9. Pharmacologic Approaches toGlycemic Treatment: Standards ofMedical Care in Diabetesd2020Diabetes Care 2020;43(Suppl. 1):S98–S110 | https://doi.org/10.2337/dc20-S009

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”includes the ADA’s current clinical practice recommendations and is intended toprovide the components of diabetes care, general treatment goals and guidelines, andtools toevaluatequalityof care.Membersof theADAProfessional PracticeCommittee, amultidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsiblefor updating the Standards of Care annually, or more frequently as warranted. For adetailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standardsof Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to com-ment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

PHARMACOLOGIC THERAPY FOR TYPE 1 DIABETES

Recommendations

9.1 Mostpeoplewith type1diabetesshouldbetreatedwithmultipledaily injectionsof prandial and basal insulin, or continuous subcutaneous insulin infusion. A

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

9.3 Patients with type 1 diabetes should be trained to match prandial insulin dosesto carbohydrate intake, premeal blood glucose, and anticipated physical activity. C

Insulin TherapyBecause the hallmark of type 1 diabetes is absent or near-absent b-cell function,insulin treatment is essential for individuals with type 1 diabetes. In addition tohyperglycemia, insulinopenia can contribute to other metabolic disturbances likehypertriglyceridemia and ketoacidosis as well as tissue catabolism that can belife threatening. Severe metabolic decompensation can be, and was, mostly pre-vented with once or twice daily injections for the six or seven decades after thediscovery of insulin. However, over the past three decades, evidence has accumulatedsupporting more intensive insulin replacement, using multiple daily injections ofinsulin or continuous subcutaneous administration through an insulin pump, asproviding the best combination of effectiveness and safety for people with type 1diabetes. The Diabetes Control and Complications Trial (DCCT) demonstrated thatintensive therapy with multiple daily injections or continuous subcutaneous insulininfusion (CSII) reduced A1C and was associated with improved long-term outcomes(1–3). The study was carried out with short-acting (regular) and intermediate-acting(NPH) human insulins. In this landmark trial, lower A1C with intensive control (7%)led to ;50% reductions in microvascular complications over 6 years of treatment.

Suggested citation: American Diabetes Associa-tion. 2. Pharmacologic approaches to glycemictreatment:StandardsofMedicalCare inDiabetesd2020. Diabetes Care 2020;43(Suppl. 1):S98–S110

© 2019 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

S98 Diabetes Care Volume 43, Supplement 1, January 2020

9.PHARMACOLO

GIC

APPROACHES

TOGLYCEM

ICTR

EATM

ENT

This article includes updates in the form of annotations as of June 2020. See page S101.

However, intensive therapy was associ-ated with a higher rate of severe hypo-glycemia thanconventional treatment (62compared with 19 episodes per 100 pa-tient-years of therapy). Follow-up of sub-jects from the DCCT more than 10 yearsafter the active treatment component ofthe study demonstrated less macrovas-cular as well as less microvascular com-plications in the group that receivedintensive treatment.Over the last 25 years, rapid-acting and

long-acting insulin analogs have beendeveloped that have distinct pharmaco-kinetics compared with recombinant hu-man insulins: basal insulin analogs havelonger duration of action with flatter,more constant plasma concentrationsand activity profiles than NPH insulin;rapid-acting analogs (RAA)have aquickeronset and peak and shorter duration ofaction than regular human insulin. Inpeople with type 1 diabetes, treatmentwith analog insulins is associatedwith lesshypoglycemia and weight gain as well aslower A1C compared with human insu-lins (4–6).More recently, twonew insulinformulations with enhanced rapid actionprofiles have been introduced. Inhaledhuman insulin has a rapid peak andshortened duration of action comparedwith RAA and may cause less hypogly-cemia and weight gain (7), and faster-acting insulin aspartmay reduce prandialexcursions better than RAA (8); furtherinvestigation isneededtoestablishaclearplace for these agents in diabetes man-agement. In addition, new longer-actingbasal analogs (U-300 glargine or degludec)may confer a lower hypoglycemia riskcompared with U-100 glargine in patientswith type 1 diabetes (9,10). Despite theadvantages of insulin analogs in patientswith type1diabetes, for somepatients theexpense and/or intensity of treatmentrequired for their use is prohibitive. Thereare multiple approaches to insulin treat-ment, and the central precept in themanagement of type 1 diabetes isthat some form of insulin be given ina planned regimen tailored to the in-dividual patient to keep them safe, out ofdiabetic ketoacidosis, and avoid signifi-cant hypoglycemia, with every effortmade to reach the patient’s glycemictargets.Most studies comparing multiple daily

injections with CSII have been rela-tively small and of short duration. How-ever, a recent systematic review and

meta-analysis concluded thatpump ther-apy has modest advantages for loweringA1C (–0.30% [95%CI –0.58 to –0.02]) andfor reducing severe hypoglycemia ratesin children and adults (11). However, thereis no consensus to guide the choice ofinjection or pump therapy in a givenpatient, and research to guide thisdecision-making is needed (12). The arrivalof continuous glucose monitors to clinicalpractice has proven beneficial in specificcircumstances. Reduction of nocturnalhypoglycemia in people with type 1 di-abetes using insulin pumps with glucosesensors is improved by automatic sus-pension of insulin delivery at a presetglucose level (12–14). The U.S. Food andDrug Administration (FDA) has also ap-proved the first hybrid closed-loop pumpsystem. The safety and efficacy of hybridclosed-loop systems has been supportedin the literature in adolescents and adultswith type 1 diabetes (15,16), and recentevidence suggests that a closed-loopsystem is superior to sensor-augmentedpump therapy for glycemic controland reduction of hypoglycemia over 3months of comparison in children andadults with type 1 diabetes (17). IntensiveinsulinmanagementusingaversionofCSIIand continuous glucosemonitoring shouldbe considered in most patients. See Sec-tion 7 “Diabetes Technology” (https://doi.org/10.2337/dc20-S007) for a full discus-sion of insulin delivery devices.

In general, patients with type 1 di-abetes require 50% of their daily insulinas basal and 50% as prandial. Total dailyinsulin requirements can be estimatedbased on weight, with typical dosesranging from 0.4 to 1.0 units/kg/day.Higher amounts are required during pu-berty, pregnancy, and medical illness.The American Diabetes Association/JDRF Type 1 Diabetes Sourcebook notes0.5 units/kg/day as a typical starting dosein patients with type 1 diabetes who aremetabolically stable, with half adminis-tered as prandial insulin given to controlblood glucose after meals and the otherhalf as basal insulin to control glycemiain the periods between meal absorption(18); this guideline provides detailed in-formation on intensification of therapyto meet individualized needs. In addi-tion, the American Diabetes Associationposition statement “Type 1 DiabetesManagement Through the Life Span”provides a thorough overview of type 1diabetes treatment (19).

Typical multidose regimens for pa-tients with type 1 diabetes combinepremeal use of shorter-acting insulinswith a longer-acting formulation, usuallyat night. The long-acting basal dose istitrated to regulate overnight, fastingglucose. Postprandial glucose excur-sions are best controlled by a well-timedinjection of prandial insulin. The opti-mal time to administer prandial insulinvaries, based on the pharmacokineticsof the formulation (regular, RAA, in-haled), the premeal blood glucose level,and carbohydrate consumption. Recom-mendations for prandial insulin doseadministration should therefore be indi-vidualized. Physiologic insulin secretionvaries with glycemia, meal size, and tissuedemands for glucose. To approach thisvariability in people using insulin treat-ment, strategies have evolved to adjustprandial dosesbasedonpredictedneeds.Thus, education of patients on how toadjust prandial insulin to account forcarbohydrate intake, premeal glucoselevels, and anticipated activity can beeffective and should be offered to mostpatients (20,21). For individuals in whomcarbohydrate counting is effective, esti-mates of the fat and protein content ofmeals can be incorporated into theirprandial dosing for added benefit (22).

Insulin Injection Technique

Ensuring that patients and/or caregiversunderstand correct insulin injection tech-nique is important to optimize glucosecontrol and insulin use safety. Thus, it isimportant that insulin be delivered intothe proper tissue in the right way. Rec-ommendations have been published else-where outlining best practices for insulininjection (23). Proper insulin injection tech-nique includes injecting into appropriatebody areas, injection site rotation, ap-propriate care of injection sites to avoidinfection or other complications, and avoid-ance of intramuscular (IM) insulin delivery.

Exogenous-delivered insulin should beinjected into subcutaneous tissue, notintramuscularly. Recommended sites forinsulin injection include the abdomen,thigh, buttock, and upper arm. Becauseinsulin absorption from IM sites differsaccording to the activity of the muscle,inadvertent IM injection can lead to un-predictable insulin absorption and vari-able effects on glucose, with IM injectionbeing associated with frequent and unex-plained hypoglycemia in several reports.

care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S99

Risk for IM insulin delivery is increased inyounger, leaner patients when injectinginto the limbs rather than truncal sites(abdomen and buttocks) and when usinglonger needles. Recent evidence supportsthe use of short needles (e.g., 4-mm penneedles) as effective and well toleratedwhen compared with longer needles,including a study performed in obeseadults (24).Injection site rotation is additionally

necessary to avoid lipohypertrophy, anaccumulation of subcutaneous fat in re-sponse to theadipogenicactionsof insulinat a site of multiple injections. Lipohyper-trophy appears as soft, smooth raisedareas several centimeters in breadthand can contribute to erratic insulin ab-sorption, increased glycemic variability,and unexplained hypoglycemic episodes.Patients and/or caregivers should receiveeducation about proper injection site ro-tation and to recognize and avoid areasof lipohypertrophy. As noted in Table 4.1,examination of insulin injection sites forthe presence of lipohypertrophy, as wellas assessment of injection device useand injection technique, are key compo-nents of a comprehensive diabetes med-ical evaluation and treatment plan. Asreferenced above, there are now numer-ous evidence-based insulin delivery rec-ommendations that havebeenpublished.Proper insulin injection technique maylead to more effective use of this therapyand, as such, holds the potential for im-proved clinical outcomes.

Noninsulin Treatments for Type 1DiabetesInjectable and oral glucose-loweringdrugs have been studied for their efficacyas adjuncts to insulin treatment of type 1diabetes. Pramlintide is based on thenaturally occurring b-cell peptide amylinand is approved for use in adults withtype 1 diabetes. Results from random-ized controlled studies show variablereductions of A1C (0–0.3%) and bodyweight (1–2 kg) with addition of pram-lintide to insulin (25,26). Similarly, re-sults have been reported for severalagents currently approved only forthe treatment of type 2 diabetes. Theaddition of metformin to adults withtype 1 diabetes caused small reductionsin body weight and lipid levels but didnot improve A1C (27,28). The additionof the glucagon-like peptide 1 (GLP-1)receptor agonists (RAs) liraglutide and

exenatide to insulin therapy causedsmall (0.2%) reductions in A1C comparedwith insulin alone in people with type 1diabetes and also reduced body weightby ;3 kg (29). Similarly, the additionof a sodium–glucose cotransporter 2(SGLT2) inhibitor to insulin therapy hasbeen associated with improvements inA1C and body weight when comparedwith insulin alone (30,31); however, SGLT2inhibitor use in type 1 diabetes is associ-ated with a two- to fourfold increasein ketoacidosis. The risks and benefitsof adjunctive agents continue to be eval-uated, but only pramlintide is approvedfor treatment of type 1 diabetes.

SURGICAL TREATMENT FOR TYPE 1DIABETES

Pancreas and Islet TransplantationSuccessful pancreas and islet transplan-tation can normalize glucose levels andmitigate microvascular complications oftype 1 diabetes. However, patients re-ceiving these treatments require life-long immunosuppression to preventgraft rejection and/or recurrence ofautoimmune islet destruction. Given thepotential adverse effects of immunosup-pressive therapy, pancreas transplan-tation should be reserved for patientswith type 1 diabetes undergoing si-multaneous renal transplantation, fol-lowing renal transplantation, or for thosewith recurrent ketoacidosis or severehypoglycemia despite intensive glycemicmanagement (32). With the advent ofimproved continuous glucose monitors,closed-loop pump-sensor systems, anddevices that offer alternative approachesfor patients with hypoglycemia unaware-ness, the role of pancreas transplantationalone, as well as islet transplant, will needto be reconsidered.

PHARMACOLOGIC THERAPY FORTYPE 2 DIABETES

Recommendations

9.4 Metformin is the preferred ini-tial pharmacologic agent forthe treatment of type 2 diabetes.A

9.5 Once initiated, metformin shouldbe continued as long as it is tol-erated and not contraindicated;other agents, including insulin,should be added to metformin. A

9.6 Early combination therapy canbe considered in some patients

at treatment initiation to extendthe time to treatment failure. A

9.7 The early introduction of insulinshould be considered if there isevidence of ongoing catabolism(weight loss), if symptoms ofhyperglycemia are present, orwhen A1C levels (.10% [86mmol/mol]) or blood glucose lev-els ($300 mg/dL [16.7 mmol/L])are very high. E

9.8 A patient-centered approachshould be used to guide thechoice of pharmacologic agents.Considerations include cardiovas-cular comorbidities, hypoglycemiarisk, impactonweight,cost, riskforside effects, and patient preferen-ces (Table 9.2 and Figure 9.1). E

9.9 Among patients with type 2 di-abetes who have establishedatherosclerotic cardiovasculardisease or indicators of high risk,establishedkidneydisease, orheartfailure, a sodium–glucose cotrans-porter 2 inhibitor or glucagon-likepeptide 1 receptor agonist withdemonstrated cardiovascular dis-ease benefit (Table 9.1, Table 10.3B,Table10.3C) isrecommendedas part of the glucose-loweringregimen independent of A1C andinconsiderationofpatient-specificfactors (Figure 9.1). A

9.10 In patients with type 2 diabeteswho need greater glucose low-ering than can be obtained withoral agents, glucagon-like pep-tide 1 receptor agonists are pre-ferredto insulinwhenpossible.B

9.11 Intensification of treatment forpatients with type 2 diabetesnot meeting treatment goalsshould not be delayed. B

9.12 The medication regimen andmedication-taking behaviorshould be reevaluated at regularintervals (every 3–6months) andadjusted as needed to incorpo-rate specific factors that impactchoice of treatment (Fig. 4.1 andTable 9.1). E

The American Diabetes Association/European Association for the Study ofDiabetes consensus report “Manage-ment of Hyperglycemia in Type 2 Di-abetes, 2018” and the 2019 update(33,34) recommend a patient-centered

S100 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020

Table

9.1—

Dru

g-specificandpatientfactors

toco

nsiderwhense

lectingantihyperg

lyce

mic

treatm

entin

adultswithtype2diabetes

*Foragen

t-specificdosingrecommen

dations,pleasereferto

themanufacturers’prescribinginform

ation.†FD

AapprovedforCVDben

efit.‡FD

A-approvedforheartfailure

indication;§FDA-approvedforCKD

indication.C

V,cardiovascular;DPP

-4,dipep

tidylpep

tidase4;DKA

,diabeticketoacidosis;DKD

,diabetickidney

disease;G

LP-1

RAs,glucagon-likepep

tide1receptoragonists;H

F,heartfailure;N

ASH

,nonalcoholic

steatohep

atitis;SG

LT2,

sodium–glucose

cotransporter

2;SQ

,subcutaneo

us;T2DM,type2diabetes.

care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S101

approach to choosing appropriate phar-macologic treatment of blood glucose(Fig. 9.1). This includes consideration ofefficacy and key patient factors: 1) im-portant comorbidities such as atheroscle-rotic cardiovascular disease (ASCVD) andindicators of high ASCVD risk, chronickidney disease (CKD), and heart failure(HF) (see Section 10 “Cardiovascular Dis-ease and Risk Management,” https://doi.org/10.2337/dc20-S010, and Section 11“Microvascular Complications and FootCare,” https://doi.org/10.2337/dc20-S011),2) hypoglycemia risk, 3) effects on bodyweight, 4) side effects, 5) cost, and 6)patient preferences. Lifestyle modifica-tions that improve health (see Section5 “Facilitating Behavior Change andWell-being to Improve Health Outcomes,”https://doi.org/10.2337/dc20-S005) shouldbe emphasized along with any pharma-cologic therapy. Section 12 “Older Adults”(https://doi.org/10.2337/dc20-S012)andSec-tion 13 “Children and Adolescents”(https://doi.org/10.2337/dc20-S013)have recommendations specific for olderadults and for children and adolescentswith type 2 diabetes, respectively; Sec-tion 10 “Cardiovascular Disease and RiskManagement” (https://doi.org/10.2337/dc20-S010) and Section 11 “MicrovascularComplications and Foot Care” (https://doi.org/10.2337/dc20-S011)haverecommen-dations for the use of glucose-loweringdrugs in themanagementofcardiovascularand renal disease, respectively.

Initial TherapyMetformin should be started at the timetype 2 diabetes is diagnosed unless thereare contraindications; for many patientsthis will be monotherapy in combinationwith lifestyle modifications. Metforminis effective and safe, is inexpensive, andmay reduce risk of cardiovascular eventsand death (35). Metformin is available inan immediate-release form for twice-daily dosing or as an extended-releaseform that can be given once daily. Com-pared with sulfonylureas, metformin asfirst-line therapy hasbeneficial effects onA1C, weight, and cardiovascular mortal-ity (36); there is little systematic dataavailable for other oral agents as initialtherapy of type 2 diabetes. The principalside effects of metformin are gastroin-testinal intolerance due to bloating, ab-dominal discomfort, and diarrhea; thesecanbemitigatedbygradualdose titration.The drug is cleared by renal filtration, and

very high circulating levels (e.g., as a re-sult of overdose or acute renal failure)have been associated with lactic acidosis.However, the occurrence of this compli-cation is now known to be very rare, andmetformin may be safely used in patientswith reduced estimated glomerular filtra-tion rates (eGFR); the FDA has revised thelabel for metformin to reflect its safety inpatients with eGFR $30 mL/min/1.73 m2

(37). A recent randomized trial confirmedpreviousobservations thatmetforminuseis associated with vitamin B12 deficiencyand worsening of symptoms of neurop-athy (38). This is compatible with a recentreport from the Diabetes Prevention Pro-gramOutcomesStudy (DPPOS) suggestingperiodic testing of vitamin B12 (39).

In patients with contraindications orintolerance to metformin, initial therapyshould be based on patient factors;consider a drug from another class de-picted in Fig. 9.1. When A1C is $1.5%(12.5 mmol/mol) above the glycemictarget (see Section 6 “Glycemic Targets,”https://doi.org/10.2337/dc20-S006, forselecting appropriate targets), many pa-tients will require dual combination ther-apy to achieve their target A1C level (40).Insulin has the advantage of being effec-tive where other agents are not and shouldbe considered as part of any combinationregimen when hyperglycemia is severe,especially if catabolic features (weightloss, hypertriglyceridemia, ketosis) arepresent. It is common practice to initiateinsulin therapy for patients who presentwith blood glucose levels $300 mg/dL(16.7 mmol/L) or A1C.10% (86 mmol/mol)or if the patient has symptoms of hy-perglycemia (i.e., polyuria or polydipsia)or evidence of catabolism (weight loss)(Fig. 9.2). As glucose toxicity resolves,simplifying the regimen and/or changingto oral agents is often possible. However,there is evidence that patients with un-controlled hyperglycemia associated withtype 2 diabetes can also be effectivelytreated with a sulfonylurea (41).

Combination TherapyBecause type 2 diabetes is a progressivedisease inmanypatients,maintenanceofglycemic targets with monotherapy isoften possible for only a few years, afterwhich combination therapy is necessary.Current recommendations have been touse stepwise addition of medicationsto metformin to maintain A1C at target.This allows a clearer assessment of the

positive andnegative effects of newdrugsand reducespatient risk andexpense (42);based on these factors, sequential addi-tion of oral agents tometformin has beenthe standard of care. However, there isdata to support initial combination ther-apyformore rapidattainment of glycemicgoals (43,44), and a recent clinical trialhas demonstrated that this approach issuperior to sequential addition of medica-tions forextendingprimaryandsecondaryfailure (45). In the VERIFY trial, partic-ipants receiving the initial combination ofmetformin and thedipeptidyl peptidase 4(DPP-4) inhibitor vildagliptin had a slowerdecline of glycemic control comparedwith metformin alone and to vildagliptinadded sequentially to metformin. Theseresults have not been generalized to oralagents other than vildagliptin, but theysuggest that more intensive early treat-ment has some benefits and should beconsidered through a shared decision-makingprocesswithpatients, as appropriate.Moreover, since theabsoluteeffectivenessof most oral medications rarely exceeds1%, initial combination therapy should beconsidered in patients presenting withA1C levels 1.5–2.0% above target.

The choice of medication added tometformin is based on the clinical char-acteristics of the patient and their pref-erences. Important clinical characteristicsinclude the presence of establishedASCVD or indicators of high ASCVD risk,other comorbidities, and risk for specificadverse drug effects, as well as safety,tolerability, and cost. Although there arenumerous trials comparing dual therapywith metformin alone, there is little ev-idence to support one combination overanother. A comparative effectivenessmeta-analysis suggests that each newclass of noninsulin agents added to initialtherapy with metformin generally lowersA1C approximately 0.7–1.0% (46,47). If theA1C target is not achieved after approxi-mately 3 months, metformin can be com-bined with any one of the preferred sixtreatment options: sulfonylurea, thiazolidine-dione,DPP-4 inhibitor, SGLT2 inhibitor,GLP-1RA,orbasal insulin; thechoiceofwhichagentto add is based on drug-specific effects andpatient factors (Fig. 9.1 and Table 9.1).

ForpatientswithestablishedASCVDorindicators of high ASCVD risk (such aspatients$55 years of age with coronary,carotid, or lower-extremity artery steno-sis .50% or left ventricular hypertro-phy), established kidney disease, or heart

S102 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020

Figure

9.1—

Glucose-loweringmed

icationintype

2diabetes:overallapproach.Forappropriatecontext,see

Fig.4.1.ASCVD,atheroscleroticcardiovasculardisease;CKD

,chronickidney

disease;CV,cardiovascular;

CVD,cardiovasculardisease;C

VOTs,cardiovascularoutcomes

trials;D

PP-4i,dipep

tidylpeptidase4inhibitor;eG

FR,estim

ated

glomerularfiltrationrate;G

LP-1

RA,glucago

n-likepep

tide1receptoragonist;HF,

heart

failure;SG

LT2i,sodium–glucose

cotran

sporter

2inhibitor;SU

,sulfonylurea;

TZD,thiazolid

ined

ione.

Adap

tedfrom

Daviesan

dcolleagues

(33,34

).

care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S103

Figure9.2—Intensifying to injectable therapies.DSMES,diabetes self-managementeducationandsupport; FPG, fastingplasmaglucose;FRC,fixed-ratiocombination; GLP-1 RA, glucagon-like peptide 1 receptor agonist; max, maximum; PPG, postprandial glucose. Adapted from Davies et al. (33).

S104 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020

failure, anSGLT-2 inhibitororGLP-1RAwithdemonstrated CVD benefit (Table 9.1,Table 10.3B, Table 10.3C) is recommendedas part of the glucose-lowering regimenindependentofA1Candinconsiderationofpatient-specific factors (Figure 9.1). Forpatients without established ASCVD, indi-cators of high ASCVD risk, HF, or CKD, thechoice of a second agent to add to met-formin is not yet guided by empiric evi-dence. Rather, drug choice is based onavoidance of side effects, particularly hy-poglycemia and weight gain, cost, andpatient preferences (48). Similar consider-ationsareapplied inpatientswhorequire athirdagent toachieveglycemicgoals; thereis very little trial-based evidence to guidethischoice. Inall cases, treatment regimensneed to be continuously reviewed forefficacy, side effects, and patient burden(Table 9.1). In some instances, patientswillrequiremedication reduction or discontin-uation. Common reasons for this includeineffectiveness, intolerable side effects, ex-pense, or a change in glycemic goals (e.g., inresponse to development of comorbiditiesor changes in treatment goals). Section12 “Older Adults”(https://doi.org/10.2337/dc20-S012) has a full discussion of treat-ment considerations in older adults, asettingwhere changes of glycemic goalsand de-escalation of therapy is common.Although most patients prefer oral

medications to drugs that need to beinjected, the eventual need for thegreater potency of injectable medica-tions is common, particularly in peoplewith a longer duration of diabetes. Theaddition of basal insulin, either humanNPH or one of the long-acting insulinanalogs, to oral agent regimens is a well-established approach that is effective formany patients. In addition, recent evi-dence supports the utility of GLP-1 RAs inpatients not reaching glycemic targetswith use of non-GLP-1 RA oral agentregimens. While most GLP-1 RA productsare injectable, an oral formulation ofsemaglutide is now commercially avail-able (49). In trials comparing the ad-dition of an injectable GLP-1 RAs orinsulin in patients needing further glu-cose lowering, the efficacy of the twotreatments was similar (50–52). How-ever, GLP-1 RAs in these trials had alower risk of hypoglycemia andbeneficialeffects on body weight compared withinsulin, albeit with greater gastroin-testinal side effects. Thus, trial resultssupport injectable GLP-1 RAs as the

preferred option for patients requiringthe potency of an injectable therapy forglucose control (Fig. 9.2). However, highcosts and tolerability issues are impor-tant barriers to the use of GLP-1 RAs.

Cost for diabetes medicine has in-creased dramatically over the past twodecades, and an increasing proportion isnowpassedon topatientsandtheir families(53).Table9.2provides cost information forcurrently approved noninsulin therapies. Ofnote, prices listed are average wholesaleprices (AWP) (54) and National AverageDrug Acquisition Costs (NADAC) (55), sep-aratemeasures to allow for a comparisonofdrugpricesbutdonotaccountfordiscounts,rebates, or other price adjustments ofteninvolved in prescription sales that affect theactual cost incurred by the patient. Med-ication costs can be amajor source of stressfor patientswith diabetes and contribute toworse adherence with medications (56);cost-reducing strategies may improve ad-herence in some cases (57).

Cardiovascular Outcomes TrialsThere arenowmultiple large randomizedcontrolled trials reporting statisticallysignificant reductions in cardiovascularevents in patients with type 2 diabetestreated with an SGLT2 inhibitor (em-pagliflozin, canagliflozin, dapagliflozin)or GLP-1 RA (liraglutide, semaglutide,dulaglutide); see Section 10 “Cardiovas-cular Disease and Risk Management”(https://doi.org/10.2337/dc20-S010) fordetails. The subjects enrolled in the cardio-vascular outcome trials using empagliflozin,canagliflozin, liraglutide, and semaglutidehad A1C$7%, and more than 70% weretaking metformin at baseline. Thus, a prac-tical extension of these results to clinicalpractice is to use these drugs preferen-tially in patients with type 2 diabetes andestablished ASCVD or indicators of highASCVD risk. For these patients, incorpo-rating one of the SGLT2 inhibitors orGLP-1 RAs that have been demonstratedto have cardiovascular disease benefit isrecommended(Table9.1). Incardiovascularoutcomes trials, empagliflozin, canagliflozin,dapagliflozin, liraglutide,semaglutide, anddulaglutide all had beneficial effects onindices of CKD. See Section 11 “Microvas-cularComplicationsandFootCare” (https://doi.org/10.2337/dc20-S011) for a detaileddiscussion on how CKD may impact treat-ment choices. Additional large randomizedtrials of other agents in these classes areongoing.

Insulin TherapyManypatientswith type2diabetes even-tually require and benefit from insulintherapy (Fig. 9.2). See the section INSULIN

INJECTION TECHNIQUE above, for guidance onhow to administer insulin safely andeffectively. The progressive nature oftype 2 diabetes should be regularlyand objectively explained to patients,and providers should avoid using insulinas a threat or describing it as a sign ofpersonal failure or punishment. Rather,the utility and importance of insulin tomaintain glycemic control once progres-sion of the disease overcomes the effect ofother agents should be emphasized. Ed-ucating and involving patients in insulinmanagement is beneficial. For example,instruction of patients in self-titration ofinsulin doses based on self-monitoring ofblood glucose improves glycemic controlin patients with type 2 diabetes initiatinginsulin (58). Comprehensive education re-garding self-monitoring of blood glucose,diet, and the avoidance and appropriatetreatment of hypoglycemia are criticallyimportant in any patient using insulin.

Basal Insulin

Basal insulinalone is themost convenientinitial insulin regimen and can be addedto metformin and other oral agents.Starting doses can be estimated basedon body weight (0.1–0.2 units/kg/day)and the degree of hyperglycemia, withindividualized titration over days to weeksas needed. The principal action of basalinsulin is to restrain hepatic glucose pro-duction and limit hyperglycemia overnightand between meals (59,60). Control offasting glucose can be achieved withhumanNPH insulinor a long-acting insulinanalog. In clinical trials, long-acting basalanalogs (U-100 glargine or detemir) havebeen demonstrated to reduce the risk ofsymptomaticandnocturnalhypoglycemiacompared with NPH insulin (61–66), al-though these advantages are modest andmay not persist (67). Longer-acting basalanalogs (U-300 glargine or degludec) mayconvey a lower hypoglycemia risk com-pared with U-100 glargine when used incombination with oral agents (68–74).Despite evidence for reduced hypoglyce-mia with newer, longer-acting basal in-sulin analogs in clinical trial settings, inpractice these effects may be modestcompared with NPH insulin (75).

The cost of insulin has been risingsteadily over the past two decades, at

care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S105

a pace several fold that of other medicalexpenditures (76). This expense contrib-utes significant burden to patients asinsulin has become a growing “out-of-pocket” cost for people with diabetes,and direct patient costs contribute totreatment nonadherence (76). Therefore,consideration of cost is an important com-ponent of effective management. Formany patients with type 2 diabetes(e.g., individuals with relaxed A1C goals,low ratesofhypoglycemia, andprominentinsulin resistance, as well as those withcost concerns), human insulin (NPH andregular) may be the appropriate choiceof therapy, and clinicians should be

familiar with its use (75). Human regularinsulin, NPH, and 70/30 NPH/regular prod-ucts can be purchased for considerablyless than the AWP and NADAC prices listedin Table 9.3 at select pharmacies.

Prandial Insulin

Many individuals with type 2 diabetesrequire doses of insulin before meals, inaddition to basal insulin, to reach glyce-mic targets. A dose of 4 units or 10% ofthe amount of basal insulin at the largestmeal or the meal with the greatest post-prandial excursion is a safe estimate forinitiating therapy. The prandial insulinregimen can then be intensified based on

patient needs (see Figure 9.2). Peoplewith type 2 diabetes are generally moreinsulin resistant than those with type 1diabetes, require higher daily doses (;1unit/kg), and have lower rates of hypo-glycemia (77). Titration can be basedon home glucose monitoring or A1C.With significant additions to the prandialinsulin dose, particularly with the eveningmeal, consideration should be given todecreasing basal insulin. Meta-analysesof trials comparing rapid-acting insulinanalogs with human regular insulin inpatients with type 2 diabetes have notreported important differences in A1Cor hypoglycemia (78,79).

Table 9.2—Median monthly (30-day) 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, $85) $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 ($87, $7,412) $5 ($5, $988) 2,000 mg750 mg (ER) $74 ($65, $74) $4 1,500 mg1,000 mg (ER) $242 ($242, $7,214) $224 ($224, $910) 2,000 mg

Sulfonylureas (2ndgeneration)

c Glimepiride 4 mg $74 ($71, $198) $4 8 mgc Glipizide 10 mg (IR) $75 ($67, $97) $5 40 mg (IR)

10 mg (XL) $48 $15 20 mg (XL)c Glyburide 6 mg (micronized) $50 ($48, $71) $4 12 mg (micronized)

5 mg $93 ($63, $103) $11 20 mg

Thiazolidinediones c Pioglitazone 45 mg $348 ($283, $349) $4 45 mgc Rosiglitazone 4 mg $407 $330 8 mg

a-Glucosidaseinhibitors

c Acarbose 100 mg $106 ($104, $106) $23 300 mgc Miglitol 100 mg $241 $311 300 mg

Meglitinides (glinides) c Nateglinide 120 mg $155 $39 360 mgc Repaglinide 2 mg $878 ($162, $897) $39 16 mg

DPP-4 inhibitors c Alogliptin 25 mg $234 $168 25 mgc Saxagliptin 5 mg $505 $403 5 mgc Linagliptin 5 mg $523 $419 5 mgc Sitagliptin 100 mg $541 $433 100 mg

SGLT2 inhibitors c Ertugliflozin 15 mg $338 $271 15 mgc Dapagliflozin 10 mg $591 $473 10 mgc Empagliflozin 25 mg $591 $473 25 mgc Canagliflozin 300 mg $593 $475 300 mg

GLP-1 RAs c Exenatide (extended release) 2 mg powder forsuspension or pen

$840 $672 2 mg**

c Exenatide 10 mg pen $876 $730 20 mgc Dulaglutide 1.5/0.5 mL pen $911 $730 1.5 mg**c Semaglutide 1 mg pen $927 $745 1 mg**

14 mg (tablet) $927 N/A 14 mgc Liraglutide 18 mg/3 mL pen $1,106 $886 1.8 mgc Lixisenatide 300 mg/3 mL pen $744 N/A 20 mg

Bile acid sequestrant c Colesevelam 625 mg tabs $712 ($674, $712) $177 3.75 g3.75 g suspension $675 $415 3.75 g

Dopamine-2 agonist c Bromocriptine 0.8 mg $906 $729 4.8 mg

Amylin mimetic c Pramlintide 120 mg pen $2,623 $2,097 120 mg/injection†††

AWP, average wholesale price; DPP-4, dipeptidyl peptidase 4; ER and XL, extended release; GLP-1 RA, glucagon-like peptide 1 receptor agonist; IR,immediate release; N/A, data not available; NADAC, National Average Drug Acquisition Cost; SGLT2, sodium–glucose cotransporter 2. †Calculatedfor30-day supply (AWP [54]orNADAC [55] unit price3numberof doses required toprovidemaximumapproveddaily dose330days);medianAWPor NADAC listed alone when only one product and/or price. *Utilized to calculate median AWP and NADAC (min, max); generic prices used, ifavailable commercially. **Administered once weekly. †††AWP and NADAC calculated based on 120 mg three times daily.

S106 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020

Concentrated Insulins

Several concentrated insulin prepara-tions are currently available. U-500 reg-ular insulin is, by definition, five timesmore concentrated than U-100 regularinsulin. Regular U-500 has distinct phar-macokinetics with delayed onset andlonger duration of action, has character-istics more like an intermediate-acting(NPH) insulin, and can be used as two orthree daily injections (80). U-300 glargineand U-200 degludec are three and twotimes as concentrated as their U-100formulations, and allow higher dosesof basal insulin administration per vol-ume used. U-300 glargine has a longerduration of action than U-100 glarginebut modestly lower efficacy per unitadministered (81,82). The FDA has alsoapproved a concentrated formulation ofrapid-acting insulin lispro, U-200 (200

units/mL).Theseconcentratedpreparationsmay be more convenient and comfortablefor patients to inject and may improveadherence in those with insulin resistancewho require large doses of insulin. WhileU-500 regular insulin is available in bothprefilled pens and vials (a dedicated syringewas approved in July 2016), other concen-trated insulins are available only in prefilledpens to minimize the risk of dosing errors.

Inhaled Insulin

Inhaled insulin is available for prandialuse with a limited dosing range; studies inpeoplewith type1diabetes suggest rapidpharmacokinetics (7). A pilot study foundevidence that compared with injectablerapid-acting insulin, supplemental dosesof inhaled insulin taken based on post-prandial glucose levels may improve bloodglucose management without additional

hypoglycemia or weight gain (83), al-though results from a larger study areneeded for confirmation. Inhaled insulinis contraindicated in patientswith chroniclung disease, such as asthma and chronicobstructive pulmonary disease, and is notrecommended in patients who smoke orwho recently stopped smoking. All pa-tients require spirometry (FEV1) testing toidentifypotential lungdiseaseprior toandafter starting inhaled insulin therapy.

Combination Injectable TherapyIf basal insulin has been titrated to anacceptable fasting blood glucose level (orif the dose is.0.5 units/kg/day) and A1Cremains above target, consider advancingto combination injectable therapy (Fig.9.2). This approach can use a GLP-1 RAadded tobasal insulin ormultiple doses ofinsulin. The combination of basal insulin

Table 9.3—Median cost of insulin products in theU.S. calculated as AWP (54) andNADAC (55) per 1,000units of specified dosageform/product

Insulins Compounds Dosage form/product MedianAWP (min,max)* MedianNADAC(min,max)*

Rapid-acting c Lispro follow-onproduct

U-100 vial $157 $126U-100 prefilled pen $202 $162

c Lispro U-100 vial $330 $264U-100 3 mL cartridges $408 $327U-100 prefilled pen; U-200prefilled pen

$424 $340

c Glulisine U-100 vial $341 $273U-100 prefilled pen $439 $353

c Aspart U-100 vial $347† $278†U-100 3 mL cartridges $430 $345U-100 prefilled pen $447† $358†

c Inhaled insulin Inhalation cartridges $924 $606

Short-acting c human regular U-100 vial $165 ($165, $178)†† $134 ($134, $146)††

Intermediate-acting c human NPH U-100 vial $165 ($165, $178)†† $135 ($135, $146)††U-100 prefilled pen $377 $304

Concentrated humanregular insulin

c U-500 human regularinsulin

U-500 vial $178 $144U-500 prefilled pen $230 $184

Long-acting c Glargine follow-onproduct

U-100 prefilled pen $261 $210

c Glargine U-100 vial; U-100 prefilled pen $340 $272U-300 prefilled pen $346 $280

c Detemir U-100 vial; U-100 prefilled pen $370 $295c Degludec U-100 vial; U-100 prefilled pen;

U-200 prefilled pen$407 $326

Premixed insulin products c NPH/regular 70/30 U-100 vial $165 ($165, $178) $134 ($134, $145)U-100 prefilled pen $377 $303

c Lispro 50/50 U-100 vial $342 $274U-100 prefilled pen $424 $338

c Lispro 75/25 U-100 vial $342 $274U-100 prefilled pen $424 $340

c Aspart 70/30 U-100 vial $360 $289U-100 prefilled pen $447 $358

Premixed insulin/GLP-1 RAproducts

c Glargine/Lixisenatide 100/33 prefilled pen $565 $454c Degludec/Liraglutide 100/3.6 prefilled pen $832 $668

AWP, average wholesale price; GLP-1, glucagon-like peptide 1; NADAC, National Average Drug Acquisition Cost. *AWP or NADAC calculated as inTable 9.2. †Inclusive of both the original and “faster-acting” products. ††AWP and NADAC data presented do not include vials of regular humaninsulin and NPH available at Walmart for approximately $25/vial; median listed alone when only one product and/or price.

care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S107

and GLP-1 RA has potent glucose-lower-ing actions and less weight gain and hypo-glycemia comparedwith intensified insulinregimens (84–86). Twodifferentonce-dailyfixed-dual combination products contain-ing basal insulin plus a GLP-1 RA areavailable: insulin glargine plus lixisenatideand insulin degludec plus liraglutide.Intensification of insulin treatment can

be done by adding doses of prandial tobasal insulin. Starting with a single pran-dial dose with the largest meal of the dayis simple and effective, and it can beadvanced to a regimen with multipleprandial doses if necessary (87). Alter-natively, in a patient on basal insulin inwhom additional prandial coverage isdesired, the regimen can be convertedto two doses of a premixed insulin. Eachapproach has advantages and disadvan-tages. For example, basal/prandial regi-mens offer greater flexibility for patientswho eat on irregular schedules. On theother hand, two doses of premixed in-sulin is a simple, convenient means ofspreading insulin across the day. More-over,humaninsulins,separately,self-mixed,or as premixed NPH/regular (70/30)formulations, are less costly alternativesto insulin analogs. Figure 9.2 outlinesthese options, as well as recommendationsfor further intensification, if needed, toachieve glycemic goals. When initiatingcombination injectable therapy, metformintherapy should be maintained while sulfo-nylureas and DPP-4 inhibitors are typicallydiscontinued. In patients with suboptimalblood glucose control, especially those re-quiring large insulin doses, adjunctive useof a thiazolidinedione or an SGLT2 inhibitormayhelp to improvecontrol and reduce theamountof insulinneeded, thoughpotentialside effects should be considered. Once abasal/bolus insulin regimen is initiated,dose titration is important, with adjust-ments made in both mealtime and basalinsulins based on the blood glucose levelsand an understanding of the pharma-codynamic profile of each formulation(pattern control). As people with type 2diabetesgetolder, itmaybecomenecessaryto simplify complex insulin regimens be-cause of a decline in self-managementability (see Section 12 “Older Adults,”https://doi.org/10.2337/dc20-S012).

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S110 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020