Diabetes challenging cases

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Case #1: Joan Sullivan: 52-year-old woman, maternal history of type 2 diabetes

Vital signs and clinical and laboratory findings

Initial presentation One year later, after counseling, diet, and exercise

Age, years 52 53Body weight, kg (lb.) 77.6 (171) 78.5 (173)Hb A1c 7.0% 7.5%Blood pressure, mm Hg 118/78 122/82Fasting plasma glucose, mg/dL 122 140 (retest: 145)Total cholesterol, mg/dL 195 212LDL cholesterol, mg/dL 119 136HDL cholesterol, mg/dL 35 34Triglycerides, mg/dL 205 212Proteinuria Negative Negative

At her initial presentation, Mrs Sullivan was prescribed a program of counseling, diet, and exercise based on her laboratory results and weight. However, despite counseling for diet and exercise, she has been unsuccessful in her attempts to lose weight, her weight has increased, and her glycemic control has worsened. On her return visit 1 year later, her fasting plasma glucose value was 140 mg/dL. On repeat, it was 145 mg/dL. She therefore satisfies the criteria for type 2 diabetes.1 Most likely, her beta cell function has continued to decline.

This scenario is common in patients with insulin resistance. Regardless of their sincerity and intent to carry out the required lifestyle modifications, patients’ efforts often produce little success. There are many reasons for this, including social and environmental factors, such as the time required for exercise, familial and social patterns of overeating and underactivity, lack of access to skilled counseling and support, unhealthy nutritional environments (eg, the higher cost of healthy foods and the ubiquitous presence of cheap fast foods and junk foods), and other barriers that challenge patients’ achievement of their goals.

There may also be biological reasons for the difficulty in losing weight, such as a mismatch between insulin production and blood glucose peaks. This mismatch is due to a reduction or loss of first-phase insulin production. The diminution of first-phase insulin release occurs because: (1) the patient is producing maximal quantities of insulin to take care of the glucose the body is producing from gluconeogenesis (basal glucose production); and (2) there is a loss of meal-stimulated insulin release (loss of the incretin effect) (see Figure 1). As a result, insulin release in response to food ingestion is delayed, which in some instances may even precipitate late postprandial hypoglycemia, which in turn could precipitate hunger. This loss of first-phase insulin release is considered to be the earliest detectable evidence of impaired beta cell function.

What is the best therapeutic approach to improve Mrs Sullivan’s glycemic control in the short term AND to maintain or improve her beta cell function in the long term?

According to current guidelines from the American Diabetes Association (ADA; Figure 2), initiation of metformin

2012: Challenging Cases in the Treatment of Type 2 Diabetes

FacultyRattan Juneja, MDAssociate Professor of Clinical MedicineIndiana University School of MedicineMedical Director, Indiana University Diabetes CenterChief of Endocrinology, Wishard Memorial HospitalIndianapolis, IN

Learning ObjectivesThis activity is designed for specialists in primary care and endocrinology. There are no prerequisites for this activity. At the conclusion of this activity, participants should be able to:

• Preserve beta cell function, delay disease progression, and minimize the risk of diabetes-related complications by formulating an individualized treatment plan that addresses the multiple pathophysiologic mechanisms of diabetes.

• Recognizethefundamentalfeatures,benefits,andrisksunderlyingcurrent treatment recommendations when developing individualized treatment plans.

• Employ multiple strategies to identify and reduce clinical inertia to achieve optimal patient outcomes.

• Foster good patient self-management by establishing a collaborative relationship with patients based on respect for individual patient preferences, needs, and values.

• Establish a comprehensive conceptual framework for disease management of diabetes, hypertension, and hypercholesterolemia so as to provide effective primary care based on current standards.

CME InformationRelease Date: June 25, 2012.Valid for credit through June 24, 2013.

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Indiana University School of Medicine and Heath Focus, Inc. Indiana University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. Indiana University School of Medicine designates this enduring activity for a maximum of 4 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.To receive credit, participants must review the slides and audio components of this website, and submit the activity evaluation form and posttest (passing score = 75% or higher).Length of time to complete the activity: 4 hours

Disclosure InformationCommercial SupportIndiana University School of Medicine and Health Focus, Inc. gratefully acknowledge the unrestricted educational grant provided by EliLilly&Company,Merck,NovoNordisk,Sanofi.

Faculty DisclosureIn accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards for Commercial Support, educational programs sponsored by Indiana University School of Medicine (IUSM) must demonstrate balance, independence, objectivity, and scientific rigor. Allfaculty, authors, editors, and planning committee members participating in an IUSM-sponsored activity are required to disclose any relevant financial interest or other relationship with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services that are discussed in an educational activity. Dr. Juneja reported that he has received consulting fees and/or honoraria from Alere, Amylin, Boehringer Ingelheim,Merck,EliLilly&Company,andSanofi.

Staff: Hassan Danesh, PhD, Monica Armin, and Dr. Deborah Teplow have disclosedthattheyhavenopotentialoractualconflictsofinterest.

CME Reviewer: Statements of disclosure of relevant financialrelationships have been obtained from Charles Clark Jr, MD. Dr. Clark hasdisclosedthathehasnopotentialoractualconflictsofinterest.

Note: Although it offers CME credits, this activity is not intended to provideextensivetrainingorcertificationinthefield.

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monotherapy is the recommended approach.2,3 Metformin monotherapy is usually successful in lowering hemoglobin A1c (Hb A1c) levels to less than 7.0% in patients whose initial Hb A1c levels are equal to or greater than 7.5%. However, it may not be the most advantageous approach because it is not likely to achieve the dual goals of therapy: improve glycemic control and preserve beta cell function.

Figure 3 shows beta cell function over time, estimated using Homeostasis Model Assessment (HOMA), in patients who participated in the United Kingdom Prospective Diabetes Study (UKPDS).4 Time zero represents the time at which patients were given the diagnosis of type 2 diabetes and started treatment. It was estimated that beta cell function had already declined by approximately 50% in these patients, but treatment with metformin, a sulfonylurea, or insulin did not prevent further decline in beta cell function.

Figure 4 illustrates the implications of declining beta cell function on Hb A1c levels among patients in A Diabetes Outcome Progression Trial (ADOPT).5 These patients had mean initial Hb A1c values of approximately 7.3%, and the introduction of metformin, glyburide, or rosiglitazone rapidly reduced Hb A1c values to acceptable levels. However, during the subsequent years, Hb A1c levels progressively worsened, so that most patients had Hb A1c levels of greater than 7.0% again within 3 years to 5 years, despite continued treatment.

All 3 monotherapies tested reduced mean Hb A1c levels soon after initiation in patients with newly diagnosed type 2 diabetes. However, Hb A1c levels progressively worsened during the ensuing years, so that mean levels were greater than 7.0% within 4 to 5 years of treatment initiation.

Using metformin monotherapy, we would expect Mrs Sullivan’s Hb A1c level to decline to less than 7.0% soon after initiation of treatment. But it is likely that it would return to a level above 7.0% within a few years, requiring the addition of a second drug at that time. Unfortunately, Mrs Sullivan’s beta cell function is likely to have deteriorated

Time, min

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in type 2 diabetes.

Adapted with permission from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.

Figure 1. Demonstration of the Incretin Effect. The graphic on the left is from patients without diabetes. As can be seen, insulin production is much greater in response to oral glucose than IV glucose, because the incretin hormones GLP-1 and GIP are produced when glucose stimulates the intestine. In contrast, in patients with type 2 diabetes the incretin effect is diminished,eitherduetodeficiencyordecreasedaction,orboth,ofGLP-1.

weight gain by optimal medication selec-tion and dose titration.

For all medications, considerationshould also be given to overall tolerability.Even occasional hypoglycemia may bedevastating, if severe, or merely irritating,if mild (81). Gastrointestinal side effects

may be tolerated by some, but not others.Fluid retention may pose a clinical ormerely an aesthetic problem (82). Therisk of bone fracturesmay be a specific con-cern in postmenopausal women (57).

It must be acknowledged that costsare a critical issue driving the selection of

glucose-lowering agents in many environ-ments. For resource-limited settings, lessexpensive agents should be chosen. How-ever, due consideration should be alsogiven to side effects and any necessarymonitoring, with their own cost impli-cations. Moreover, prevention of morbid

Figure 2dAntihyperglycemic therapy in type 2 diabetes: general recommendations. Moving from the top to the bottom of the figure, potentialsequences of antihyperglycemic therapy. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis(unless there are explicit contraindications). If the HbA1c target is not achieved after;3months, consider one of the five treatment options combinedwith metformin: a sulfonylurea, TZD, DPP-4 inhibitor, GLP-1 receptor agonist, or basal insulin. (The order in the chart is determined by historicalintroduction and route of administration and is notmeant to denote any specific preference.) Choice is based on patient and drug characteristics, withthe over-riding goal of improving glycemic control while minimizing side effects. Shared decision making with the patient may help in the selection oftherapeutic options. The figure displays drugs commonly used both in the U.S. and/or Europe. Rapid-acting secretagogues (meglitinides) may beused in place of sulfonylureas. Other drugs not shown (a-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used whereavailable in selected patients but have modest efficacy and/or limiting side effects. In patients intolerant of, or with contraindications for, metformin,select initial drug from other classes depicted and proceed accordingly. In this circumstance, while published trials are generally lacking, it isreasonable to consider three-drug combinations other than metformin. Insulin is likely to be more effective than most other agents as a third-linetherapy, especially when HbA1c is very high (e.g., $9.0%). The therapeutic regimen should include some basal insulin before moving to morecomplex insulin strategies (Fig. 3). Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a two-drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycemia (e.g., HbA1c $10.0–12.0%). DPP-4-i, DPP-4inhibitor; Fx’s, bone fractures; GI, gastrointestinal; GLP-1-RA, GLP-1 receptor agonist; HF, heart failure; SU, sulfonylurea. aConsider beginning at thisstage in patients with very high HbA1c (e.g.,$9%). bConsider rapid-acting, nonsulfonylurea secretagogues (meglitinides) in patients with irregularmeal schedules or who develop late postprandial hypoglycemia on sulfonylureas. cSee Table 1 for additional potential adverse effects and risks, under“Disadvantages.” dUsually a basal insulin (NPH, glargine, detemir) in combination with noninsulin agents. eCertain noninsulin agents may becontinued with insulin (see text). Refer to Fig. 3 for details on regimens. Consider beginning at this stage if patient presents with severe hyperglycemia($16.7–19.4 mmol/L [$300–350 mg/dL]; HbA1c $10.0–12.0%) with or without catabolic features (weight loss, ketosis, etc.).

8 DIABETES CARE care.diabetesjournals.org

Position Statement

Figure 2. Algorithm for Individualized Management of Type 2 Diabetes According to the ADA.The algorithm recommends initial monotherapy using metformin, followed by addition of a second antihyperglycemic agent if Hb A1c target levels are not achieved.

aConsider beginning at this stage in patients with very high HbA1c (e.g., $9%). bConsider rapid-acting, nonsulfonylurea secreta-gogues (meglitinides) in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas. cUsually a basal insulin (NPH, glargine, detemir) in combination with noninsulin agents. dCertain noninsulin agents may be continued with insulin.

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over this time, and deteriorating beta cell function could make treatment more challenging.

To prevent long-term loss of beta cell function and reduce glycemic levels in the short term, I recommend starting patients on monotherapy (usually using metformin) and then introducing a second oral agent as soon as metformin is titrated to the maximum tolerated dosage, regardless of the patient’s Hb A1c level. The second drug should have a different mechanism of action than the first drug, have no risk or low risk of hypoglycemia, and facilitate weight loss or weight maintenance, according to patient needs. This approach is more similar to the glycemic control algorithm recommended by the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) (Figure 5).6 This algorithm recommends that patients start with dual therapy if their Hb A1c is equal to or lower than 7.6%.

Although Mrs Sullivan’s Hb A1c level is just below the recommended threshold for use of 2 drugs, for reasons discussed, I would advocate planning to use dual therapy with her. However, therapies often need to be introduced gradually. Note also that the Hb A1c goal in the AACE/ACE algorithm (6.5%) is lower than the ADA-recommended goal of 7.0%, and that all guidelines recommend adding a second antihyperglycemic agent if the goal is not reached within 2 months to 3 months.

Although there is no direct clinical trial evidence to support the approach outlined above, it is clear that the traditional approach—monotherapy, followed by waiting until the Hb A1c level returns to unacceptable levels, and then adding the second drug—appears to perpetuate beta cell failure and fails to provide long-term glycemic control in most patients. For this reason, the dual-therapy approach is advocated by experts on the basis of indirect evidence from the UKPDS data and other studies, such as the Insulin Resistance Atherosclerosis Study.7,8

Beyond considerations of beta cell function, we should consider how Hb A1c targets should be individualized. This patient is relatively young and

healthy, has a long life-expectancy with few comorbidities, and appears to be motivated and capable of self-care. Principles of individualizing Hb A1c targets and therapeutic approaches (see next case and Figure 8)9,10 should lead us to discuss with Mrs Sullivan the goal of

pursuing more stringent glycemic goals than the standard of less than 7.0%, such as an Hb A1c level of 6.5%.

Tighter glycemic targets, as well as lower body weight, blood pressure, and blood lipid levels, have been advocated

Reproduced with permission from Kahn SE, et al. N Engl J Med. 2006;355:2427-2443.

Long-term Efficacy of Monotherapy: ADOPT

Annualized slope (95% Cl)

Rosiglitazone, 0.07 (0.06 to 0.09)

Metformin, 0.14 (0.13 to 0.16)

Glyburide, 0.24 (0.23 to 0.26)6.0

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Rosiglitazone vs glyburide

-.042 (-0.50 to -0.33); P<.001

Figure 4. Mean Hb A1c Levels in Patients in the ADOPT Trial.

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* Dashed line shows extrapolation forward and backward from years 0 to 6 from diagnosis based on

Homeostasis Model Assessment (HOMA) data from UKPDS.† IGT=impaired glucose testing‡ The data points for the time of diagnosis (0) and the subsequent 6 years are taken from a subset of the

UPKDS population and were determined by the HOMA model.

Lebovitz HE. Diabetes Rev. 1999;7:139-153.

UKPDS: β-Cell Loss Over Time

Figure 3. Beta Cell Function Estimated Using the HOMA Model for Patients With Pre-diabetes and Type 2 Diabetes.

Long-term Efficacy of Monotherapy: ADOPT


in such patients as a way to prevent or forestall disease progression and the development of complications, and to preserve quality of life.9, 10

Oral diabetes therapies need to be initiated gradually and titrated to optimize compliance, minimize adverse effects, and reduce the risk of hypoglycemia. One important barrier to good self-management is adverse effects. By immediately beginning dual-agent therapy at full dosages, Mrs Sullivan could have adverse effects that she may consider intolerable and be less motivated to adhere to recommended treatment. This problem is especially prevalent with the use of metformin.

As shown in Figure 6, metabolic defects in diabetes include increases in the appearance of glucose in the blood, as well as defects in the disposal or use of glucose. Figure 7 shows that different classes of oral antihyperglycemic agents target different aspects of the glucose control system. Metformin primarily reduces glucose output from the liver, thereby reducing glucose appearance, so a good choice for a second drug would be one that affects glucose disposal, such as a thiazolidinedione (TZD), a dipeptidyl peptidase-4 (DPP-4) inhibitor, or a GLP-1 agonist.11

What is a good strategy for initiating treatment with metformin?

Metformin is often associated with adverse side effects, especially diarrhea, causing difficulties in tolerability and lack of compliance. These problems often can be overcome by introducing the drug at a low dosage and titrating the dosage to the maximum that can be tolerated (not exceeding a maximum of 2000 mg to 2500 mg per day). The problem can also be mitigated by using an extended-release formulation of the drug, but titration is still important.

At any dosage, if the diarrhea becomes intolerable, I advise the patient to back off to the last dosage they found tolerable, wait 1 week, and then try again. If, despite this approach, they still are unable to tolerate the dosage required to achieve target Hb A1c levels,

Plasma glucose

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appearance (Ra)

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is increased and disposal

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Rd, or both.

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Figure 6. Normal and Abnormal Glucose Control.In type 2 diabetes, hepatic glucose production is increased and disposal of blood glucose is impaired. Both effects contribute to high blood glucose levels.

Available at www.aace.com/pub© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

AACE/ACE Diabetes Algorithm For Glycemic Control A1C Goal≤ 6.5%*

L i f e s t y L e M o d i f i C At i o n

Figure 5. From the AACE/ACE Algorithm for Glycemic Control.6

* May not be appropriate for all patients** For patients with diabetes and A1c <6.5%,

pharmacologix Rx may be considered*** If A1c goal not achieved safely Prefered initial agent1 DPP4 if PPG and FPG or GLP-1 if PPG2 TZD if metabolic syndrome and/or nonalcoholic

fatty liver disease (NAFLD)3 AGI if PPG 4 Blinide if PPG or SU if FPG5 Low-dose secretagogue recommended6 a) Discontinue insulin secretagogue with

multidose insulin b) Can use pramlintide with prandial insulin

7 Decrease secretagogue by 50% when added to GLP-1 or DPP-4

8 If A1c <8.5%, combination Rx with agents that cause hypoglycemia should be used with caution

9 If A1c >8.5%, in patients on Dual Therapy, insulin should be considered



especially if they are already taking an extended-release formulation, I might consider a metformin formulation that is released more slowly in the intestines, such as Glumetza.

How would you discuss the treatment plan with Mrs Sullivan?

It is important to combine active pharmacologic treatment with patient education and counseling about the goals of therapies, the therapeutic strategy, and future treatment plans, such as the plan to introduce a second agent after metformin therapy is established. The goals of education and counseling are to increase Mrs Sullivan’s understanding of the disease process and the potential of her diabetes to worsen, and enhance her confidence in her ability to follow an effective treatment plan.

My discussion with Mrs Sullivan will include several important topics, including:

• Why treatment is necessary and important

• Goals of treatment• Rationale for the treatment plan• How to manage side effects• Plans for monitoring• Managing any barriers or challenges

she anticipates

More specifically, here is an example of how I would cover these issues with Mrs Sullivan:

Why is treatment necessary and important?Your blood sugar level (known as Hb A1c) is 7.5%, indicating that your blood sugar level is above the level known to increase your risk for damage to your eyes, nerves, and kidneys. So, we need to bring this blood sugar level down.

What are our goals of treatment?There are 2 main goals in bringing this blood sugar down. One goal is to reduce the chances that you’ll have complications related to high glucose values. Keeping your Hb A1c values below 7.0% will do that.

The second goal is to help your body use glucose efficiently for energy. To do this, we need to do 2 things: (1) decrease the

amount of glucose that enters your body, and (2) improve the way your body uses the glucose to produce the energy you need to carry out your daily activities.

What is the rationale for the treatment plan?To achieve these goals, we need to use 2 different drugs that work together. The safest drug – the one that has been around for the longest time – is metformin. Its main effect is to reduce the amount of glucose that your liver produces. Our first step is to get you started on metformin during this first month. After 2 to 3 months, your Hb A1c level may drop below 7.0% or even 6.5%. But from the results of many studies, I know that it is likely that your blood sugar level may not stay low for very long; therefore, we also need to use a drug that improves how your body uses glucose.

So, I plan to introduce a second drug at your next visit. This drug targets a different part of the disease process in a different way than metformin. We will, however, need to make sure that the 2 drugs together do not cause your blood sugar to go too low.

What are the possible side effects of the medicine and how can they be avoided or managed?

Because metformin can cause diarrhea, I’m going to start you at a low dosage and then gradually increase it, because the diarrhea goes away in most people once their body gets used to the medication. I want you to start taking 500 mg metformin as a single pill with every evening meal. Taking it with the evening meal does 2 things: (1) it makes the diarrhea less bothersome, and (2) your liver tends to make the most glucose at nighttime, so taking metformin in the evening will have the greatest effect.

Metformin will lower your blood sugar without making it go below normal limits because it only reduces the glucose your liver is making, and, therefore, doesn’t carry the risk of making your blood sugar bottom out. The goal is to eventually get you on the maximum dosage because it is most effective that way. So, I will ask you to gradually increase the amount you take in weekly increments. You start now by taking 500 mg for the first week with your evening meal. Next week, you’ll take 500 mg in the morning with breakfast and 500 mg in the evening with dinner. During the third week, you’ll take 500 mg in the morning and 1000 mg (2 pills) in the evening. And by the fourth week, you’ll take 1000 mg (2 pills) in the morning and 1000 mg (2 pills) in the evening.

Alpha-Alpha-

Glucosidase Glucosidase

InhibitorsInhibitors1,21,2

MeglitinidesMeglitinides33 SUsSUs4,54,5

TZDsTZDs6,76,7 MetforminMetformin88

Incretin Incretin

Mimetics/Mimetics/

DPP-4 DPP-4

InhibitorsInhibitors

Insulin deficiency

Insulin resistance

Excess hepatic glucose output

No Single Class of Oral Antihyperglycemic

Monotherapy Targets All Key Pathophysiologies

Majo

r P

ath

ophysio

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s

1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004.

3. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 4. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007.

5. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004.

7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.

8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.

* Applies only to GLP1 agonists

Intestinal glucose absorption

*

Figure 7. Pathophysiologic Processes Targeted by Different Antihyperglycemic Agents. Although metformin improves insulin resistance, its main effect is to reduce hepatic glucose output.


If diarrhea is a problem and becomes intolerable when you start taking 4 pills per day, for example, then you can go back to 3 pills per day, 1 in the morning and 2 in the evening. Wait 1 week and then try the 4 pills again. If diarrhea is still intolerable, then go back to the 3 pills that you could tolerate and that will be the dosage that you will continue to use because we want you to take as much as you can tolerate up to a maximum of 2000 mg per day.

How will you know that the treatment is working?At this time, I also want you to see a diabetes educator who will teach you how to monitor your own blood glucose levels. The purpose of this monitoring is so you can see for yourself if you are reaching your blood sugar target. Our treatment plan is designed to get your blood sugar level between 70 mg/dL and 130 mg/dL before you eat.

With the knowledge that Mrs Sullivan is concerned about gaining weight, what antihyperglycemic agents are the best choice to add after her appropriate metformin dosage is established?

The choices of add-on therapy for Mrs Sullivan are a sulfonylurea, a TZD, a DPP-4 inhibitor, or a GLP-1 receptor agonist. Since sulfonylureas are known to be associated with weight gain in patients with type 2 diabetes and may actually worsen beta cell function, they would not be our choice here.2,12

The TZDs, pioglitazone and rosiglitazone, have many characteristics that would make them good agents for use in combination with metformin. These drugs activate peroxisome proliferator-activated receptor-gamma leading to direct improvements in peripheral insulin sensitivity.13 There is also evidence that they may improve beta cell function,14,15 and they are associated with very low incidence of hypoglycemia. However, both agents are also associated with weight gain, so Mrs Sullivan would not benefit from either of these drugs.2 Furthermore, rosiglitazone is now available only through an enrollment-based access program because of the potential risk for cardiovascular disease. Pioglitazone is also associated with edema and

should be avoided in patients with heart failure. Both drugs are associated with an increased risk of bone fracture,16 and some experts have argued that pioglitazone should be limited to a dosage of 30 mg per day to minimize the risk of bladder cancer.17

The GLP-1 receptor agonists, which include exenatide, liraglutide, and exenatide extended-release (a once-a-week formulation), increase insulin secretion in a glucose-dependent manner, decrease glucagon secretion, and thereby reduce hepatic glucose output, slow gastric emptying, and suppress appetite.2 They are also associated with weight loss, making them valuable treatment options for overweight or obese patients. But patients need to be counseled about how much weight loss to expect. A realistic weight loss associated with GLP-1 receptor agonist therapy is 3 kg to 5 kg, though some patients can lose much more. These agents have also been reported to improve beta cell function in some studies.18-20

GLP-1 receptor agonists do have several disadvantages. Most notably, they are administered via injection and are associated with gastrointestinal side effects (nausea, vomiting, diarrhea).2 However, the drugs are better tolerated when the dose is titrated gradually. New, long-acting formulations of GLP-1 receptor agonists (once-weekly exenatide) may be good options to minimize nausea (they are administered in a fixed dose and do not need titration) and for patients uncomfortable with frequent injections. Cases of pancreatitis have been reported in patients receiving GLP-1 receptor agonists, and patients should be cautioned about this risk. There is also an increase in medullary c-cell hyperplasia in animal studies reported with some of these agents; thus, it is recommended that they not be used in patients with multiple endocrine neoplasia type 2.

The DPP-4 inhibitors include sitagliptin, saxagliptin, and linagliptin. They are oral agents that inhibit the breakdown of incretin hormones and thus increase endogenous GLP-1 and glucose-dependent insulinotropic

polypeptide. In turn, this stimulates glucose-mediated insulin release and suppresses glucagon. These drugs do not suppress appetite and do not slow gastric emptying, thus their use is not associated with nausea. Although they lower Hb A1c levels in patients with diabetes,21,22 they usually are less potent than GLP-1 receptor agonists. The DPP-4 inhibitors also have little effect on body weight and are considered weight neutral.2 These agents may also be a good option for Mrs Sullivan, depending on whether her goal is to maintain her weight or lose weight. Two key advantages of the DPP-4 inhibitors are that they are administered orally and are usually well tolerated. Furthermore, there is evidence that these agents improve beta cell function, lower Hb A1c levels in patients already taking metformin, and are associated with low rates of hypoglycemia.23-25 Cases of acute pancreatitis have been reported in patients receiving DPP-4 inhibitors.

CASE SUMMARY

Metformin is most often the first agent recommended for treatment initiation. When considering dual therapy, numerous factors affect the choice of which antihyperglycemic agent to use in combination with metformin. Mrs Sullivan has achieved a reasonable Hb A1c level (6.5%), which is within the targets recommended by the ADA and on the border for targets recommended by AACE/ACE. In either case, a second drug is important to prevent the worsening of the Hb A1c control that has been shown to occur with monotherapy alone.5,15 The second agent should be one that works by a different mechanism than metformin, does not cause weight gain, and has a low potential for hypoglycemia. A DPP-4 inhibitor would be a good choice for Mrs Sullivan, but because she has expressed concerns about her weight, a GLP-1 receptor agonist might be a better choice for her because the GLP-1 agonists have more of an effect on Hb A1c levels and also facilitate weight loss. The recent availability of a once-weekly formulation of exenatide may reduce concerns about the frequency of required injections and also minimize nausea.



The importance of lifestyle modifications within a comprehensive treatment plan should be re-emphasized, preferably as part of a formal diabetes education program. This program should include guidance on starting and maintaining an exercise regimen that includes at least 150 minutes of moderate-intensity aerobic exercise spread out throughout the week, and resistance training at least twice per week.2

CLINICAL RECOMMENDATIONS

• When selecting noninsulin therapies for patients with type 2 diabetes, incorporate considerations for weight loss and long-term maintenance of glycemic control, minimizing hypoglycemia.

• Incorporate patient education into every clinic visit, including how to minimize and respond to any side effects of medications, the importance of continued lifestyle modifications, and the rationale for each patient’s individualized treatment plan.

Case #2: Frederick Hamilton: 62-year-old man, given a diagnosis of type 2 diabetes 7 years agoVital signs and clinical and laboratory findings

Body weight, kg (lb) 101.4 (223.5)Blood pressure, mm Hg 134/84Hb A1c 7.9%Urinary albumin/creatinine ratio > 30 mg/g on 2

determinations

Mr Hamilton is a 62-year-old white man who works as a short-haul truck driver. On his time off, he is devoted to his hobby of landscape gardening. He was given a diagnosis of type 2 diabetes 7 years ago, at which time he was prescribed lifestyle modification and glimepiride (initially 2 mg/day, then 4 mg/day). Two years later, his Hb A1c was 8.1%, so pioglitazone was added at 30 mg per day, then increased to 45 mg per day. Six months later, his Hb A1c was down to 7.1%, but his weight had increased to 105 kilograms. His pioglitazone dose was reduced to 30 mg per day because of concerns about the risk of bladder cancer at the 45 mg dose.

His Hb A1c is now back up to 7.9%, and Mr Hamilton has curtailed some of his favorite activities: He reveals that, although he used to love to work in his garden on evenings and weekends, he recently hired someone to mow the grass and just lets everything else go because he gets tired too easily to do yard work. In discussing treatment options for him, Mr Hamilton states that he never wanted to use a glucose meter and just wants medication that will allow him to eat his favorite foods without worrying about his blood sugar, though he is becoming concerned about his increasing weight.

How would you develop a treatment plan for Mr Hamilton that has a strong chance of success?

Mr Hamilton’s diabetes control is suboptimal, and probably has been for some time. He clearly has difficulty adhering to lifestyle modifications, which are an important element of diabetes treatment. If treatment goals are to be achieved, it is crucial that he embraces the treatment plan, believes it is realistic, and is willing and capable of following it. A recent Position Statement from the ADA and the European Association for the Study of Diabetes (EASD) has emphasized the importance of using a patient-centered approach to the treatment diabetes, stating that “recommendations should be considered within the context of the needs, preferences, and tolerances of each patient; individualization of treatment is the cornerstone of success.”9

Using a patient-centered approach requires us to have a conversation with each patient to elicit their needs, preferences, and tolerances. As we review this case and develop a treatment plan for Mr Hamilton, we will provide examples of how to engage patients in the kinds of conversations that establish a patient-centered approach and foster better self-management.

Physician: I know that a number of factors, such as your job, have made managing your diabetes a challenge. I’m sure there are some things we can talk about to make some of this easier. First, let’s discuss what goals

are important to you because everyone is unique and has individual interests and goals. What are one or two things that you want to achieve from the treatment of your diabetes?

Patient: Well, I know I need to get my blood sugar down, but nothing seems to work.

Physician: Yes, I agree that we need to get your blood sugar level down, and that the treatments you’ve had up to now have not worked as well as we’d hoped. Your lab results already show some signs of damage to your kidneys, probably caused by a high blood sugar level.

In a very simple, nonjudgmental way, we’ve raised the issue of his difficulties in managing his care, expressed empathy, and given him the opportunity to express his goals in his own words. By echoing those goals back to him and reinforcing them, we have taken an important first step toward increasing his motivation to develop and adhere to a plan that can be more successful in controlling his diabetes. We’ve also reframed his statement that “nothing seems to work” by introducing a timeframe (“up to now”) and a relative value (“as well as we’d hoped”). By reframing his treatment experience from a failure to one that suggests the potential for change, we introduce hope. Using a patient-centered approach like this helps many patients feel more engaged in their treatment plan and can improve their motivation to adhere to the recommended treatment plan.

Mr Hamilton’s belief that nothing works can be addressed through questioning that may help to elicit the reasons for this.

Physician: Let’s talk about some problems you’ve run into so we understand a little more about your situation. I’m confident that we can find treatments that work better for you.

• I know that you’re a truck driver. Does this make it hard for you to get healthy foods while you’re on the road?

• Do you have trouble taking your medicine at the right time?

• Are these medicines too expensive? Are you taking the full doses?

• Have you had any problems with low blood sugar? Is that a concern for you while you’re driving?


• Are there other problems, such as family or social problems, that could be creating some challenges for you in controlling your diabetes?

Patient: Well, driving does make it hard, and my medicine doesn’t always make me feel better. Like, sometimes when I take all my medicine, I feel weak and light-headed. That worries me when I’m driving, so I sometimes skip taking it if I know I’m going to be driving. Other times when I feel light-headed after taking my medicine, I just eat something and it gets better, but I can’t always do that when I’m driving.

This conversation has helped us understand some of the reasons why he is having trouble getting his diabetes under control. We can use this knowledge, along with his input, to design an alternative treatment plan that is more compatible with his lifestyle, potentially improving his adherence to therapy.9

These discussions can also help us to set and adjust realistic Hb A1c goals that are achievable and that obtain the greatest benefits without exposing him to excessive risks of hypoglycemia or to treatment side effects that may jeopardize compliance. Factors based on recent opinions and position statements influencing the selection of an Hb A1c target are shown in Figure 8.9,10 We have learned that Mr Hamilton has poor access to support resources, difficulty with compliance, high risks associated with hypoglycemia, and some evidence of microvascular complications. Therefore, we may choose to individualize his target Hb A1c level to a goal of less than 7.0% to minimize worsening of his microvascular complications; but at the same time, given his fear of hypoglycemia , we need to choose a drug that mitigates that risk. We also need to consider a drug that he can take once a day with no relationship to meals, since his eating habits can be inconsistent.

After factoring in Mr Hamilton’s individual needs, goals, and desires, what are the best treatment options for him?

Mr Hamilton is already showing early signs of microvascular damage, probably related to poor glycemic control. In addition, his lifestyle and

occupation make it difficult for him to comply with diet and exercise regimens. He needs more aggressive treatment that can help him achieve key clinical goals while enabling him to adhere to the treatment over time.

Our initial goal for Mr Hamilton is to negotiate a plan that works for him, which should involve reducing his risk of hypoglycemia, thereby improving his ability to comply with treatment. The drug that is causing the hypoglycemia is glimepiride, so it should be discontinued. He can continue to take the pioglitazone that had been added to his treatment plan after 2 years since he seems to be tolerating that well.

To replace the glimepiride, we can consider a DPP-4 inhibitor. Even though they are less potent than GLP-1 receptor agonists in terms of reducing Hb A1c levels, the DPP-4 inhibitors have been reported to reduce blood sugar levels by 0.5% to 0.8%.26 With improved adherence to treatment from better tolerance of a DPP-4 inhibitor (versus a sulfonylurea), it is realistic to expect that we will be able

to bring him to an Hb A1c target of less than 7%. Note that although the DPP-4 inhibitors are generally well tolerated, cases of pancreatitis have been reported in patients using these drugs.

We may choose to switch to a GLP-1 receptor agonist in 6 months to 12 months if Mr Hamilton shows good compliance with all changes necessary to improve his diabetes control. One could argue that if Mr Hamilton has achieved his desired Hb A1c goals with a DPP-4 inhibitor and pioglitazone, there would be no need to change his medications. This would, indeed, be a suitable decision. However, if we want to work with him to achieve his personal goal of weight loss, then switching the DPP-4 inhibitor to a GLP-1 receptor agonist would be a better choice for him. As shown in Figures 9 and 10, both liraglutide and extended-release exenatide were associated with weight loss in clinical trials.22,27 In contrast, the DPP-4 inhibitors are considered weight neutral. Another reason to consider this change would be if his blood sugar goals were not being met with the DPP-4/pioglitazone combination.

Factors Influencing Individualization of A1c Targets

A1c targetMost intensive Least intensive6.0% 8.0%è

Patient attitude and expected treatment efforts

Highly motivated,adherent, excellentself-care capabilities

Less motivated, nonadherent,poor self-carecapabilities

Risks associated with hypoglycemia

Low High

Disease duration 0-10 20+Life expectancy Long ShortImportant comorbidities

Absent Severe

Established vascular complications

Absent Severe

Resources, support system

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Figure 8. Factors that Influence the Selection of an Hb A1c Target for Individual Patients.9,10



Although short-acting exenatide is likely to reduce Mr Hamilton’s Hb A1c to desirable levels, it has a number of characteristics that would be drawbacks for this particular patient. He mentioned that he doesn’t always know when he will be able to eat because of his driving schedule. Short-acting exenatide, however, needs to be administered within a 60-minute window before meals.28 Furthermore, when beginning treatment with short-acting exenatide, many patients experience nausea. This side effect could be especially problematic considering Mr Hamilton’s occupation and history of skipping treatment doses to avoid potential side effects.

CASE SUMMARY

My approach would be to discontinue glimepiride and start one of the established DPP-4 inhibitors at full dose. I would arrange for Mr Hamilton to participate in a formal educational program on diabetes self-management, even if he has participated in the past. The reason for him to repeat the class is to reinforce his self-management skills and help him recognize the critical importance of blood glucose monitoring, which he has been reluctant to do in the past. He should return to the clinic after 3 months so we can assess how this new treatment regimen is working for him. It could be argued that stopping the glimepiride completely might actually result in worsening of glycemic control. This is indeed possible, but by getting the patient engaged in a diabetes self-management program, we might gain better glucose control than was being achieved with glimepiride. There are data showing that seeing a certified diabetes educator can result in substantial Hb A1c reduction.2 My philosophy is that the best care for patients with diabetes is the care they believe in.

By discontinuing the drug that causes hypoglycemia, we may even reduce “defensive eating,” and we might find that his Hb A1c level actually improves after the change. We can always add in another agent—after a 3-month period—if his glycemic control continues to deteriorate. It is in his best interest to give him a chance to try his best.

In addition to his elevated Hb A1c level, Mr Hamilton currently has high blood pressure, which should be treated. And he has evidence of microalbuminuria, so controlling both his diabetes and blood pressure is crucial. An angiotensin-

converting enzyme (ACE) inhibitor is a preferred choice in this setting because of their dual antihypertensive and renal-protective properties. These drugs should to be titrated up to target blood pressure of less than 130/80 mm

Pratley R et al. Lancet. 2010;375:1447-1456.

Liraglutide or sitagliptin added to metformin in patients not achieving adequate

glycemic control on metformin alone

LAG 1.2 mg LAG 1.8 mg SITA 100 mg

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Figure 9. Change in Body Weight Associated with Adding Liraglutide (1.2 mg or 1.8 mg) or Sitagliptin to Metformin in Patients with Type 2 Diabetes.

Exenatide Once Weekly vs Twice Daily in T2DM

Reproduced with permission from Drucker D, et al. Lancet. 2008;372:1240-1250.

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Figure 10. Change in Body Weight in Patients with Type 2 Diabetes During Treatment with Twice-Daily or Once-Weekly Formulations of Exenatide.

Liraglutide and Sitagliptin: Weight from Baseline


Hg and until his urine albumin declines into the normal range.


• Identify each patient’s goals for treatment, preferences, and tolerances to optimize the chances for long-term success in the treatment of type 2 diabetes.

• Use a nonjudgmental conversational style to prompt patients to openly discuss their individual concerns and barriers, and echo those challenges back to them, so they recognize that you are incorporating their concerns into the treatment plan and working to overcome their barriers.

• Use existing guidelines as a starting point for clinical decision-making, then individualize glycemic targets and treatment strategies to develop a plan that works best for each patient.

Case #3: Frank Molson: 51-year-old man, metabolic syndromeVital signs and clinical and laboratory findings

Height, cm (in) 175 (5’9”)

Body weight, kg (lb) 91.4 kg (201)

Waist circumference, cm (in) 104 cm (41)

Blood pressure, mm Hg 138/86

Hb A1c 7.6%

Fasting plasma glucose, mg/dL 146

LDL cholesterol, mg/dL 137

HDL cholesterol, mg/dL 39

Total cholesterol, mg/dL 220

Triglycerides, mg/dL 220

Urine albumin Negative

Serum creatinine 1.1 mg/dL (reference range = 0.9-1.3 mg/dL)

Frank Molson is a 51-year-old white man. He is a self-employed construction contractor with an unpredictable work schedule and a busy family life. He has indicated that he would like some advice on weight loss. He has a tight budget, and his insurance co-pay for nongeneric medications is very high.

Mr Molson was prescribed the following medications:

• Lisinopril: 10 mg per day• Metformin: 1000 mg twice daily• Sitagliptin: 100 mg once daily• Simvastatin: 20 mg once daily

Because of his budgetary restrictions, he had been taking sitagliptin every other day, but recently has not renewed his sitagliptin prescription because he cannot afford the co-pay for (nongeneric) sitagliptin.

Would you try to address all of Mr Molson’s problems at one clinic visit?

Mr Molson has most of the hallmarks of metabolic syndrome (Figure 11), including a waist circumference greater than 40 inches (> 102 cm), type 2 diabetes mellitus with ongoing poor glycemic control, hypertension (blood pressure > 130/85 while taking an ACE inhibitor), elevated triglycerides (≥ 150mg/dL), and low high-densitylipoprotein (HDL) cholesterol levels (< 40 mg/dL for men).1 Together and individually, these characteristics are risk factors for cardiovascular disease, and all need to be addressed. Clinical goals for each risk factor, according to the ADA, are shown in Figure 12.

Smoking

Elevated BP

Elevated LDL-C

Insulin resistance

Elevated blood glucose

InflammationLow HDL-C

Elevated triglycerides

Abdominal adiposity

Figure 11. Hallmarks of Metabolic Syndrome.

Goals to Prevent Complications

Measure ADA Standard/Goal

A1c <7%

Blood pressure <130/80, lower if kidney disease

Dilated eye exam At least once a year

Foot exam Check feet every day

Smoking Stop!!!

LDL (mg/dL) <100 md/dL if no known CVC<70 mg/dL if known CVD

Triglycerides (mg/dL) <150

HDL (mg/dL) >45 (men)>55 (women)

American Diabetes Association. Diabetes Care . 2011;34(supp 1):S11-S61

Figure 12. Clinical Goals for Each Risk Factor According to the ADA.



Even though each of these problems must be addressed, addressing them one at a time is more practical and more likely to succeed than intensifying or changing numerous medications at one time. Doing everything at once is impractical given that medication changes may produce side effects and compound the challenges to adherence and compliance. Therefore, my approach is to change only 1 medication regimen per clinic visit unless absolutely necessary. This approach gives the patient time to adjust to the regimen and identify and resolve any side effects that may interfere with treatment adherence.

In a case such as presented by Mr Molson, the choice of which problem to address first is probably not important from a clinical standpoint. However, there is an overarching issue that must be addressed before any success will be achieved with this patient. That issue is cost. Mr Molson is committed to his treatment plan, but is nonadherent to his sitagliptin prescription because of the cost. Addressing this problem is an essential element of individualizing his treatment. He needs to know that I understand that the cost of medications is an important issue and that I will make a concerted effort to resolve it. Therefore, it is vital that I discuss this issue with him and work with him to find a replacement therapy that he can afford. He must also be educated about how to use the replacement medication and what to expect in terms of any side effects. By demonstrating my understanding of his desires to adhere to the treatment we’ve agreed on previously and the barriers he faces, Mr Molson will regard me as an ally and will more likely work with me to find solutions for his ongoing care. I would introduce Mr Molson to a less expensive option, probably a sulfonylurea, such as glimepiride. Although a sulfonylurea is probably not the best option for long-term glycemic control, considering that cost of medications is the most significant barrier for him, it is probably the best option at this time.

Physician: I understand that the cost of medications is a problem we need to address, especially the cost of sitagliptin. There is a less expensive alternative available, though it carries some risks, especially that of low blood sugar.

At 51 years old, you’re still young, but we know that high blood sugar levels can cause damage to your kidneys and eyes. We want to get your Hb A1c level down to less than 7.0% and your blood glucose levels to be between 80 and 130 mg/dL before meals to prevent such damage.

The medication I am considering is called glimepiride, which will cost you only about $4 per month. As I mentioned earlier, it can cause your blood sugars to go too low. But we can reduce this risk if we start slowly and you monitor your blood glucose frequently.

We are going to use this drug instead of sitagliptin, and I am going to start you on 2 mg of glimepiride every day. While taking this drug, it is important that you keep very regular eating habits. You can’t skip meals because this drug will continue to make insulin, which could make your blood sugar go too low. We’ll give it a try for 3 months, during which time I want you to send me your blood sugar log every week so we can adjust the dose as necessary.

I also want to make you aware that your blood pressure and cholesterol levels are not where they should be. However, for now, let’s just take one step at a time. I’d like to see you back here in a month so we can talk about how to address the other issues. During that month, I’d like you to take regular blood pressure readings, either at home or at a blood pressure station that is convenient for you. A week before that next visit, I’ll give you a prescription so you can get a fasting cholesterol test done.

After getting his fasting plasma glucose levels within the target range, what problem would you address next?

Lipid levels and weight loss are important considerations for this patient, but his lipid profile may improve as his glycemic control improves, possibly obviating the need to adjust his cholesterol medications. A weight-loss program may be instituted with the patient’s cooperation as part of the lifestyle modification that is essential to all diabetes treatments.2 Even though modest (5%) decreases in body weight can yield improvements in cardiovascular risk factors,29 it may take several months for that weight loss to be achieved, if it can be

achieved at all. Therefore, I recommend addressing this patient’s blood pressure at this time. Elevated blood pressure is a significant cause of renal failure and getting his blood pressure to a target of less than 130/80 mm Hg will help reduce another microvascular risk factor. An increase in the lisinopril dosage to 20 mg per day may be sufficient to decrease his blood pressure to levels recommended for patients with diabetes (Figure 12). An alternative would be to add a low dose of hydrochlorothiazide, which works synergistically with an ACE inhibitor to lower blood pressure. Such combination pills are available as low-cost generics.

Three months after his initial visit, Mr Molson’s low-density lipoprotein (LDL) cholesterol levels are still elevated. His fasting LDL is 120 mg/dL, total cholesterol is 207 mg/dL, triglycerides are 225 mg/dL, and HDL is 42 mg/dL. Since the target LDL level we are aiming for is less than 100 mg/dL, at this point I would increase his dose of simvastatin to the maximum dosage of 40 mg per day. If this is not successful at achieving target LDL levels, I might consider switching him to a more powerful generic statin, such as atorvastatin at 20 mg per day, since he will have already been taking simvastatin at 40 mg (the starting doses of simvastatin and atorvastatin are 20 mg and 10 mg, respectively, for most patients).

Although his triglyceride levels are elevated and there are data suggesting that elevated triglyceride levels are associated with an increased risk of stroke,30 there are few data telling us that reducing his triglyceride levels will have an impact on cardiovascular outcomes.2

If Mr Molson’s triglyceride levels exceed 400 mg/dL, then I would take steps to address that issue. At this time, because his triglyceride levels are only moderately elevated and because he has difficulty with the cost of medication, I would not choose to start him on another drug to treat his triglyceride level.

How would you approach the issue of weight loss with Mr Molson?

Mr Molson is overweight and bordering on obese (body mass index = 29.7 kg/m2) and would clearly benefit from weight loss. In various studies, a lifestyle intervention that included modest weight


loss was associated with improved insulin sensitivity, decrease in fasting blood glucose levels, and reduction in the incidence of new-onset type 2 diabetes or need for diabetes medications in people with an established diagnosis.31-37 He has indicated a readiness to address the issue, so I would use his interest as a hook to initiate a discussion about it and tailor the intervention to Mr Molson’s individual needs. For example, although he has been counseled about strategies for weight loss in the past, it is important to ask him about his previous experiences and attempts at weight loss. The discussion should touch on strategies that have worked for him and those that haven’t. By engaging him in this conversation, I can begin to develop a plan for weight loss that incorporates dietary modification, physical exercise, and behavioral therapy.38 In addition, by having a perspective on his past successes and failures, I can capitalize on his unique strengths and help him manage his weaknesses. However, because sulfonylureas are associated with weight gain, whereas his previous medication (sitagliptin) is considered weight neutral, weight loss may be especially challenging with this new treatment regimen.

A simple, but effective, strategy that has demonstrated effectiveness in helping patients lose weight is a food diary. By writing down everything that he eats over a period of 1 or 2 weeks will help give Mr Molson a new perspective on his eating habits. Regardless of what dietary plan he ultimately chooses to follow, a fundamental understanding of what, when, how much, and why he eats will increase Mr Molson’s mindfulness about his eating, and set the stage for more intensive interventions.39 Some readily available Web-based food diary tools may be found at: www.myfooddiary.com, www.my-calorie-counter.com, and www.mynetdiary.com/mobile-calorie-counters.html.

Current guidelines from the ADA recommend that patients receive medical nutrition therapy (MNT) from a registered dietitian who is familiar with MNT for patients with diabetes.32 Furthermore, lifestyle interventions and weight-loss strategies and goals should be individualized to the needs, tolerances, and desires of each patient. Valuable patient handouts are available to guide

goal setting and other practical aspects involved in increasing physical activity, dietary intervention, and behavioral intervention for weight loss, so every office should have these on hand to give to patients.38

Case #3, continued: Frank Molson, 3 years later

During the ensuing 3 years, Mr Molson’s glimepiride dose was incrementally increased to a maximum of 8 mg, and he continued to take metformin 1000 mg twice daily. Despite efforts to lose weight, his weight continued to increase to 220 pounds. He again has microalbuminuria and has had laser treatment for diabetic retinopathy.

Key clinical values, 3 years later

Blood pressure, mm Hg 150/90

Hb A1c 9.5%

LDL cholesterol, mg/dL 130

Albumin/creatinine ratio, mg/g 155, 180 (on 2 successive tests)

Serum creatinine 1.1 mg/dL (reference range = 0.9-1.3 mg/dL)

eGFR, mL/min 76

What would you consider to be the best treatment regimen for Mr Molson at this time?

This is an example of the all-too-common situation in which successive use of oral antihyperglycemic agents fails to prevent worsening glycemic control, probably accompanied by declines in beta cell function.

As shown in Figure 13, the combination of basal and bolus insulin is designed to mimic the physiologic secretion of insulin from the healthy pancreas.

However, switching to a basal plus bolus regimen all at once can be complex for many patients, so it is often advantageous to start insulin therapy by adding basal insulin to existing oral agents. As shown in Figure 14, adding basal insulin to existing oral agents typically yields decreases in Hb A1c levels of approximately 2.0%, even in patients already taking metformin in combination with a sulfonylurea.40 Some experts might argue that Mr Molson could use a premixed insulin

at suppertime, but given that he is already taking a sulfonylurea, starting basal insulin alone at this time should be enough to provide coverage.

Although starting basal insulin is the correct approach for this patient, starting insulin is not a trivial endeavor for the patient, and I am not in favor of a weight-based introduction of insulin. It is always a guessing game to determine how much insulin a patient needs, and there is no hurry to get his glucose levels to target immediately. My goal is to get the patient comfortable with giving himself injections and learning how to self-titrate. As his comfort level increases, he is more likely to be compliant with the therapy and less likely to get hypoglycemia. A single episode of hypoglycemia is often sufficient to scare the patient into backing off therapy, and then it becomes more difficult to achieve goals. Also, insulin therapy is likely to cause the patient’s weight to increase, and that issue is likely to worsen if he is eating more to ward off potential hypoglycemia. Gradual titration of the insulin dose is, therefore, my preferred approach.

Mr Molson should titrate the dose in weekly increments on the basis of his fasting blood sugar levels. This is my preferred approach for this patient for 2 reasons. First, neutral protamine Hagedorn (NPH) insulin is inexpensive and does not even require a prescription. Second, he can be given instructions to self-titrate his insulin dose based on a simple algorithm: increase insulin by 4 units every week until his fasting blood glucose level is less than 140 mg/dL, and then by 2 units every week until it is below 130 mg/dL (target range = 80 mg/dL -130 mg/dL). Even though the ADA recommends a target range of 70 mg/dL to 130 mg/dL, in patients taking insulin, I prefer to leave a little buffer to minimize the risk for hypoglycemia. Because NPH insulin has a peak blood concentration, I ask my patients using this formulation to check their blood glucose levels in the middle of the night (generally around 2:00 or 3:00 am) to make sure they are not getting hypoglycemic. Patients can call/fax/email their blood glucose readings to the clinic every week and then come in, if necessary. Once a patient is


www.myfooddiary.com

www.myfooddiary.com

http://www.mynetdiary.com/mobile-calorie-counters.html

http://www.mynetdiary.com/mobile-calorie-counters.html


taking approximately 30 units of NPH before bedtime, I would then consider adding another dose of NPH in the morning to get daytime glucose levels on target. An alternative approach would be to consider a long-acting insulin analog, such as insulin glargine or insulin detemir, which needs to be administered only once a day.

The 3 choices of basal insulin and their approximate durations of action are shown in Figure 15 and Figure 16.41 These kinetic parameters can vary among different patients and even within an individual patient, as well as according to dosage.

These insulin analogs are significantly more expensive than NPH insulin, but NPH insulin has a shorter duration of action than insulin glargine or insulin detemir, making it a less attractive option for mimicking basal insulin secretion from the pancreas. Also, the vial of NPH insulin must be rolled approximately 20 times before administration to ensure uniform distribution of the suspension. Although all insulins can be associated with hypoglycemia, the hypoglycemia associated with the use of NPH insulin is often unpredictable. If NPH insulin is chosen because of cost considerations (as in the case of Mr Molson), the patient should be educated about the unpredictable nature of hypoglycemic episodes, and about the potential need to use more than 1 injection per day.3 Between the other 2 long-acting insulins, insulin glargine is often the preferred option because it seems to have a longer duration of action than insulin detemir.

After 3 months, Mr Molson has titrated his basal insulin to 42 units per day at bedtime without experiencing any hypoglycemic episodes. His Hb A1c level has declined from 9.5% to 7.8%, and his fasting blood glucose, determined by self-monitoring, has generally been between 90mg/dL and 140 mg/dL. His body weight has increased from 220 to 225 pounds.

Do you recommend continuing to titrate his basal insulin dose until his Hb A1c level is lower than 7.0%?

Mr Molson’s fasting blood glucose levels have been close to the target range of 80 mg/dL to 130 mg/dL, but his Hb A1c level is still elevated; so, it is likely that either his postprandial glucose levels are high or he does not have sufficient basal insulin coverage during the day.

He already has evidence of diabetic retinopathy and nephropathy, so, yes, it is important that we continue to work to reduce his Hb A1c levels, preferably to below 7.0%. Because his fasting glucose appears to be reasonably well-controlled in the morning, this

Insulin

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Adapted with permission from McCall A. In: Leahy J, Cefalu W, eds. Insulin Therapy.

New York, NY: Marcel Dekker Inc;2002:193

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Figure 13. Combination of Bolus and Basal Insulin to Mimic Secretion of Insulin.

Yki-Järvinen, et al. Ann Intern Med. 1999;1:389-396.

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necessitates checking his blood glucose levels during the day. These readings are likely to show that his pre-meal readings, especially at dinnertime, are outside the target range. Adding bolus insulin at dinnertime would be an option, but my preferred approach is to maximize basal insulin replacement first. It may be worthwhile to have him extend his self-monitoring of blood glucose to 2 hours after meals in order to confirm that his postprandial blood glucose levels are elevated, but if his pre-lunch and pre-dinner readings are high, I would introduce a morning dose of NPH insulin, starting at 10 mg per dose and using the same titration schedule as for the evening dose.

Discontinuation (or tapering to discon-tinuation) of glimepiride is a prudent step once bolus insulin is started, but it is premature at this time. Discontinuing metformin, however, is not recommended for several reasons:3 (1) metformin does not increase the risk of hypoglycemia in most people, (2) it can help blunt the increase in weight gain associated with insulin therapy,40 and (3) it targets a different functional pathway than does insulin.

What is the most practical approach for introducing bolus (mealtime) insulin to most patients?

It can be challenging to introduce patients to the use of bolus (mealtime) insulin, and the adage “start low and go slow” is valuable advice and the most practical approach in most cases. The goal of therapy is long-term control of blood glucose levels, and there is no need to achieve glycemic targets immediately.3 Thus, to avoid the risk of hypoglycemia, it is usually most practical to introduce bolus insulin at a low dose before the largest meal of the day. As patients learn to dose their bolus insulin without inducing hypoglycemia, then dosing can be extended to other mealtimes.

Figure 17 shows an algorithm from ADA guidelines for initiating and adjusting bolus insulin therapy.3 This algorithm relies on self-monitoring of glucose levels to select the meal at which to initiate bolus insulin. According to this algorithm, if blood glucose levels are elevated at bedtime or before lunch, then

bolus insulin should be introduced at the preceding meal (dinner or breakfast, respectively). If blood glucose levels are elevated before dinner, then the algorithm recommends adding NPH insulin at breakfast or rapid-acting insulin at lunch. (Presumably, pre-breakfast glucose levels are adequately managed by basal insulin

administered at bedtime.) In any case, patients often need time to understand and adjust to a bolus insulin regimen, so it is advisable to initiate this phase of treatment at a single meal.

A common scenario is to introduce bolus insulin at dinnertime. The first

Basal Insulin Formulations

Insulin Preparations

Onset of Action Peak Duration of Action

Human NPH Insulin

1-2 hours 4-8 hours 10-20 hours

Insulin detemir 1-2 hours flat ~24 hours

Insulin glargine 1-2 hours flat ~24 hours

Figure 15. Three Choices of Basal Insulin and Their Approximate Duration of Action.41

Insulin Profiles

0 2 4 6 8 10 12 14 16 18 20 22 24

Pla

sm

a I

nsu

lin

Levels

Time (hr)

NPH (10–20 hr)

Regular (6–10 hr)

Aspart, Glulisine, Lispro (4–5 hr)

Glargine/Detemir (~24 hr)

Rosenstock J. Clin Cornerstone. 2001;4:50

Figure 16. Pharmacokinetic Profiles of Different Insulin Formulations.41

Basal Insulin Formulations

Insulin Profiles



consideration is which formulation to use. As shown in Figure 16, regular human insulin has a slower onset of action than the rapid-acting insulin analogs currently on the market. The rapid-acting analogs can be administered just before a meal or even during the meal; whereas, NPH should be administered 30 minutes to 60 minutes before the meal. If the meal is further delayed, it can lead to hypoglycemia. NPH also has a longer half-life in the blood, leading to the potential for late postprandial hypoglycemia. Patients may still choose to use regular human insulin because of its lower cost, but they must be educated about the risk of hypoglycemia and how to avoid it.

The next consideration is how to dose bolus insulin. Two dosing strategies are used: (1) adjusted dosing based on pre-meal glucose levels and carbohydrate consumption, and (2) fixed dosing with controlled carbohydrate consumption. The first option often seems daunting to patients, though most can learn how to calculate the required dose and adapt to it without too much difficulty. For simplicity, however, it is often easier to start with a fixed dose of insulin and teach the patient how to measure and control their carbohydrate consumption. A typical approach is to introduce 4 units of bolus insulin at (or before) dinner and concomitantly reduce their basal insulin dose by the same amount (4 units). In that scenario, the patient should consume about 50 g to 60 g carbohydrates (roughly 12 g - 15 g per unit of insulin). Again, patients should be educated about how to avoid hypoglycemia. For example, if they inject their usual 4-unit dose of insulin and then just consume a light meal instead of the expected 50 g to 60 g carbohydrates, they are at risk of hypoglycemia.

As with basal insulin, target blood glucose levels should be set and insulin dosages titrated accordingly. For Mr Molson, I would recommend a bedtime blood glucose level of 150 mg/dL, for example. If that is not reached with the initial insulin dosage of 4 units at dinnertime, then the dose of dinnertime insulin can be increased by 2 units, and bedtime basal insulin decreased by the same amount.

Once the bedtime glycemic targets are achieved and hypoglycemia has been avoided, then Mr Molson can begin introducing bolus insulin at another meal by following a similar strategy. At some point, it is often worthwhile to introduce patients to the concepts of carbohydrate counting so they can adjust their insulin dose at each meal. Patients will vary in their ability or motivation to adopt carbohydrate counting.

What frequency of hypoglycemic episodes should be considered acceptable or tolerable?

In the past, we often told patients that 1 or 2 hypoglycemic episodes per week were

tolerable, as long as they were not too severe and the patient was able to quickly restore euglycemia. Since then, we have learned about hypoglycemia-associated autonomic failure, in which hypoglycemia blunts the metabolic, neuroendocrine, and autonomic responses to subsequent hypoglycemic episodes.41,42 As a consequence, patients who have had a previous hypoglycemic episode become unable to recognize the symptoms of hypoglycemia to take corrective action, setting up a vicious cycle of hypoglycemic episodes. Thus, no number of hypoglycemic episodes should be considered acceptable or tolerable. I tell my patients to contact me if they have more than 1 episode of hypoglycemia (blood glucose < 70 mg/dL).

Figure 1—Initiation and adjustment of insulin regimens. Insulin regimens should be designed taking lifestyle and meal schedule into account. Thealgorithm can only provide basic guidelines for initiation and adjustment of insulin. See reference 90 for more detailed instructions. aPremixedinsulins not recommended during adjustment of doses; however, they can be used conveniently, usually before breakfast and/or dinner, if proportionof rapid- and intermediate-acting insulins is similar to the fixed proportions available. bg, blood glucose.

Consensus Statement

198 DIABETES CARE, VOLUME 32, NUMBER 1, JANUARY 2009

Figure 17. ADA Algorithm for Initiating and Adjusting Bolus Insulin.3


Just as important is that patients and those around them know how to respond to a hypoglycemic episode. A simple rule of thumb is known as the “rule of 15.”43 For a hypoglycemic episode, take 15 g simple carbohydrates (eg, fruit juice, hard candy, pretzels, or crackers) and wait 15 minutes, during which other essential functions (eg, airway, breathing, circulation, and so forth) should be monitored. Check the blood glucose level again after those 15 minutes, and if still hypoglycemic, take another 15 g carbohydrates. Repeat this process until hypoglycemia resolves. A very useful source of information about foods containing 15 g carbohydrates can be found at http://iuhealth.org/images/ril-doc-upl/Carbohydrate%20Counting%20Food%20List.pdf. Another list available on the same website provides the carbohydrate content of popular candies: http://iuhealth.org/images/ri l -doc-upl/Halloween%20Candy%20List.pdf.

CASE SUMMARY

Mr Molson’s case illustrates a practical approach for addressing the medical needs of someone who has multiple problems related to the metabolic syndrome. It also demonstrates the importance of adapting therapeutic strategies to accommodate a patient’s financial situation and other lifestyle factors that can affect his or her ability to comply with treatment. It is usually impractical to solve all of a patient’s metabolic problems in a single clinic visit. Furthermore, determining the diabetes therapy with which each patient can most easily comply may reduce the severity of related metabolic complaints, such as dyslipidemia, making those problems easier to address in subsequent visits.

Mr Molson is typical in that, like most patients, he continues to exhibit declines in glycemic control and beta cell function even while receiving oral therapy. Physicians should closely monitor patients for poor glycemic control and be prepared to initiate insulin therapy when target Hb A1c levels are no longer achieved using oral therapy alone. Although insulin therapy is complex, most patients can adapt if the insulin is introduced gradually. The

many types of insulin now available allow patients to mimic physiologic insulin secretion to a reasonable degree, but this goal requires the eventual use of both basal and bolus insulin in most patients. As with all stages of diabetes therapy, thorough patient education is crucial for patients initiating insulin therapy.

Finally, this case illustrates the importance of establishing and maintaining trusting relationships so your patients know that you are aware of their concerns regarding treatment costs, whether a particular therapy fits with their lifestyle, and any potential side effects. This awareness should translate into a willingness to work collaboratively with patients to develop a strategy that the patient embraces.


• For patients with a limited budget, find an affordable medication that will increase compliance with the chosen regimen.

• Unless medically necessary to make changes quickly, make changes to complex medication regimens gradually, allowing patients to adjust and detect and resolve any side effects that may hinder compliance.

• Work collaboratively with each patient to develop goals and strategies for weight loss that are achievable and sensitive to the patient’s needs, desires, and tolerances.

• If not using a weight-based regimen for basal insulin, a simple approach is to initiate treatment using 10 units per day at bedtime and to titrate the dose up in weekly increments (2-4 units per week) until target fasting blood glucose levels are achieved (or a maximum dosage of 30-40 units is reached).

• In most cases, continue metformin therapy when patients begin both basal insulin and basal plus bolus insulin therapy.

• All patients using insulin should be educated about avoiding hypoglycemia and about how to manage a hypoglycemic episode.

REFERENCES1. American Diabetes Association. Diabetes Care. 2010;33 (suppl 1):

S62-S699. 2. American Diabetes Association. Diabetes Care. 2012;35 (suppl

1):S11-S63. 3. Nathan DM, et al. Diabetes Care. 2009;32(1):193-203. Epub 2008

Oct 22.4. Prospective Diabetes Study Group. Diabetes. 1995;44(11):1249-1258.5. Kahn SE, et al. N Engl J Med. 2006;355(23):2427-2443.6. Rodbard HW, et al. Endocr Pract. 2009;15(6):540-559.7. Festa A, et al. Diabetes. 2006;55(4):1114-1120.8. Gale EA. Diabet Med. 2008;25(suppl 2):9-129. Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379. Epub

2012 Apr 19.10. Ismail-Beigi F, et al. Ann Intern Med. 2011;154(8):554-559. 11. Deacon CF, et al. Diabetes Obes Metab. 2012;14(8):762-7.12. Maedler K, et al. J Clin Endocrinol Metab. 2005;90(1):501-506.

Epub 2004 Oct 13.13. Papanas N, et al. Expert Opin Pharmacother. 2011;12(10):1457-1461. 14. DeFronzo RA, et al. N Engl J Med. 2011;364(12):1104-1115.15. U.K. Prospective Diabetes Study Group, et al. Diabetes.

1995;44(11):1249-1258.16. Meier C, et al. Arch Intern Med. 2008;168(8):820-825.17. Piccinni C, et al. Diabetes Care. 2011;34(6):1369-1371. Epub

2011 Apr 22.18. Bunck MC, et al. Diabetes Care. 2011;34(9):2041-2047.19. Bunck MC, et al. Diabetes Care. 2009;32(5):762-768. Epub 2009

Feb 5.20. Derosa G, et al. Diabet Med. April 30, 2012. [Epub ahead of print]21. Amori RE, et al. JAMA. 2007;298(2):194-206.22. Pratley RE, et al. Lancet. 2010;375(9724):1447-1456.23. Aschner P, et al. Diabetes Care. 2006;29(12):2632-2637.24. Charbonnel B, et al. Diabetes Care. 2006;29(12):2638-2643.25. Nauck M, et al. Diabetes Care. 2009;32(1):84-90. Epub 2008 Oct 17.26. Davidson JA. Mayo Clin Proc. 2010;85(12 suppl):S27-S37. Epub

2010 Nov 26.27. Drucker DJ, et al. Lancet. 2008;372(9645):1240-1250.28. Pinelli NR, et al. J Clin Pharmacol. 2011;51(2):165-172. Epub

2010 May 19.29. Klein S, et al. Diabetes Care. 2004;27(8):2067-2073. 30. Varbo A, et al. Ann Neurol. 2011;69(4):628-634. Epub 2011 Feb 18.31 UK Prospective Diabetes Study 7. Metabolism. 1990;39(9):905-912..32. Bantle JP, et al. Diabetes Care. 2008;31 (suppl 1):S61-S78.33. Knowler WC, et al. N Engl J Med. 2002;346(6):393-403.34. Penn L, et al. BMC Public Health. 2009;9:342.35. Tuomilehto J, et al. N Engl J Med. 2001;344(18):1343-1350.36 Williams KV, et al. Diabetes Obes Metab. 2000;2(3):121-129.37 Siebenhofer A, et al. Cochrane Database Syst Rev (Online).

2011(9):CD008274.38.ThePracticalGuide:Identification,Evaluation,andTreatment

of Overweight and Obesity in Adults. Rockville, MD: 2000. NIH Publication Number 00-4084. Available at: www.nhlbi.nih.gov/guidelines/obesity/prctgd_c.pdf. Accessed June 30, 2012.

39. Hollis JF, et al. Am J Prev Med.. 2008;35(2):118-126.40. Yki-Järvinen H, et al. Ann Intern Med. 1999;130(5):389-396.41. Cryer PE. Am J Physiol Endocrinol Metab. 2001;281(6):E1115-

E1121. 42. Diedrich L, et al.Clin Auton Res. 2002;12(5):358-365.43. American Diabetes Association website. Living with Diabetes:

Hypoglycemia. Available at: http://www.diabetes.org/living-with-diabetes/treatment-and-care/blood-glucose-control/hypoglyce-mia-low-blood.html. Accessed June 30, 2012.

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www.nhlbi.nih.gov/guidelines/obesity/prctgd_c.pdf

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