8. Pharmacologic Approaches toGlycemic Treatment: Standards ofMedical Care in Diabetesd2018Diabetes Care 2018;41(Suppl. 1):S73–S85 | https://doi.org/10.2337/dc18-S008

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”includes ADA’s current clinical practice recommendations and is intended to providethe components of diabetes care, general treatment goals and guidelines, and toolsto evaluate quality of care. Members of the ADA Professional Practice Committee, amultidisciplinary expert committee, are responsible for updating the Standardsof Care annually, or more frequently as warranted. For a detailed description ofADA standards, statements, and reports, as well as the evidence-grading systemfor ADA’s clinical practice recommendations, please refer to the Standards of CareIntroduction. Readers who wish to comment on the Standards of Care are invited todo so at professional.diabetes.org/SOC.

PHARMACOLOGIC THERAPY FOR TYPE 1 DIABETES

Recommendations

c Most people with type 1 diabetes should be treated with multiple daily in-jections of prandial insulin and basal insulin or continuous subcutaneousinsulin infusion. A

c Most individuals with type 1 diabetes should use rapid-acting insulin analogs toreduce hypoglycemia risk. A

c Consider educating individuals with type 1 diabetes onmatching prandial insulindoses to carbohydrate intake, premeal blood glucose levels, and anticipatedphysical activity. E

c Individuals with type 1 diabetes who have been successfully using continuoussubcutaneous insulin infusion should have continued access to this therapy afterthey turn 65 years of age. E

Insulin TherapyInsulin is the mainstay of therapy for individuals with type 1 diabetes. Generally,the starting insulin dose is based on weight, with doses ranging from 0.4 to1.0 units/kg/day of total insulin with higher amounts required during puberty.The American Diabetes Association/JDRF Type 1 Diabetes Sourcebook notes0.5 units/kg/day as a typical starting dose in patients with type 1 diabetes whoare metabolically stable, with higher weight-based dosing required immediatelyfollowing presentation with ketoacidosis (1), and provides detailed informationon intensification of therapy to meet individualized needs. The American DiabetesAssociation (ADA) position statement “Type 1 Diabetes Management Throughthe Life Span” additionally provides a thorough overview of type 1 diabetestreatment (2).

Suggested citation: American Diabetes Associ-ation. 8. Pharmacologic approaches to glyce-mic treatment: Standards of Medical Care inDiabetesd2018. Diabetes Care 2018;41(Suppl. 1):S73–S85

© 2017 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered. More infor-mation is available at http://www.diabetesjournals.org/content/license.

American Diabetes Association

Diabetes Care Volume 41, Supplement 1, January 2018 S73

8.PHARMACOLO

GIC

APPROACHES

TOGLYCEM

ICTR

EATM

ENT

Education regarding matching prandialinsulin dosing to carbohydrate intake,premeal glucose levels, and anticipatedactivity should be considered, and se-lected individuals who have masteredcarbohydrate counting should be edu-cated on fat and protein gram estimation(3–5). Although most studies of multipledaily injections versus continuous subcu-taneous insulin infusion (CSII) have beensmall and of short duration, a systematicreview and meta-analysis concluded thatthere are minimal differences betweenthe two forms of intensive insulin therapyin A1C (combined mean between-groupdifference favoring insulin pump therapy–0.30% [95% CI –0.58 to –0.02]) and se-vere hypoglycemia rates in children andadults (6). A 3-month randomized trial inpatients with type 1 diabeteswith noctur-nal hypoglycemia reported that sensor-augmented insulin pump therapy withthe threshold suspend feature reducednocturnal hypoglycemia without increas-ing glycated hemoglobin levels (7). TheU.S. Food and Drug Administration (FDA)has also approved the first hybrid closed-loop system pump. The safety and effi-cacy of hybrid closed-loop systems hasbeen supported in the literature in ado-lescents and adults with type 1 diabetes(8,9).Intensive management using CSII and

continuous glucose monitoring should beencouraged in selected patients whenthere is active patient/family participa-tion (10–12).The Diabetes Control and Complica-

tions Trial (DCCT) clearly showed that in-tensive therapy with multiple dailyinjections or CSII delivered by multidisci-plinary teams of physicians, nurses, dieti-tians, and behavioral scientists improvedglycemia and resulted in better long-termoutcomes (13–15). The study was carriedout with short-acting and intermediate-acting human insulins. Despite better mi-crovascular, macrovascular, and all-causemortality outcomes, intensive therapywas associated with a high rate of severehypoglycemia (61episodesper100patient-yearsof therapy). Since theDCCT, anumberof rapid-acting and long-acting insulin an-alogs have beendeveloped. These analogsare associated with less hypoglycemia,less weight gain, and lower A1C than humaninsulins in people with type 1 diabetes(16–18). Longer-acting basal analogs(U-300 glargine or degludec) may addi-tionally convey a lower hypoglycemia risk

compared with U-100 glargine in patientswith type 1 diabetes (19,20).

Rapid-acting inhaled insulin used be-fore meals in patients with type 1 diabe-tes was shown to be noninferior whencomparedwith aspart insulin for A1C low-ering, with less hypoglycemia observedwith inhaled insulin therapy (21). How-ever, the mean reduction in A1C wasgreater with aspart (–0.21% vs. –0.40%,satisfying the noninferiority margin of0.4%), and more patients in the insulinaspart group achieved A1C goals of#7.0% (53 mmol/mol) and #6.5% (48mmol/mol). Because inhaled insulin car-tridges are only available in 4-, 8-, and12-unit doses, limited dosing incrementsto fine-tune prandial insulin doses in type 1diabetes are a potential limitation.

Postprandial glucose excursions maybe better controlled by adjusting the tim-ing of prandial (bolus) insulin dose admin-istration. The optimal time to administerprandial insulin varies, based on the typeof insulin used (regular, rapid-acting ana-log, inhaled, etc.), measured blood glucoselevel, timing of meals, and carbohydrateconsumption. Recommendations for pran-dial insulin dose administration shouldtherefore be individualized.

PramlintidePramlintide, an amylin analog, is an agentthat delays gastric emptying, blunts pan-creatic secretion of glucagon, and en-hances satiety. It is FDA-approved for usein adults with type 1 diabetes. It has beenshown to induce weight loss and lower in-sulin doses. Concurrent reduction of pran-dial insulin dosing is required to reduce therisk of severe hypoglycemia.

Investigational Agents

Metformin

Adding metformin to insulin therapy mayreduce insulin requirements and improvemetabolic control in patients with type 1diabetes. In one study, metformin wasfound to reduce insulin requirements(6.6 units/day, P , 0.001), and led tosmall reductions in weight and total andLDL cholesterol but not to improved gly-cemic control (absolute A1C reduction0.11%, P5 0.42) (22). A randomized clin-ical trial similarly found that, among over-weight adolescents with type 1 diabetes,the addition of metformin to insulin didnot improve glycemic control and in-creased risk for gastrointestinal adverseevents after 6 months compared with

placebo (23). TheReducingWithMetforminVascular Adverse Lesions in Type1Diabetes(REMOVAL) trial investigated the additionof metformin therapy to titrated insulintherapy in adults with type 1 diabetes atincreased risk for cardiovascular diseaseand found that metformin did not signifi-cantly improve glycemic control beyondthe first 3 months of treatment and thatprogression of atherosclerosis (measuredby carotid artery intima-media thickness)was not significantly reduced, althoughother cardiovascular risk factors such asbody weight and LDL cholesterol im-proved (24). Metformin is not FDA-approved for use in patients with type 1diabetes.

Incretin-Based Therapies

Due to their potential protection of b-cellmass and suppressionof glucagon release,glucagon-like peptide 1 (GLP-1) receptoragonists (25) and dipeptidyl peptidase4 (DPP-4) inhibitors (26) are being studiedin patients with type 1 diabetes but arenot currently FDA-approved for use in pa-tients with type 1 diabetes.

Sodium–Glucose Cotransporter 2 Inhibitors

Sodium–glucose cotransporter 2 (SGLT2)inhibitors provide insulin-independentglucose lowering by blocking glucose re-absorption in theproximal renal tubule byinhibiting SGLT2. These agents providemodest weight loss and blood pressurereduction in type 2 diabetes. There arethree FDA-approved agents for patientswith type 2 diabetes, but none are FDA-approved for the treatment of patientswith type 1 diabetes (2). SGLT2 inhibitorsmay have glycemic benefits in patientswith type 1 or type 2 diabetes on insulintherapy (27). The FDA issued a warningabout the risk of ketoacidosis occurringin the absence of significant hyperglyce-mia (euglycemic diabetic ketoacidosis)in patients with type 1 or type 2 diabe-tes treated with SGLT2 inhibitors.Symptoms of ketoacidosis include dysp-nea, nausea, vomiting, and abdominalpain. Patients should be instructed tostop taking SGLT2 inhibitors and seekmedical attention immediately if theyhave symptoms or signs of ketoacidosis(28).

SURGICAL TREATMENT FORTYPE 1 DIABETES

Pancreas and Islet TransplantationPancreas and islet transplantation havebeen shown to normalize glucose levels

S74 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

but require life-long immunosuppressionto prevent graft rejection and recurrenceof autoimmune islet destruction. Giventhe potential adverse effects of immuno-suppressive therapy, pancreas transplan-tation should be reserved for patientswith type 1 diabetes undergoing simulta-neous renal transplantation, following re-nal transplantation, or for those withrecurrent ketoacidosis or severe hypogly-cemia despite intensive glycemic man-agement (29).

PHARMACOLOGIC THERAPY FORTYPE 2 DIABETES

Recommendations

c Metformin, if not contraindicatedand if tolerated, is the preferred ini-tial pharmacologic agent for thetreatment of type 2 diabetes. A

c Long-term use of metformin may beassociated with biochemical vitaminB12 deficiency, and periodic mea-surementofvitaminB12 levels shouldbe considered in metformin-treatedpatients, especially in those with ane-mia or peripheral neuropathy. B

c Consider initiating insulin therapy(with or without additional agents)in patients with newly diagnosedtype 2 diabetes who are symptom-atic and/or have A1C $10% (86mmol/mol) and/or blood glucoselevels$300mg/dL (16.7mmol/L). E

c Consider initiating dual therapy inpatients with newly diagnosedtype 2 diabetes who have A1C$9% (75 mmol/mol). E

c In patients without atheroscleroticcardiovascular disease, if mono-therapy or dual therapy does notachieve or maintain the A1C goalover 3 months, add an additionalantihyperglycemic agent based ondrug-specific and patient factors(Table 8.1). A

c A patient-centered approach shouldbe used to guide the choice ofpharmacologic agents. Consider-ations include efficacy, hypoglyce-mia risk, history of atheroscleroticcardiovascular disease, impact onweight, potential side effects, re-nal effects, delivery method (oralversus subcutaneous), cost, andpatient preferences. E

c In patients with type 2 diabetes andestablished atherosclerotic cardio-vascular disease, antihyperglycemic

therapy should begin with lifestylemanagement and metformin andsubsequently incorporate an agentproven to reduce major adverse car-diovascular events and cardiovascu-lar mortality (currently empagliflozinand liraglutide), after consideringdrug-specific and patient factors(Table 8.1). A*

c In patients with type 2 diabetes andestablished atherosclerotic cardiovascu-lar disease, after lifestyle managementand metformin, the antihyperglycemicagent canagliflozin may be consideredto reduce major adverse cardiovascularevents, based on drug-specific and pa-tient factors (Table 8.1). C*

c Continuous reevaluationof themed-ication regimen and adjustment asneeded to incorporate patient fac-tors (Table 8.1) and regimen com-plexity is recommended. E

c For patients with type 2 diabeteswhoarenot achieving glycemic goals,drug intensification, including consid-eration of insulin therapy, should notbe delayed. B

c Metformin should be continuedwhenused in combinationwithotheragents, including insulin, if not contra-indicated and if tolerated. A

See Section 12 for recommendationsspecific for children and adolescentswith type 2 diabetes. The use of metfor-min as first-line therapywas supported byfindings from a large meta-analysis, withselection of second-line therapies basedon patient-specific considerations (30).An ADA/European Association for the Studyof Diabetes position statement “Manage-ment of Hyperglycemia in Type 2 Diabe-tes, 2015: A Patient-Centered Approach”(31) recommended a patient-centered ap-proach, including assessment of efficacy,hypoglycemia risk, impact on weight, sideeffects, costs, and patient preferences. Re-nal effects may also be considered whenselecting glucose-loweringmedications forindividual patients. Lifestyle modificationsthat improvehealth (see Section4 “LifestyleManagement”) should be emphasizedalong with any pharmacologic therapy.

Initial TherapyMetformin monotherapy should bestarted at diagnosis of type 2 diabetes un-less there are contraindications. Metfor-min is effective and safe, is inexpensive,

and may reduce risk of cardiovascularevents and death (32). Compared withsulfonylureas, metformin as first-linetherapy has beneficial effects on A1C,weight, and cardiovascular mortality(33). Metformin may be safely used inpatients with estimated glomerular filtra-tion rate (eGFR) as low as 30 mL/min/1.73 m2, and the FDA recently revisedthe label for metformin to reflect itssafety in patients with eGFR $30 mL/min/1.73 m2 (34). Patients should be ad-vised to stop the medication in cases ofnausea, vomiting, or dehydration. Met-formin is associated with vitamin B12deficiency, with a recent report from theDiabetes Prevention Program OutcomesStudy (DPPOS) suggesting that periodictesting of vitamin B12 levels should beconsidered in metformin-treated pa-tients, especially in those with anemiaor peripheral neuropathy (35).

In patients with metformin contrain-dications or intolerance, consider an ini-tial drug from another class depicted inFig. 8.1 under “Dual Therapy” and pro-ceed accordingly. When A1C is $9% (75mmol/mol), consider initiating dual com-bination therapy (Fig. 8.1) to more expe-ditiously achieve the target A1C level.Insulin has the advantage of being effec-tive where other agents may not be andshould be considered as part of any com-bination regimen when hyperglycemia issevere, especially if catabolic features(weight loss, ketosis) are present. Con-sider initiating combination insulin in-jectable therapy (Fig. 8.2) when bloodglucose is$300 mg/dL (16.7 mmol/L) orA1C is$10% (86 mmol/mol) or if the pa-tient has symptoms of hyperglycemia(i.e., polyuria or polydipsia). As the pa-tient’s glucose toxicity resolves, the regi-men may, potentially, be simplified.

Combination TherapyAlthough there are numerous trialscomparing dual therapy with metforminalone, few directly compare drugs as add-on therapy. A comparative effectivenessmeta-analysis (36) suggests that eachnew class of noninsulin agents added toinitial therapy generally lowers A1C ap-proximately 0.7–1.0%. If the A1C targetisnotachievedafterapproximately3monthsand patient does not have atheroscleroticcardiovascular disease (ASCVD), considera combination of metformin and any oneof the preferred six treatment options:sulfonylurea, thiazolidinedione, DPP-4

care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S75

inhibitor, SGLT2 inhibitor, GLP-1 receptoragonist, orbasal insulin (Fig. 8.1); the choiceof which agent to add is based on drug-specific effects and patient factors (Table8.1). For patients with ASCVD, add a

second agent with evidence of cardiovas-cular risk reduction after consideration ofdrug-specific and patient factors (see p. S77CARDIOVASCULAR OUTCOMESTRIALS). If A1C targetis still not achieved after ;3 months of

dual therapy, proceed to a three-drugcombination (Fig. 8.1). Again, if A1C targetis not achieved after;3 months of tripletherapy, proceed to combination injectabletherapy (Fig. 8.2). Drug choice is based on

Figure 8.1—Antihyperglycemic therapy in type 2 diabetes: general recommendations. *If patient does not tolerate or has contraindications tometformin,consider agents from another class in Table 8.1. #GLP-1 receptor agonists and DPP-4 inhibitors should not be prescribed in combination. If a patient withASCVD is not yet on an agent with evidence of cardiovascular risk reduction, consider adding.

S76 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

Tab

le8.1—Dru

g-sp

ecificandpatien

tfacto

rsto

consid

erwhensele

ctingan

tihyperglyce

mic

treatm

entin

adults

with

type2diab

etes

*Seeref.31

fordescriptio

nofefficacy.

†FDAapp

rovedfor

CVDbene

fit.CVD,cardio

vascular

disease;DKA

,diabetic

ketoacidosis;DKD

,diabetic

kidney

disease;NASH

,nonalcoh

olicsteatohepatitis;

RAs,receptor

agonists;SQ,sub

cutaneous;T2D

M,type

2diabetes.

care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S77

patient preferences (37), as well as variouspatient, disease, and drug characteristics,with the goal of reducing blood glucoselevelswhileminimizing side effects, espe-cially hypoglycemia. If not already in-cluded in the treatment regimen, additionof an agent with evidence of cardiovas-cular risk reduction should be consid-ered in patients with ASCVD beyond

dual therapy, with continuous reevalu-ation of patient factors to guide treat-ment (Table 8.1).

Table 8.2 lists drugs commonly used inthe U.S. Cost-effectiveness models of thenewer agents based on clinical utility andglycemic effect have been reported (38).Table 8.3 provides cost information forcurrently approved noninsulin therapies.

Of note, prices listed are average whole-sale prices (AWP) (39) and National Aver-age Drug Acquisition Costs (NADAC) (40)and do not account for discounts, re-bates, or other price adjustments ofteninvolved in prescription sales that affectthe actual cost incurred by the patient.While there are alternative means to esti-mate medication prices, AWP and NADAC

Figure 8.2—Combination injectable therapy for type 2 diabetes. FBG, fasting blood glucose; hypo, hypoglycemia. Adapted with permission from Inzucchiet al. (31).

S78 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

Tab

le8.2—Pharmac

ologyofav

ailable

gluco

se-loweringag

ents

intheU.S.forthetrea

tmen

toftype2diabetes

Class

Compound(s)

Cellularmechanism(s)

Prim

aryphysiologicalaction(s)

Ren

aldosingrecommen

dations(63–66)*

Biguanides

cMetform

inActivates

AMPkinase(?

other)

↓Hepaticglucoseprod

uction

cNodo

seadjustmentifeG

FR.45;

donotinitiateORassessrisk/benefitifcurrently

onmetform

inifeG

FR30–45;

discon

tinu

eifeG

FR,30

Sulfo

nylureas

(2nd

generation

)cGlybu

ride

ClosesK A

TPchannelson

b-cell

plasmamem

branes

↑Insulin

secretion

cAvoiduseinpatientswithrenalimpairment

cGlipizide

cInitiate

conservativelyat

2.5mgdaily

toavoidhypo

glycem

iacGlim

epiride

cInitiate

conservativelyat

1mgdaily

toavoidhypo

glycem

ia

Meglitinides

(glinides)

cRepaglinide

ClosesK A

TPchannelson

b-cell

plasmamem

branes

↑Insulin

secretion

cInitiate

conservativelyat

0.5mgwithmealsifeG

FR,30

cNateglinide

cInitiate

conservativelyat

60mgwithmealsifeG

FR,30

Thiazolidinediones

cPioglitazon

eActivates

thenuclear

tran

scriptionfactorPP

AR-g

↑Insulin

sensitivity

cNodo

seadjustmentrequ

ired

cRosiglitazon

e§cNodo

seadjustmentrequ

ired

a-Glucosidase

inhibitors

cAcarbose

Inhibitsintestinala-glucosidase

Slowsintestinalcarbohydrate

digestion/absorption

cAvoidifeG

FR,30

cMiglitol

cAvoidifeG

FR,25

DPP-4

inhibitors

cSitagliptin

InhibitsDPP

-4activity,

increasingpostprandialincretin

(GLP-1,GIP)concentrations

↑Insulin

secretion(glucose

depend

ent);

↓Glucagonsecretion(glucose

depend

ent)

c100mgdaily

ifeG

FR.50;

50mgdaily

ifeG

FR30–50;

25mgdaily

ifeG

FR,30

cSaxagliptin

c5mgdaily

ifeG

FR.50;

2.5mgdaily

ifeG

FR#50

cLinagliptin

cNodo

seadjustmentrequ

ired

cAlogliptin

c25

mgdaily

ifeG

FR.60;

12.5mgdaily

ifeG

FR30–60;

6.25

mgdaily

ifeG

FR,30

Bile

acid

sequ

estrants

cColesevelam

Bindsbile

acidsin

intestinal

tract,increasinghep

aticbile

acid

production

?↓Hepaticglucoseprod

uction

;?↑Incretinlevels

cNospecificdo

seadjustmentrecommendedby

manufacturer

Dop

amine-2

agon

ists

cBromocriptine(quick

release)§

Activates

dopam

inergicreceptors

Mod

ulates

hypo

thalam

icregulation

ofmetabolism;

↑Insulin

sensitivity

cNospecificdo

seadjustmentrecommendedby

manufacturer

SGLT2inhibitors

cCanagliflozin

InhibitsSG

LT2in

theproximal

nep

hron

Blocksglucose

reab

sorptionbythe

kidney,increasingglucosuria

cNodo

seadjustmentrequ

ired

ifeG

FR$60;

100mgdaily

ifeG

FR45–59;

avoiduseanddiscon

tinu

einpatientswitheG

FRpersistently,45

cDapagliflozin

cAvoidinitiating

ifeG

FR,60;

notrecommendedwitheG

FR30–60;

contraindicatedwitheG

FR,30

cEm

pagliflozin

cCon

traind

icated

witheG

FR,30

GLP-1

receptor

agon

ists

cExenatide

Activates

GLP-1

receptors

↑Insulin

secretion(glucose

depend

ent)

cNot

recommendedwitheG

FR,30

cExenatideextend

edrelease

cNot

recommendedwitheG

FR,30

Continuedon

p.S80

care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S79

Tab

le8.2—Continued

Class

Compound(s)

Cellularmechanism(s)

Prim

aryphysiologicalaction(s)

Ren

aldosingrecommen

dations(63–66)*

↓Glucagonsecretion(glucose

depend

ent);

Slow

sgastricem

ptying;

↑Satiety

cLiraglutide

cNospecificdo

seadjustmentrecommendedby

themanufacturer;lim

ited

experience

inpatientswithsevere

renalimpairment

cAlbiglutide

cNodo

seadjustmentrequ

ired

foreG

FR15–89permanufacturer;lim

ited

experience

inpatientswithsevere

renalimpairment

cLixisenatide

cNodo

seadjustmentrequ

ired

foreG

FR60–89;

nodo

seadjustmentrequ

ired

foreG

FR30–59,bu

tpatientsshou

ldbe

mon

itored

foradverseeffectsandchangesinkidn

eyfunction

;clinicalexperience

islim

ited

witheG

FR15–29;patientsshou

ldbe

mon

itored

foradverseeffectsandchangesinkidn

eyfunction

;avoidifeG

FR,15

cDulaglutide

cNospecificdo

seadjustmentrecommendedby

themanufacturer;lim

ited

experience

inpatientswithsevere

renalimpairment

Amylinmimetics

cPram

lintide§

Activates

amylin

receptors

↓Glucagonsecretion;

Slow

sgastricem

ptying;

↑Satiety

cNospecificdo

seadjustmentrecommendedby

manufacturer

Insulins

cRapid-actinganalogs

Activates

insulin

receptors

↑Glucose

disposal;

↓Hepaticglucoseprod

uction

;Supp

resses

ketogenesis

cLower

insulin

dosesrequ

ired

withadecrease

ineG

FR;titrate

perclinical

respon

seLispro

Aspart

Glulisine

Inhaledinsulin

cShort-acting

analogs

Hum

anRegular

cInterm

ediate-actinganalogs

Hum

anNPH

cBasalinsulin

analogs

Glargine

Detem

irDegludec

cPrem

ixed

insulin

prod

ucts

NPH

/Regular

70/30

70/30aspartmix

75/25lispromix

50/50lispromix

*eGFR

isgiveninmL/min/1.73m

2.§Not

licensedinEurope

fortype

2diabetes.G

IP,glucose-dependent

insulinotropicpeptide;PPAR-g,peroxisom

eproliferator–activatedreceptor

g.

S80 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

were utilized to provide two separatemea-sures to allow for a comparison of drugprices with the primary goal of highlightingthe importance of cost considerationswhen prescribing antihyperglycemic treat-ments. The ongoing Glycemia ReductionApproaches in Diabetes: A Comparative Ef-fectiveness Study (GRADE) will comparefour drug classes (sulfonylurea, DPP-4 in-hibitor, GLP-1 receptor agonist, and basalinsulin) when added tometformin therapyover 4 years on glycemic control and othermedical, psychosocial, and health economicoutcomes (41).Rapid-actingsecretagogues (meglitinides)

may be used instead of sulfonylureas inpatients with sulfa allergies or irregularmeal schedules or in those who develop

late postprandial hypoglycemia whentaking a sulfonylurea. Other drugs notshown in Table 8.1 (e.g., inhaled insulin,a-glucosidase inhibitors, colesevelam,bro-mocriptine, and pramlintide) may be triedin specific situations but considerationsincludemodest efficacy in type 2 diabetes,frequency of administration, potential fordrug interactions, cost, and/or side effects.

Cardiovascular Outcomes Trials

There are now three large randomizedcontrolled trials reporting statistically sig-nificant reductions in cardiovascular eventsfor two SGLT2 inhibitors (empagliflozinand canagliflozin) and one GLP-1 receptoragonist (liraglutide) where themajority, ifnot all patients, in the trial had ASCVD.

The empagliflozin and liraglutide trialsdemonstrated significant reductions incardiovascular death. Exenatide once-weekly did not have statistically sig-nificant reductions in major adversecardiovascular events or cardiovascu-lar mortality but did have a significantreduction in all-cause mortality. In con-trast, other GLP-1 receptor agonistshave not shown similar reductions incardiovascular events (Table 9.4).Whether the benefits of GLP-1 receptoragonists are a class effect remains to bedefinitively established. See ANTIHYPERGLYCEMIC

THERAPIES AND CARDIOVASCULAR OUTCOMES inSection 9 “Cardiovascular Disease andRisk Management” and Table 9.4 for a de-tailed description of these cardiovascular

Table 8.3—Median monthly cost of maximum approved daily dose of noninsulin glucose-lowering agents in the U.S.

Class Compound(s)Dosage strength/product

(if applicable)Median AWP(min, max)†

Median NADAC(min, max)†

Maximum approveddaily dose*

Biguanides c Metformin 500 mg (IR) $84 ($4, $93) $2 2,000 mg850 mg (IR) $108 ($6, $109) $3 2,550 mg1,000 mg (IR) $87 ($4, $88) $2 2,000 mg500 mg (ER) $89 ($82, $6,671) $5 ($5, $3,630) 2,000 mg750 mg (ER) $72 ($65, $92) $5 1,500 mg1,000 mg (ER) $1,028 ($1,028,

$7,214)$539 ($539, $5,189) 2,000 mg

Sulfonylureas(2nd generation)

c Glyburide 5 mg $93 ($63, $103) $17 20 mg6 mg (micronized) $50 ($48, $71) $12 12 mg (micronized)

c Glipizide 10 mg (IR) $75 ($67, $97) $4 40 mg (IR)10 mg (XL) $48 $16 20 mg (XL)

c Glimepiride 4 mg $71 ($71, $198) $7 8 mg

Meglitinides (glinides) c Repaglinide 2 mg $659 ($122, $673) $40 16 mgc Nateglinide 120 mg $155 $56 360 mg

Thiazolidinediones c Pioglitazone 45 mg $348 ($283, $349) $5 45 mgc Rosiglitazone 4 mg $387 $314 8 mg

a-Glucosidaseinhibitors

c Acarbose 100 mg $104 ($104, $106) $25 300 mgc Miglitol 100 mg $241 N/A†† 300 mg

DPP-4 inhibitors c Sitagliptin 100 mg $477 $382 100 mgc Saxagliptin 5 mg $462 $370 5 mgc Linagliptin 5 mg $457 $367 5 mgc Alogliptin 25 mg $449 $357 25 mg

Bile acid sequestrants c Colesevelam 625 mg tabs $713 $570 3.75 g1.875 g suspension $1,426 $572 3.75 g

Dopamine-2 agonists c Bromocriptine 0.8 mg $784 $629 4.8 mg

SGLT2 inhibitors c Canagliflozin 300 mg $512 $411 300 mgc Dapagliflozin 10 mg $517 $413 10 mgc Empagliflozin 25 mg $517 $415 25 mg

GLP-1 receptoragonists

c Exenatide 10 mg pen $802 $642 20 mgc Lixisenatide 20 mg pen $669 N/A†† 20 mgc Liraglutide 18 mg/3 mL pen $968 $775 1.8 mgc Exenatide (extendedrelease)

2 mg powder forsuspension or pen

$747 $600 2 mg**

c Albiglutide 50 mg pen $626 $500 50 mg**c Dulaglutide 1.5/0.5 mL pen $811 $648 1.5 mg**

Amylin mimetics c Pramlintide 120 mg pen $2,336 N/A†† 120 mg/injection†††

ER and XL, extended release; IR, immediate release. †Calculated for 30-day supply (AWP or NADAC unit price3 number of doses required to providemaximum approved daily dose3 30 days); median AWP or NADAC listed alone when only one product and/or price. *Utilized to calculate median AWPand NADAC (min, max); generic prices used, if available commercially. ††Not applicable; data not available. **Administered once weekly. †††AWPand NADAC calculated based on 120 mg three times daily.

care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S81

outcomes trials. Additional large random-ized trials of other agents in these classesare ongoing.Of note, these studies examined the

drugs in combination with metformin(Table 9.4) in the great majority of pa-tients for whom metformin was not con-traindicated or not tolerated. For patientswith type 2 diabetes who have ASCVD, onlifestyle and metformin therapy, it is rec-ommended to incorporate an agent withstrong evidence for cardiovascular risk re-duction especially those with proven ben-efit on both major adverse cardiovascularevents and cardiovascular death after con-sideration of drug-specific patient factors(Table 8.1). See Fig. 8.1 for additional rec-ommendations on antihyperglycemictreatment in adults with type 2 diabetes.

Insulin TherapyMany patients with type 2 diabetes even-tually require and benefit from insulintherapy. The progressive nature of type 2diabetes shouldbe regularly andobjectivelyexplained to patients. Providers should

avoid using insulin as a threat or de-scribing it as a sign of personal failureor punishment.

Equipping patientswith an algorithm forself-titration of insulin doses based on self-monitoring of blood glucose improvesglycemic control in patients with type 2 di-abetes initiating insulin (42). Comprehen-sive education regarding self-monitoringof blood glucose, diet, and the avoidanceof and appropriate treatment of hypogly-cemia are critically important in any pa-tient using insulin.

Basal Insulin

Basal insulin alone is themost convenientinitial insulin regimen, beginning at 10unitsper day or 0.1–0.2 units/kg/day, depend-ing on the degree of hyperglycemia. Basalinsulin is usually prescribed in conjunc-tion with metformin and sometimes oneadditional noninsulin agent. When basalinsulin is added to antihyperglycemicagents in patients with type 2 diabetes,long-acting basal analogs (U-100 glargineor detemir) can be used instead of NPH

to reduce the risk of symptomatic and noc-turnal hypoglycemia (43–48). Longer-acting basal analogs (U-300 glargine ordegludec) may additionally convey alower hypoglycemia risk compared withU-100 glargine when used in combinationwith oral antihyperglycemic agents (49–55). While there is evidence for reducedhypoglycemia with newer, longer-actingbasal insulin analogs, people without ahistory of hypoglycemia are at decreasedrisk and could potentially be switched tohuman insulin safely. Thus, due to highcosts of analog insulins, use of human in-sulin may be a practical option for somepatients, and clinicians should be familiarwith its use (56). Table 8.4 provides AWP(39) and NADAC (40) information (costper 1,000 units) for currently available in-sulin and insulin combination productsin the U.S. There have been substantialincreases in the price of insulin over thepast decade and the cost-effectivenessof different antihyperglycemic agents isan important consideration in a patient-centered approach to care, along with

Table 8.4—Median cost of insulin products in the U.S. calculated as AWP (39) and NADAC (40) per 1,000 units of specified dosageform/product

Insulins Compounds Dosage form/productMedian AWP(min, max)*

Median NADAC(min, max)*

Rapid-actinganalogs

c Lispro U-100 vial; $330 $264U-100 3 mL cartridges; $408 $326U-100 prefilled pen; U-200 prefilled pen $424 $339

c Aspart U-100 vial; $331 $265U-100 3 mL cartridges; $410 $330U-100 prefilled pen $426 $341

c Glulisine U-100 vial; $306 $245U-100 prefilled pen $394 $315

c Inhaled insulin Inhalation cartridges $725 ($544, $911) N/A†

Short-acting analogs c Human Regular U-100 vial $165 ($165, $178) $135 ($135, $145)

Intermediate-acting analogs c Human NPH U-100 vial; $165 ($165, $178) $135 ($135, $145)U-100 prefilled pen $377 $305

Concentrated HumanRegular insulin

c U-500 HumanRegular insulin

U-500 vial; $178 $143U-500 prefilled pen $230 $184

Basal analogs c Glargine U-100 vial; U-100 prefilled pen;U-300 prefilled pen

$298 $239 ($239, $241)

c Glargine biosimilar U-100 prefilled pen $253 $203c Detemir U-100 vial; U-100 prefilled pen $323 $259c Degludec U-100 prefilled pen; U-200 prefilled pen $355 $285

Premixed insulin products c NPH/Regular 70/30 U-100 vial; $165 ($165, $178) $134 ($134, $146)U-100 prefilled pen $377 $305

c Lispro 50/50 U-100 vial; $342 $278U-100 prefilled pen $424 $339

c Lispro 75/25 U-100 vial; $342 $273U-100 prefilled pen $424 $340

c Aspart 70/30 U-100 vial; $343 $275U-100 prefilled pen $426 $341

Premixed insulin/GLP-1receptor agonist products

c Degludec/Liraglutide 100/3.6 prefilled pen $763 N/A†c Glargine/Lixisenatide 100/33 prefilled pen $508 $404

*AWP or NADAC calculated as in Table 8.3; median listed alone when only one product and/or price. †Not applicable; data not available.

S82 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

efficacy, hypoglycemia risk, weight, andother patient and drug-specific factors(Table 8.1) (57).

Bolus Insulin

Many individuals with type 2 diabetesmay require mealtime bolus insulin dos-ing in addition to basal insulin. Rapid-acting analogs are preferred due to theirprompt onset of action after dosing. InSeptember 2017, the FDA approved a newfaster-acting formulation of insulin aspart.The recommended starting dose of meal-time insulin is 4 units, 0.1 units/kg, or 10%of the basal dose. If A1C is,8% (64 mmol/mol) when starting mealtime bolus in-sulin, consideration should be given todecreasing the basal insulin dose.

Premixed Insulin

Premixed insulin products contain both abasal and prandial component, allowingcoverage of both basal and prandial needswith a single injection. NPH/Regular 70/30insulin, for example, is composed of 70%NPH insulin and30% regular insulin. Theuseof premixed insulin products has its advan-tages and disadvantages, as discussed be-low in COMBINATION INJECTABLE THERAPY.

Concentrated Insulin Products

Several concentrated insulin preparationsare currently available. U-500 regular insu-lin, by definition, is five times as concen-trated as U-100 regular insulin and has adelayed onset and longer duration of ac-tion than U-100 regular, possessing bothprandial and basal properties. U-300 glar-gine and U-200 degludec are three andtwo times as concentrated as their U-100formulationsandallowhigherdosesofbasalinsulin administration per volume used.U-300 glargine has a longer duration of ac-tion than U-100 glargine. The FDA has alsoapproved a concentrated formulation ofrapid-acting insulin lispro, U-200 (200units/mL). These concentrated preparationsmay be more comfortable for the patientand may improve adherence for patientswith insulin resistance who require largedoses of insulin.While U-500 regular insulinis available in both prefilled pens and vials (adedicated syringe was FDA approved in July2016), other concentrated insulins are avail-able only in prefilled pens to minimize therisk of dosing errors.

Inhaled Insulin

Inhaled insulin is available for prandial usewithamore limiteddosing range. It is contra-indicated in patients with chronic lung dis-ease such as asthma and chronic obstructive

pulmonarydisease and is not recommendedinpatientswho smokeorwho recently stop-ped smoking. It requires spirometry (FEV1)testing to identifypotential lungdisease inallpatients prior to and after starting therapy.

Combination Injectable TherapyIf basal insulin has been titrated to an ac-ceptable fasting blood glucose level (or ifthedose is.0.5 units/kg/day) andA1C re-mains above target, consider advancingto combination injectable therapy (Fig.8.2). When initiating combination inject-able therapy, metformin therapy shouldbe maintained while other oral agentsmay be discontinued on an individual ba-sis to avoid unnecessarily complex orcostly regimens (i.e., adding a fourth anti-hyperglycemic agent). In general, GLP-1receptor agonists should not be discon-tinued with the initiation of basal insulin.Sulfonylureas, DPP-4 inhibitors, and GLP-1 receptor agonists are typically stoppedonce more complex insulin regimens be-yond basal are used. In patients with sub-optimal blood glucose control, especiallythose requiring large insulin doses, adjunc-tive use of a thiazolidinedione or SGLT2inhibitor may help to improve controland reduce the amount of insulin needed,though potential side effects should beconsidered. Once an insulin regimen is ini-tiated, dose titration is important with ad-justments made in both mealtime andbasal insulins based on the blood glucoselevels and an understanding of the phar-macodynamic profile of each formulation(pattern control).

Studies have demonstrated the non-inferiority of basal insulin plus a singleinjectionof rapid-acting insulin at the larg-est meal relative to basal insulin plus aGLP-1 receptor agonist relative to twodaily injections of premixed insulins(Fig. 8.2). Basal insulin plus GLP-1 recep-tor agonists are associated with less hy-poglycemia and with weight loss insteadof weight gain but may be less tolerableand have a greater cost (58,59). In No-vember 2016, the FDA approved two dif-ferent once-daily fixed-dual combinationproducts containing basal insulin plus aGLP-1 receptor agonist: insulin glargineplus lixisenatide and insulin degludecplus liraglutide. Other options for treat-ment intensification include adding a sin-gle injection of rapid-acting insulin analog(lispro, aspart, or glulisine) before thelargest meal or stopping the basal insulinand initiating a premixed (or biphasic)

insulin (NPH/Regular 70/30, 70/30 aspartmix, 75/25 or 50/50 lispro mix) twicedaily, usually before breakfast and beforedinner. Each approach has its advan-tages and disadvantages. For example,providers may wish to consider regimenflexibility when devising a plan for the ini-tiation and adjustment of insulin therapyin people with type 2 diabetes, with rapid-acting insulin offering greater flexibility interms of meal planning than premixed in-sulin. If one regimen is not effective (i.e.,basal insulin plus GLP-1 receptor agonist),consider switching to another regimen toachieve A1C targets (i.e., basal insulin plussingle injectionof rapid-acting insulinorpre-mixed insulin twice daily) (60,61). Regularhuman insulin and human NPH/Regularpremixed formulations (70/30) are lesscostly alternatives to rapid-acting insulinanalogs and premixed insulin analogs,respectively, but their pharmacody-namicprofilesmaymake them lessoptimal.

Fig. 8.2 outlines these options, as wellas recommendations for further intensifi-cation, if needed, to achieve glycemicgoals. If a patient is still above the A1Ctarget on premixed insulin twice daily,consider switching to premixed analog in-sulin three times daily (70/30 aspart mix,75/25 or 50/50 lispro mix). In general,three times daily premixed analog insu-lins have been found to be noninferiorto basal-bolus regimens with similar ratesof hypoglycemia (62). If a patient is stillabove the A1C target on basal insulinplus single injection of rapid-acting insulinbefore the largest meal, advance to abasal-bolus regimen with $2 injectionsof rapid-acting insulin before meals. Con-sider switching patients from one regimento another (i.e., premixed analog insulinthree times daily to basal-bolus regimenor vice-versa) if A1C targets are not beingmet and/or depending on other patientconsiderations (60,61).Metformin shouldbe continued in patients on combinationinjectable insulin therapy, if not contra-indicated and if tolerated, for further gly-cemic benefits.

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