics in the outpatient primary care setting

centering on the impact of NPI regiments on the HBA1c.

Search History

The EBSCO host database was used in the literature review to locate articles. These

databases included, but not limited to the Cumulative Index to Nursing and Allied Health

Literature (CINAHL), Cochrane, Medical Literature Online (Medline), Google Scholar, and

ProQuest. The databases yielded multiple articles for the key terms: insulin therapy, type II

diabetes, primary care, basal-bolus insulin but none for nonphysiologic insulin (NPI) regimen.


The author considered publications that described NPI for the research study. The inclusion

criteria consisted of studies in English and circulated from 2012 to 2017 and allowed two earlier

writings from 1981 and 1997 due to the scarcity of articles on NPI regimens. A total of 350

publications were available for review. After further refining the search to publications with

adults 18 years and older, consideration of 35 articles were included for this project. The Centers

for Disease Control and Prevention website supplied the source for the diabetes statistical data

while the diabetes standards came from the American Diabetes Association (ADA, 2017; CDC,

2017).

Glucose optimization, hypoglycemia prevention, insulin safety, insulin replacement

therapy, basal and basal-bolus regimen including total daily dose and insulin ratio, barriers in

primary care settings and disease management are the major themes in the literature review. Jean

Watson’s Nursing Theory of Human Caring illustrates the theoretical framework in applying

patient-centeredness in this project while the Cognitive Load Theory (CLT) will provide

guidance in the understanding of nonphysiologic insulin regimens by promoting learning through

schemas in the outpatient setting. This framework demonstrates methods of providing knowledge

in a meaningful pattern to prevent information overload in learners (Sweller, 2010).

Insulin replacement therapy consists of initiation, optimization, and intensification. Insulin

initiation consists of the first exposure to insulin. Optimization include down-titration or

decreasing the dose and up-titration or increasing the dose with maximum benefit without

hypoglycemia. Insulin intensification is the process where a patient’s insulin regimens are

actively adjusted to maintain glucose control (Kunt & Snoek, 2009).


Glucose Optimization

Glucose optimization comprises the highest priority in the management of patients with

types I and II diabetes and is the first prominent theme in the review of the literature (Brunton et

al., 2016; Dailey et al., 2014; Kuroda et al., 2011; Porcellati et al., 2017). Attaining the target

HbA1c was the overarching goal in these studies to prevent complications and decrease

morbidity and mortality. The United Kingdom Prospective Diabetes Study (UKPDS) findings

validated the need to optimize glucose control promptly (UKPDS, 2014). The study

demonstrated that a link between diabetes complications and glycemic control exist. Each 1%

decrease in the mean HbA1c related to a 21% reduction in risk for any endpoint related to

diabetes, 21% reduction for diabetes-related deaths, 14% reduction for myocardial infarctions,

and 37% for microvascular complications with a p < 0.0001 for all arms. The authors concluded

that the risk of complications in patients with type II diabetes is firmly related to past

hyperglycemia. The reduction of the HbA1c at any level strongly diminished the risk of

complications with the lowest risk being with those who have a normal level of less than 6%

(UKPDS, 2014). All providers must aim to reduce the HbA1c promptly to lower the death risk of

patients with type II diabetes.

Hypoglycemia Prevention

The next major theme in the literature was preventing hypoglycemia. This adverse event

occurs when the plasma glucose falls below the standard range which causes symptoms. The

ADA described hypoglycemia as symptom with a glucose level less than or equal to 70

milligrams per deciliter in patients with type I and type II diabetes (ADA, 2017). Hypoglycemia

may increase the mortality risk in a patient with type II diabetes. In the Action to Control

Cardiovascular Risk in Diabetes (ACCORD) trial, patients who were in the intensive group had


three times higher risk for minor and major hypoglycemia events compared to the conventional

group (Gerstein et al., 2008). It is still unclear whether hypoglycemia was the reason for the

increased mortality in the ACCORD intensive treatment group (Inzucchi et al., 2012) hence,

preventing low blood sugar should be a critical consideration in insulin management. A

randomized study demonstrated that hypoglycemia is becoming an apparent concern because of

the higher risk of brain injury resulting to neurological deficits with repeated events (Launer et

al., 2011).

Varying degrees of complaints occur with hypoglycemia, from severe, necessitating help

from others to non-severe which patients can treat themselves. This symptom is the most feared

by both patient and provider. Low blood glucose negatively impacts lifestyle quality and

decreases work efficiency (Elliott, Fidler, Ditchfield & Stissing, 2016). Hypoglycemia events

may adversely affect adherence to insulin therapy due to the debilitating effect on the patient.

One commonly describes this experience as an extreme feeling of impending doom and most

patients will avoid hypoglycemia at all costs. Reducing or omitting the dose, injecting

infrequently, and self-decreasing insulin amounts are ways that patients evade hypoglycemia.

These actions result in sub-optimum glycemic control which can cause persistent hyperglycemia

leading to increased risk for complications (Wild et al., 2007). Providers must consider

hypoglycemia prevention as a routine assessment to promote insulin therapy adherence.

Insulin

Insulin is the hormone that balances blood glucose to prevent it from rising. Presently

there are about 20 types of insulin available in the United States for use in diabetes management

(ADA, 2017). Insulin safety, insulin replacement therapy, and the insulin ratios for the basal


monotherapy, split-mixed, premixed and basal-bolus regimens are essential factors when

focusing on insulin management.

Insulin Safety

Disputes on insulin safety continue to be an issue in the scientific arena and the medical

field the past 20 years. Two recent retrospective reviews with large sample sizes studying the

potential link between increasing insulin dose and addition of insulin to the regimen to an

increased risk of all-cause mortality and nonfatal cardiovascular events resulted to a non-

conclusive association (Holden, Jenkin-Jones, Morgan, Schernthaner, & Currie, 2015; Roumie et

al., 2014). The authors recommended further investigation using an experimental approach to

clarify the relationship between insulin use and all-cause mortality.

A meta-analysis by Price, Agnew, and Gamble (2015), investigated the association

between insulin and increased death risk. The authors reported that a significant gap exist in the

literature on cardiovascular morbidity and mortality with using different insulin therapies. The

authors reported that there is a substantial chasm in the writings on insulin and increased

mortality link (Price et al., 2015). Previous observational studies and randomized controlled

trials provided conflicting findings about insulin and its possible harmful effect in the

management of type II diabetes. Gamble et al. (2017) conducted a cohort study of 165,308 adults

with type II diabetes and discovered the cause of the disparity. The influencing effect of the

insulin dose caused the discrepancy. After adjusting for this effect, the authors concluded that

there was no connection between higher insulin dose and increased mortality rate (Gamble et al.,

2017). This finding supported insulin safety in managing type II diabetes. Encouraging the use of

physiologic insulin replacement therapy in the primary care setting is the overall goal of this

research project. Alleviating the fears of providers in the safety of insulin can promote that


purpose. Early initiation and frequent insulin adjustments using physiologic concepts and

steering clear from NPI utilization are ways to maintain insulin safety.

Insulin Replacement Therapy

The progressive nature of type II diabetes necessitates insulin replacement therapy to

attain glucose control (ADA, 2017; Brunton, et al., 2016; Inzucchi et al., 2012; Lasalle & Berria,

2013). The pancreas eventually ceased to produce insulin in most type II diabetes requiring the

use of exogenous insulin or insulin injections. Studies suggested that patients with type II

diabetes will require insulin within six years of the diagnosis (Brunton et al., 2016; Home et al.,

2014; Muharrem et al., 2015). According to Lasalle and Berria (2013), the varying degrees of

interpretation of insulin guidelines resulted in a diminished implementation of insulin therapy in

the primary care setting. However, simplified insulin algorithms, and practical approaches to

insulin management are currently available.

Increasing the utilization of physiologic insulin replacement therapy in patient-centered

medical homes may be an approach to improve the HbA1c of patients with type II diabetes who

mostly obtain management from primary care clinics. Several diabetes medical societies

recommend using straightforward insulin initiation with 10 units basal insulin at bedtime after

maximum oral antidiabetic drugs failed (ADA, 2017; Brunton et al., 2016; Galdo, Thurston, &

Bourg, 2014; Inzucchi et al., 2012). However, the ADA recommended an individualized

approach (ADA, 2017).

An individualized approach added to diabetes management prevents severe

hypoglycemia events that may hinder long-term insulin adherence for some patients. A patient

who works flexible hours or who has an irregular eating habit may benefit from a basal-bolus

insulin analog. A patient, who eats a scheduled meal, may prefer a split-mixed or premixed


insulin regimen injected twice daily. An insulin regimen that complements a patient's lifestyle

may improve adherence. It is easier for a patient to adhere to an insulin therapy that correlates to

one’s daily activity than changing a lifestyle to fit an insulin intervention that may cause

hypoglycemia. The individualized HbA1c goals also differ for patients with and without

comorbidities. A patient with no comorbidities may have an HbA1c target of 7% while it is

acceptable for patients with several comorbidities to have an HbA1c goal of 8% (ADA, 2017).

Providers must consider these personalized approaches as a significant element in insulin

replacement therapy to promote patient engagement.

Catering to a patient’s insulin therapy preference may sustain long-term insulin

compliance. Simplifying an insulin regimen by transitioning from oral antidiabetic medication to

injectable treatment may take a few weeks. Allowing the patient to adjust to injectable therapy

must be a major consideration (Brunton et al., 2016; Galdo et al., 2014; Lasalle & Berria, 2013).

At the author’s setting, a simplified insulin initiation algorithm is available on the local hospital

intranet. At the culmination of this research project, identifying the three NPI regimens and its

minimal impact on the HbA1c may ensure prompt delivery of physiologic insulin management

to patients with uncontrolled type II diabetes in primary care.

Basal Insulin

Basal coverage in insulin replacement therapy mimics the background or long-acting

insulin that the pancreas produces hourly. The early initiation of basal insulin becomes vital in

diabetes management due to elevated fasting glucose being an absolute indicator for the adverse

cardiovascular outcomes (Anand et al., 2011; Gerstein et al., 2012; Sarwar et al., 2010; Selvin et

al., 2010). A fasting glucose level of less than 100 milligrams per deciliter is the goal to maintain

glycemic control (ADA, 2017). The body needs a sufficient amount of insulin to achieve this


glucose level. Elevation in the fasting glucose indicates inadequate endogenous insulin

production to overcome underlying insulin resistance (Gerstein et al., 2012). Sarwar et al. (2010)

in a meta-analysis of 102 prospective studies found an association between diabetes and fasting

glucose level with the risk of heart disease and significant strokes. In this investigation of

698,792 patients, diabetes accounted for 11% of vascular deaths. Every provider’s responsibility

includes decreasing a patient’s risks from detrimental cardiovascular events by promoting the

early initiation of basal insulin.

As a rule, once the patient has reached the maximum oral antidiabetic drugs, providers

must consider initiating basal insulin at bedtime. The inability to achieve glycemic control with

maximum oral antidiabetic drugs must alert the health care professionals that insulin therapy is

necessary (Raccah, 2016). Basal insulin corrects the rise in the fasting glucose levels by

controlling gluconeogenesis (production of glucose during sleep) and counteracting insulin

resistance in the morning (Gerstein et al., 2012). The starting dose of basal insulin depends on

the hyperglycemia level, but a basal initiation of 10 units daily is the recommended dose (ADA,

2017). Although the ADA provided an algorithm for basal insulin initiation and optimization,

there is no mention of the maximum total daily dose necessary to achieve glucose control for a

basal regimen. Two meta-analyses totaling 14 randomized controlled trials illustrated a definitive

regimen. A basal total daily dose between 0.41 to 0.51 units per kilogram per day sufficed in

preventing fasting glucose elevation and achieved the HbA1c target goal (Dailey et al., 2014;

Porcellati et al., 2017).

An example of the first nonphysiologic insulin regimen is a basal insulin monotherapy of

60 units or higher at bedtime or 30 units or higher twice a day for a 75-kilogram patient.

Dividing the total daily dose of 60 units by 75 equals 0.8 units per kilogram per day. This dose


contradicts the basal therapeutic regimen by using higher than 0.51 units per kilogram per day of

basal insulin monotherapy daily. Once a basal monotherapy reaches 0.5 units per kilogram per

day in a patient's regimen, providers should consider adding bolus coverage for meals to

optimize glucose control. Going beyond 0.5 units per kilogram per day of basal monotherapy

aligns with the nonphysiologic insulin regimen.

Basal-Bolus Insulin

If basal insulin is the background or the slow-acting insulin secreted by the pancreas in

small amount the whole day in a fasting state, the bolus insulin is the insulin released in a

considerable amount during meals to prevent post-meal glucose elevation (Cai, Han, Luo, & Ji,

2012). A basal-bolus approach mimics the 24-hour pancreatic insulin secretion. This physiologic

avenue in insulin management prevents persistent hyperglycemia. This method provides the most

efficient coverage to counter hyperglycemia and has succeeded in reaching the HbA1c target of

less than 7% in most patients with type II diabetes in clinical trials. Several studies concluded

that the basal-bolus insulin regimen in absolute terms was best for achieving glycemic goals

(Bellido et al., 2015; Giugliano et al., 2016; Giugliano et al., 2011; Riddle et al., 2014; Owens,

2013).

Using premixed insulin also called biphasic insulin (two insulins mixed in the same

bottle) is effective as well. Studies using a premixed insulin versus basal-bolus insulin regimen

demonstrated increased hypoglycemia events with the premixed regimen compared to the basal-

bolus, but no significant difference in the attainment of the target HbA1c (Bellido et al., 2015;

Owens, 2012). Both regimens succeeded in reaching euglycemia. The chances of achieving a

HbA1c less than 7% was higher with the basal-bolus compared to the premixed insulin, due to

frequent hypoglycemia events with the premixed insulin (Giugliano et al., 2016); but both


premixed and basal-bolus regimens achieved glycemic control compared to basal insulin therapy

alone (Giugliano et al., 2011). When basal monotherapy reaches the total daily dose of 0.51 units

per kilogram per day and hyperglycemia persist, one must consider prompt intensification of

treatment with either split-mixed, premixed insulin or a rapid-acting insulin analog.

Patients with type II diabetes who are exhibiting signs of decreased endogenous insulin

production serve as a signal to start optimizing insulin replacement. An influential predictor of

reduced endogenous insulin production, besides elevated fasting glucose (Gerstein et al., 2012),

is an elevation in the post-meal glucose levels which requires initiation of a rapid-acting insulin

regimen (Giugliano et al., 2016). Coverage of mealtime glucose will increase the chance of

glycemic control. The total daily dose of a basal-bolus regimen may start at 0.5 units per

kilogram per day and may go up as high as 1.53 units per day in the EDITION-1 trial (Riddle et

al., 2014). Physiologically more insulin coverage goes to the bolus dose and less to the basal

dose.

An example for the third nonphysiologic insulin regimen is a basal dose of 50 units at

bedtime and a bolus dose of five units three times a day for a 75-kilogram patient. The total daily

dose is 65 units per day (50 basal+ 15 bolus) divided by 75 (weight) which equals 0.86 units per

kilogram per day. Fifty units is equivalent to 76% basal and 15 units bolus is equivalent to 26%

bolus. This ratio is nonphysiologic with a basal greater than 55% and a bolus of less than 45% of

the total daily dose; an overestimation of the basal dose and an underestimation of the bolus dose

(Kuroda et al., 2011).

Insulin Ratio and Total Daily Dose

Insulin ratio refers to the percentage of the basal and the bolus insulin of the total daily

dose. Total daily dose (TDD) is the overall amount of insulin used daily. Many patients with type


II diabetes will need one unit per kilogram per day of insulin as the TDD to achieve the target

HbA1c (Riddle et al., 2014). Various endocrine medical societies do not state a specific insulin

ratio in insulin management. Most researchers suggest a 50:50 percent basal-bolus as the ideal

dose for insulin initiation (ADA, 2017; Davidson, Hebblewhite, Steed, & Bode, 2008; Giugliano

et al., 2016). A 50:50 percent basal-bolus insulin ratio means allocating 50% of the total daily

insulin dose to the basal (long-acting) and 50% to the bolus (rapid-acting) insulin covering

meals.

An earlier prospective study by Schiffrin and Belmonte (1981) suggested a more concise

ratio. The authors analyzed the basal insulin requirement using an overnight continuous

subcutaneous insulin infusion and pre-meal boluses during the day on patients with type I

diabetes. The researchers suggested that a 40% basal dosage was the appropriate amount needed

for long-acting coverage which means that 60% remained for the bolus insulin for meals

(Schiffrin & Belmonte, 1981).

An example is a 75-kilogram patient using a 40% basal to 60% bolus insulin ratio starting

at 50% per unit of body weight would follow these calculations; 75 x 0.5= 38 units as the total

daily dose. The total daily dose will be multiplied by a basal ratio of 40% (38 x 0.4) will yield 15

units of insulin. A bolus ratio of 60% (38 x 0.6) will generate 23 units by multiplying the total

daily dose by 60%. Twenty-three units divided equally into three meals will yield eight units per

meal. Providers prescribed this regimen as 15 units basal to be injected at bedtime and eight units

of bolus insulin before each meal. More bolus insulin (60%) covered meals and less basal (40%)

acted as long-acting insulin.

In later years, various studies investigated the appropriate basal-bolus insulin ratio

effective to reach HbA1c goals in patients with types I and II diabetes. Mao et al., (1997) studied


patients with type II diabetes using the same earlier approach by Schiffrin and Belmonte (1981)

on type I diabetics. Again a 40% to 60% basal-bolus ratio conveyed an appropriate proportion to

reach target glucose levels (Mao et al., 1997). In a retrospective and cross-sectional approach in

2012 and 2017 respectively (Cai et al., 2012; Yamada et al., 2017) both populations responded to

insulin ratios between 20% to 30% basal and 70% to 80% bolus of the total daily dose. These

insulin ratios attained a target HbA1c of less than 7.5% for patients with type I diabetes and less

than 7% for patients with type II diabetes. In two prospective studies done in 2008 and 2011, a

40% to 60% for type II diabetes, and a 30% to 70% basal-bolus ratio for type I diabetes

succeeded in achieving HbA1c goals (Kuroda et al., 2011; Tamaki et al., 2008). The study by

King (2010) on patients with type I diabetes also concluded that current formulas give a higher

estimate of the basal dose and lower value of the bolus dose. The author further recommended a

40% to 60% basal-bolus approach in insulin replacement therapy (King, 2010). This ratio also

accounted for both the premixed (i.e., 70/30 insulin) and the self-mixed/split (i.e., NPH and RHI)

insulins given twice daily.

Increased awareness of the possible connection between NPI regimens and delayed

HbA1c improvement may reduce NPI utilization in primary care. Promoting the importance of

assessing the insulin ratios in a patient’s injectable therapy may decrease hypoglycemia risks in

patients with type II diabetes. Recommending evaluation of the insulin ratio and encouraging

physiologic regimens may impact diabetes management in primary care.

Primary Care Barriers

Even with the availability of simplified insulin initiation algorithms, delays in insulin

replacement therapy continue in the primary care setting settings, which can aggravate diabetes

control (Brunton et al., 2016). Various studies identified lack of skills and knowledge, feelings of


incompetence, and time constraints as the most common obstacles in initiating insulin by

providers (Kunt & Snoek, 2009; Muharrem et al., 2015; Ng, Lai, Lee, Azmi, & Teo, 2015).

Primary providers are hesitant in initiating insulin, more so with insulin intensification. Most

patients remain in their first insulin regimen longer due to reluctance in insulin intensification

(Kunt & Snoek, 2009). Pantalone et al. (2018) described this reluctance and hesitancy in

intensifying insulin treatment as clinical inertia, the failure of clinicians to optimize insulin

adjustment until achieving the target HbA1c.

The authors of a 2017 unpublished retrospective study surveying 55 clinic providers and

150 adults with diabetes analyzed if providers and staff are an additional impediment to insulin

initiation. Using a survey questionnaire with a Likert scale, the investigators discovered that

clinic personnel and healthcare professionals were obstacles in commencing insulin therapy.

Inadequate understanding of five patient’s concerns including fears of needles, the difficulty of

understanding insulin usage, insulin interference with life, negative judgment by others for

needing insulin and insulin use leads to loss of independence; prevented insulin treatment

initiation (Childress et al., 2017).

The marked discrepancies between the providers and staff and the patient’s interpretation

of these five patient’s barriers to insulin therapy resulted in a significant difference with a p-

value of >0.05 for all five obstacles. Providers and staff overestimated the patient’s issues about

insulin treatment which may prevent early insulin intervention for diabetes management

(Childress et al., 2017). Addressing these impediments with patients at every visit may break

down some barriers in insulin initiation. Encouraging patients to discuss these fears may promote

self-management and patient engagement to insulin replacement therapy.


Disease Management

An article by Huckfeld et al. (2012) from the National Health Institute stated that disease

management programs made an impact on the reduction on the HbA1c levels of people with type

II diabetes mellitus. The study findings demonstrated a decreased of 2 to 4.5 points in the HbA1c

from the start of disease management until achieving the HbA1c goal of less than 8% (Huckfeldt

et al., 2012). Using disease management in the initiation of insulin therapy may be an impetus

for bringing the HbA1c level to the stated goal (Pettitt et al., 2005).

A team approach is critical and comprehensively treating a patient is advantageous

because it bolsters collaboration and patient-centeredness. This strategy fosters a patient-focused

approach encouraging self-management (Brunton et al., 2016). Providers must attend to patients

in an individualized manner and enlist the expertise of other health care professionals to assist in

diabetes management which may promote insulin adherence. Providers may consider the

potential contributions of diabetes educators, pharmacists, social workers, and registered

dieticians by including them in patient care to improve the interdisciplinary collaboration.

Literature Critique

This section will provide a critique of the methodology of the reviewed literature to

evaluate the credibility and rigor of the studies regarding the different insulin regimens, the total

daily dose, and the basal-bolus insulin ratios. The critical appraisal guide discloses the accuracy

of the studies by identifying the strengths, weaknesses, gaps, and limitations of the research

procedures (Christenbery, 2011).

Strengths

Various meta-analyses, randomized controlled trials, and rigorous retrospective literature

reviews in this research paper validated the ideal insulin total daily dose and therapeutic ratio for


insulin replacement therapy. Most of the studies cited in this paper had large sample sizes with

inclusion and exclusion criteria adequate for generalization to patients with type II diabetes.

Using randomized controlled trials by the authors in the research studies bestowed vigor to the

results.

All hypothesis and clinical questions aimed to answer the improvement in HbA1c from

baseline using different insulin regimens. Patients with type II diabetes comprised the study

population in most studies, with type I diabetes utilized on a few retrospective studies. Primary

outcomes on all reviews are the HbA1c results and the secondary endpoint is hypoglycemia

prevention. All studies measured diabetes control with the HbA1c, an accurate tool in diabetes

management with high validity and reliability (ADA, 2017). Written patient consents were

obtained by all the study authors and approved by institutional review boards which protected

patient’s human rights and confidentiality.

Attention to bias is present in all the studies. For example, Gamble et al. (2017) addressed

the different conclusions on insulin safety by using a marginal structural model in the statistical

analysis versus a standard multiple regression analysis which increases bias, to conclude that

there is no link between insulin dose and mortality. Reliability is high in the literature for this

scholarly inquiry. For instance, Yamada et al. (2017) replicated a similar method from Kuroda et

al. (2011) in which they studied type 1 diabetics using an insulin pump to estimate the insulin

ratio in the well-controlled and uncontrolled cohorts. The meta-analyses used the Preferred

Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to assure a

comprehensive review.


Weaknesses

Identification of weaknesses in the literature was also addressed. Employing a

retrospective approach in research design prevented the analysis of the effect of the insulin dose

on the HbA1c, although the method may infer a relationship. Causality is absent in the

retrospective approach that depreciated the inferential potential to a larger population of patients

with type II diabetes. A small sample size and nonrandomization method of sampling in a few of

the studies evoked weakness in the analyses regarding insulin ratio. The authors acknowledged

this weakness. An experimental approach for future studies may guide investigators to a

prospective avenue to promote applicability to other populations (Kuroda et al., 2011; Yamada et

al., 2017).

Another weakness affecting the results is utilizing a lower level of HbA1c in the different

articles. Most studies started off with a measurement of about 8% to 9%. An HbA1c of 8% is

acceptable for sicker patients with comorbidities (ADA, 2017). It will be interesting to test on a

HbA1c greater than 10%, which most patients with persistent hyperglycemia retain.

The study done by Dailey et al. (2014) identified using basal insulin only at night as a

weakness due to a possibility of a different effect of a daytime basal therapy on the patient’s

changing insulin sensitivity throughout the day. A patient is more insulin resistant in the early

morning hours due to the hormonal impacts and sensitivity increases during the day. According

to the authors, using basal insulin both in the morning and at night may strengthen the analysis.

Gaps

Giugliano et al. (2016) discussed premixed insulin versus basal-bolus regimen with a

conclusion that the basal-bolus had an 8% chance of achieving a HbA1c less than 7% compared

to the premixed insulin. The cause for this result remains ambiguous. This difference is an


unexplained gap. Based on the author’s experience, it is harder to achieve an HbA1c of less than

7% with premixed insulin because patients start having hypoglycemia once reaching an HbA1c

of 8%. It is challenging adjusting premixed insulin because there are two insulins in the same

bottle (long-acting and short-acting); fine-tuning either insulin is problematic because one will

also increase or decrease the other insulin concurrently. It is easier for providers to adjust a

basal-bolus insulin regimen by increasing or decreasing both insulins separately, compared to the

premixed insulin. The identification of this gap is missing in the literature (Giugliano et al.,

2016). One approach to correct this gap is to transition patients to a self-mixed/split insulin

regimen of NPH (long-acting) and regular insulin regimen (short-acting) to promote accurate

insulin adjustments and still maintain twice daily injections.

Another identified gap is the remoteness of the self-mixed/split insulin regimens in most

of the recent literature. A self-mixed/split regimen is the mixing of two human insulins, neutral

protamine Hagedorn (NPH) and regular human insulin (RHI) in the same syringe by the patient

and injected twice daily for diabetes management (Davidson, 2014). Although a joint statement

by the ADA and the European Association in the Study of Diabetes (EASD) eliminated this

therapy (Inzucchi et al., 2012), patients in an inner-city outpatient clinic preferred this method

with the option of a twice a day injection because both insulins are inexpensive compared to the

current insulin analogs (Davidson, 2014). In a public system hospital-based outpatient primary

care clinic, where most patients do not have medical plans, a self-mixed/split insulin is an

everyday standard regimen.

Limitations

The authors mentioned that high heterogeneity among patients with type II diabetes and

shortened study durations were study limitations. A longer study duration may reveal an accurate


time to maintain and sustain euglycemia. Inability to include a macro and microvascular

complications as a measurement for clinical outcomes were additional limitations acknowledged

by the researchers. Most of the primary results were an improvement in the HbA1c and

hypoglycemia prevention (Giugliano et al., 2016). Critical findings beside learning the total daily

dose and insulin ratio in insulin replacement therapy are strategies to sustain euglycemia. Future

research in maintaining long-term glycemic control of patients with type II diabetes in outpatient

primary care clinics is another worthwhile aim.

Concepts and Definitions

Basal Insulin: Refers to the slow-acting insulins that are used to mimic the background

insulin secreted by the pancreas in small amounts to maintain normal glucose during fasting. An

example is insulin glargine or Lantus. These insulins provide coverage in 24 hours to control

blood glucose by suppressing hepatic glucose production in between meals and during sleep

(Inzucchi et al., 2012).

Bolus Insulin: Refers to the rapid-acting insulins that mimic pancreatic response to a

meal to prevent post-prandial hyperglycemia. An example is Lispro or Humalog. This insulin is

given before a meal to prevent post-prandial glucose elevation (Inzucchi et al., 2012).

Basal-Bolus Insulin (BB): Refers to the use of insulin analogs to provide long-acting and

rapid-acting coverage throughout the day. This regimen is considered the gold standard in insulin

therapy and is also called the multiple injection basal-bolus treatment (Giugliano et al., 2016).

Hemoglobin A1c (HbA1c): A blood test that measures a person's average blood glucose

level over the past two to three months (ADA, 2014). A HbA1c less than 7% is the target goal

for patients with no comorbid conditions and less than 7.5% for patients with comorbid

conditions; however, individualized targets are recommended (ADA, 2017).


Insulin Dose: The insulin regimen a health care provider prescribes to manage glucose

level (ADA, 2017).

Insulin Ratio: The percentage of the basal and bolus insulin of the total daily dose

(Yamada et al., 2017).

Insulin Replacement Therapy: Refers to the exogenous insulin (outside the body) given

due to the progressive beta cell dysfunction and inability to produce sufficient endogenous

(released by the pancreas) insulin (Inzucchi et al., 2012).

Nonphysiologic insulin dose: This regimen does not mimic normal insulin secretion by

the pancreas. It is the overestimation of the total basal dose and underestimation of the total

bolus dose (DeWitt & Hirsch, 2003; Kuroda et al., 2011).

Total Daily Dose (TDD): The estimated daily insulin requirement, often defined as 50%

of the body weight when used for insulin initiation (Inzucchi et al., 2012; Yamada et al., 2017).

Theoretical Frameworks

Jean Watson’s Theory of Human Caring is the theoretical framework utilized to guide

this research study. This nursing theory has four essential concepts; the person, health,

environment, and nursing (Nursing Theory, 2016). This principle states that healthcare

professionals are to view a person as a valuable individual, respected, understood, assisted, and

regarded as a complete being. This model considers health as a high level physical, mental and

social agility, without illness and a well-adapted level of functioning. It acknowledges that the

profession continues the cycle of nursing practice to the next era as a unique way of coping with

the environment. This philosophy states that nursing involves health promotion, disease

prevention, and health restoration. It consists of caring for the sick and the ill and focuses on


supporting a person's well-being, as well as the treating of diseases. This theory of human care

believed that the principal element to nurturing in nursing is holistic (NT, 2016).

Management of diabetes in the primary care setting cannot be in a silo. The potential

contributions of other health care professionals including diabetes educators and specialists may

be an effective means of reducing the HbA1c of patients with uncontrolled diabetes (Brunton et

al., 2016). Collaborating with other diabetes experts advocates a comprehensive approach to

patient care promoting the Theory of Human Caring.

The Cognitive Load Theory (CLT) is another theoretical framework that will be utilized

in this research study. This framework can promote understanding of the three nonphsiologic

insulin replacement therapies in primary care. Sweller (1988) first described this concept as a

strategy in promoting learning by using schemas. Schemas are the presentations of complex

information into categories. This principle delivers data through instructional means, in chunks

or bundles by categorizing and grouping the information. It also involves the working memory.

Young, Van Merrienboer, Durning, & Ten Cate (2014) described working memory as the ability

of the brain to maintain seven instructions at one point, process two to four directions, and other

information is lost after 30 seconds unless rehearsal occurs.

Sweller (2010) further described the CLT theory with three underpinnings: (a) the

intrinsic load, (b) the extraneous load and, (c) the germane load. These principles are all related

to learning. Intrinsic load equates with the depth and difficulty of learning the new skill. This

stage refers to the complexity of the information, be it a concept, or a principle, which can be

simple or complex, for example nonphysiologic insulin replacement therapy. This phase in CLT

is constant. Extraneous load refers to the presentation of the information to the learner. This step

indicates the delivery method of the information. The extraneous load addresses an educator’s


instructional approaches used to deliver the information. A mediocre or inferior instructional

approach may increase the extraneous load, which can burden the working memory capacity.

Germane load deals with the understanding and retention of the information. The goal is to

accelerate this step. The germane load has an opposing relationship with the extraneous load. As

external capacity decreases, the germane load augments and this process promotes learning

(Sweller, 2010).

Understanding nonphysiologic insulin regimens demands a high intrinsic load on the

working memory. It is essential to decrease the extraneous load to augment the germane process.

Decreasing the extraneous load is possible by using schemas in teaching insulin replacement

therapy. This project aims to present insulin replacement therapy in schemas of two principles to

promote learning. These schemas include the total daily dose and insulin ratio which can

decrease the extraneous load and add to the beneficial effect of knowledge acquisition. Using

schemas promotes retention and retrieval of information. To supplement the reduction of the

extraneous load, a scheduled training session for the advanced practice nurses, nursing personnel

and providers prevents interruptions in the learning process. The additional reduction in this load

will accelerate the germane load thereby achieving learning, data absorption, and information

rehearsal. Educating all diabetes management personnel about the impact of nonphysiologic

insulin regimens on the HbA1c using the Cognitive Load Theory may guide practitioners to

utilize appropriate insulin replacement therapy to improve glucose control in patients with type II

diabetes.

Conclusion

The rising number of people with type II diabetes in Los Angeles remains in epidemic

proportion (LADPH, 2012). Increasing the awareness and understanding of the impact of


nonphysiologic insulin (NPI) regimens on the HbA1c is crucial. Overestimating and

underestimating both the bolus and basal dose of the total daily dose interferes with improvement

in the HbA1c and may cause hypoglycemia. Prompt glucose control and avoidance of

hypoglycemia are priority in the management of type II diabetes. Insulin regulates the blood

sugar by preventing hyperglycemia. Disagreement about insulin safety persist in the medical

field, but a recent rigorous study determined that there is no link between higher insulin dose and

increased death risk (Gamble et al., 2017). Promoting the use of appropriate insulin replacement

therapy in the outpatient clinics can help patients with type II diabetes manage their disease

process better. It can assist nurses and providers in utilizing physiologic insulin regimens,

decrease hypoglycemia events and may possibly achieve the HbA1c target.

Basal insulin functions as the background or the long-acting insulin and bolus insulin acts

on the elevation of post-meal glucose. The basal-bolus insulin regimen follows the physiological

insulin action and regarded as the gold standard in insulin therapy. The ratio of an insulin dose

and the total daily dose can influence the target HbA1c. Literature reviewed in this study suggest

that an insulin ratio between 20% to 40% basal and 60% to 80% bolus of the total daily dose are

physiologic and appropriate. A split-mixed NPH, regular insulin or premixed insulin given at a

65% to 35% ratio in the morning and afternoon are also accepted as physiologic regimens.

Therefore, the three NPIs described in chapter one falls within the nonphysiologic regimens. All

other insulin regimens (AOI) that do not meet the NPI definitions will be considered physiologic.

Insulin therapy issues persists in the primary care outpatient clinics. Examining insulin

practices in primary care may reveal insulin ratios that may be inappropriate to achieve the

HbA1c target. Measuring the three NPIs and comparing the impact of these regimens on the

HbA1c with more physiologic insulin doses will be the goal of this scholarly project.


Implementing a team approach and collaborating with a multidisciplinary group may assist in the

disease management of patients with type II diabetes utilizing physiologic principles in insulin

replacement therapy.


Chapter 3

Methodology

This chapter addressed the study needs analysis, project design, data collection

procedure, instruments used, resources needed, project budget, timeline and the protection of

human subjects for the project. To be more specific, the purpose of this chapter was to describe

the steps used to examine the association between three nonphysiologic insulin regimens (NPI)

and the HbA1c. A control group accounted for all other insulin (AOI) regimens not meeting the

NPI definitions. The research question was: In adults with type II diabetes, does nonphysiologic

insulin replacement therapy based on three identified insulin regimens affect HbA1c levels? The

investigator hypothesized that NPI regimens did not impact the HbA1c and may be related to

increased hypoglycemia risks in adults with type II diabetes.

Needs Assessment

Nonphysiologic insulin management may increase the risk of hypoglycemia and

jeopardize patient safety (Inzucchi et al., 2012; Launer et al., 2011). The investigator quantified

this phenomenon scientifically in the primary care setting and explored if it had any relationship

with the HbA1c of adult patients with type II diabetes. This research project is significant to

health care because it can potentially increase the utilization of physiologic insulin replacement

therapy in the primary care setting. Examining the different insulin regimens and its relationship

with the HbA1c may guide providers in utilizing the appropriate insulin replacement therapy for

patients with type II diabetes.

The delay in implementing insulin therapy in the primary care settings are due to

different barriers. Some barriers are patient-related, and some obstacles are providers and staff

(Childress et al., 2017). The diabetes team can potentially break down these barriers by


promoting physiologic insulin replacement therapy in the primary care setting; thereby,

promoting glucose optimization promptly. There is also the potential for health care cost savings

by decreasing complications and hospital admissions and emergency room visits.

Research Design

The research design used was a quantitative, retrospective chart review of existing data

from the clinic’s electronic health record (EHR) and the pharmacy database. The study included

a sample of 891 available patients established from February 1, 2017 to October 31, 2017 from

outpatient primary care clinics located in Los Angeles, California. After applying the inclusion

and exclusion criteria, 113 patients qualified for the nonphysiologic insulin (NPI) group and 88

patients qualified for all other insulin (AOI) regimens group. The NPI group consisted of patients

on the three NPI regimens, and the AOI group were patients on insulin regimens that did not

meet the three NPI criteria. The three NPIs were: (a) basal insulin monotherapy of greater than

0.5 units per kilogram per day, (b) neutral protamine Hagedorn (NPH) and short-acting or

premixed insulin given in equal doses (+10%) twice a day, and (c) basal-bolus insulin therapy in

which the basal dose is greater than 55%, and the bolus dose is less than 45% of the total daily

dose. Demographics and patient characteristics were collected using the data collection sheet

developed by the primary investigator (see Appendix E).

Sample

The study subjects consisted of 891 available patients with type II diabetes on insulin

replacement therapy between February 1, 2017 to October 31, 2017 in two pre-specified clinics.

A power analysis suggested 64 subjects for each cohort yielding a 0.5 medium effect at 80%

power and a significance of p < 0.05 (Cohen, 1988; Mateo & Foreman, 2013). A pharmacy list

provided the insulin regimens of the subjects. The investigator accepted all 891 patients in the


pharmacy list, and qualified samples were selected. The inclusion criteria included: (a) 18 years

and older, (b) diagnosis of type II diabetes, and (c) on insulin replacement therapy between

February 1, 2017 and October 31, 2017. The exclusion criteria consisted of: (a) age less than 18

years, (b) documented type I diabetes, (c) documented gestational diabetes, and (d) seen in the

clinics before February 1, 2017 and after October 31, 2017. The excluded pediatric, type I and

pregnant diabetics receive different insulin intervention approaches as compared with type II

diabetes. The author omitted these groups to maintain homogeneity among the samples. The

investigator also excluded patients who were on the U-500 concentrated insulin, an insulin five

times stronger than regular insulin, due to the complexity of the insulin regimen.

Further exclusions included subjects with missing pre and post-HbA1c levels, without

any clinical encounter or deceased during the study period, and subjects on insulin regimens less

than 0.5 units per kilogram per day. A key factor to poor diabetes control is insulin under-dosing.

To accurately compare the impact of the NPI and AOI on the HbA1c warranted excluding

patients who were under-dosed.

Setting

The setting for this research project was two primary care clinics of the Los Angeles

Department of Health Services (LADHS). Both are hospital-based outpatient clinics providing

health care to the uninsured, the low-income and minority patients in the surrounding Los

Angeles area. The LADHS is the second largest metropolitan health system in the nation,

established in 1946 as a station hospital for the port of embarkation (LADHS, 2017). Today,

LADHS is an integrated health system with 19 health centers, four hospitals and cares for


600,000 patients a year. These two primary care clinics are also affiliated with the University of

California Los Angeles (UCLA) academic teaching program.

Data Collection Instrument

Collection of data in this quantitative retrospective chart review materialized through the

hospital’s electronic health record (EHR) and the pharmacy database for patients with type II

diabetes on insulin replacement therapy. The investigator developed a data collection sheet to

document the data abstracted from the EHR (see Appendix E). The study variables included in

the data collection instrument were age, diagnosis of type II diabetes, gender, body mass index

(BMI), diabetes duration, comorbidities, ethnicity, insulin usage, and HbA1c. Comorbidities

included hypertension, hyperlipidemia or both. Diabetes duration counted as the number of years

that a patient had this chronic condition. The pharmacy database provided the insulin regimen of

patients with type II diabetes, including the date of the new and refilled prescriptions, insulin

dose change, duration of insulin regimen, and the total daily insulin dose.

Data Collection Procedure

The researcher first merged the two pharmacy files with 5,978 prescriptions. Second,

each insulin prescription was examined and classified into NPI and AOI group. After identifying

all the insulin regimens, a software program removed duplicates for the patient’s name, and

medical record number resulting to 891 patients for screening. A total of 251 patients qualified

for the NPI and 640 for the AOI. Sorting of the 891 samples generated 13 groups. The sub-

groups for the NPI and AOI regimens cohorts were: (a) qualified NPI 1, (b) qualified NPI 2, (c)

qualified NPI 3, (d) NPI regimens on less than 0.5 units per kilogram per day, (e) NPI with

missing HbA1c, (f) AOI regimens on less than 0.5 units per kilogram per day, (g) AOI regimens

with missing HbA1c, (h) patients seen in a Diabetes Clinic, (i) patients with no clinic encounter,


(j) type I and gestational diabetes, (k) on U-500 concentrated insulin, (l) deceased during study

period and, (m) qualified patients on AOI regimens.

The third step involved applying the exclusion criteria. Patients in the NPI and AOI

group who were on insulin dose of less than 0.5 units per kilogram body weight were excluded.

This step involved calculating 891 insulin total daily doses divided by the patient’s weight. After

applying the exclusion criteria for both cohorts, 113 and 88 patients qualified for the NPI and

AOI, respectively. Steps four and five calculated the mean pre and post HbA1c for each group

and compared the mean difference. Step six involved comparing the mean HbA1c difference

between the NPI and AOI groups to see which insulin regimens impacted the HbA1c level.

In summary, the investigator divided all 891 patients into two groups by identifying each

insulin regimen. Patients on the three NPI regimens went to the NPI cohort (experimental group),

and patients on all other insulin regimens outside of the three NPI definitions, which were the

designated AOI cohort (control group) comprised the subjects. All subjects in the study were on

insulin replacement therapy and seen in one of the two outpatient primary care clinics at least

once during the study period. The flow diagram (shown in Figure 1) demonstrated the pathway

for each step of the subject selection with the number of samples sorted for each sub-group.


Figure 1.

Selection of Subjects Flow Diagram

Data Analysis Plan

Descriptive statistics allow investigators and researchers to organize, describe and

summarize scientific information in logical terms (Polit & Beck, 2017). This research project

used descriptive statistics to synthesize data and numerical measurement to describe insulin dose

and its association with HbA1c. Descriptive statistics were used to obtain the mean average for

all subjects for age, gender, comorbidities, body mass index (BMI), ethnicity, insulin usage

including dose change, insulin duration in weeks, total daily dose and HbA1c.

A paired samples t-Test calculated the mean HbA1c difference between the pre and post

HbA1c within the group for both the NPI and AOI. An independent samples t-Test computed the

mean HbA1c, patient characteristics and insulin usage differences between the NPI and AOI

cohorts. Kim and Mallory (2017) stated that a paired samples t-Test is a statistical approach to

use when comparing two means within a group and an independent samples t-Test is valuable in

analyzing the mean difference between two independent groups. A p value of < 0.05 was the

Pharmacy List pts on Insulin

from 2/1/2017 to 10/31/20171st file (n=

3,547)2nd file (n=

2,431)Merged 1st +2nd

files= 5,978Multiple entries

same patient 5,978 = 891

Total Patients(n=891)

NPI GroupTotal

(n=251)

Excluded NPI (n=138)

1. <0.5 u/k/d (n=36)2. Missing HbA1C (n=102)

Qualified NPI(n=113)

NPI Group Compare pre

and post HbA1C

NPIPre HbA1C Mean= 9.145Post HbA1C Mean= 9.042

Mean Diff= .10P=.420

AOI Group Total

(n=640)

Excluded AOI (n=552)1. <0.5 u/k/d (n=234)2. Missing HbA1C (n=76)3. Currently in DM CM (n=130)4. No clinical encounters during study period (n=102)5. Pediatric/Type I (n=7)6. U-500 Insulin (n=2)7. Deceased (n=1)

Qualified AOI(n=88)

AOI Group Compare pre

and post HbA1C

AOIPre HbA1C Mean= 9.351Post HbA1C Mean= 8.730

Mean Diff= .62P= .000

NPI and AOI Mean Diff= .52

P= .009


alpha used to consider significance. The investigator utilized the Statistical Package for the

Social Sciences (SPSS Version 25) software program in all the statistical calculations.

Resources

The researcher retrieved data from the hospital’s electronic health record (EHR) of the

two outpatient primary care clinics in southern California after IRB approval per the university.

The chief medical officer of the section of Diabetes and Metabolism of the hospital supported

this research project and supervised the study (see Appendix A). A research coordinator with

more than a decade of research experience provided additional support and contributed ideas for

improvement. A university statistician assigned to the program provided support for statistical

consultations and questions. The capstone chair from Maryville University who was assigned to

work with the researcher offered tremendous support and guidance in each phase of the scholarly

project development. The chair was available anytime via email communication which made the

process easier. The data from both the pharmacy system and EHR was accessible in the

researcher’s office. Examination and analysis of all data took place in the same location.

Budget

This research project required the examination of selected variables from an electronic

database that are accessible to the researcher in her office due to its retrospective design. The

time spent performing chart reviews and extraction of data from the electronic health record and

the pharmacy system was donated to the scholarly project. Finances involved the purchase of the

IBM-SPSS software program for statistical analysis, a pen, paper, and a calculator to distinguish

between NPI and AOI regimens.


Timeline

Existing pharmacy data from February 1, 2017 to October 31, 2017, combined with data

from the EHR were the sources of the analysis. The researcher obtained approval from the

Maryville University Institutional Review Board (IRB) and the hospital’s IRB by the end of

February 2018 and started data collecting from March 1 to July 31, 2018. Data cleaning and

statistical analysis began from August 1st to the 30th. The scholarly project was presented during

DNP presentation day on December 7, 2018. Dissemination of the findings includes a

presentation at the Western Medical Research Conference in Carmel, California on January 25,

2019.

Protection of Human Subjects

This research project obtained IRB approval from the Los Angeles Bio Medical Research

Institute at Harbor UCLA Medical Center on January 10, 2018, and from Maryville University

on February 26, 2018 (see Appendices B and C). An IRB amendment to add a comparison group

to the study was submitted to Maryville University on June 27, 2018 and approval was obtained

on June 29, 2018 (see Appendix D). Since this project is a retrospective study of existing

pharmacy data and information from the electronic health records, the investigator requested an

exempt status and a consent waiver.

There was minimal risk for a breach of patient’s confidentiality and privacy because all

data were de-identified in the data collection sheet. Only the investigator had access to the

password protected computer kept in a locked office. This research study was a retrospective

chart review and the author did not have any interaction with the participants. The researcher

eliminated all patient identifiers from the data collection sheet and pharmacy lists after

completing the analysis for this scholarly project.


Conclusion

In summary, this chapter has discussed the methodology of this research project. The

investigator addressed the research design, sampling method, study location, instrument, the data

collection procedure, timeline, budget, resources, and protection of human subjects. Examining

the association between insulin dose and its impact on the HbA1c was the purpose of this

research project. A quantitative retrospective chart review allowed detailed evaluation of insulin

regimens utilized in two hospital-based outpatient clinics in Los Angeles, California. An IRB

approval from Maryville University and the Los Angeles Bio Medical Research Institute at

Harbor UCLA Medical Center ensured the protection of human subjects.

A pharmacy list with 5,978 prescriptions provided the insulin regimens of adult patients

with type II diabetes in the two pre-specified clinics. The author examined the patient's insulin

regimens and designated each to the NPI and AOI cohorts. Multiple insulin entries of the same

patients were eliminated resulting to 891 samples. After applying the inclusion and exclusion

criteria, 201 patients remained. Of the 201 subjects, 113 qualified for the nonphysiologic insulin

(NPI) and 88 for all other insulin (AOI) regimens cohorts. The NPI experimental group consisted

of patients on the three NPI regimens and the AOI control group consisted of patients on all

other insulin regimens not meeting the three NPI definitions. The investigator developed and

used a data collection sheet for the variables abstracted from the EHR and eliminated all patient

identifiers after analysis of this scholarly project.

Statistical analysis included the use of the IBM-SPSS software version 25. The

independent and paired samples t-Test calculated the mean HbA1c difference within and

between the two cohorts. The calculation and analysis of the mean HbA1c difference between


the NPI and AOI groups brought a better understanding of the impact of these insulin regimens

on a patient’s diabetes control. Statistical significance was set at p <0.05.

This scholarly project received support from the chief medical officer from the section of

Diabetes and Metabolism at Harbor UCLA Medical Center (see Appendix A); from a research

assistant with a decade experience in database management and from the hospital pharmacist

who provided the pharmacy lists of patients on insulin therapy. The author donated her time in

the extraction of data and performing the EHR chart review of this retrospective analysis.

It is a worthy endeavor to identify avenues to improve the HbA1c of adult patients with

type II diabetes in the primary care setting due to a 1% improvement in the HbA1c can reduce

diabetes-related death by 21% (UKPDS, 2014). Many of these patients obtain care from

providers in the outpatient clinics, but less than 50% achieved the target HbA1c. Increased

awareness of the delay in the HbA1c improvements with NPI regimens may increase adapting

physiologic approaches in insulin management by primary care providers. Defining and

quantifying the three nonphysiologic insulin regimens in this study may open an alternate means

to emphasizing the critical significance of insulin ratio in insulin replacement therapy.


Chapter 4

Results

The purpose of this chapter is to present the findings of this research study. The results

will be presented by describing the patient characteristics, insulin usage, and hemoglobin A1c. A

comprehensive analysis including a statistical calculation of patient demographics and the mean

differences in the HbA1c of the experimental and control group was completed. The goal of this

research was to explore the impact of nonphysiologic insulin regimens on the HbA1c of adult

patients with type II diabetes in two outpatient primary care clinics.

Statistical Tests and Rationale

A paired samples t-test analyzed the mean difference in the HbA1c reduction within the

NPI and AOI group. An independent samples t-Test calculated the mean HbA1c difference

between the NPI and AOI cohorts, and the mean difference between both group’s patient

demographics and insulin usage. Kim and Mallory (2017) stated that a paired t-Test is a

statistical approach used when comparing two means within a group and an independent samples

t-Test was used to compare means between two independent groups. A p value of < 0.05

demonstrated significance. The SPSS Version 25 software program was utilized in the analysis

of this project.

Patient Characteristics

The investigation of two outpatient primary care clinics on the utilization of NPI and its

impact on the HbA1c in adult patients with type II diabetes in a retrospective chart review

revealed the following results. Table 1 presented the patient characteristic for both groups. The

mean age for both groups was similar at 58 years with more females than males. The

predominant ethnicity was Hispanic followed by another ethnicity (Asian, Filipinos, Pakistani,


and Samoan), African-American and lastly, Caucasian. Both groups started with similar body

mass index (BMI) demonstrating cohorts of obese populations. Most patients, NPI 88% and AOI

84% had both hypertension and hyperlipidemia as comorbid conditions. At baseline, both group

demographics were similar for all patient characteristics (age, gender, ethnicity, BMI and co-

morbidities) p= >0.05. The independent samples t-Test showed no significant variances between

the NPI and AOI cohorts in patient demographics which affirmed homogeneity.

Table 1.

NPI and AOI Patient Demographics

Patient Demographics NPI% (n) or mean ±

SD Patient Demographics AOI% (n) or mean ±

SDAge (years) 58.64 ±9.8 Age (years) 57.78 ± 9.49Gender Gender Male 35.4 (40) Male 40.9 (36) Female 64.6 (73) Female 59.1 (52)Ethnicity Ethnicity Hispanic 67.3 (76) Hispanic 69.3 (61) Caucasian 4.4 (5) Caucasian 5.7 (5) African American 8.8 (10) African American 4.5 (4) Other 19.5 (22) Other 20.5 (18)BMI (Kg/m2) 33.03 ± 6.96 BMI (Kg/m2) 32.90 ± 7.62Comorbidities Comorbidities None 0.9 (1) None 3.4 (3) HTN 2.7 (3) HTN 4.5 (4) HLD 8 (9) HLD 8 (7) Both 88.5 (100) Both 84.1 (74)

Descriptive statistics and means for the NPI and AOI patient demographics for age,

gender, ethnicity, BMI and co-morbidities are presented in Table 2.


Table 2.

NPI and AOI Group Statistics (Patient Characteristics)

Group Statistics NPI and AOI Patient CharacteristicsNPIAOI N Mean Std. Deviation Std. Error Mean

Age (years) NPI 113 58.64 9.828 .925AOI 88 57.78 9.495 1.012

Gender NPI 113 1.65 .480 .045AOI 88 1.59 .494 .053

Ethnicity NPI 113 1.81 1.231 .116AOI 88 1.76 1.232 .131

BMI (Kg/m2) NPI 113 33.03 6.965 .655AOI 88 32.90 7.623 .813

Comorbidities NPI 113 2.84 .492 .046AOI 88 2.73 .707 .075

An independent samples t-Test calculated for the mean difference between the NPI and

AOI patient demographics was not statistically significant with all p values greater than 0.05 as

shown in Table 3.

Table 3.


Independent Samples t-Test Patient Characteristics

Independent Samples t-Test NPI and AOI Patient CharacteristicsLevene's

Test for Eq of Var. t-test for Equality of Means

F Sig. t dfSig. (2-tailed)

Mean Diff.

Std. Error Diff.

95% CI of the Diff.

Lower UpperAge (years) EVA .155 .694 .620 199 .536 .853 1.377 -1.86 3.57

EVNA .622 190.00 .534 .853 1.371 -1.85 3.56Gender EVA 2.31 .130 .797 199 .427 .055 .069 -.081 .192

EVNA .794 184.46 .428 .055 .069 -.082 .192Ethnicity EVA .106 .745 .251 199 .802 .044 .175 -.301 .389

EVNA .251 187.06 .802 .044 .175 -.301 .389Comorbidities EVA 7.137 .008 1.34 199 .182 .113 .085 -.054 .280

EVNA 1.28 148.66 .202 .113 .088 -.061 .288BMI (Kg/m2) EVA 1.153 .284 .125 199 .901 .129 1.032 -1.91 2.16

EVNA .123 178.33 .902 .129 1.044 -1.93 2.19

EVA- equal variances assumed.EVNA- equal variances not assumed.

Insulin Usage and HbA1c

The following are the descriptive statistics for the insulin usage and HbA1c. Table 4

indicated that for the AOI group the mean pre-HbA1c level was 9.35%, with a range of 6.30% to

16.10%, and a standard deviation of 1.61. The mean post-HbA1c level was 8.72% with a range


of 6.10% to 13.70%. The HbA1c difference was a mean of -0.62% reduction in HbA1c, having a

range of an increase of 2.30% to a decrease of 6.40%, with a standard deviation of 1.40.

Table 4.

AOI Group Descriptive Statistics

N Minimum Maximum Mean Std. Deviation

Pre-HbA1c (%) 88 6.30 16.10 9.3511 1.60817

Post-HbA1c (%) 88 6.10 13.70 8.7295 1.41382

HbA1c Diff (%) 88 +2.30 -6.40 -.6216 1.39576

Table 5 indicated that for the NPI group the mean pre-HbA1c level was 9.15%, with a

range of 5.80% to 15.10%, and a standard deviation of 1.93. The mean post-HbA1c level was

9.04% with a range of 5.00% to 14.20%. The HbA1c difference was a mean of -0.10% reduction

in HbA1c, having a range of an increase of 4.80% to a decrease of 5.10%, with a standard

deviation of 1.36.

Table 5.

NPI Group Descriptive Statistics

N Minimum Maximum Mean Std. Deviation

Pre-HbA1c (%) 113 5.80 15.10 9.1451 1.93261

Post-HbA1c (%) 113 5.00 14.20 9.0416 1.88181

HbA1c Difference (%) 113 +4.80 -5.10 -.1035 1.36027

An independent samples t-Test was calculated to determine if there was a statistically

significant difference in the change in HbA1c levels between the experimental group NPI and the

control group AOI. Descriptive statistics and means for both groups are presented in Table 6.


This indicated that the mean decrease in HbA1c level for group NPI was -0.10% and for group

AOI the mean change in HbA1c was -0.62%.

Table 6.

NPI and AOI Group Statistics

TREATMENT N Mean Std. Deviation Std. Error Mean

HbA1c Difference (%)

AOI 88 -0.6216 1.39576 .14879

NPI 113 -0.1035 1.36027 .12796

This difference was found to be statistically significant with those in the AOI group,

having a greater reduction in HbA1c levels than the NPI group (p = 0.009) (see Table 7).

Table 7.

Independent Samples t-Test NPI and AOI HbA1c Difference

Levene's Test t-test for Equality of Means

F Sig. t df

Sig. (2-

tailed)

Mean Differenc

e

Std. Error Differenc

e

95% CI

Lower Upper

HbA1c Diff (%)

EVA .249 .618 2.65 199 .009 .518 .196 .132 .903

EVNA 2.64 184.77 .009 .518 .196 .130 .905

EVA- equal variances assumed.EVNA- equal variances not assumed.

A paired samples t-Test was calculated to determine if there was a statistically significant

difference in the HbA1c change between the pre and post HbA1c within the NPI group.

Descriptive statistics and means for the pre and post HbA1c within the NPI group are presented

in Table 8. The result indicated that the mean decrease in the HbA1c within the NPI group was


-0.10%.

Table 8.

NPI Paired Samples Statistic

Paired Samples Statistics NPIMean N Std. Deviation Std. Error Mean

NPI Pre-HbA1c (%) 9.145 113 1.933 .182Post-HbA1c (%) 9.042 113 1.882 .177

The difference between the pre and post HbA1c within the NPI group was not

statistically significant (p=0.420) as shown in Table 9.

Table 9.

NPI Paired Samples t-Test

Paired Samples t-Test NPIPaired Differences

t dfSig. (2-tailed)Mean

Std. Deviatio

n

Std. Error Mean

95% Confidence Interval of the

DifferenceLower Upper

NPI

Pre-HbA1c (%)Post-HbA1c (%)

.104 1.360 .128 -.150 .357 .809 112 .420

A paired samples t-Test was calculated to determine if there was a statistically significant

difference in the HbA1c change between the pre and post HbA1c within the AOI group.

Descriptive statistics and means for the pre and post HbA1c within the AOI group are presented

in Table 10. The results indicated that the mean decrease in the HbA1C was -0.62%.

Table 10.


Paired Samples Statistics AOI

Paired Samples Statistics AOIMean N Std. Deviation Std. Error Mean

AOI Pre-HbA1c (%) 9.35 88 1.608 .171Post-HbA1c (%) 8.73 88 1.414 .151

The difference between the pre and post HbA1c within the AOI group was statistically

significant (p=0.000) as shown in Table 11.

Table 11.

Paired Samples t-Test AOI

Paired Samples t-Test AOIPaired Differences

t dfSig. (2-tailed)

Mean

Std. Deviatio

n

Std. Error Mean


DifferenceLower Upper

AOI

Pre-HbA1c (%)Post-HbA1c (%)

.622 1.396 .149 .326 .917 4.178 87 .000

A bar graph in Figure 2 illustrated the pre and post HbA1c difference within the NPI

group with a -0.10% reduction (p=0.420) and the pre and post HbA1c difference within the AOI

group with a -0.62% HbA1c reduction (p=0.000).

Figure 2.

NPI and AOI Change in HbA1c (%)


8.2

8.4

8.6

8.8

9

9.2

9.4

9.6Change in HbA1c over the Observation Period

Start EndH

bA1c

(%)

*AOI NPI

A bar graph in Figure 3 showed the mean HbA1c decrease between the NPI and AOI

group. The AOI group illustrated a significant reduction in the HbA1c.

Figure 3.

NPI and AOI Reduction in HbA1c (%)

* p=0.000, Start HBA1c compared with End HbA1c


-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0NPI AOI

NPI AOI

HbA

1c (%

) diff

eren

ce

*

* p=0.009

Table 12 is a summary table that illustrated the results for the NPI and AOI insulin usage

and HbA1c in percentage and mean with standard deviation. The AOI group had more insulin

dose changes or adjustments at an average of 1.07 compared to the NPI at a mean of .81. This


was not statistically significant. All patients in the two cohorts remained on the same insulin

regimen at an average of 25 weeks or six months including dose changes.

Table 12.

Summary of NPI and AOI Insulin Usage and HbA1c

NPI% (n) or mean

± SD AOI% (n) or mean

± SDMean Pre-HbA1C (%) 9.14 ± 1.93 Mean Pre-HbA1C (%) 9.35 ± 1.60Mean Post-HbA1C (%) 9.04 ± 1.88 Mean Post-HbA1C (%) 8.73 ± 1.41Mean Difference (%) 0.10 ± 1.36 Mean Difference (%) 0.62 ± 1.39Insulin Dose (Unit/kg per day) 0.93 ± 0.43 Insulin Dose (Unit/kg per day) 0.94 ± 0.31Insulin Duration (Weeks) 25.5 ± 7.5 Insulin Duration (Weeks) 25.6 ± 7.8Insulin Dose Adjustment (n) 0.81 ± 0.90 Insulin Dose Adjustment (n) 1.07 ± 1.08Insulin Up titration 36.3 (41) Insulin Up titration 46.6 (41)Insulin Down titration 7.1 (8) Insulin Down titration 6.8 (6)Both Up/Down titration 10.6 (12) Both Up/Down titration 9.1 (8)No Dose Change 46.0 (52) No Dose Change 37.5 (33)Basal Mono 0.71 units/kg/d 33.6 (38) Basal Mono (Exclusion) 1.1 (1)N/R 50% am: 50% pm 29.2 (33) N/R 63% am: 37% pm 53.4 (47)Basal 67%: Bolus 33% 37.2 (42) Basal 46%: Bolus 54% 45.5 (40)

NPI Dose Change AOI Dose ChangeNPI 1 Dose Change 0.78 (30) AOI 1 Dose Change 0 (0)NPI 2 Dose Change 0.72 (24) AOI 2 Dose Change 1.25 (59)NPI 3 Dose Change 0.90 (38) AOI 3 Dose Change 0.87 (35)Total Dose Change (NPI) 0.81 (92) Total Dose Change (AOI) 1.07 (94)

An independent samples t-Test was calculated to determine if there was a statistically

significant difference in insulin usage and HbA1c between both groups. Descriptive statistics and

means in dose change or adjustment, duration in weeks or follow-up, unit per kilogram per day

and insulin titration for both groups are presented in Table 13.


Table 13.

NPI and AOI Insulin Usage

Group Statistics NPI and AOI Insulin UsageNPIAOI N Mean Std. Deviation Std. Error Mean

Dose Change

1 NPI 113 .81 .912 .0862 AOI 88 1.07 1.08 .115

Duration in Weeks

1 NPI 113 25.48 7.46 .7022 AOI 88 25.60 7.83 .834

Unit per kg/day

1 NPI 113 .934 .439 .0412 AOI 88 .945 .315 .033

Up/Down/Both

1 NPI 113 .82 .966 .0912 AOI 88 .88 .895 .095

There was no statistically significant difference in the insulin usage and HbA1c in both

groups as illustrated in Table 14. The mean insulin unit per kilogram body weight, duration in

weeks or length of follow-up, and number of insulin dose changes or adjustments were not

statistically significant. It is interesting to note that the p level for the number of insulin dose


changes or adjustments between the two groups was at an alpha level of 0.072 trending towards a

significant value.

Table 14.

Independent Sample t-Test Insulin Usage

Levene's Test for Eq

of Var t-test for Equality of Means

F Sig. t dfSig. (2-tailed)

Mean Diff.

Std. Error Diff.


Diff.Lower Upper

DoseChange

EVA 1.72 .191 -1.81 199 .072 -.254 .141 -.531 .023EVNA -1.77 169.69 .079 -.254 .144 -.538 .029

Duration Weeks

EVA .566 .453 -.106 199 .915 -.1154 1.08 -2.25 2.02EVNA -.106 182.61 .916 -.115 1.09 -2.26 2.04

Unit/kg/day

EVA 3.45 .065 -.210 199 .834 -.012 .055 -.121 .098EVNA -.218 197.78 .828 -.012 .053 -.117 .093

Up/Dw/Both

EVA 1.41 .236 -.391 199 .696 -.052 .133 -.314 .210EVNA -.395 193.06 .693 -.052 .132 -.312 .208

EVA- equality of variances assumed.EVNA- equality of variances not assumed.

Chapter 5

Discussion

The purpose of this chapter is to discuss the interpretation, implications, clinical

significance, strengths, limitations and recommendations of this research study. Investigating the


association between nonphysiologic insulin regimens (NPI) and its impact on the HbA1c was the

purpose of this scholarly project. The research question was: In adult patients with type II

diabetes, does nonphysiologic insulin dose of three identified insulin regimens affect the HbA1c?

There is a statistically (p=0.009) and a clinically significant difference between the mean post-

HbA1c of patients on NPI and all other insulin (AOI) regimens.

The researcher completed a quantitative retrospective chart review of 891 pharmacy

records in two primary care outpatient clinics to examine insulin practices and its impact on the

HbA1c. A HbA1c level of less than 7% exhibit optimal glucose control (ADA, 2014), but

currently an individualized approach for patients with comorbidities is the recommended

approach for diabetes management (ADA, 2017). In this study, a HbA1c of less than 7.5% was

acceptable as a target for glycemic control. The results disclosed that 78% of patients in the NPI

group and 80% in the AOI group had a HbA1c of greater than 7.5% at baseline. These results are

comparable to a study in 2011 suggesting that less than 50% of patients with type II diabetes

reached a hemoglobin A1c of 7% (Giugliano et al., 2011).

Interpretation of Findings

HbA1c Inertia

The investigation revealed HbA1c inertia in adult patients with type II diabetes using NPI

regimens. The Merriam Webster’s collegiate online dictionary (2018) defined inertia as a

property of matter that remains at rest, inactivity, and indisposition to change. Pantalone et al.

(2018) described clinical inertia as the failure of clinicians to intensify diabetes treatments to

achieve the target HbA1c. Hemoglobin A1c inertia then is the failure of the HbA1c to improve.

This finding is significant in diabetes management because NPI is a concept with no measurable


definition in the literature. The result in this study suggested an association between these three

NPI regimens and HbA1c inertia which is a novel report.

This investigation resulted in three working definitions for the conceptual description of

NPI regimens as not mimicking the normal insulin secretion. These three quantifiable measures

are: (a) basal monotherapy of greater than 0.5 units per kilogram per day, (b) NPH and regular

insulin in equal doses (+10%) twice daily, and (c) basal-bolus regimen where the basal dose is

greater than 55%, and the bolus dose is less than 45% of the total daily dose. An overestimated

basal and underestimated bolus insulin dose had no impact on the HbA1c throughout the study.

The NPI regimens had a minimum HbA1c reduction of - 0.1% exposing no improvement in the

glucose levels.

The mean post-HbA1c of patients on the AOI group demonstrated a more significant

reduction of -0.6% as compared to the NPI. This difference was statistically significant at a

p=0.009. The AOI group with insulin regimens that showed intention towards a physiologic

regimen, meaning covering all meals with prandial insulin and supporting sufficient background

insulin working as the 24-hour basal demonstrated a significant improvement in the HbA1c. In

this research study, the AOI regimens depicted an insulin ratio of 46% basal and 54% bolus of

the total daily dose, opposite the NPI criteria. It supported previous studies of insulin ratios

providing more coverage for the bolus and less for the basal treatment (Cai et al., 2012; King,

2010; Kuroda et al., 2011; Mao et al, 1997; Schiffrin & Belmonte, 1981; Tamaki et al., 2008;

Yamada et al., 2017).

The findings in this study confirmed NPH and regular insulin or premixed insulin at an

approximately 65% morning and 35% evening insulin ratio twice daily impacted the HbA1c. A

63% morning and 37% evening dosing was the insulin ratio for patients with the NPH and


regular or premixed insulin regimens in the AOI group. These ratios closely mimic a physiologic

approach in insulin management of patients with type II diabetes because it provides more

coverage for the morning dose (covers breakfast and lunch) and less for the evening dose (covers

dinner then overnight). A split-mixed or premixed insulin prescribed by providers in equal

amounts (+10%) twice daily (NPI) may not be best to achieve target HbA1c.

Insulin Adjustments

Pantalone et al. (2018) defined clinical inertia as inadequate treatment by providers to

intensify insulin therapy despite uncontrolled glucose levels. The study reported that the median

time to treatment after an HbA1c above target was longer than one year (Pantalone et al., 2018).

In this research study, the mean insulin follow-up or duration was not significant at 25 weeks or

6.2 months for both groups (p=0.915), but the mean insulin dose changes or adjustments

differed. The AOI group had a mean insulin adjustment of 1.07 while the NPI had .81 (p=0.072).

These findings raise the possibility but, cannot prove that the AOI group had more

dynamic insulin adjustments compared to the NPI with a p-value trending towards significance

(p=0.072). Furthermore, despite both groups having the same insulin duration or follow-up

(p=0.915), and the same daily total amount of insulin units in kilograms of the body weight

(p=0.834), the AOI had a more significant impact on the HbA1c compared to the NPI. The

marked difference between the two groups was the insulin ratios used, not the total daily dose,

providing therapeutic implications of the AOI on the HbA1c.

Bolus Insulin Phobia

Previous studies demonstrated the total daily bolus dose between 60% to 80% of the total

daily dose was sufficient to achieve target HbA1c (Cai et al., 2012; King, 2010; Kuroda et al.,


2011; Mao et al., 1997; Schiffrin, & Belmonte, 1981; Tamaki et al., 2008; Yamada et al., 2017).

In this research study, 34% (n=38) of patients in the NPI group was on a basal monotherapy of

greater than 0.5 units per kilogram per day. The proportion of patients on a single insulin

regimen was high, implicating a hesitancy in using bolus insulin for mealtime coverage. A basal-

bolus approach is the gold standard for insulin management, mimicking the normal pancreatic

insulin secretion (Bellido et al., 2015; Giugliano et al., 2016; Giugliano et al., 2011; Riddle et al.,

2014; Owens, 2013). Overcoming this bolus phobia by proactively introducing appropriate

rapid-acting coverage to the insulin regimen may counter HbA1c inertia.

Implications of Findings

Physiologic Insulin Replacement

Implications to clinical practice in this study include incorporating concepts of

physiologic insulin replacement in the primary care clinics in managing adult patients with type

II diabetes. Increasing the awareness of providers, advanced practice nurses and registered nurses

of the increased risk in hypoglycemia events and HbA1c inertia utilizing NPI regimens is

critical. Documenting hypoglycemia events during every patient assessment at each clinic visit is

also crucial to patient safety.

Study Period Duration

The United Kingdom Prospective Diabetes Study (UKPDS) is the most extensive

prospective study ever done on adult patients with type II diabetes with an average follow-up of

10 years (UKPDS, 2014). This project focused on adults with type II diabetes for a 9-month

period. The implication is that with a longer study duration, the post-HbA1c may improve better

with the AOI cohort. A more extended study period may result in a greater reduction in the


HbA1c of patients using insulin regimens that promotes physiologic concepts in insulin

management.

Clinical Significance

The HbA1c reduction of -0.6% in the AOI group is clinically significant. The UKPDS

reported that a link between diabetes complications and glycemic control exists. Each 1%

decrease in the mean HbA1c was related to a 21% reduction in diabetes-related deaths, 14%

reduction in myocardial infarctions, and 37% in microvascular complications (UKPDS, 2014).

As little as a 1% reduction in the HbA1c prevents dangerous complications and avert patients

from diabetes-related death risks. A reduction of -0.6% in the AOI group may be a small

measure, but it can make a significant improvement in the daily lives of patients with type II

diabetes. A patient may verbalize an overall sense of well-being with this HbA1c improvement

indicating clinical significance (Polit & Beck, 2017).

Insulin regimens that aim to mimic normal pancreatic insulin secretion have a lesser

chance for hypoglycemia events by following a physiologic approach which can increase patient

adherence, improving diabetes self-management. This enhanced self-management may promote

a healthier lifestyle of adult patients with type II diabetes in the primary care clinics located in

Southern California.

This study revealed that utilizing NPI regimens had a negative impact on the HbA1c of

patients with type II diabetes. These insulin doses resulted in HbA1c inertia. This outcome

represented delayed improvement in diabetes control. Informing advanced practice nurses,

registered nurses, and providers of this negative impact may increase identification of NPI

regimens in primary care clinics. Increased awareness of the physiologic use of insulin may

prevent worsening of glucose levels.


Limitations and Strengths

A barrier encountered at the end of the project is not having a comparison group to

contrast the NPI group. This cohort addition required an amendment to the current IRB

application and approval was obtained. Another limitation included using the HbA1c as a

primary outcome over hypoglycemia to measure the association of the three NPI regimens on

diabetes control of adult patients with type II diabetes. The reason for this is the difficulty in

obtaining measurable data for hypoglycemia due to the little documentation of these events in the

electronic health record. Next, was the study duration. The total observation period lasted nine

months, starting from February 1, 2017 and ending on October 31, 2017. This duration may not

be enough to demonstrate the impact of the HbA1c on insulin regimens. The United Kingdom

Prospective Diabetes Study followed patients for 10 years (UKPDS, 2014).

A larger sample size than the collected subjects may allow generalization of the findings

to other outpatient primary care clinics. A post hoc analysis using Cohen’s G-power (1988),

affirmed that this study retained a medium effect (0.377) with a 0.75 power. A priori done after

the analysis assert that one will need 128 samples for each cohort to attain 0.80 power (Cohen,

1988). Another weakness is possibly introducing bias by excluding patients on insulin regimens

that were less than 0.5 units per kilogram per day. The focus of this study was to explore the

prevalence of NPI utilization in primary care and including patients who were potentially under-

dosed may skew the NPI impact which may give the investigator a misleading result.

Insufficient insulin is a critical factor contributing to poor glucose control that is common

in primary care (Pantalone et al., 2018). Although the researcher’s goal was to perform a

rigorous and proper comparison of the NPI and AOI groups by removing under-dosed patients in

the sample population, possible introduction of bias may have occurred during the exclusion


process. Lastly, the study location is part of an academic teaching program which may not reflect

routine primary care. Previous prospective studies took place in an in-patient setting (Mao et al.,

1997). Some multi-center outpatient clinics were affiliated with teaching institutions (Cai et al.,

2012; Kuroda et al., 2011; Tamaki et al., 2008). Outpatient clinics linked with a teaching

institution may receive care based on more current diabetes interventions.

Strengths included the continuous academic views of the physician mentor and peer

reviewers each step of the research process. Provision of supplementary analysis by the

physician mentor who is a Diabetologist facilitated a comprehensive interpretation of the study

results. A weekly meeting with the mentor and reviewers increased the rigor due to

recommendations for improvement during the review. Achieving replication of this study is high

due to the availability of the pharmacy list from the same site for future studies and a study flow

diagram for subsequent research duplication.

Conclusion and Recommendations

A quantitative retrospective chart review of adult patients with type II diabetes in two

primary care clinics in Los Angeles suggested that utilizing nonphysiologic insulin regimens is

linked with HbA1c inertia. Hemoglobin A1c inertia is the failure of the HbA1c to improve. A

sample size of 891 remained after reviewing 5,978 pharmacy prescriptions for several entries of

the same patients on insulin regimen between February 1 to October 31, 2017. The results

indicated a statistically (p=0.009) and a clinically significant difference between the mean post

HbA1c of patients on nonphysiologic (NPI) and all other insulin (AOI) regimens. The HbA1c of

patients with the NPI regimens had a minor change of -0.1% compared to a -0.6% reduction in

the AOI group, suggesting HbA1c inertia in the NPI cohort. Efforts must be made to promote


collaboration with diabetes care managers and the diabetes clinic in the management of patients

with type II diabetes in primary care settings following physiologic principles in insulin therapy.

A few recommendations came about after the analysis. First, the awareness of providers,

advanced practice nurses and registered nurses of the non-therapeutic impact of the three NPI

regimens on the HbA1c resulting in HbA1c inertia. Second, providers need to utilize physiologic

principles in insulin replacement therapy with appropriate insulin ratios for both basal-bolus,

split-mixed, and premixed insulin dosing. A 46% basal and 54% bolus insulin ratio was better

but, may not be ideal when using the basal-bolus approach. The author could not test whether a

40% to 60% ratio would have been better due to a restricted sample size. Similarly, a 63%

morning and 37% evening split-mixed insulin or premixed insulin ratios achieved a better

influence on the post-HbA1c.

Third, providers and other health care professionals need to avail of the insulin initiation

algorithms in the local intranet of the same facility. Fourth, providers need to increase

collaboration with certified diabetes educators and care managers from the Diabetes specialty

clinic in the glucose management of adult patients with type II diabetes. Lastly, providers must

promote proactive insulin adjustments in primary care clinics of patients on insulin replacement

therapy. When patients are on physiologic insulin regimens that have fewer risks of

hypoglycemia events, chances of adherence and self-management may be higher. A laser-

focused approach to physiologic insulin replacement therapy should be the goal for all health

care professionals to improve diabetes management in primary care due to a crucial factor in

correcting a patient’s uncontrolled glucose is an insulin ratio that mimics normal insulin

secretion.

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Appendix A

Letter of Support


UCLA Clinical and Translational Science Institute at Los Angeles Biomedical Research Instituteand Harbor-UCLA Medical Center

HARBOR UCLA MEDICAL CENTER‐1000 W. CARSON STREET, BOX 16 P.O. BOX 2910 TORRANCE, CALIFORNIA 90509 2910 ‐

TEL: (310) 222‐2503 FAX: (310) 533‐6972

EMAIL:[email protected] http://research.labiomed.org

November 14, 2017

To Whom It May Concern, This is to confirm that Noemi Capistrano NP, CDE is conducting a QI project on insulin usage in primary care under my supervision, using data from our electronic medical records. Once IRB approved, she will have permission to use de identified data for the purposes of her doctoral thesis. ‐

Eli Ipp MD Professor, UCLA School of Medicine Head, Section of Diabetes and Metabolism Associate Director, Clinical & Translational Research Center Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute

Phone: 310 222-2503 FAX: 310 533-6972 email: [email protected]

Appendix B

Site IRB Approval of Research

Los Angeles BioMedical Research Institute


At Harbor- UCLA Medical Center

Compliance and Regulatory Affairs 1124 West Carson St.

Martin Bldg., 2nd Floor (RB-1) Torrance CA 90502-2064 p) 310.222.3624, f) 310.782.0486

APPROVAL OF RESEARCH

January 16, 2018

Eli Ipp, M.D. 310 222 2503

[email protected]

Noemi Capistrano, MSN310-222-1672 [email protected]

Dear Dr. Ipp/Ms. Capistrano:

On 01/10/2018, the John F. Wolf, M.D. Human Subjects Committee (1) reviewed the following protocol:

Type of Review/Submission:

Expedited/Initial Review, Reference #044764

Project Title: The Association between Insulin Dose and Hemoglobin A1C in Adult Patients with Type II Diabetes

Investigator: Eli Ipp, M.D./Noemi Capistrano, MSN

LABioMed Project No.: 31415-01

Funding Agency: None

Documents reviewed: Submission Packet for Initial Review (Version 1.0)

IRB Application (HRP-211) (Version 1.0)

Data Collection Sheet (Version 1.0)

Investigator Protocol (Version 1.0)

Abbreviated Institutional Research Application (Version 1.0)

Noemi Capistrano, MSN CV (Version 1.0)

Eli Ipp, MD CV (Version 1.0)

The John F. Wolf, M.D. Human Subjects Committee (1) approved the protocol from 01/10/2018 to 01/09/2019 inclusive. Within 30 days prior to the protocol’s scheduled Continuing Review (12/11/2018), you are to submit a completed “HRP-212: Continuing Review Progress Report” and required attachments to request continuing approval or “HRP-251: Final Report/Inactivation” to close the study.

Co-I Name added 1/22/2018


Regulatory Determinations: The John F. Wolf, M.D. Human Subjects Committee (1) waived the requirement of the Consent Process under 45 CFR §46.116(d). Important Note: Approval by the IRB does not, in and of itself, constitute approval for the implementation of this research. Other LA BioMed clearance and approvals or other external agency or collaborating institutional approvals may be required before study activities and initiated. Research undertaken in conjunction with outside entities, such as drug or device companies, are typically contractual in nature and require an agreement between the institute and the entity.

HRP Form-510Rev. 07/25/2014Approval of Research (Ref#044764) LABioMed Project No. 31415-01

Page 2 of 2

If continuing review approval is not granted before the expiration date of 01/09/2019 approval of this research expires on that date.

Please see iRIS for the stamped approved study documents.

In conducting this research you are required to follow the requirements listed in the INVESTIGATOR MANUAL (HRP-103).

Sincerely,

Signature applied by Elizabeth Burrola CIP on 01/28/2018 11:03:33 AM PST

Liz Burrola, CIP

Compliance Office

cc: Office of Research Administration

Appendix C

IRB Approval Maryville University

Date: February 26, 2018

To: Noemi Capistrano, doctoral candidate

From: Dr. Robert Bertolino, Chair, Institutional Review Board


Dr. Tammy M. Gocial, Integrity Officer for Institutional Review Board

RE: IRB Review of Protocol #17-74

Title: “The Association between Insulin Dose and Hemoglobin A1C in Adult Patients with Type II Diabetes”

CC: Dr. La Donna Whitten, Faculty Advisor

This is to inform you that your application to conduct research has been reviewed and accepted by the Maryville University Institutional Review Board. You are now authorized to begin the research as outlined in your proposal.

It is understood that this project will be conducted in full accordance with all applicable sections of the IRB guidelines as published by Maryville University. It is also understood that the IRB will be notified immediately of any proposed changes that may affect the status of your research proposal. As the principal investigator(s), you are required to notify the Maryville University IRB of any adverse reactions that may develop as a result of this study. Finally, when your research has concluded (or if you conclude the study sooner than anticipated), please complete the Protocol Closure Form.

Good luck on your research.

Appendix D

IRB Amendment Maryville University

Date: June 29, 2018

To: Ms. Noemi Capistrano, Doctoral Candidate, Nursing Practice


From: Dr. Robert Berolino, Chair, Institutional Review Board

Dr. Tammy M. Gocial, Integrity Officer for Institutional Review Board

RE: IRB Review of Protocol #17-74

Title: “The Association between Insulin Dose and Hemoglobin A1C in Adult Patients with Type II Diabetes”

CC: Dr. LaDonna Whitten – Associate Professor of Nursing and Project Chair

This letter is to inform you that your Application for Amendment to your Research Proposal has been reviewed and accepted by the Maryville University Institutional Review Board. You are now authorized to begin the research as amended. Please note that this approved amendment does not change your protocol initiation and termination dates.

It is understood that this project will be conducted in full accordance with all applicable sections of the IRB guidelines as published by Maryville University. It is also understood that the IRB will be notified immediately of any proposed changes that may affect the status of your research proposal. As the principal investigator(s), you are required to notify the Maryville University IRB of any adverse reactions that may develop as a result of this study. Finally, when your research has concluded (or if you conclude the study sooner than anticipated), please complete the Protocol Closure Form. If informed consent processes were a part of your proposal, an approved, stamped version is attached to this form. Please note the dates of initiation and termination for the original protocol have not changed as a result of this amendment.

Good luck on your research.

Appendix E

Data Collection Sheet

Chart # Age

> 18 years

Type II DM (yes or no)

Gender (M or F)

BMI DM Duration

Co-Morbidities

HTN, HLD or both

Nonphysiologic Insulin Regimen

(1, 2, 3)

Pre-HbA1C

Post-HbA1C

Ethnicity

1

2


3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20…

KEY: BMI- Body Mass Index; DM-Diabetes Mellitus; HLD- Hyperlipidemia; HTN-hypertension; HbA1C- Hemoglobin A1C (average blood sugar the past three months)

Nonphysiologic Insulin Regimens:

1. Basal insulin monotherapy of greater than 0.5 unit/kilogram/day.

2. Administration of NPH/short-acting or premixed insulin in equal doses twice a day.

3. Basal-bolus insulin therapy in which the basal dose is greater than 55% and the bolus dose is less than 45% of the total daily dose.