6. Glycemic Targets: Standards ofMedical Care in Diabetesd2021Diabetes Care 2021;44(Suppl. 1):S73–S84 | https://doi.org/10.2337/dc21-S006

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,and tools to evaluate quality of care. Members of the ADA Professional PracticeCommittee, a multidisciplinary expert committee (https://doi.org/10.2337/dc21-SPPC), are responsible for updating the Standards of Care annually, or morefrequently as warranted. For a detailed description of ADA standards, statements,and reports, as well as the evidence-grading system for ADA’s clinical practicerecommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc21-SINT). Readers who wish to comment on the Standards of Careare invited to do so at professional.diabetes.org/SOC.

ASSESSMENT OF GLYCEMIC CONTROL

Glycemic control is assessed by the A1C measurement, continuous glucose monitoring(CGM), and self-monitoring of blood glucose (SMBG). A1C is the metric used to datein clinical trials demonstrating the benefits of improved glycemic control. PatientSMBG can be used with self-management and medication adjustment, partic-ularly in individuals taking insulin. CGM serves an important role in assessing theeffectiveness and safety of treatment in many patients with type 1 diabetes, includingprevention of hypoglycemia, and in selected patients with type 2 diabetes, such asin those on intensive insulin regimens and in those on regimens associated withhypoglycemia.

Glycemic Assessment

Recommendations

6.1 Assess glycemic status (A1C or other glycemic measurement) at least twotimes a year in patients who are meeting treatment goals (and who havestable glycemic control). E

6.2 Assess glycemic status at least quarterly, and as needed, in patients whosetherapy has recently changed and/or who are not meeting glycemic goals. E

A1C reflects average glycemia over approximately 3 months. The performance of thetest is generally excellent for National Glycohemoglobin Standardization Program(NGSP)-certified assays (see www.ngsp.org). The test is the primary tool for assessingglycemic control and has strong predictive value for diabetes complications (1–3).Thus, A1C testing should be performed routinely in all patients with diabetes at initialassessment and as part of continuing care. Measurement approximately every3 months determines whether patients’ glycemic targets have been reached andmaintained. The frequency of A1C testing should depend on the clinical situation, thetreatment regimen, and the clinician’s judgment. The use of point-of-care A1C testingmay provide an opportunity for more timely treatment changes during encounters

Suggested citation: American Diabetes Associa-tion. 6. Glycemic targets: Standards of MedicalCare in Diabetesd2021. Diabetes Care 2021;44(Suppl. 1):S73–S84

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American Diabetes Association

Diabetes Care Volume 44, Supplement 1, January 2021 S73

6.GLYC

EMIC

TARGETS

between patients and providers. Pa-tients with type 2 diabetes with stableglycemia well within target may do wellwith A1C testing or other glucose as-sessment only twice per year. Unstableor intensively managed patients orpeople not at goal with treatment ad-justments may require testing morefrequently (every 3months with interimassessments as needed) (4).

A1C LimitationsThe A1C test is an indirect measure ofaverage glycemia and, as such, is subjectto limitations. As with any laboratorytest, there is variability in the measure-ment of A1C. Although A1C variability islower on an intraindividual basis thanthat of blood glucose measurements,clinicians should exercise judgment whenusing A1C as the sole basis for assess-ing glycemic control, particularly if theresult is close to the threshold thatmight prompt a change in medicationtherapy. For example, conditions thataffect red blood cell turnover (hemolyticand other anemias, glucose-6-phosphatedehydrogenase deficiency, recent bloodtransfusion, use of drugs that stimulateerythropoesis, end-stage kidneydisease,and pregnancy) may result in discrep-ancies between the A1C result and thepatient’s truemean glycemia. Hemoglo-bin variants must be considered, par-ticularly when the A1C result does notcorrelate with the patient’s CGM orSMBG levels. However, most assays inuse in theU.S. are accurate in individualsheterozygous for the most commonvariants (see www.ngsp.org/interf.asp).Other measures of average glycemiasuch as fructosamine and 1,5-anhydro-glucitolareavailable,but their translationinto average glucose levels and theirprognostic significance are not as clearas for A1C and CGM. Though somevariability in the relationship betweenaverage glucose levels and A1C existsamong different individuals, generallythe association between mean glucoseand A1C within an individual correlatesover time (5).A1C does not provide a measure of

glycemic variability or hypoglycemia. Forpatients prone to glycemic variability,especially patientswith type 1 diabetes ortype 2 diabetes with severe insulin de-ficiency, glycemic control is best evaluatedby the combination of results from SMBGor CGM and A1C. A1Cmay also inform the

accuracy of the patient’s CGM or meter(or the patient’s reported SMBG re-sults) and the adequacy of the SMBGmonitoring.

Correlation Between SMBG and A1CTable 6.1 shows the correlation be-tween A1C levels and mean glucoselevels based on the international A1C-Derived Average Glucose (ADAG) study,which assessed the correlation betweenA1C and frequent SMBG and CGM in507 adults (83% non-Hispanic Whites)with type 1, type 2, and no diabetes (6),and an empirical study of the averageblood glucose levels at premeal, post-meal, and bedtime associated with spec-ifiedA1C levels usingdata fromtheADAGtrial (7). The American Diabetes Associa-tion (ADA) and the American Associationfor Clinical Chemistry have determinedthat the correlation (r 5 0.92) in theADAG trial is strong enough to justifyreporting both the A1C result and theestimated average glucose (eAG) resultwhen a clinician orders the A1C test.Clinicians should note that the meanplasma glucose numbers in Table 6.1are based on ;2,700 readings per A1Cin the ADAG trial. In a recent report,mean glucose measured with CGM versuscentral laboratory–measured A1C in 387participants in three randomized trialsdemonstrated that A1C may underesti-mate or overestimate mean glucose inindividuals (5). Thus, as suggested, a pa-tient’s SMBG or CGM profile has consid-erable potential for optimizing his orher glycemic management (5).

A1C Differences in Ethnic Populationsand ChildrenIn the ADAG study, there were no sig-nificantdifferencesamongracial andethnicgroups in the regression lines betweenA1Candmeanglucose,althoughthestudywas underpowered to detect a differenceand therewas a trend toward a differencebetweentheAfricanandAfricanAmericanand the non-HispanicWhite cohorts, withhigher A1C values observed in AfricansandAfricanAmericans comparedwith non-Hispanic Whites for a given mean glucose.Other studies have also demonstratedhigher A1C levels in African Americansthan in Whites at a given mean glucoseconcentration (8,9).

A1C assays are available that do notdemonstrate a statistically significantdifference in individuals with hemoglobin

variants. Other assays have statisticallysignificant interference, but the differ-ence is not clinically significant. Use of anassay with such statistically significantinterference may explain a report thatfor any level of mean glycemia, AfricanAmericans heterozygous for the com-mon hemoglobin variant HbS had lowerA1C by about 0.3 percentage pointswhen compared with those without thetrait (10,11). Another genetic variant,X-linked glucose-6-phosphate dehydro-genase G202A, carried by 11% of AfricanAmericans, was associated with a de-crease in A1C of about 0.8% in hemi-zygous men and 0.7% in homozygouswomen compared with those withoutthe trait (12).

A small study comparing A1C to CGMdata in children with type 1 diabetesfound a highly statistically significantcorrelation between A1C and meanblood glucose, although the correlation(r 5 0.7) was significantly lower than inthe ADAG trial (13). Whether there areclinically meaningful differences in howA1Crelates toaverageglucose in childrenor in different ethnicities is an area forfurther study (8,14,15). Until furtherevidence is available, it seems prudentto establish A1C goals in these popula-tions with consideration of individual-ized CGM, SMBG, and A1C results. Thislimitation does not interfere with theusefulness of CGM for insulin doseadjustments.

Table 6.1—Estimated average glucose(eAG)

A1C (%) mg/dL* mmol/L

5 97 (76–120) 5.4 (4.2–6.7)

6 126 (100–152) 7.0 (5.5–8.5)

7 154 (123–185) 8.6 (6.8–10.3)

8 183 (147–217) 10.2 (8.1–12.1)

9 212 (170–249) 11.8 (9.4–13.9)

10 240 (193–282) 13.4 (10.7–15.7)

11 269 (217–314) 14.9 (12.0–17.5)

12 298 (240–347) 16.5 (13.3–19.3)

Data in parentheses are 95% CI. A calculatorfor converting A1C results into eAG, ineither mg/dL or mmol/L, is available atprofessional.diabetes.org/eAG. *Theseestimates are based onADAGdata of;2,700glucose measurements over 3 months perA1C measurement in 507 adults with type 1,type 2, or no diabetes. The correlationbetween A1C and average glucose was 0.92(6,7). Adapted from Nathan et al. (6).

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Glucose Assessment by ContinuousGlucose Monitoring

Recommendations

6.3 Standardized, single-page glucosereports from continuous glucosemonitoring (CGM) devices withvisual cues, such as the ambula-tory glucose profile (AGP), shouldbe considered as a standard print-out for all CGM devices. E

6.4 Time in range (TIR) is associatedwith the risk of microvascularcomplications, should be an ac-ceptable end point for clinicaltrialsmoving forward, and can beused for assessment of glycemiccontrol. Additionally, time belowtarget (,70 and,54 mg/dL [3.9and 3.0mmol/L]) and time abovetarget (.180mg/dL [10.0mmol/L])are useful parameters for reeval-uation of the treatment regimen. C

CGM is rapidly improving diabetesman-agement. As stated in the recommen-dations, time in range (TIR) is a usefulmetric of glycemic control and glucosepatterns and it correlates well with A1Cin most studies (16–21). New data sup-port that increased TIR correlates withthe risk of complications. The studiessupporting this assertion are reviewedin more detail in Section 7 “DiabetesTechnology” (https://doi.org/10.2337/dc21-S007); they include cross-sectionaldata and cohort studies (22–24) dem-onstrating TIR as an acceptable end pointfor clinical trials moving forward andthat it can be used for assessment ofglycemic control. Additionally, time be-low target (,70and,54mg/dL [3.9 and3.0 mmol/L]) and time above target(.180 mg/dL [10.0 mmol/L]) are usefulparameters for reevaluation of the treat-ment regimen.For many people with diabetes, glu-

cose monitoring is key for achievingglycemic targets. Major clinical trials ofinsulin-treated patients have includedSMBG as part of multifactorial inter-ventions to demonstrate the benefit ofintensive glycemic control on diabetescomplications (25). SMBG is thus an in-tegral component of effective therapy ofpatients taking insulin. In recent years,CGM has emerged as a complementarymethod for assessing glucose levels. Bothapproaches to glucose monitoring allowpatients to evaluate individual response

to therapy and assess whether glycemictargets are being safely achieved. Theinternational consensus on TIR providesguidance on standardized CGM metrics(see Table 6.2) and considerations forclinical interpretation and care (26). Tomake these metrics more actionable,standardized reports with visual cues,such as the ambulatory glucose profile(see Fig. 6.1), are recommended (26) andmay help the patient and the providerbetter interpret the data to guide treat-ment decisions (16,19). SMBG and CGMcan be useful to guide medical nutritiontherapy and physical activity, preventhypoglycemia, and aid medication man-agement. While A1C is currently theprimary measure to guide glucose man-agement and a valuable risk marker fordeveloping diabetes complications, theglucose management indicator (GMI)along with the other CGM metrics pro-vide for a more personalized diabetesmanagement plan. The incorporation ofthese metrics into clinical practice is inevolution, and optimization and harmo-nization of CGM terminology will evolveto suit patient and provider needs. Thepatient’s specific needs and goals shoulddictate SMBG frequency and timing andconsideration of CGM use. Please refer toSection 7 “Diabetes Technology” (https://doi.org/10.2337/dc21-S007) for a ful-ler discussion of the use of SMBG andCGM.

With the advent of new technology,CGMhasevolved rapidly inbothaccuracyand affordability. As such, many patientshave these data available to assist withboth self-management and assessmentby providers. Reports can be generatedfrom CGM that will allow the provider todetermine TIR and to assess hypoglyce-mia, hyperglycemia, and glycemic vari-ability. As discussed in a recent consensusdocument,a report formattedasshown inFig. 6.1 can be generated (26). Publisheddata suggest a strong correlationbetweenTIR and A1C, with a goal of 70% TIRaligning with an A1C of ;7% in twoprospective studies (18,27).

GLYCEMIC GOALS

For glycemic goals in older adults, pleaserefer to Section12, “OlderAdults” (https://doi.org/10.2337/dc21-S012). For glycemicgoals in children, please refer to Section 13“Children and Adolescents” (https://doi.org/10.2337/dc21-S013). For glycemic

goals in pregnant women, please referto Section 14 “Management of Diabetesin Pregnancy” (https://doi.org/10.2337/dc21-S014). Overall, regardless of thepopulation being served, it is critical forthe glycemic targets to bewoven into theoverall patient-centered strategy. For ex-ample, in a very young child safety andsimplicity may outweigh the need forperfect control in the short run. Simpli-fication may decrease parental anxietyand build trust and confidence, whichcould support further strengthening ofglycemic targets and self-efficacy. Simi-larly, in healthy older adults, there is noempiric need to loosencontrol. However,the provider needs to work with anindividual and should consider adjustingtargets or simplifying the regimen if thischange is needed to improve safety andadherence.

Recommendations

6.5a An A1C goal for many nonpreg-nantadultsof,7%(53mmol/mol)without significant hypoglycemiais appropriate. A

6.5b If using ambulatory glucose pro-file/glucose management indica-tor to assess glycemia, a parallelgoal is a time in range of.70%with time below range ,4%(Fig. 6.1). B

6.6 On the basis of provider judg-ment and patient preference,achievement of lower A1C lev-els than the goal of 7% may beacceptable, and even beneficial,if it can be achieved safely with-out significant hypoglycemia orother adverse effects of treat-ment. C

6.7 Less stringent A1C goals (suchas,8% [64mmol/mol]) may beappropriate for patients withlimited life expectancy, or wheretheharmsof treatmentaregreaterthan the benefits. B

6.8 Reassess glycemic targets overtime based on the criteria in Fig.6.2 and in older adults (Table12.1). E

A1C and Microvascular ComplicationsHyperglycemia defines diabetes, and gly-cemic control is fundamental to diabetesmanagement. The Diabetes Control andComplications Trial (DCCT) (25), a pro-spective randomized controlled trial of in-tensive(meanA1Cabout7%[53mmol/mol])

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versus standard (mean A1C about 9%[75 mmol/mol]) glycemic control in pa-tients with type 1 diabetes, showed de-finitively that better glycemic control isassociated with 50–76% reductions inrates of development and progression ofmicrovascular (retinopathy, neuropathy,and diabetic kidney disease) complica-tions. Follow-up of the DCCT cohorts inthe Epidemiology of Diabetes Interven-tions and Complications (EDIC) study(28,29) demonstrated persistence of

these microvascular benefits over twodecades despite the fact that the glycemicseparation between the treatment groupsdiminished and disappeared duringfollow-up.

The Kumamoto Study (30) and UKProspective Diabetes Study (UKPDS) (31,32)confirmed that intensive glycemic con-trol significantly decreased rates of mi-crovascular complications in patientswithshort-duration type2 diabetes. Long-termfollow-up of the UKPDS cohorts showed

enduring effects of early glycemic con-trol on most microvascular complications(33).

Therefore, achieving A1C targets of,7% (53 mmol/mol) has been shownto reduce microvascular complicationsof type 1 and type 2 diabetes wheninstituted early in the course of disease(1,34). Epidemiologic analyses of theDCCT (25) andUKPDS (35) demonstrate acurvilinear relationship between A1C andmicrovascular complications. Such anal-yses suggest that, on a population level,the greatest number of complicationswill be averted by taking patients fromvery poor control to fair/good control.These analyses also suggest that furtherlowering of A1C from 7% to 6% [53 mmol/mol to 42 mmol/mol] is associated withfurther reduction in the risk of microvas-cular complications, although the abso-lute risk reductionsbecomemuchsmaller.The implication of these findings is thatthere is noneed todeintensify therapy foran individualwithanA1Cbetween6%and7% and low hypoglycemia risk with a longlife expectancy. There are now neweragents that do not cause hypoglycemia,making it possible to maintain glucosecontrol without risk of hypoglycemia (seeSection 9 “Pharmacologic Approaches toGlycemic Treatment,” https://doi.org/10.2337/dc21-S009).

Table 6.2—Standardized CGM metrics for clinical care

1. Number of days CGMdevice isworn (recommend 14 days)

2. Percentage of time CGM device is active(recommend 70% of data from 14 days)

3. Mean glucose

4. Glucose management indicator

5. Glycemic variability (%CV) target #36%*

6. TAR: % of readings and time .250 mg/dL(.13.9 mmol/L) Level 2 hyperglycemia

7. TAR: % of readings and time 181–250 mg/dL(10.1–13.9 mmol/L) Level 1 hyperglycemia

8. TIR: % of readings and time 70–180 mg/dL (3.9–10.0 mmol/L) In range

9. TBR: % of readings and time 54–69 mg/dL (3.0–3.8 mmol/L) Level 1 hypoglycemia

10. TBR: % of readings and time,54 mg/dL (,3.0 mmol/L) Level 2 hypoglycemia

CGM, continuous glucose monitoring; CV, coefficient of variation; TAR, time above range; TBR,time below range; TIR, time in range. *Some studies suggest that lower %CV targets (,33%)provide additional protection against hypoglycemia for those receiving insulin or sulfonylureas.Adapted from Battelino et al. (26).

Figure 6.1—Key points included in standard ambulatory glucose profile (AGP) report. Adapted from Battelino et al. (26).

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Given the substantially increased riskof hypoglycemia in type 1 diabetes andwith polypharmacy in type 2 diabetes,the risks of lower glycemic targets mayoutweigh the potential benefits on micro-vascular complications. Three landmarktrials (Action to Control CardiovascularRisk in Diabetes [ACCORD], Action inDiabetes and Vascular Disease: Preteraxand DiamicronMR Controlled Evaluation[ADVANCE], and Veterans Affairs Diabe-tes Trial [VADT]) were conducted to testtheeffects ofnearnormalizationofbloodglucose on cardiovascular outcomes inindividuals with long-standing type 2 di-abetes and either known cardiovasculardisease (CVD) or high cardiovascular risk.These trials showed that lowerA1C levelswere associated with reduced onset orprogression of some microvascular com-plications (36–38).The concerning mortality findings in

the ACCORD trial (39), discussed below,and the relatively intense efforts requiredto achieve near euglycemia should alsobeconsidered when setting glycemic targetsfor individuals with long-standing diabe-tes, such as those studied in ACCORD,ADVANCE, andVADT. Findings from thesestudies suggest caution is needed in treat-ing diabetes aggressively to near-normal

A1C goals in people with long-standingtype2diabeteswithorat significant riskofCVD. These landmark studies need to beconsidered with an important caveat; glu-cagon like peptide 1 (GLP-1) receptor ago-nists and sodium–glucose cotransporter2 (SGLT2) inhibitorswerenotapprovedatthe time of these trials. As such, theseagents with established cardiovascular andrenal benefit appear tobe safe in this groupofhigh-riskpatients.Clinical trialsexaminingthese agents for cardiovascular safety werenotdesignedtotesthigherversuslowerA1C;therefore, beyondpost hoc analysis of thesetrials, we do not have evidence that it is theglucose lowering by these agents that con-fers the CVD and renal benefit (40). As such,on the basis of physician judgment andpatient preferences, select patients, es-pecially those with little comorbidity andlong life expectancy, may benefit fromadopting more intensive glycemic targetsif they can achieve them safely withouthypoglycemia or significant therapeuticburden.

A1C and Cardiovascular DiseaseOutcomes

Cardiovascular Disease and Type 1 Diabetes

CVD is a more common cause of deaththan microvascular complications in

populations with diabetes. There is ev-idence for a cardiovascular benefit ofintensive glycemic control after long-term follow-up of cohorts treated earlyin the course of type 1 diabetes. In theDCCT, there was a trend toward lower riskofCVDeventswith intensivecontrol. In the9-year post-DCCT follow-up of the EDICcohort, participants previously random-ized to the intensive armhadasignificant57% reduction in the risk of nonfatalmyocardial infarction (MI), stroke, orcardiovascular death compared withthose previously randomized to the stan-dard arm (41). The benefit of intensiveglycemic control in this cohortwith type1diabetes has been shown to persist forseveral decades (42) and tobe associatedwith a modest reduction in all-causemortality (43).

Cardiovascular Disease and Type 2 Diabetes

In type 2 diabetes, there is evidence thatmore intensive treatment of glycemia innewly diagnosed patients may reducelong-term CVD rates. In addition, datafrom the Swedish National Diabetes Reg-istry (44) and the Joint Asia DiabetesEvaluation (JADE) demonstrate greaterproportions of people with diabetes be-ing diagnosed at,40 years of age and ademonstrably increased burden of heartdisease and years of life lost in peoplediagnosed at a younger age (45–48).Thus, for prevention of both microvas-cular andmacrovascular complicationsofdiabetes, there is a major call to over-come therapeutic inertia and treat totarget for an individual patient (47,49).During the UKPDS, there was a 16%reduction in CVD events (combined fatalor nonfatal MI and sudden death) in theintensive glycemic control arm that didnot reach statistical significance (P 50.052), and there was no suggestion ofbenefit on other CVD outcomes (e.g.,stroke). Similar to the DCCT/EDIC, after10 years of observational follow-up,those originally randomized to intensiveglycemic control had significant long-termreductions in MI (15% with sulfonylureaor insulin as initial pharmacotherapy,33% with metformin as initial pharma-cotherapy) and in all-cause mortality (13%and 27%, respectively) (33).

ACCORD, ADVANCE, and VADT sug-gested no significant reduction in CVDoutcomes with intensive glycemic con-trol in participants followed for shorterdurations (3.5–5.6 years) and who had

Figure 6.2—Patient and disease factors used to determine optimal glycemic targets. Character-istics and predicaments toward the left justify more stringent efforts to lower A1C; those towardthe right suggest less stringent efforts. A1C 7%5 53 mmol/mol. Adapted with permission fromInzucchi et al. (59).

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more advanced type 2 diabetes thanUKPDS participants. All three trials wereconducted in relatively older participantswith longer known duration of diabetes(mean duration 8–11 years) and eitherCVD or multiple cardiovascular risk fac-tors. The target A1C among intensive-control subjects was,6% (42mmol/mol)in ACCORD, ,6.5% (48 mmol/mol) inADVANCE, and a 1.5% reduction in A1Ccompared with control subjects in VADT,with achieved A1C of 6.4% vs. 7.5%(46 mmol/mol vs. 58 mmol/mol) in AC-CORD, 6.5% vs. 7.3% (48 mmol/mol vs.56mmol/mol) in ADVANCE, and 6.9% vs.8.4% (52 mmol/mol vs. 68 mmol/mol) inVADT. Details of these studies are re-viewed extensively in the joint ADA po-sition statement, “Intensive GlycemicControl and the Prevention of Cardio-vascular Events: Implications of theACCORD, ADVANCE, and VA DiabetesTrials” (50).The glycemic control comparison in

ACCORD was halted early due to an in-creased mortality rate in the intensivecompared with the standard treatmentarm (1.41% vs. 1.14% per year; hazardratio 1.22 [95% CI 1.01–1.46]), with asimilar increase in cardiovascular deaths.Analysis of the ACCORD data did notidentify a clear explanation for theexcess mortality in the intensive treat-ment arm (39).Longer-term follow-up has shown no

evidence of cardiovascular benefit or harmin the ADVANCE trial (51). The end-stagerenaldisease ratewas lower in the intensivetreatment group over follow-up. However,10-year follow-up of the VADT cohort (52)showed a reduction in the risk of cardio-vascularevents(52.7[controlgroup]vs.44.1[intervention group] events per 1,000person-years) with no benefit in cardiovascular oroverallmortality. Heterogeneity ofmortalityeffects across studies was noted, whichmay reflect differences in glycemic targets,therapeutic approaches, and, importantly,population characteristics (53).Mortality findings in ACCORD (39) and

subgroup analyses of VADT (54) suggestthat the potential risks of intensive glyce-mic control may outweigh its benefitsin higher-risk patients. In all three trials,severehypoglycemiawas significantlymorelikely in participants who were randomlyassigned to the intensive glycemic controlarm. Those patients with long duration ofdiabetes, a knownhistory of hypoglycemia,advanced atherosclerosis, or advanced

age/frailty may benefit from less aggres-sive targets (55,56).

As discussed further below, severehypoglycemia is a potent marker of highabsolute risk of cardiovascular events andmortality (57). Providers should be vigilant inpreventing hypoglycemia and should notaggressivelyattempttoachievenear-normalA1C levels in patients in whom suchtargets cannot be safely and reasonablyachieved.Asdiscussed inSection9 “Phar-macologic Approaches to Glycemic Treat-ment” (https://doi.org/10.2337/dc21-S009),addition of specific (SGLT2) inhibitors orGLP-1 receptor agonists that have dem-onstrated CVD benefit is recommendedfor use in patients with established CVD,chronic kidney disease, and heart failure.As outlined in more detail in Section 9“Pharmacologic Approaches to GlycemicTreatment” (https://doi.org/10.2337/dc21-S009) and Section 10 “Cardiovascular Dis-ease and Risk Management” (https://doi.org/10.2337/dc21-S010), the cardiovas-cular benefits of SGLT2 inhibitors orGLP-1receptor agonists are not dependent uponA1C lowering; therefore, initiation canbeconsidered in peoplewith type 2 diabetesand CVD independent of the current A1Cor A1C goal or metformin therapy. Basedon these considerations, the followingtwo strategies are offered (58):

1. If already on dual therapy or multipleglucose-lowering therapies and not onan SGLT2 inhibitor or GLP-1 receptoragonist, consider switching to one ofthese agents with proven cardiovas-cular benefit.

2. Introduce SGLT2 inhibitors or GLP-1receptor agonists in patients with CVDat A1C goal (independent ofmetformin)for cardiovascular benefit, independentof baseline A1C or individualized A1Ctarget.

Setting and Modifying A1C GoalsNumerous factors must be consideredwhen setting glycemic targets. The ADAproposes general targets appropriate formany patients but emphasizes the im-portance of individualization based onkey patient characteristics. Glycemic tar-getsmust be individualized in the contextof shared decision-making to address theneeds and preferences of each patientand the individual characteristics thatinfluence risks andbenefits of therapy foreach patient in order to optimize patientengagement and self-efficacy.

The factors to consider in individual-izing goals are depicted in Fig. 6.2. Thisfigure is notdesigned tobeapplied rigidlybut to be used as a broad construct toguide clinical decision-making (59) andengage in shared decision-making inpeople with type 1 and type 2 diabetes.More stringent targets may be recom-mended if they can be achieved safelyand with acceptable burden of therapyand if life expectancy is sufficient to reapbenefits of stringent targets. Less strin-gent targets (A1C up to 8% [64 mmol/mol]) may be recommended if the lifeexpectancy of the patient is such that thebenefits of an intensive goal may not berealized, or if the risks and burdensoutweigh the potential benefits. Severeor frequent hypoglycemia is an absoluteindication for the modification of treat-ment regimens, including setting higherglycemic goals.

Diabetes is a chronic disease that pro-gresses over decades. Thus, a goal thatmight be appropriate for an individualearly in the course of their diabetes maychange over time. Newly diagnosed pa-tients and/or thosewithout comorbiditiesthat limit lifeexpectancymaybenefit fromintensive control proven to prevent mi-crovascular complications. Both DCCT/EDIC andUKPDS demonstratedmetabolicmemory, or a legacy effect, in which afinite period of intensive control yieldedbenefits that extended for decades afterthat control ended. Thus, a finite periodof intensive control to near-normal A1Cmay yield enduring benefits even if con-trol is subsequently deintensified as pa-tient characteristics change. Over time,comorbidities may emerge, decreasinglife expectancy and thereby decreasingthe potential to reap benefits from in-tensive control. Also, with longer dura-tion of disease, diabetes may becomemore difficult to control, with increasingrisks and burdens of therapy. Thus, A1Ctargets should be reevaluated over timeto balance the risks and benefits as patientfactors change.

Recommended glycemic targets formany nonpregnant adults are shown inTable 6.3. The recommendations includeblood glucose levels that appear to cor-relate with achievement of an A1Cof ,7% (53 mmol/mol). Pregnancy rec-ommendations are discussed in moredetail in Section 14 “Managementof Diabetes in Pregnancy” (https://doi.org/10.2337/dc21-S014).

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The issue of preprandial versus post-prandial SMBG targets is complex (60).Elevated postchallenge (2-h oral glucosetolerance test) glucose values have beenassociated with increased cardiovascularrisk independent of fasting plasma glu-cose in some epidemiologic studies,whereas intervention trials havenot shownpostprandial glucose to be a cardiovas-cular risk factor independent of A1C. Inpeoplewithdiabetes, surrogatemeasuresof vascular pathology, such as endothelialdysfunction, are negatively affected bypostprandial hyperglycemia. It is clearthat postprandial hyperglycemia, like pre-prandial hyperglycemia, contributes toelevated A1C levels, with its relativecontribution being greater at A1C levelsthat are closer to 7% (53 mmol/mol).However, outcome studies have clearlyshownA1C to be theprimary predictor ofcomplications, and landmark trials ofglycemic control such as the DCCT andUKPDS relied overwhelmingly on pre-prandial SMBG. Additionally, a random-ized controlled trial in patients withknown CVD found no CVD benefit ofinsulin regimens targeting postprandialglucose compared with those targetingpreprandial glucose (61). Therefore, it isreasonable for postprandial testing to berecommended for individuals who havepremeal glucose values within target butA1C values above target. In addition,when intensifying insulin therapy, mea-suring postprandial plasma glucose 1–2 h after the start of a meal and usingtreatments aimed at reducing post-prandial plasma glucose values to,180 mg/dL (10.0 mmol/L) may helpto lower A1C.An analysis of data from 470 partici-

pants in the ADAG study (237with type 1diabetes and 147 with type 2 diabetes)found that the glucose ranges highlightedin Table 6.1 are adequate tomeet targetsand decrease hypoglycemia (7,62). These

findings support that premeal glucosetargets may be relaxed without under-mining overall glycemic control as mea-sured by A1C. These data prompted therevision in the ADA-recommended pre-meal glucose target to 80–130 mg/dL(4.4–7.2 mmol/L) but did not affect thedefinition of hypoglycemia.

HYPOGLYCEMIA

Recommendations

6.9 Occurrence and risk for hypo-glycemia should be reviewed atevery encounter and investigatedas indicated. C

6.10 Glucose (approximately 15–20g)is the preferred treatment fortheconscious individualwithbloodglucose,70mg/dL(3.9mmol/L],although any form of carbohy-drate that contains glucose maybe used. Fifteen minutes aftertreatment, if self-monitoring ofblood glucose (SMBG) showscontinued hypoglycemia, thetreatment should be repeated.Once the SMBGor glucosepatternis trending up, the individualshould consume a meal or snackto prevent recurrence of hypogly-cemia. B

6.11 Glucagon should be prescribedfor all individuals at increasedrisk of level 2 or 3 hypoglycemiaso that it is available should it beneeded. Caregivers, school per-sonnel, or family members ofthese individuals should knowwhere it is andwhen and how toadminister it. Glucagon admin-istration is not limited to healthcare professionals. E

6.12 Hypoglycemia unawareness orone or more episodes of level 3hypoglycemia should trigger hy-poglycemia avoidance education

and reevaluation of the treat-ment regimen. E

6.13 Insulin-treatedpatientswithhy-poglycemia unawareness, onelevel 3 hypoglycemic event, ora pattern of unexplained level 2hypoglycemia should be advisedto raise their glycemic targets tostrictly avoid hypoglycemia forat least several weeks in orderto partially reverse hypoglyce-mia unawareness and reducerisk of future episodes. A

6.14 Ongoing assessment of cogni-tive function is suggested withincreased vigilance for hypogly-cemia by the clinician, patient,and caregivers if low cognitionordeclining cognition is found.B

Hypoglycemia is the major limiting fac-tor in the glycemicmanagement of type1and type 2 diabetes. Recommendationsregarding the classification of hypogly-cemia are outlined in Table 6.4 (63–68).Level 1 hypoglycemia is defined as ameasurable glucose concentration ,70mg/dL (3.9 mmol/L) but $54 mg/dL (3.0mmol/L). A blood glucose concentra-tion of 70 mg/dL (3.9 mmol/L) has beenrecognized as a threshold for neuroendo-crine responses to falling glucose in peo-ple without diabetes. Because manypeople with diabetes demonstrate im-paired counterregulatory responses tohypoglycemia and/or experience hypo-glycemia unawareness, a measured glu-cose level ,70 mg/dL (3.9 mmol/L) isconsidered clinically important (indepen-dentof the severityofacutehypoglycemicsymptoms). Level 2 hypoglycemia (de-fined as a blood glucose concentration,54 mg/dL [3.0 mmol/L]) is the thresh-old at which neuroglycopenic symptomsbegin to occur and requires immediateaction to resolve the hypoglycemic event.If a patient has level 2 hypoglycemiawithout adrenergic or neuroglycopenicsymptoms, they likely have hypoglyce-mia unawareness (discussed furtherbelow). This clinical scenario warrantsinvestigation and review of the medicalregimen. Lastly, level 3 hypoglycemia isdefined as a severe event characterizedby altered mental and/or physical func-tioning that requires assistance fromanother person for recovery.

Symptoms of hypoglycemia include,but are not limited to, shakiness,

Table 6.3—Summary of glycemic recommendations for many nonpregnantadults with diabetesA1C ,7.0% (53 mmol/mol)*#

Preprandial capillary plasma glucose 80–130 mg/dL* (4.4–7.2 mmol/L)

Peak postprandial capillary plasma glucose† ,180 mg/dL* (10.0 mmol/L)

*More or less stringent glycemic goals may be appropriate for individual patients. #CGMmay beused to assess glycemic target as noted in Recommendation 6.5b and Fig. 6.1. Goals should beindividualized based on duration of diabetes, age/life expectancy, comorbid conditions, knownCVDor advancedmicrovascular complications, hypoglycemia unawareness, and individual patientconsiderations (as per Fig. 6.2). †Postprandial glucose may be targeted if A1C goals are not metdespite reaching preprandial glucose goals. Postprandial glucose measurements should be made1–2 h after the beginning of the meal, generally peak levels in patients with diabetes.

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irritability, confusion, tachycardia, andhunger. Hypoglycemia may be inconve-nient or frightening to patients with di-abetes. Level 3 hypoglycemia may berecognized or unrecognized and canprogress to loss of consciousness, sei-zure, coma, or death. Hypoglycemia isreversedbyadministrationof rapid-actingglucose or glucagon. Hypoglycemia cancause acute harm to the person withdiabetes or others, especially if it causesfalls, motor vehicle accidents, or otherinjury. Recurrent level 2 hypoglycemiaand/or level 3 hypoglycemia is an urgentmedical issue and requires interven-tion with medical regimen adjustment,behavioral intervention, and, in somecases, use of technology to assist withhypoglycemia prevention and identifica-tion (64,69–72). A large cohort studysuggested that among older adults withtype 2 diabetes, a history of level 3 hy-poglycemia was associated with greaterrisk of dementia (73). Conversely, in asubstudy of the ACCORD trial, cognitiveimpairment at baseline or decline incognitive function during the trial wassignificantly associated with subsequentepisodes of level 3 hypoglycemia (74).Evidence from DCCT/EDIC, which in-volved adolescents and younger adultswith type 1 diabetes, found no associa-tion between frequency of level 3 hypo-glycemia and cognitive decline (75).Studiesof ratesof level3hypoglycemia

that rely on claims data for hospitaliza-tion, emergency department visits, andambulance use substantially underesti-mate rates of level 3 hypoglycemia (76)yet reveal a high burden of hypoglycemiain adults over 60 years of age in thecommunity (77). African Americans areat substantially increased risk of level3 hypoglycemia (77,78). In addition toage and race, other important risk factorsfound in a community-based epidemio-logic cohort of older Black and Whiteadults with type 2 diabetes include

insulin use, poor or moderate versusgood glycemic control, albuminuria, andpoor cognitive function (77). Level 3 hy-poglycemiawas associatedwithmortalityin participants in both the standard andthe intensive glycemia arms of the AC-CORD trial, but the relationships betweenhypoglycemia, achieved A1C, and treat-ment intensity were not straightforward.An association of level 3 hypoglycemiawith mortality was also found in theADVANCE trial (79). An association be-tween self-reported level 3 hypoglycemiaand 5-year mortality has also been re-ported in clinical practice (80).

Young children with type 1 diabetesand the elderly, including those withtype 1 and type 2 diabetes (73,81), arenoted as particularly vulnerable to hypo-glycemia because of their reduced abilityto recognize hypoglycemic symptoms andeffectively communicate their needs. In-dividualized glucose targets, patient ed-ucation,dietary intervention (e.g.,bedtimesnack to prevent overnight hypoglycemiawhen specifically needed to treat lowblood glucose), exercise management,medication adjustment, glucose moni-toring, and routine clinical surveillancemay improve patient outcomes (82).CGM with automated low glucose sus-pend has been shown to be effective inreducinghypoglycemia in type1diabetes(83). For patients with type 1 diabeteswith level 3 hypoglycemia and hypogly-cemia unawareness that persists despitemedical treatment, human islet trans-plantation may be an option, but theapproach remains experimental (84,85).

In 2015, the ADA changed its prepran-dial glycemic target from 70–130 mg/dL(3.9–7.2 mmol/L) to 80–130 mg/dL (4.4–7.2 mmol/L). This change reflects theresults of the ADAG study, which dem-onstrated that higher glycemic targetscorresponded to A1C goals (7). An ad-ditional goal of raising the lower rangeof the glycemic target was to limit

overtreatment and provide a safety mar-gin in patients titrating glucose-loweringdrugs such as insulin to glycemic targets.

Hypoglycemia TreatmentProviders should continue to counsel pa-tients to treat hypoglycemia with fast-acting carbohydrates at the hypoglycemiaalert value of 70 mg/dL (3.9 mmol/L) orless. This should be reviewed at eachpatient visit. Hypoglycemia treatment re-quires ingestionof glucose- or carbohydrate-containing foods (86–88). The acuteglycemic response correlates betterwith the glucose content of food thanwith the carbohydrate content of food.Pure glucose is the preferred treatment,but any form of carbohydrate that con-tains glucose will raise blood glucose.Added fat may retard and then prolongthe acute glycemic response. In type 2diabetes, ingested protein may increaseinsulin response without increasingplasmaglucoseconcentrations (89). There-fore, carbohydrate sources high in proteinshould not be used to treat or preventhypoglycemia. Ongoing insulin activity orinsulin secretagogues may lead to recur-rent hypoglycemia unless more food isingestedafter recovery.Once theglucosereturns to normal, the individual shouldbe counseled to eat a meal or snack toprevent recurrent hypoglycemia.

Glucagon

The use of glucagon is indicated for thetreatment of hypoglycemia in peopleunable or unwilling to consume carbo-hydrates by mouth. Those in close con-tact with, or having custodial care of,people with hypoglycemia-prone diabetes(family members, roommates, schoolpersonnel, childcare providers, correc-tional institution staff, or coworkers)should be instructed on the use of glu-cagon, including where the glucagonproduct is kept and when and how toadminister it. An individual does not needto be a health care professional to safelyadminister glucagon. In addition totraditional glucagon injection powderthat requires reconstitution prior toinjection, intranasal glucagon and glu-cagon solution for subcutaneous injec-tion are available. Care should be takento ensure that glucagon products arenot expired.

Hypoglycemia PreventionHypoglycemia prevention is a criticalcomponent of diabetes management.

Table 6.4—Classification of hypoglycemia

Glycemic criteria/description

Level 1 Glucose ,70 mg/dL (3.9 mmol/L) and $54 mg/dL(3.0 mmol/L)

Level 2 Glucose ,54 mg/dL (3.0 mmol/L)

Level 3 A severe event characterized by altered mental and/orphysical status requiring assistance for treatment ofhypoglycemia

Reprinted from Agiostratidou et al. (63).

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SMBG and, for some patients, CGM areessential tools to assess therapy anddetect incipient hypoglycemia. Patientsshould understand situations that in-crease their risk of hypoglycemia, such aswhen fasting for tests or procedures,whenmeals are delayed, during and after theconsumption of alcohol, during and afterintense exercise, and during sleep. Hypo-glycemia may increase the risk of harm toself or others, such as with driving. Teach-ing people with diabetes to balance insulinuse and carbohydrate intake and exerciseare necessary, but these strategies are notalways sufficient for prevention.In type 1 diabetes and severely insulin-

deficient type 2 diabetes, hypoglycemiaunawareness (or hypoglycemia-associ-ated autonomic failure) can severelycompromise stringent diabetes controland quality of life. This syndrome ischaracterized by deficient counterregu-latory hormone release, especially inolder adults, andadiminishedautonomicresponse, which are both risk factors for,and caused by, hypoglycemia. A corollaryto this “vicious cycle” is that severalweeks of avoidance of hypoglycemia hasbeen demonstrated to improve counter-regulation and hypoglycemia awarenessin many patients (90). Hence, patientswith one or more episodes of clinicallysignificant hypoglycemia may benefitfrom at least short-term relaxation ofglycemic targets and availability of glu-cagon (91).

Use of CGM Technology in Hypoglycemia

Prevention

With the advent of CGM and CGM-assisted pump therapy, there has beena promise of alarm-based prevention ofhypoglycemia (92,93). To date, therehave been a number of randomizedcontrolled trials in adults with type 1diabetes and studies in adults and chil-drenwith type 1 diabetes using real-timeCGM (see Section 7 “Diabetes Technol-ogy,” https://doi.org/10.2337/dc21-S007).These studies had differing A1C at entryand differing primary end points and thusmust be interpreted carefully. Real-timeCGM studies can be divided into studieswith elevated A1C with the primary endpoint of A1C reduction and studies withA1Cnear targetwith theprimary endpointof reduction in hypoglycemia (93–109). Inpeoplewithtype1andtype2diabeteswithA1C above target, CGM improved A1Cbetween 0.3% and 0.6%. For studies

targetinghypoglycemia,moststudiesdem-onstrated a significant reduction in timespent between 54 and 70 mg/dL. A recentreport in people with type 1 diabetesover the age of 60 years revealed a smallbut statistically significant decrease in hy-poglycemia (110). No study to date hasreported a decrease in level 3 hypogly-cemia. In a single study using intermit-tently scanned CGM, adults with type 1diabeteswithA1Cnear goal and impairedawareness of hypoglycemia demonstratedno change in A1C and decreased level2 hypoglycemia (100). For people withtype 2 diabetes, studies examining theimpact of CGM on hypoglycemic eventsare limited; a recent meta-analysis doesnot reflect a significant impact on hypo-glycemic events in type 2 diabetes (111),whereas improvements in A1C wereobserved inmost studies (111–117).Over-all, real-time CGM appears to be a usefultool for decreasing time spent in a hypo-glycemic range in people with impairedawareness. For type 2 diabetes, otherstrategies to assist patients with insulindosing can improve A1C with minimalhypoglycemia (118).

INTERCURRENT ILLNESS

For further information on managementof patients with hyperglycemia in thehospital, see Section 15 “Diabetes Carein theHospital” (https://doi.org/10.2337/dc21-S015).

Stressful events (e.g., illness, trauma,surgery, etc.) may worsen glycemic con-trol and precipitate diabetic ketoacidosisor nonketotic hyperglycemic hyperosmolarstate, life-threatening conditions that re-quire immediate medical care to preventcomplications and death. Any conditionleading to deterioration in glycemic controlnecessitates more frequent monitoringof blood glucose; ketosis-prone patientsalso require urine or blood ketone moni-toring. If accompanied by ketosis, vomiting,or alteration in the level of consciousness,marked hyperglycemia requires tempo-rary adjustment of the treatment regi-men and immediate interaction with thediabetes care team. The patient treatedwith noninsulin therapies or medical nu-trition therapy alone may require insulin.Adequate fluid and caloric intake must beensured. Infection or dehydration is morelikely to necessitate hospitalization ofindividuals with diabetes versus thosewithout diabetes.

A physician with expertise in diabetesmanagement should treat the hospital-ized patient. For further information onthemanagement ofdiabetic ketoacidosisand thenonketotic hyperglycemic hyper-osmolar state, please refer to the ADAconsensus report “Hyperglycemic Crisesin Adult Patients With Diabetes” (119).

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