6. Glycemic Targets: Standards ofMedical Care in Diabetesd2018Diabetes Care 2018;41(Suppl. 1):S55–S64 | https://doi.org/10.2337/dc18-S006

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”includes ADA’s current clinical practice recommendations and is intended to providethe components of diabetes care, general treatment goals and guidelines, and tools toevaluate quality of care. Members of the ADA Professional Practice Committee, amultidisciplinary expert committee, are responsible for updating the Standards ofCare annually, or more frequently as warranted. For a detailed description of ADAstandards, statements, and reports, aswell as the evidence-grading system forADA’sclinical practice recommendations, please refer to the Standards of Care Introduction.Readers who wish to comment on the Standards of Care are invited to do so atprofessional.diabetes.org/SOC.

ASSESSMENT OF GLYCEMIC CONTROL

Patient self-monitoring of blood glucose (SMBG) and A1C are available to healthcare providers and patients to assess the effectiveness and safety of a manage-ment plan on glycemic control. Continuous glucose monitoring (CGM) also hasan important role in assessing the effectiveness and safety of treatment in sub-groups of patients with type 1 diabetes and in selected patients with type 2 di-abetes. Data indicate similar A1C and safety with the use of CGM compared withSMBG (1).

Recommendations

c Most patients using intensive insulin regimens (multiple-dose insulin or in-sulin pump therapy) should perform self-monitoring of blood glucose (SMBG)prior to meals and snacks, at bedtime, occasionally postprandially, prior toexercise, when they suspect low blood glucose, after treating low bloodglucose until they are normoglycemic, and prior to critical tasks such asdriving. B

c When prescribed as part of a broad educational program, SMBG may help toguide treatment decisions and/or self-management for patients taking less fre-quent insulin injections B or noninsulin therapies. E

c When prescribing SMBG, ensure that patients receive ongoing instruction andregular evaluation of SMBG technique, SMBG results, and their ability to useSMBG data to adjust therapy. E

c When used properly, continuous glucose monitoring (CGM) in conjunction withintensive insulin regimens is a useful tool to lower A1C in adults with type 1diabetes who are not meeting glycemic targets. A

c CGM may be a useful tool in those with hypoglycemia unawareness and/orfrequent hypoglycemic episodes. C

c Given the variable adherence to CGM, assess individual readiness for continuingCGM use prior to prescribing. E

Suggested citation: American Diabetes Associa-tion. 6. Glycemic targets: Standards of MedicalCare in Diabetesd2018. Diabetes Care 2018;41(Suppl. 1):S55–S64

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

American Diabetes Association

Diabetes Care Volume 41, Supplement 1, January 2018 S55

6.GLYC

EMIC

TARGETS

c When prescribing CGM, robust di-abetes education, training, and sup-port are required for optimal CGMimplementation and ongoing use. E

c People who have been successfullyusing CGM should have continuedaccess after they turn 65 years ofage. E

Self-monitoring of Blood GlucoseMajor clinical trials of insulin-treated pa-tients have included SMBG as part ofmultifactorial interventions to demon-strate the benefit of intensive glycemiccontrol on diabetes complications. SMBGis thus an integral component of effectivetherapy (2). SMBG allows patients to eval-uate their individual response to therapyand assess whether glycemic targets arebeing achieved. Integrating SMBG resultsinto diabetes management can be auseful tool for guiding medical nutritiontherapy and physical activity, preventinghypoglycemia, and adjusting medications(particularly prandial insulindoses). Amongpatients with type 1 diabetes, there is acorrelation between greater SMBG fre-quency and lower A1C (3). The patient’sspecific needs and goals should dictateSMBG frequency and timing.

Optimization

SMBGaccuracy is dependent on the instru-ment and user, so it is important to evalu-ate each patient’s monitoring technique,both initially and at regular intervalsthereafter. Optimal use of SMBG requiresproper review and interpretation of thedata, by both the patient and the pro-vider. Among patients who check theirblood glucose at least once daily, manyreport taking no action when results arehigh or low. In a yearlong study of insulin-naive patients with suboptimal initialglycemic control, a group trained in struc-tured SMBG (a paper tool was used atleast quarterly to collect and interpret7-point SMBG profiles taken on 3 consec-utive days) reduced their A1C by 0.3 per-centage points more than the controlgroup (4). Patients should be taughthow to use SMBG data to adjust food in-take, exercise, or pharmacologic therapyto achieve specific goals. The ongoingneed for and frequency of SMBG shouldbe reevaluated at each routine visit toavoid overuse (5–7). SMBG is especiallyimportant for insulin-treated patients tomonitor for and prevent asymptomatichypoglycemia and hyperglycemia. Patients

should be advised against purchasing orreselling preowned or secondhand teststrips, as these may give incorrect results.Only unopened vials of glucose test stripsshould be used to ensure SMBG accuracy.

For Patients on Intensive Insulin Regimens

Most patients using intensive insulinregimens (multiple-dose insulin or insulinpump therapy) should perform SMBGprior to meals and snacks, at bedtime, oc-casionally postprandially, prior toexercise,when they suspect low blood glucose, af-ter treating low blood glucose until theyare normoglycemic, and prior to criticaltasks such as driving. For many patients,this will require testing 6–10 (or more)times daily, although individual needsmay vary. A database study of almost27,000 children and adolescents withtype 1 diabetes showed that, after adjust-ment for multiple confounders, increaseddaily frequency of SMBG was significantlyassociated with lower A1C (–0.2% per ad-ditional test per day) and with feweracute complications (8).

For Patients Using Basal Insulin and/or Oral

Agents

The evidence is insufficient regardingwhen to prescribe SMBG and how oftentesting is needed for patientswhodonotuseintensive insulin regimens, such as thosewith type 2 diabetes using oral agentsand/or basal insulin. For patients usingbasal insulin, assessing fasting glucosewith SMBG to inform dose adjustmentsto achieve blood glucose targets resultsin lower A1Cs (9,10).

For individuals with type 2 diabetes onless intensive insulin therapy, more fre-quent SMBG (e.g., fasting, before/aftermeals) may be helpful, as increased fre-quency is associated with meeting A1Ctargets (11).

Several randomized trials have calledinto question the clinical utility and cost-effectiveness of routine SMBG in noninsu-lin-treatedpatients (12–15).Meta-analyseshave suggested that SMBGcan reduceA1Cby 0.25–0.3% at 6months (16,17), but theeffect was attenuated at 12 months inone analysis (16). A key consideration isthat performing SMBG alone does notlower blood glucose levels. To be useful,the information must be integrated intoclinical and self-management plans.

Continuous Glucose MonitoringCGMmeasures interstitial glucose (whichcorrelates well with plasma glucose), and

mostCGMdevices include alarms for hypo-and hyperglycemic excursions. The inter-mittent or “flash” CGM device, very re-cently approved for adult use only (18),differs from previous CGM devices. Spe-cifically, it does not have alarms, does notrequire calibration with SMBG, and doesnot communicate continuously (only ondemand). It is reported to have a lowercost than traditional systems. A study inadults with well-controlled type 1 diabe-tes found that flash CGM users spent lesstime in hypoglycemia than those usingSMBG (19). However, due to significantdifferences between flash CGMand otherCGM devices, more discussion is neededon outcomes and regarding specific rec-ommendations.

For most CGM systems, confirmatorySMBG is required to make treatment de-cisions, though a randomized controlledtrial of 226 adults suggested that an en-hanced CGM device could be used safelyand effectively without regular confirma-tory SMBG in patients with well-controlledtype 1 diabetes at low risk of severe hy-poglycemia (1). TwoCGMdevices are nowapproved by the U.S. Food and Drug Ad-ministration (FDA) for making treatmentdecisions without SMBG confirmation(18,20), including the flash CGM device.

Although performed with older gener-ation CGM devices, a 26-week random-ized trial of 322 patients with type 1diabetesshowedthatadultsaged$25 yearsusing intensive insulin therapy and CGMexperienced a 0.5% reduction in A1C(from ;7.6% to 7.1% [;60 mmol/molto 54 mmol/mol]) compared with thoseusing intensive insulin therapy with SMBG(21). The greatest predictor of A1C lower-ing for all age-groups was frequency ofsensor use, which was highest in thoseaged $25 years and lower in youngerage-groups. Two clinical trials in adultswith type 1 diabetes not meeting A1Ctargets and using multiple daily injectionsalso found that the use of CGM comparedwith usual care resulted in lower A1C levelsthan SMBG over 24–26 weeks (22,23).Other small, short-term studies havedemonstrated similar A1C reductions us-ing CGM compared with SMBG in adultswith A1C levels $7% (53 mmol/mol)(24,25).

A registry study of 17,317 participantsconfirmed thatmore frequent CGMuse isassociated with lower A1C (26), whereasanother study showed that childrenwith.70% sensor use (i.e., $5 days per

S56 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018

week) missed fewer school days (27).Small randomized controlled trials inadults and children with baseline A1C,7.0–7.5% (53–58 mmol/mol) have con-firmed favorable outcomes including areduced frequency of hypoglycemia (de-fined as a blood glucose level,70 mg/dL[3.9 mmol/L]) and maintaining A1C ,7%(53mmol/mol) during the study period ingroups using CGM, suggesting that CGMmay provide further benefit for individu-als with type 1 diabetes who already havegood glycemic control (28–30).A meta-analysis suggests that com-

pared with SMBG, CGM is associatedwith short-term A1C lowering of ;0.26%in insulin-treated patients (31). The long-term effectiveness of CGM needs to bedetermined. This technology may be par-ticularly useful in insulin-treated patientswith hypoglycemia unawareness and/orfrequent hypoglycemic episodes, althoughstudies have not shown consistent reduc-tions in severe hypoglycemia (31–33). ACGM device equipped with an automaticlow glucose suspend feature has beenapproved by the FDA. The Automationto Simulate Pancreatic Insulin Response(ASPIRE) trial of 247 patients with type 1diabetes anddocumentednocturnal hypo-glycemia showed that sensor-augmentedinsulin pump therapy with a low glucosesuspend function significantly reducednocturnal hypoglycemia over 3 monthswithout increasing A1C levels (34).These devices may offer the opportunityto reduce hypoglycemia for those witha history of nocturnal hypoglycemia.The FDA has also approved the firsthybrid closed-loop system. The safety ofhybrid closed-loop systems has been sup-ported in the literature (35) andmay haveadvantages over sensor-augmentedpump therapy in specific populations,such as pregnant women with type 1diabetes (36).Due to variable adherence, optimal

CGM use requires an assessment of indi-vidual readiness for the technology aswell as initial and ongoing educationand support (26,37). Additionally, pro-viders need to provide robust diabeteseducation, training, and support for opti-mal CGM implementation and ongoinguse. As people with type 1 or type 2diabetes are living longer, healthier lives,individuals who have been successfullyusing CGM should have continued accessto these devices after they turn 65 yearsof age (38).

A1C TESTING

Recommendations

c Perform the A1C test at least twotimes a year in patients who aremeeting treatment goals (and whohave stable glycemic control). E

c Perform the A1C test quarterly inpatientswhose therapy has changedor who are not meeting glycemicgoals. E

c Point-of-care testing for A1Cprovidesthe opportunity for more timelytreatment changes. E

A1C reflects average glycemia overapproximately 3 months and has strongpredictive value for diabetes complica-tions (39,40). Thus, A1C testing shouldbe performed routinely in all patientswith diabetesdat initial assessment andas part of continuing care. Measurementapproximately every 3 months deter-mines whether patients’ glycemic targetshave been reached and maintained. Thefrequency of A1C testing should dependon the clinical situation, the treatmentregimen, and the clinician’s judgment.The use of point-of-care A1C testing mayprovide an opportunity for more timelytreatment changes during encounters be-tween patients and providers. Patientswith type 2 diabetes with stable glycemiawell within target may do well with A1Ctesting only twice per year. Unstable orintensively managed patients (e.g., preg-nant women with type 1 diabetes) mayrequire testingmore frequently than every3 months (41).

A1C LimitationsThe A1C test is an indirect measure ofaverage glycemia and, as such, is subjectto limitations. Aswith any laboratory test,there is variability in the measurement ofA1C. Although such variability is less onanintraindividual basis than that of bloodglucose measurements, clinicians shouldexercise judgment when using A1C as thesole basis for assessing glycemic control,particularly if the result is close to thethreshold that might prompt a change inmedication therapy. Conditions that affectred blood cell turnover (hemolytic andother anemias, recent blood transfusion,use of drugs that stimulate erythropo-esis, end-stage kidney disease, andpregnancy) may result in discrepanciesbetween the A1C result and the pa-tient’s true mean glycemia. Hemoglobinvariants must be considered, particularly

when the A1C result does not correlatewith the patient’s SMBG levels. Optionsfor monitoring include more frequent and/or different timing of SMBG or CGM use.Othermeasures of average glycemia suchas fructosamine and 1,5-anhydroglucitolare available, but their translation intoaverage glucose levels and their prog-nostic significance are not as clear asfor A1C. Though some variability existsamong different individuals, generallythe association between mean glucoseand A1C within an individual correlatesover time (42).

A1C does not provide a measure ofglycemic variability or hypoglycemia. Forpatients prone to glycemic variability,especially patients with type 1 diabetesor type 2 diabetes with severe insulin de-ficiency, glycemic control is best evalu-ated by the combination of results fromA1C and SMBG or CGM. A1C may alsoconfirm the accuracy of the patient’s me-ter (or the patient’s reported SMBG re-sults) and the adequacy of the SMBGtesting schedule.

A1C and Mean GlucoseTable 6.1 shows the correlation betweenA1C levels and mean glucose levels basedon two studies: 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 (43),and an empirical study of the averageblood glucose levels at premeal, post-meal, and bedtime associated with spec-ified A1C levels using data from theADAG trial (37). The American DiabetesAssociation (ADA) and the American As-sociation for Clinical Chemistry have de-termined that the correlation (r5 0.92) inthe ADAG trial is strong enough to justifyreporting both the A1C result and the es-timated average glucose (eAG) resultwhen a clinician orders the A1C test. Clini-cians should note that the mean plasmaglucose numbers in the table are based on;2,700 readings per A1C in the ADAGtrial. In a recent report, mean glucosemeasured with CGM versus central labo-ratory–measured A1C in 387 participantsin three randomized trials demonstratedthat A1C may underestimate or overesti-mate mean glucose. Thus, as suggested, apatient’s CGM profile has considerablepotential for optimizing his or her glyce-mic management (42).

care.diabetesjournals.org Glycemic Targets S57

A1C Differences in Ethnic Populationsand ChildrenIn the ADAG study, there were no signif-icant differences among racial and ethnicgroups in the regression lines betweenA1C and mean glucose, although thestudy was underpowered to detect adifference and there was a trend towarda difference between the African/AfricanAmerican and non-Hispanic white co-horts, with higher A1C values observedin Africans/African Americans comparedwith non-Hispanic whites for a givenmean glucose. Other studies have alsodemonstratedhigher A1C levels inAfricanAmericans than in whites at a given meanglucose concentration (44,45). Moreover,African Americans heterozygous for thecommon hemoglobin variant HbS mayhave, for any level of mean glycemia,lowerA1C by about 0.3 percentage pointsthan those without the trait (46). Anothergenetic variant, X-linked glucose-6-phosphatedehydrogenase G202A, carried by 11% ofAfrican Americans, was associated with adecrease in A1C of about 0.8% in hemi-zygous men and 0.7% in homozygouswomen compared to those without thetrait (47).

A small study comparing A1C to CGMdata in children with type 1 diabetesfound a highly statistically significant cor-relation between A1C and mean blood glu-cose, although the correlation (r5 0.7) wassignificantly lower than in the ADAG trial(48). Whether there are clinically mean-ingful differences in how A1C relates toaverage glucose in children or in differentethnicities is an area for further study(44,49,50). Until further evidence is avail-able, it seems prudent to establish A1Cgoals in these populations with consider-ation of both individualized SMBG andA1C results.

A1C GOALS

Forglycemicgoals in children,please refer toSection 12 “Children and Adolescents.”For glycemic goals in pregnant women,please refer to Section 13 “Managementof Diabetes in Pregnancy.”

Recommendations

c A reasonable A1C goal for manynonpregnant adults is ,7% (53mmol/mol). A

c Providers might reasonably suggestmore stringent A1C goals (suchas ,6.5% [48 mmol/mol]) for se-lected individual patients if thisT

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164(159

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8.4(8.2–8.7)

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S58 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018

can be achieved without significanthypoglycemia or other adverse ef-fects of treatment (i.e., polyphar-macy). Appropriate patients mightinclude thosewith short duration ofdiabetes, type 2 diabetes treatedwith lifestyle or metformin only,long life expectancy, or no signifi-cant cardiovascular disease. C

c Less stringent A1C goals (suchas,8% [64mmol/mol]) may be ap-propriate for patients with a historyof severe hypoglycemia, limited lifeexpectancy, advanced microvascu-lar or macrovascular complications,extensive comorbid conditions, orlong-standing diabetes in whomthe goal is difficult to achieve de-spite diabetes self-managementeducation, appropriate glucosemonitoring, and effective doses ofmultiple glucose-lowering agentsincluding insulin. B

A1C and Microvascular ComplicationsHyperglycemia defines diabetes, and gly-cemic control is fundamental to diabetesmanagement. The Diabetes Control andComplications Trial (DCCT) (2), a prospec-tive randomized controlled trial of inten-sive versus standard glycemic control inpatients with type 1 diabetes, showed de-finitively that better glycemic control isassociated with significantly decreasedrates of development and progression ofmicrovascular (retinopathy [51], neurop-athy, and diabetic kidney disease) compli-cations. Follow-up of the DCCT cohorts inthe Epidemiology of Diabetes Interven-tions and Complications (EDIC) study(52) demonstrated persistence of thesemicrovascular benefits despite the factthat the glycemic separation betweenthe treatment groups diminished and dis-appeared during follow-up.The Kumamoto Study (53) and UK Pro-

spective Diabetes Study (UKPDS) (54,55)confirmed that intensive glycemic controlsignificantly decreased rates of microvas-cular complications in patients with type 2diabetes. Long-term follow-up of theUKPDS cohorts showed enduring effectsof early glycemic control on most micro-vascular complications (56).Therefore, achieving A1C targets

of ,7% (53 mmol/mol) has been shownto reduce microvascular complications ofdiabetes. Epidemiological analyses of theDCCT (2) and UKPDS (57) demonstrate a

curvilinear relationship between A1C andmicrovascular complications. Such anal-yses suggest that, on a population level,the greatest number of complicationswillbe averted by taking patients from verypoor control to fair/good control. Theseanalyses also suggest that further lower-ing of A1C from 7% to 6% [53 mmol/molto 42 mmol/mol] is associated with fur-ther reduction in the risk of microvascularcomplications, although the absolute riskreductions become much smaller. Giventhe substantially increased risk of hypo-glycemia in type 1 diabetes trials andwith polypharmacy in type 2 diabetes,the risks of lower glycemic targets out-weigh the potential benefits on microvas-cular complications.

ACCORD, ADVANCE, and VADT

Three landmark trials (Action to ControlCardiovascular Risk in Diabetes [ACCORD],Action in Diabetes and Vascular Disease:Preterax and Diamicron MR ControlledEvaluation [ADVANCE], and Veterans Af-fairs Diabetes Trial [VADT]) showed thatlower A1C levels were associated with re-ducedonset or progression of somemicro-vascular complications (58–60).

The concerning mortality findings inthe ACCORD trial (61), discussed below,and the relatively intense efforts requiredto achieve near-euglycemia should alsobe considered when setting glycemic tar-gets. However, on the basis of physicianjudgment and patient preferences, selectpatients, especially those with little co-morbidity and long life expectancy, maybenefit from adopting more intensive gly-cemic targets (e.g., A1C target ,6.5%[48 mmol/mol]) as long as significant hy-poglycemia does not become a barrier.

A1C and Cardiovascular DiseaseOutcomes

Cardiovascular Disease and Type 1 Diabetes

Cardiovascular disease (CVD) is a morecommoncauseof death thanmicrovascularcomplications in populations with diabetes.There is evidence for a cardiovascular ben-efit of intensive glycemic control after long-term follow-up of cohorts treated early inthe course of type 1 diabetes. In the DCCT,there was a trend toward lower risk of CVDevents with intensive control. In the 9-yearpost-DCCT follow-up of the EDIC cohort,participants previously randomized to theintensive arm had a significant 57% reduc-tion in the risk of nonfatal myocardial in-farction (MI), stroke, or cardiovascular

death compared with those previously ran-domized to the standard arm (62). Thebenefit of intensive glycemic control inthis cohort with type 1 diabetes hasbeen shown to persist for several decades(63) and to be associated with a modestreduction in all-cause mortality (64).

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. During the UKPDS,there was a 16% reduction in CVD events(combined fatal or nonfatal MI and sud-den death) in the intensive glycemic con-trol arm that did not reach statisticalsignificance (P 5 0.052), and there wasno suggestion of benefit on other CVDoutcomes (e.g., stroke). However, after10 years of observational follow-up, thoseoriginally randomized to intensive glyce-mic control had significant long-term re-ductions in MI (15% with sulfonylurea orinsulin as initial pharmacotherapy, 33%with metformin as initial pharmacother-apy) and in all-cause mortality (13% and27%, respectively) (56).

ACCORD, ADVANCE, and VADT sug-gested no significant reduction in CVDoutcomes with intensive glycemic controlin participants followed for 3.5–5.6 yearswho had more advanced type 2 diabetesthan UKPDS participants. All three trialswere conducted in relatively older partic-ipants with longer known duration of di-abetes (mean duration 8–11 years) andeither CVD or multiple cardiovascular riskfactors. The target A1C among intensivecontrol subjects was,6% (42 mmol/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%(46mmol/molvs. 58mmol/mol) inACCORD,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 “Intensive GlycemicControl and the Prevention of Cardiovas-cular Events: Implications of the ACCORD,ADVANCE, and VA Diabetes Trials” (65).

The glycemic control comparison inACCORD was halted early due to an in-creased mortality rate in the intensivecompared with the standard treatmentarm (1.41% vs. 1.14% per year; hazard ra-tio 1.22 [95% CI 1.01–1.46]), with a similarincrease in cardiovascular deaths. Analysis

care.diabetesjournals.org Glycemic Targets S59

of the ACCORD data did not identify aclear explanation for the excess mortalityin the intensive treatment arm (61).Longer-term follow-uphas shownnoev-

idence of cardiovascular benefit or harm inthe ADVANCE trial (66). The end-stage re-nal disease ratewas lower in the intensivetreatment group over follow-up. However,10-year follow-up of the VADT cohort(67) showed a reduction in the risk of car-diovascular events (52.7 [control group]vs. 44.1 [intervention group] events per1,000 person-years) with no benefit incardiovascular or overall mortality. Hetero-geneity of mortality effects across studieswas noted, which may reflect differencesin glycemic targets, therapeutic approaches,and population characteristics (68).Mortality findings in ACCORD (61) and

subgroup analyses of VADT (69) suggestthat the potential risks of intensive glyce-mic control may outweigh its benefits inhigher-risk patients. In all three trials, se-vere hypoglycemia was significantlymorelikely in participants who were randomlyassigned to the intensive glycemic controlarm. Those patients with long duration ofdiabetes, a known history of hypoglyce-mia, advanced atherosclerosis, or ad-vanced age/frailty may benefit from lessaggressive targets (70,71).Providers shouldbevigilant inpreventing

hypoglycemia and should not aggressivelyattempt to achieve near-normal A1C levelsin patients in whom such targets cannot besafely and reasonably achieved. Severe orfrequent hypoglycemia is an absolute indi-cation for the modification of treatmentregimens, including setting higher glycemicgoals.Many factors, including patient prefer-

ences, should be taken into accountwhendeveloping a patient’s individualizedgoals (Table 6.2).

A1C and Glycemic TargetsNumerous aspects must be consideredwhen setting glycemic targets. The ADA

proposes optimal targets, but each targetmust be individualized to the needs of eachpatient and his or her disease factors.

When possible, such decisions should bemade with the patient, reflecting his or herpreferences, needs, and values. Fig. 6.1is not designed to be applied rigidly butto be used as a broad construct to guideclinical decision-making (72), in both type 1and type 2 diabetes.

Recommended glycemic targets formany nonpregnant adults are shown inTable 6.2. The recommendations includeblood glucose levels that appear to corre-late with achievement of an A1C of,7%(53 mmol/mol). The issue of preprandialversus postprandial SMBG targets is com-plex (73). Elevatedpostchallenge (2-h oralglucose tolerance test) glucose values

have been associated with increased car-diovascular risk independent of fastingplasma glucose in some epidemiologicalstudies, but intervention trials have notshown postprandial glucose to be a cardio-vascular risk factor independent of A1C. Insubjectswith diabetes, surrogatemeasuresof vascular pathology, such as endothelialdysfunction, are negatively affected bypost-prandial hyperglycemia. It is clear that post-prandial hyperglycemia, like preprandialhyperglycemia, contributes to elevatedA1C levels, with its relative contribution be-ing greater at A1C levels that are closer to7% (53 mmol/mol). However, outcomestudies have clearly shown A1C to be theprimary predictor of complications, andlandmark trials of glycemic control such asthe DCCT andUKPDS relied overwhelminglyon preprandial SMBG. Additionally, a ran-domized controlled trial in patients withknown CVD found no CVD benefit of insulinregimens targeting postprandial glucosecompared with those targeting preprandialglucose (74). Therefore, it is reasonable forpostprandial testing to be recommendedfor individuals who have premeal glucosevalues within target but have A1C valuesabove target. Measuring postprandialplasma glucose 1–2 h after the start of ameal and using treatments aimed at

Table 6.2—Summary of glycemic recommendations for many nonpregnant adultswith 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. Goals should beindividualized based on duration of diabetes, age/life expectancy, comorbid conditions, known CVDor advanced microvascular complications, hypoglycemia unawareness, and individual patientconsiderations. †Postprandial glucose may be targeted if A1C goals are not met despite reachingpreprandial glucose goals. Postprandial glucose measurements should be made 1–2 h after thebeginning of the meal, generally peak levels in patients with diabetes.

Figure 6.1—Depicted are patient and disease factors used to determine optimal A1C targets.Characteristics and predicaments toward the left justify more stringent efforts to lower A1C; thosetoward the right suggest less stringent efforts. Adapted with permission from Inzucchi et al. (72).

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reducing postprandial plasma glucose val-ues to ,180 mg/dL (10.0 mmol/L) mayhelp to lower A1C.Ananalysisofdata from470participants

in the ADAG study (237 with type 1 diabe-tes and 147 with type 2 diabetes) foundthat actual average glucose levels associ-ated with conventional A1C targets werehigher than older DCCT and ADA targets(Table 6.1) (37,39). These findings supportthatpremeal glucose targetsmaybe relaxedwithout undermining overall glycemic con-trol asmeasuredbyA1C. Thesedatapromp-ted the revision in the ADA-recommendedpremeal glucose target to 80–130 mg/dL(4.4–7.2 mmol/L) but did not affect thedefinition of hypoglycemia.

HYPOGLYCEMIA

Recommendations

c Individuals at risk for hypoglycemiashould be asked about symptom-atic and asymptomatic hypoglyce-mia at each encounter. C

c Glucose (15–20 g) is the preferredtreatment for the conscious individ-ual with blood glucose #70 mg/dL[3.9mmol/L]), although any form ofcarbohydrate that contains glucosemay be used. Fifteen minutes aftertreatment, if SMBG shows contin-ued hypoglycemia, the treatmentshould be repeated. Once SMBGreturns to normal, the individualshould consume a meal or snack toprevent recurrenceofhypoglycemia.E

c Glucagon should be prescribed forall individuals at increased risk ofclinically significant hypoglycemia,defined as blood glucose,54 mg/dL(3.0 mmol/L), so it is available shouldit be needed. Caregivers, schoolpersonnel, or family members ofthese individuals should knowwhere it is and when and how toadminister it. Glucagon administra-tion is not limited to health careprofessionals. E

c Hypoglycemia unawareness or oneor more episodes of severe hypo-glycemia should trigger reevalua-tion of the treatment regimen. E

c Insulin-treated patients with hy-poglycemia unawareness or anepisode of clinically significant hy-poglycemia should be advised toraise their glycemic targets tostrictly avoid hypoglycemia for atleast several weeks in order to par-tially reverse hypoglycemia un-awareness and reduce risk of futureepisodes. A

c Ongoing assessment of cognitivefunction is suggestedwith increasedvigilance for hypoglycemia by theclinician, patient, and caregivers iflow cognition or declining cognitionis found. B

Hypoglycemia is the major limiting factorin the glycemic management of type 1and type 2 diabetes. Recommendationsfrom the International Hypoglycemia StudyGroup regarding the classification of hypo-glycemia in clinical trials are outlined in Ta-ble 6.3 (75). Of note, this classificationscheme considers a blood glucose ,54mg/dL (3.0 mmol/L) detected by SMBG,CGM (for at least 20 min), or laboratorymeasurement of plasma glucose as suffi-ciently low to indicate clinically significanthypoglycemia that should be included inreports of clinical trials of glucose-loweringdrugs for the treatment of diabetes (75).However, a hypoglycemia alert valueof#70mg/dL (3.9mmol/L) can be impor-tant for therapeutic dose adjustment ofglucose-lowering drugs in clinical care andis often related to symptomatic hypogly-cemia. Severe hypoglycemia is defined assevere cognitive impairment requiring as-sistance from another person for recov-ery (76).

Symptoms of hypoglycemia include,but are not limited to, shakiness, irritabil-ity, confusion, tachycardia, and hunger.

Hypoglycemia may be inconvenient orfrightening to patients with diabetes. Se-vere hypoglycemia may be recognized orunrecognized and can progress to loss ofconsciousness, seizure, coma, or death. It isreversed by administration of rapid-actingglucose or glucagon. Clinically significanthypoglycemia can cause acute harm tothe person with diabetes or others, espe-cially if it causes falls, motor vehicle acci-dents, or other injury. A large cohort studysuggested that among older adults withtype 2 diabetes, a history of severe hypo-glycemia was associated with greater riskof dementia (77). Conversely, in a sub-study of the ACCORD trial, cognitiveimpairment at baseline or decline in cog-nitive function during the trial was sig-nificantly associated with subsequentepisodes of severe hypoglycemia (78). Ev-idence from DCCT/EDIC, which involvedadolescents and younger adults withtype 1 diabetes, found no association be-tween frequency of severe hypoglycemiaand cognitive decline (79), as discussed inSection 12 “Children and Adolescents.”

Severe hypoglycemia was associatedwith mortality in participants in both thestandard and the intensive glycemia armsof the ACCORD trial, but the relationshipsbetween hypoglycemia, achieved A1C,and treatment intensity were not straight-forward. An association of severe hypo-glycemia with mortality was also foundin the ADVANCE trial (80). An associationbetween self-reported severe hypoglyce-mia and 5-year mortality has also beenreported in clinical practice (81).

Young childrenwith type 1 diabetes andthe elderly, including thosewith type1andtype 2 diabetes (77,82), are noted as par-ticularly vulnerable to clinically significanthypoglycemia because of their reducedability to recognize hypoglycemic symp-toms and effectively communicate theirneeds. Individualized glucose targets, pa-tient education, dietary intervention (e.g.,bedtime snack to prevent overnight hypo-glycemiawhen specifically needed to treat

Table 6.3—Classification of hypoglycemia*

Level Glycemic criteria Description

Hypoglycemia alert value (level 1) #70 mg/dL (3.9 mmol/L) Sufficiently low for treatment with fast-acting carbohydrate and doseadjustment of glucose-lowering therapy

Clinically significant hypoglycemia (level 2) ,54 mg/dL (3.0 mmol/L) Sufficiently low to indicate serious, clinically important hypoglycemia

Severe hypoglycemia (level 3) No specific glucose threshold Hypoglycemia associated with severe cognitive impairment requiringexternal assistance for recovery

*Adapted from ref. 75.

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low blood glucose), exercisemanagement,medication adjustment, glucose monitor-ing, and routine clinical surveillance mayimprove patient outcomes (76). CGM withautomated low glucose suspend has beenshown to be effective in reducing hypogly-cemia in type 1 diabetes (34). For patientswith type 1 diabetes with severe hypogly-cemia and hypoglycemia unawarenessthat persists despite medical treatment,human islet transplantationmay be an op-tion, but the approach remains experimen-tal (83,84).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 (4.4–7.2mmol/L). This changereflects the resultsof the ADAG study, which demonstratedthat higher glycemic targets correspondedto A1C goals (37). An additional goal ofraising the lower range of the glycemictarget was to limit overtreatment andprovide a safety margin in patients titrat-ing glucose-lowering drugs such as insulinto glycemic targets.

Hypoglycemia TreatmentProviders should continue to counselpatients to treat hypoglycemia with fast-acting carbohydrates at the hypoglycemiaalert value of 70 mg/dL (3.9 mmol/L) orless. Hypoglycemia treatment requiresingestion of glucose- or carbohydrate-containing foods. The acute glycemic re-sponse correlates better with the glucosecontent of food than with the carbohy-drate content of food. Pure glucose isthe preferred treatment, but any formof carbohydrate that contains glucosewill raise blood glucose. Added fat mayretard and then prolong the acute glyce-mic response. In type 2 diabetes, ingestedprotein may increase insulin responsewithout increasing plasma glucose con-centrations (85). Therefore, carbohydratesources high in protein should not beused to treat or prevent hypoglycemia.Ongoing insulin activity or insulin secreta-gogues may lead to recurrent hypoglyce-mia unless further food is ingested afterrecovery. Once the glucose returns tonormal, the individual should be coun-seled to eat a meal or snack to preventrecurrent hypoglycemia.

Glucagon

The use of glucagon is indicated for thetreatment of hypoglycemia in people un-able or unwilling to consume carbohy-drates by mouth. Those in close contactwith, or having custodial care of, people

with hypoglycemia-prone diabetes (fam-ily members, roommates, school person-nel, child care providers, correctionalinstitution staff, or coworkers) should beinstructed on the use of glucagon kits in-cluding where the kit is and when andhow toadminister glucagon.An individualdoes not need to be a health care pro-fessional to safely administer glucagon.Care should be taken to ensure that glu-cagon kits are not expired.

Hypoglycemia PreventionHypoglycemia prevention is a critical com-ponent of diabetes management. SMBGand, for some patients, CGM are essentialtools to assess therapy anddetect incipienthypoglycemia. Patients should understandsituations that increase their risk of hypo-glycemia, such as fasting for tests or pro-cedures, delayed meals, during or afterintense exercise, and during sleep. Hypo-glycemia may increase the risk of harm toself or others, such as with driving. Teach-ing peoplewith 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-associatedautonomic failure) can severely com-promisestringentdiabetescontrolandqualityof life. This syndrome is characterized by de-ficient counterregulatory hormone release,especially in older adults, and a diminishedautonomic response, which both are risk fac-tors for, and caused by, hypoglycemia. A cor-ollary to this “vicious cycle” is that severalweeks of avoidance of hypoglycemia hasbeen demonstrated to improve counterregu-lation and hypoglycemia awareness in manypatients (86). Hence, patients with one ormore episodes of clinically significant hy-poglycemia may benefit from at leastshort-term relaxation of glycemic targets.

INTERCURRENT ILLNESS

For further information on managementof patients with hyperglycemia in the hos-pital, please refer to Section 14 “DiabetesCare in the Hospital.”

Stressful events (e.g., illness, trauma, sur-gery, etc.)mayworsenglycemic control andprecipitate diabetic ketoacidosis or nonke-totic hyperosmolar state, life-threateningconditions that require immediate medicalcare to prevent complications and death.Any condition leading to deteriorationin glycemic control necessitates more fre-quentmonitoring of blood glucose; ketosis-

prone patients also require urine orblood ketone monitoring. If accompa-nied by ketosis, vomiting, or alteration inthe level of consciousness, marked hyper-glycemia requires temporary adjustment ofthe treatment regimen and immediate in-teraction with the diabetes care team. Thepatient treatedwith noninsulin therapies ormedical nutrition therapy alone may tem-porarily require insulin. Adequate fluid andcaloric intakemust be ensured. Infection ordehydration is more likely to necessitatehospitalization of the person with diabetesthan the person without diabetes.

A physician with expertise in diabetesmanagement should treat the hospital-ized patient. For further information onthe management of diabetic ketoacidosisand the hyperglycemic nonketotic hyper-osmolar state, please refer to theADAcon-sensus report “Hyperglycemic Crises inAdult Patients With Diabetes” (87).

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S64 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018