8. Pharmacologic Approaches toGlycemic TreatmentDiabetes Care 2017;40(Suppl. 1):S64–S74 | DOI: 10.2337/dc17-S011

PHARMACOLOGIC THERAPY FOR TYPE 1 DIABETES

Recommendations

c Mostpeoplewith type1diabetes shouldbe treatedwithmultiple daily injections ofprandial insulin and basal insulin or continuous subcutaneous insulin infusion. A

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

c Consider educating individuals with type 1 diabetes on matching prandialinsulin doses to carbohydrate intake, premeal blood glucose levels, and antic-ipated physical activity. E

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

Insulin TherapyInsulin is the mainstay of therapy for individuals with type 1 diabetes. Generally, thestarting insulin dose is based on weight, with doses ranging from 0.4 to 1.0 units/kg/day of total insulin with higher amounts required during puberty. The American DiabetesAssociation/JDRF Type 1 Diabetes Sourcebook notes 0.5 units/kg/day as a typical startingdose in patients who are metabolically stable, with higher weight-based dosing requiredimmediately following presentation with ketoacidosis (1), and provides detailed informa-tion on intensification of therapy to meet individualized needs. The American DiabetesAssociation (ADA) position statement “Type 1 Diabetes Management Through the LifeSpan” additionally provides a thorough overview of type 1 diabetes treatment and asso-ciated recommendations (2).Education regarding matching prandial insulin dosing to carbohydrate intake, pre-

meal glucose levels, and anticipated activity should be considered, and selected indi-viduals who have mastered carbohydrate counting should be educated on fat andprotein gram estimation (3–5). Although most studies of multiple daily injections(MDI) versus continuous subcutaneous insulin infusion (CSII) have been small and ofshort duration, a systematic review andmeta-analysis concluded that there areminimaldifferences between the two forms of intensive insulin therapy in A1C (combinedmeanbetween-group difference favoring insulin pump therapy 20.30% [95% CI 20.58to 20.02]) and severe hypoglycemia rates in children and adults (6). A 3-month ran-domized trial in patients with type 1 diabetes with nocturnal hypoglycemia reportedthat sensor-augmented insulin pump therapy with the threshold suspend feature re-duced nocturnal hypoglycemia without increasing glycated hemoglobin levels (7). In-tensive management using CSII and continuous glucose monitoring (CGM) should beencouraged in selected patientswhen there is active patient/family participation (8–10).The Diabetes Control and Complications Trial (DCCT) clearly showed that intensive

therapy with MDI or CSII delivered by multidisciplinary teams of physicians, nurses, dieti-tians, and behavioral scientists improved glycemia and resulted in better long-term out-comes (11–13). The study was carried out with short-acting and intermediate-actinghuman insulins. Despite better microvascular, macrovascular, and all-causemortalityoutcomes, intensive therapy was associated with a high rate of severe hypoglycemia(61 episodes per 100 patient-years of therapy). Since the DCCT, a number of rapid-acting and long-acting insulin analogs have been developed. These analogs are as-sociated with less hypoglycemia in type 1 diabetes, while matching the A1C loweringof human insulins (14,15).

Suggested citation: American Diabetes Associa-tion. Pharmacologic approaches to glycemictreatment. Sec. 8. In Standards of MedicalCare in Diabetesd2017. Diabetes Care 2017;40(Suppl. 1):S64–S74

© 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

S64 Diabetes Care Volume 40, Supplement 1, January 2017

8.PHARMACOLO

GIC

APPROACHES

TOGLYCEM

ICTR

EATM

ENT

Rapid-acting inhaled insulin used be-fore meals in type 1 diabetes was shownto be noninferior when compared withaspart insulin for A1C lowering, with lesshypoglycemia observed with inhaled in-sulin therapy (16). However, the meanreduction in A1C was greater with aspart(20.21% vs. 20.40%, satisfying the non-inferiority margin of 0.4%), and more pa-tients in the insulin aspart groupachieved A1C goals of #7.0% (53mmol/mol) and #6.5% (48 mmol/mol).Because inhaled insulin cartridges areonly available in 4, 8, and 12 unit doses,people with type 1 diabetes may havelimited dosing increments to fine-tuneprandial insulin doses when using thistherapy.Postprandial glucose excursions may be

better controlled by adjusting the timingof prandial (bolus) insulin dose adminis-tration. The optimal time to administerprandial insulin varies, based on thetype of insulin used (regular, rapid-actinganalog, inhaled, etc.), the measuredblood glucose level, timing of meals,and carbohydrate consumption. Rec-ommendations for prandial insulindose administration should thereforebe individualized.

PramlintidePramlintide, an amylin analog, is anagent that delays gastric emptying,blunts pancreatic secretion of glucagon,and enhances satiety. It is U.S. Food andDrug Administration (FDA)–approvedfor use in adults with type 1 diabetes. Ithas been shown to induce weight lossand lower insulin doses. Concurrent re-duction of prandial insulin dosing is re-quired to reduce the risk of severehypoglycemia.

Pancreas and Islet TransplantationPancreas and islet transplantation havebeen shown to normalize glucose levelsbut require lifelong 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, followingrenal transplantation, or for those withrecurrent ketoacidosis or severe hypogly-cemia despite intensive glycemic manage-ment (17). Islet transplantation remainsinvestigational. Autoislet transplantationmay be considered for patients requiring

total pancreatectomy for medically refrac-tory chronic pancreatitis.

Investigational Agents

Metformin

Adding metformin to insulin therapy mayreduce insulin requirements and improvemetabolic control in overweight/obese pa-tients with poorly controlled type 1 diabe-tes. In ameta-analysis,metformin in type1diabetes was found to reduce insulin re-quirements (6.6 units/day, P, 0.001) andled to small reductions in weight and totaland LDL cholesterol but not to improvedglycemic control (absolute A1C reduction0.11%, P 5 0.42) (18). Metformin is notFDA-approved for use in patients withtype 1 diabetes.

Incretin-Based Therapies

Due to their potential protection of b-cellmass and suppression of glucagon release,glucagon-like peptide 1 (GLP-1) receptoragonists and dipeptidyl peptidase 4 (DPP-4)inhibitors are being studied in patients withtype 1 diabetes but are not currently FDA-approved for use in patients with type 1diabetes.

Sodium–Glucose Cotransporter

2 Inhibitors

Sodium–glucose cotransporter 2 (SGLT2)inhibitors provide insulin-independent glu-cose lowering by blocking glucose reab-sorption in the proximal 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). The FDA issued awarning about the risk of ketoacidosis oc-curring in the absence of significant hyper-glycemia (euglycemic diabetic ketoacidosis)in patients with type 1 and type 2 diabetestreatedwith SGLT2 inhibitors. Symptomsofketoacidosis includedyspnea, nausea, vom-iting, and abdominal pain. Patients shouldbe instructed to stop taking SGLT2 inhibi-tors and seek medical attention immedi-ately if they have symptoms or signs ofketoacidosis (19).

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 maybe associated with biochemicalvitamin B12 deficiency, and peri-odic measurement of vitamin B12levels should be considered inmetformin-treated patients, es-pecially in those with anemia orperipheral 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$300 mg/dL (16.7 mmol/L). E

c If noninsulin monotherapy atmaximum tolerated dose does notachieve or maintain the A1C targetafter 3 months, add a second oralagent, a glucagon-like peptide 1 re-ceptor agonist, or basal insulin. A

c A patient-centered approach shouldbe used to guide the choice of phar-macologic agents. Considerations in-clude efficacy, hypoglycemia risk,impact on weight, potential side ef-fects, cost, and patient preferences. E

c For patients with type 2 diabeteswho are not achieving glycemicgoals, insulin therapy should notbe delayed. B

c In patients with long-standingsuboptimally controlled type 2 di-abetes and established athero-sclerotic cardiovascular disease,empagliflozin or liraglutide shouldbe considered as they have beenshown to reduce cardiovascularand all-cause mortality whenadded to standard care. Ongoingstudies are investigating the cardio-vascular benefits of other agents inthese drug classes. B

The use of metformin as first-line ther-apy was supported by findings froma large meta-analysis, with selectionof second-line therapies based onpatient-specific considerations (20).An ADA/European Association for theStudy of Diabetes position statement(21) recommended a patient-centeredapproach, including assessment of ef-ficacy, hypoglycemia risk, impact onweight, side effects, costs, and patientpreferences. Renal effectsmayalsobe con-sidered when selecting glucose-loweringmedications for individual patients. Life-style modifications that improve health

care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S65

(see Section 4 “Lifestyle Management”)should be emphasized along with anypharmacologic therapy.

Initial TherapyMetforminmonotherapy should be startedat diagnosis of type 2 diabetes unlessthere are contraindications. Metforminis effective and safe, is inexpensive, andmay reduce risk of cardiovascular eventsand death (22). Metforminmay be safelyused in patients with estimated glo-merular filtration rate (eGFR) as low as30 mL/min/1.73 m2 (23), and the U.S.label for metformin was recently re-vised to reflect its safety in patientswith eGFR $30 mL/min/1.73 m2 (24).Patients should be advised to stop the

medication in cases of nausea, vomiting,or dehydration. Metformin is associatedwith vitamin B12 deficiency, with a recentreport from the Diabetes Prevention Pro-gram Outcomes Study (DPPOS) suggestingthat periodic testing of vitamin B12 levelsshould be considered inmetformin-treatedpatients, especially in those with anemia orperipheral neuropathy (25).

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%(75 mmol/mol), consider initiating dualcombination therapy (Fig. 8.1) to moreexpeditiously achieve the target A1Clevel. Insulin has the advantage of being

effective where other agents may not beand should be considered as part of anycombination regimen when hyperglycemiais severe, especially if symptoms are pre-sent or any catabolic features (weightloss, ketosis) are present. Consider ini-tiating combination insulin injectabletherapy (Fig. 8.2) when blood glucoseis $300 mg/dL (16.7 mmol/L) or A1Cis$10% (86 mmol/mol) or if the patienthas symptoms of hyperglycemia (i.e.,polyuria or polydipsia). As the patient’sglucose toxicity resolves, the regimenmay, potentially, be simplified.

Combination TherapyAlthough there are numerous trials com-paring dual therapywithmetformin alone,

Figure 8.1—Antihyperglycemic therapy in type 2 diabetes: general recommendations. The order in the chart was determined by historical availability andthe route of administration, with injectables to the right; it is not meant to denote any specific preference. Potential sequences of antihyperglycemictherapy for patients with type 2 diabetes are displayed, with the usual transition moving vertically from top to bottom (although horizontal movementwithin therapy stages is also possible, depending on the circumstances). DPP-4-i, DPP-4 inhibitor; fxs, fractures; GI, gastrointestinal; GLP-1 RA, GLP-1receptor agonist; GU, genitourinary; HF, heart failure; Hypo, hypoglycemia; SGLT2-i, SGLT2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. *See ref. 21 fordescription of efficacy and cost categorization. §Usually a basal insulin (NPH, glargine, detemir, degludec). Adapted with permission from Inzucchi et al. (21).

S66 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 40, Supplement 1, January 2017

fewdirectly comparedrugs as add-on ther-apy. A comparative effectiveness meta-analysis (23) suggests that each new classof noninsulin agents added to initial ther-apy generally lowers A1C approximately0.9–1.1%. If the A1C target is not achievedafter approximately 3 months, consider acombination of metformin and one of

the six available treatment options: sul-fonylurea, thiazolidinedione, DPP-4 in-hibitor, SGLT2 inhibitor, GLP-1 receptoragonist, or basal insulin (Fig. 8.1). If A1Ctarget is still not achieved after ;3months of dual therapy, proceed tothree-drug combination (Fig. 8.1). Again,if A1C target is not achieved after

;3 months of triple therapy, proceedto combination injectable therapy(Fig. 8.2).

Drug choice is based on patient pref-erences (26), as well as various patient,disease, and drug characteristics, withthe goal of reducing blood glucose levelswhile minimizing side effects, especially

Figure 8.2—Combination injectable therapy for type 2 diabetes. FBG, fasting blood glucose; GLP-1 RA, GLP-1 receptor agonist; hypo, hypoglycemia.Adapted with permission from Inzucchi et al. (21).

care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S67

Table

8.1—Pro

pertiesofava

ilable

gluco

se-loweringagents

intheU.S.thatmayguideindividualize

dtreatm

entch

oicesin

patients

withtype2diabetes(21)

Class

Compound(s)

Cellularmechanism(s)

Prim

aryphysiological

action(s)

Advantages

Disadvantages

Cost*

Biguanides

cMetform

inActivates

AMP-kinase

(?other)

c↓Hep

aticglucose

production

cExtensive

experience

cRarehypoglycem

iac↓CVDeven

ts(UKPD

S)cRelativelyhigher

A1C

efficacy

cGastrointestinalsideeffects

(diarrhea,abdo

minalcram

ping,nausea)

cVitam

inB12

deficiency

cCo

ntraindications:eG

FR,30

mL/min/1.73m

2,acidosis,hypoxia,

dehydration,etc.

cLacticacidosisrisk

(rare)

Low

Sulfonylureas

2ndgeneration

cGlyburide

cGlipizide

cGlim

epiride

ClosesKATPchan

nelsonb-cell

plasm

amem

branes

c↑Insulin

secretion

cExtensive

experience

c↓Microvascularrisk

(UKPD

S)cRelativelyhigher

A1C

efficacy

cHypoglycem

iac↑Weight

Low

Meglitinides

(glinides)

cRep

aglin

ide

cNateglinide

ClosesKATPchan

nelsonb-cell

plasm

amem

branes

c↑Insulin

secretion

c↓Po

stprandialglucose

excursions

cDosingflexibility

cHypoglycem

iac↑Weight

cFreq

uen

tdosingsched

ule

Moderate

TZDs

cPioglitazone‡

cRosiglitazone§

Activates

thenuclear

transcriptionfactor

PPAR-g

c↑Insulin

sensitivity

cRarehypoglycem

iacRelativelyhigher

A1C

efficacy

cDurability

c↓Triglycerides

(pioglitazone)

c?↓CVDeven

ts(PROactive,p

ioglitazone)

c↓Risk

ofstroke

andMIin

patientswithoutdiabetes

andwith

insulin

resistance

andhistoryof

recent

stroke

orTIA

(IRISstudy[42],pioglitazone)

c↑Weight

cEdem

a/heartfailure

cBonefractures

c↑LD

L-C(rosiglitazone)

Low

a-Glucosidase

inhibitors

cAcarbose

cMiglitol

Inhibitsintestinal

a-glucosidase

cSlow

sintestinalcarbohydrate

digestion/absorption

cRarehypoglycem

iac↓Po

stprandialglucose

excursions

c?↓CVDeven

tsin

prediabetes

(STO

P-NIDDM)

cNonsystem

ic

cGen

erallymodestA1C

efficacy

cGastrointestinalsideeffects

(flatulence,d

iarrhea)

cFreq

uen

tdosingsched

ule

Lowto

moderate

DPP

-4inhibitors

cSitagliptin

cSaxagliptin

cLinaglip

tin

cAlogliptin

InhibitsDPP-4activity,increasing

postprandialincretin(GLP-1,G

IP)

concentrations

c↑Insulin

secretion

(glucose

dep

enden

t)c↓Glucago

nsecretion

(glucose

dep

enden

t)

cRarehypoglycem

iacWelltolerated

cAngioedem

a/urticariaandother

immune-mediatedderm

atologicaleffects

c?Acute

pancreatitis

c↑Heartfailure

hospitalizations

(saxagliptin;?alogliptin

)

High

Bile

acid

sequestran

tscColesevelam

Bindsbileacidsinintestinaltract,

increasing

hepatic

bileacid

production

c?↓Hep

aticglucose

production

c?↑Incretin

levels

cRarehypoglycem

iac↓LD

L-C

cModestA1C

efficacy

cConstipation

c↑Triglycerides

cMay

↓absorptionofother

med

ications

High

Con

tinu

edon

p.S69

S68 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 40, Supplement 1, January 2017

Table

8.1—Continued

Class

Compound(s)

Cellularmechanism(s)

Prim

aryphysiological

action(s)

Advantages

Disadvantages

Cost*

Dopam

ine-2

agonists

cBromocriptine

(quickrelease)§

Activates

dopam

inergic

receptors

cModulateshypothalam

icregu

lationofmetabolism

c↑Insulin

sensitivity

cRarehypoglycem

iac?↓CVDeven

ts(CyclosetSafety

Trial)

cModestA1C

efficacy

cDizziness/syncope

cNau

sea

cFatigue

cRhinitis

High

SGLT2

inhibitors

cCan

aglifl

ozin

cDap

aglifl

ozin‡

cEm

paglifl

ozin

InhibitsSG

LT2in

the

proximalnep

hron

cBlocksglucose

reab

sorption

bythekidney,increasing

glucosuria

cRarehypoglycem

iac↓Weight

c↓Bloodpressure

cAssociatedwithlower

CVDevent

rate

andmortalityinpatientswith

CVD(empagliflozinEM

PA-REG

OUTCOME)

cGen

itourinaryinfections

cPo

lyuria

cVolum

edepletion/hypotension/dizziness

c↑LDL-C

c↑Creatin

ine(transient)

cDKA

,urinarytractinfections

leading

tourosepsis,pyelonephritis

High

GLP-1

receptor

agonists

cExen

atide

cExen

atideextended

release

cLiraglutide

cAlbiglutide

cLixisenatide

cDulaglutide

Activates

GLP-1

receptors

c↑Insulin

secretion

(glucose

dep

enden

t)c↓Glucago

nsecretion

(glucose

dep

enden

t)cSlowsgastricem

ptying

c↑Satiety

cRarehypoglycem

iac↓Weight

c↓Po

stprandialglucose

excursions

c↓Somecardiovascular

risk

factors

cAssociatedwithlower

CVDevent

rate

andmortalityinpatientswith

CVD(liraglutideLEADER)(30)

cGastrointestinalsideeffects

(nau

sea/vomiting/diarrhea)

c↑Heartrate

c?Acute

pancreatitis

cC-cellh

yperplasia/med

ullary

thyroid

tumors

inanim

als

cInjectab

lecTrainingrequirem

ents

High

Amylinmimetics

cPram

lintide§

Activates

amylin

receptors

c↓Glucago

nsecretion

cSlowsgastricem

ptying

c↑Satiety

c↓Po

stprandialglucose

excursions

c↓Weight

cModestA1C

efficacy

cGastrointestinalsideeffects

(nau

sea/vomiting)

cHypoglycem

iaunless

insulin

dose

issimultan

eouslyreduced

cInjectab

lecFreq

uen

tdosingsched

ule

cTrainingrequirem

ents

High

Insulins

cRapid-actinganalogs

-Lispro

-Aspart

-Glulisine

-Inhaled

insulin

cShort-acting

-Human

Regular

cInterm

ediate-acting

-Human

NPH

Activates

insulin

receptors

c↑Glucose

disposal

c↓Hep

aticglucose

production

cSuppresses

ketogenesis

cNearlyuniversalresponse

cTheo

retically

unlim

ited

efficacy

c↓Microvascularrisk

(UKPD

S)

cHypoglycem

iacWeightgain

cTrainingrequirem

ents

cPatien

tandprovider

reluctan

cecInjectab

le(excep

tinhaled

insulin)

cPu

lmonarytoxicity

(inhaled

insulin)

High#

Con

tinu

edon

p.S70

care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S69

hypoglycemia. Table 8.1 lists drugs com-monly used in the U.S. Cost-effectivenessmodels have suggested that some of thenewer agents may be of relatively lowerclinical utility based on high cost andmoderate glycemic effect (27). Table 8.2provides cost information for currently ap-proved noninsulin therapies. Of note, pri-ces listed are average wholesale prices(AWP) and do not account for discounts,rebates, 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 was utilizedto provide a comparison of list prices withthe primary goal of highlighting the impor-tance of cost considerations when pre-scribing antihyperglycemic treatments. Theongoing Glycemia Reduction Approachesin Diabetes: A Comparative EffectivenessStudy (GRADE) will compare four drugclasses (sulfonylurea, DPP-4 inhibitor,GLP-1 receptor agonist, and basal insulin)when added to metformin therapy over4 years on glycemic control and othermedical, psychosocial, and health eco-nomic outcomes (28).

Rapid-acting secretagogues (megliti-nides) may be used instead of sulfonyl-ureas in patients with sulfa allergies,irregularmeal schedules, or thosewho de-velop late postprandial hypoglycemiawhen taking a sulfonylurea. Other drugsnot shown in Fig. 8.1 (e.g., inhaled insulin,a-glucosidase inhibitors, colesevelam, bro-mocriptine, and pramlintide) may be triedin specific situations but are not often useddue to modest efficacy in type 2 diabetes,the frequency of administration, the po-tential for drug interactions, and/or sideeffects.

Cardiovascular Outcome TrialsSeveral recently published cardiovascularoutcome trials (CVOTs) have provideddata on patients with type 2 diabeteswith cardiovascular disease or at highrisk for cardiovascular disease. The BI10773 (Empagliflozin) CardiovascularOutcome Event Trial in Type 2 DiabetesMellitus Patients (EMPA-REG OUTCOME)was a randomized, double-blind trial thatassessed the effect of empagliflozin, aSGLT2 inhibitor, versus placebo and stan-dard care, on cardiovascular outcomes inpatients with type 2 diabetes and existingcardiovascular disease. Study participantshad a mean age of 63 years, 57% had di-abetes for more than 10 years, and 99%

Table

8.1—Continued

Class

Compound(s)

Cellularmechanism(s)

Prim

aryphysiological

action(s)

Advantages

Disadvantages

Cost*

cBasalinsulin

analogs

-Glargine

-Detem

ir-Degludec

cPrem

ixed

insulin

products

-NPH

/Regular70/30

270/30aspartmix

275/25lispromix

250/50lispromix

CVD,cardiovasculardisease;EM

PA-REG

OUTC

OME,

BI10

773(Empaglifl

ozin)CardiovascularOutcomeEven

tTrialinType2Diabetes

MellitusPatien

ts(29);GIP,glucose-dep

enden

tinsulinotropicpep

tide;

HDL-C,H

DLcholesterol;IRIS,Insulin

Resistance

Interven

tionAfter

Stroke

Trial;LD

L-C,LDLcholesterol;PP

AR-g,peroxisomeproliferator–activatedreceptorg;PROactive,Prospective

PioglitazoneClinicalTrialin

MacrovascularEven

ts(43);STO

P-NIDDM,Studyto

Preven

tNon-Insulin-Dep

enden

tDiabetes

Mellitus(44);TIA,transien

tischem

icattack;TZD

,thiazolidined

ione;UKP

DS,UKProspective

Diabetes

Study(45,46

).Cyclosettrialofq

uick-releasebromocriptine(47).*Costisbased

onlowest-pricedmem

ber

oftheclass(21).‡lnitialconcernsregardingbladder

cancerrisk

aredecreasingaftersubsequen

tstudy.§N

otlicen

sedin

Europefortype2diabetes.#C

ostishighlydep

enden

tontype/brand(analogs

.human

insulins)anddosage.Adap

tedwithpermissionfrom

Inzucchietal.(21).

S70 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 40, Supplement 1, January 2017

had established cardiovascular disease.EMPA-REG OUTCOME showed that over amedian follow-up of 3.1 years, treatmentreduced the composite outcome of MI,stroke, and cardiovascular death by 14%(absolute rate 10.5% vs. 12.1% in the pla-cebo group) and cardiovascular death by38% (absolute rate 3.7%vs. 5.9%) (29). TheFDA recently added a new indication forempagliflozin, to reduce the risk of cardio-vascular death in adults with type 2 diabe-tes and cardiovascular disease. Whetherother SGLT2 inhibitors will have the sameeffect in high-risk patients and whetherempagliflozin or other SGLT2 inhibitorswill have a similar effect in lower-risk pa-tients with diabetes remains unknown.The Liraglutide Effect and Action in Di-

abetes: Evaluation of Cardiovascular Out-come Results: A Long Term Evaluation

(LEADER) trial was a randomized double-blind trial that assessed the effect ofliraglutide, a GLP-1 receptor agonist, ver-sus placebo and standard care, on cardio-vascular outcomes in patients with type 2diabetes at high risk for cardiovascular dis-ease or with cardiovascular disease. Studyparticipants had a mean age of 64 yearsand amean duration of diabetes of nearly13 years. Over 80% of study participantshad established cardiovascular diseaseinclusive of a prior myocardial infarction(MI), prior stroke or transient ischemicattack, prior revascularization procedure,or $50% stenosis of coronary, carotid,or lower-extremity arteries. LEADERshowed that the composite primary out-come (MI, stroke, or cardiovascular death)occurred in fewer participants in the treat-ment group (13.0%) when compared with

the placebo group (14.9%) after a medianfollow-up of 3.8 years (30). Whether otherGLP-1 receptor agonists will have the sameeffect inhigh-riskpatientsor if thisdrugclasswill havesimilareffects in lower-riskpatientswith diabetes remains unknown.

CVOT data for the DPP-4 inhibitorssitagliptin (31), saxagliptin (32), andalogliptin (33) have also been reported,with no significant difference in rates ofmajor cardiovasculareventsnotedbetweentreatment and placebo groups in any ofthese trials.

Insulin TherapyMany patients with type 2 diabetes even-tually require and benefit from insulintherapy. The progressive nature of type2 diabetes should be regularly and objec-tively explained to patients. Providers

Table 8.2—Median monthly cost of maximum approved daily dose of noninsulin glucose-lowering agents in the U.S. (48)

Class Compound(s)Dosage strength/product

(if applicable)Median AWP(min, max)†

Maximum approveddaily dose*

Biguanides c Metformin 500 mg (IR) $84 ($5, $94) 2,000 mg

850 mg (IR) $108 ($5, $108) 2,550 mg

1,000 mg (IR) $86 ($4, $87) 2,000 mg

500 mg (ER) $90 ($82, $6,672) 2,000 mg

750 mg (ER) $72 ($65, $92) 1,500 mg

1,000 mg (ER) $1,028 ($1,010, $7,213) 2,000 mg

Sulfonylureas (2nd Gen) c Glyburide 5 mg $94 ($64, $103) 20 mg6 mg (micronized) $50 ($48, $71) 12 mg (micronized)

c Glipizide 10 mg (IR) $74 ($67, $97) 40 mg (IR)10 mg (XL) $97 20 mg (XL)

c Glimepiride 4 mg $74 ($71, $198) 8 mg

Meglitinides (glinides) c Repaglinide 2 mg $799 ($163, $878) 16 mgc Nateglinide 120 mg $156 360 mg

TZDs c Pioglitazone 45 mg $349 ($348, $349) 45 mgc Rosiglitazone 4 mg $355 8 mg

a-Glucosidase inhibitors c Acarbose 100 mg $104 ($104, 105) 300 mgc Miglitol 100 mg $241 300 mg

DPP-4 inhibitors c Sitagliptin 100 mg $436 100 mgc Saxagliptin 5 mg $436 5 mgc Linagliptin 5 mg $428 5 mgc Alogliptin 25 mg $436 25 mg

Bile acid sequestrant c Colesevelam 625 mg tabs $679 3.75 g1.875 g suspension $1,357 3.75 g

Dopamine-2 agonists c Bromocriptine 0.8 mg $719 4.8 mg

SGLT2 inhibitors c Canagliflozin 300 mg $470 300 mgc Dapagliflozin 10 mg $470 10 mgc Empagliflozin 25 mg $470 25 mg

GLP-1 receptor agonists c Exenatide 10 mg pen $729 20 mgc Exenatide(extended-release)

2 mg powder for suspension or pen $692 2 mg**

c Liraglutide 18 mg/3 mL pen $831 1.8 mgc Albiglutide 50 mg pen $527 50 mg**c Dulaglutide 1.5/0.5 mL pen $690 1.5 mg**

Amylin mimetics c Pramlintide 120 mg pen $2,124 120 mg/injection††

ER and XL, extended release; IR, immediate release; TZD, thiazolidinedione. †Calculated for 30 day supply (AWP unit price3 number of doses required toprovidemaximum approved daily dose3 30 days); median AWP listed alonewhen only one product and/or price. *Utilized to calculatemedian AWP(min, max); generic prices used, if available commercially. **Administered once weekly. ††AWP calculated based on 120 mg three times daily.

care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S71

should avoid using insulin as a threat ordescribing it as a sign of personal failureor punishment.Equipping patients with an algorithm for

self-titration of insulin doses based on self-monitoring of blood glucose (SMBG) im-proves glycemic control in patients withtype 2 diabetes initiating insulin (34). Com-prehensive education regarding SMBG,diet, and the avoidance of and appropriatetreatment of hypoglycemia are criticallyimportant in any patient using insulin.

Basal Insulin

Basal insulin alone is the most convenientinitial insulin regimen, beginning at 10 unitsper day or 0.1–0.2 units/kg/day, dependingon the degree of hyperglycemia. Basal in-sulin is usually prescribed in conjunctionwith metformin and sometimes one addi-tional noninsulin agent. While there is evi-dence for reduced risk of hypoglycemiawith newer, longer-acting basal insulinanalogs, people with type 2 diabetes

without a history of hypoglycemia mayuse NPH insulin safely and at much lowercost (27,35). Table 8.3 provides averagewholesale price information (cost per1,000 units) for currently available insulinproducts in the U.S. There have been sub-stantial increases in the price of insulin overthe past decade and the cost-effectivenessof different antihyperglycemic agents is animportant consideration when selectingtherapies (36). A follow-on U-100 (100units/mL) glargine product (basaglar) isnow available in the U.S. This product wasapproved through an abbreviated FDA ap-proval pathway based, in part, on the FDA’sfinding of safety and effectiveness for thereference U-100 glargine product.

Bolus Insulin

Many individuals with type 2 diabetesmayrequire mealtime bolus insulin dosing inaddition to basal insulin. Rapid-actinganalogs are preferred due to theirprompt onset of action after dosing. The

recommended starting dose of mealtimeinsulin is 4 units, 0.1 U/kg, or 10% of thebasal dose. If A1C is ,8% (64 mmol/mol)when starting mealtime bolus insulin, con-sideration should be given to decreasingthe 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 of70% NPH insulin and 30% regular insulin.The use of premixed insulin products hasits advantages and disadvantages, asdiscussed below 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

Table 8.3—Median cost of insulins in the U.S. calculated as average wholesale price per 1,000 units of specified dosageform/product (48)

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

Rapid-acting analogs

c Lispro U-100 vial $306U-100 3 mL cartridges $306 ($306, $379)U-100 prefilled pen; U-200 prefilled pen $394

c Aspart U-100 vial $306U-100 3 mL cartridges $380U-100 prefilled pen $395

c Glulisine U-100 vial $283U-100 prefilled pen $365

c Inhaled insulin Inhalation cartridges $557 ($453, $754)

Short-acting

c Human Regular U-100 vial $165

Intermediate-acting

c Human NPH U-100 vial $165U-100 prefilled pen $350

Concentrated Human Regular insulin

c U-500 Human Regular insulin U-500 vial $165U-500 prefilled pen $213

Basal analogs

c Glargine U-100 vial; U-100 prefilled pen; U-300 prefilled pen $298

c Detemir U-100 vial; U-100 prefilled pen $323

c Degludec U-100 prefilled pen; U-200 prefilled pen $355

Premixed products

c NPH/Regular 70/30 U-100 vial $165U-100 prefilled pen $350

c Lispro 50/50 U-100 vial $317U-100 prefilled pen $394

c Lispro 75/25 U-100 vial $317U-100 prefilled pen $394

c Aspart 70/30 U-100 vial $318U-100 prefilled pen $395

AWP listed alone when only one product and/or price.

S72 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 40, Supplement 1, January 2017

action thanU-100 regular, posessing bothprandial and basal properties. U-300glargine and U-200 degludec are threeand two times as concentrated as theirU-100 formulations, have longer dura-tions of action, and allow higher dosesof basal insulin administration per volumeused. The FDA has also approved a concen-trated formulation of rapid-acting insulinlispro, U-200 (200 units/mL). These concen-trated preparations may be more comfort-able for the patient and may improveadherence for patients with insulin resis-tance who require large doses of insulin.While U-500 regular insulin is available inboth prefilled pens and vials (a dedicatedsyringe was FDA approved in July 2016),other concentrated insulins are availableonly in prefilled pens to minimize the riskof dosing errors.

Inhaled Insulin

Inhaled insulin is available for prandialuse with a more limited dosing range.It is contraindicated in patients withchronic lung disease such as asthmaand chronic obstructive pulmonarydisease and is not recommended inpatients who smoke or who recentlystopped smoking. It requires spirometry(FEV1) testing to identify potential lungdisease in all patients prior to and afterstarting therapy.

Combination Injectable TherapyIf basal insulin has been titrated to anacceptable fasting blood glucose level(or if the dose is .0.5 units/kg/day)and A1C remains above target, consideradvancing to combination injectabletherapy (Fig. 8.2). When initiating com-bination injectable therapy, metformintherapy should be maintained whileother oral agents may be discontinuedon an individual basis to avoid unneces-sarily complex or costly regimens (i.e.,adding a fourth antihyperglycemicagent). In general, GLP-1 receptor ago-nists should not be discontinued with theinitiation of basal insulin. Sulfonylureas,DPP-4 inhibitors, and GLP-1 receptor ago-nists are typically stopped oncemore com-plex insulin regimens beyond basal areused. In patients with suboptimal bloodglucose control, especially those requiringlarge insulin doses, adjunctive use of a thia-zolidinedione or SGLT2 inhibitor may helpto improve control and reduce the amountof insulin needed, though potential sideeffects should be considered. Once an in-sulin regimen is initiated, dose titration is

important with adjustments made in bothmealtime and basal insulins based on theblood glucose levels and an understandingof the pharmacodynamic profile of eachformulation (pattern control).

Studies have demonstrated the non-inferiority of basal insulin plus a singleinjection of rapid-acting insulin at thelargest meal relative to basal insulinplus a GLP-1 receptor agonist relativeto two daily injections of premixed insulins(Fig. 8.2). Basal insulin plus GLP-1 receptoragonists are associated with less hypogly-cemia and with weight loss instead ofweight gain but may be less tolerableand have a greater cost (37,38). In No-vember 2016, the FDA approved twodifferent once-daily combination productscontaining basal insulin plus a GLP-1 recep-tor agonist: insulin glargine plus lixisenatideand insulin degludec plus liraglutide. Otheroptions for treatment intensification includeadding a single injection of rapid-acting in-sulin analog (lispro, aspart, or glulisine) be-fore the largest meal or stopping the basalinsulin and initiating a premixed (or bi-phasic) insulin (NPH/Regular 70/30, 70/30aspartmix, 75/25 or 50/50 lispromix) twicedaily, usually before breakfast and beforedinner. Each approach has its advantagesand disadvantages. For example, providersmay wish to consider regimen flexibilitywhen devising a plan for the initiation andadjustment of insulin therapy in peoplewith type 2 diabetes, with rapid-acting in-sulin offering greater flexibility in termsof meal planning than premixed insulin. Ifone regimen is not effective (i.e., basal in-sulin 1 GLP-1 receptor agonist), considerswitching to another regimen to achieveA1C targets (i.e., basal insulin1 single in-jection of rapid-acting insulin or premixedinsulin twice daily) (39,40). Regular humaninsulin and human NPH/Regular premixedformulations (70/30) are less costly alter-natives to rapid-acting insulin analogs andpremixed insulin analogs, respectively,but their pharmacodynamic profiles maymake them less optimal.

Figure 8.2 outlines these options, aswell as recommendations for further in-tensification, if needed, to achieve gly-cemic goals. If a patient is still above theA1C target on premixed insulin twicedaily, consider switching to premixedanalog insulin three times daily (70/30aspartmix, 75/25 or 50/50 lispromix). Ingeneral, three times daily premixed an-alog insulins have been found to be non-inferior to basal-bolus regimens with

similar rates of hypoglycemia (41). If apatient is still above the A1C target onbasal insulin1 single injection of rapid-acting insulin before the largest meal, ad-vance to a basal-bolus regimen with $2injections of rapid-acting insulin beforemeals. Consider switching patients fromone regimen to another (i.e., premixedanalog insulin three times daily to basal-bolus regimen or vice-versa) if A1C targetsare not being met and/or depending onother patient considerations (39,40).

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