Description: The American Diabetes Association (ADA) pub- Committee of the ADA Board of Directors, which includes health
lished the 2016 Standards of Medical Care in Diabetes (Stan- care professionals, scientists, and laypersons. Feedback from
dards) to provide clinicians, patients, researchers, payers, and the larger clinical community was incorporated into the 2016
other interested parties with the components of diabetes care, revision.
general treatment goals, and tools to evaluate the quality of care.
Recommendations: The synopsis focuses on 8 key areas that
Methods: The ADA Professional Practice Committee performed are important to primary care providers. The recommendations
a systematic search on MEDLINE to revise or clarify recommen- highlight individualized care to manage the disease, prevent or
dations based on new evidence. The committee assigns the rec- delay complications, and improve outcomes.
ommendations a rating of A, B, or C, depending on the quality of
evidence. The E rating for expert opinion is assigned to recom- Ann Intern Med. 2016;164:542-552. doi:10.7326/M15-3016 www.annals.org
mendations based on expert consensus or clinical experience. For author afliations, see end of text.
The Standards were reviewed and approved by the Executive This article was published at www.annals.org on 1 March 2016.
Hemoglobin Mean Plasma Mean Fasting Mean Preprandial Mean Postprandial Mean Bedtime
A1c Level, % Glucose Level Glucose Level Glucose Level Glucose Level Glucose Level
mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL
6 7.0 126
<6.5 6.8 122 6.5 118 8.0 144 7.5 136
6.506.99 7.9 142 7.7 139 9.1 164 8.5 153
7 8.6 154
>7.007.49 8.4 152 8.4 152 9.8 176 9.8 177
7.507.99 9.3 167 8.6 155 10.5 189 9.7 175
8 10.2 183
>8.08.5 9.9 178 9.9 179 11.4 206 12.3 222
9 11.8 212
10 13.4 240
11 14.9 269
12 16.5 298
* Data from references 6 and 7. A calculator for converting hemoglobin A1c results into estimated average glucose levels in either mg/dL or mmol/L
is available at http://professional.diabetes.org/eAG.
These estimates are based on A1c-Derived Average Glucose (ADAG) data of about 2700 glucose measurements over 3 months, which were
correlated with hemoglobin A1c measurement in 507 adults with type 1, type 2, and no diabetes. The correlation between hemoglobin A1c level and
average glucose level was 0.92 (7).
www.annals.org Annals of Internal Medicine Vol. 164 No. 8 19 April 2016 543
Hemoglobin A1c Goals in Nonpregnant Adults to partially reverse hypoglycemia unawareness and re-
The HbA1c goal for most nonpregnant adults is less duce the risk for future episodes.
than 7% (Appendix Table, available at www.annals Providers should be vigilant in preventing hypogly-
.org). Glycemic control has been shown to reduce mi- cemia in patients with advanced disease and should
crovascular complications of diabetes in persons with not aggressively attempt to achieve near-normal HbA1c
T1DM and T2DM and mortality in those with T1DM (11, levels in patients in whom such targets cannot be safely
12). If implemented soon after the diagnosis of diabe- and reasonably reached. Severe or frequent hypogly-
tes, this target is associated with long-term reduction in cemia is an absolute indication for the modication of
macrovascular disease (A rating). Providers might sug- treatment regimens.
gest more stringent HbA1c goals (such as <6.5%) for
selected patients (such as those with short duration of
diabetes, T2DM treated with lifestyle or metformin, MEDICAL MANAGEMENT OF DIABETES
long life expectancy, or no cardiovascular disease) (C Foundations of Care
rating). More stringent goals are associated with in- Optimal diabetes care addresses behavioral, di-
creased hypoglycemia, and studies have shown no fur- etary, lifestyle, and pharmaceutical interventions. All
ther improvement in cardiovascular disease or mortal- patients should participate in diabetes self-management
ity (1315). Less stringent HbA1c goals (such as <8%) education and support (B rating). An individualized
may be appropriate for patients with a history of severe medical nutrition therapy program, preferably pro-
hypoglycemia (plasma glucose level <2.22 mmol/L vided by a registered dietitian, is recommended for all
[<40 mg/dL]), limited life expectancy, advanced micro- persons with diabetes (A rating). A physical activity plan
vascular or macrovascular complications, extensive co- should include at least 150 minutes of moderate-
morbid conditions, or long-standing diabetes. The gen- intensity aerobic activity per week, reduced sedentary
eral goal is difcult to attain in such patients despite time, and resistance training at least twice per week for
diabetes self-management education; appropriate glu- most adults with diabetes.
cose monitoring; and effective doses of multiple
Type 1 Diabetes
glucose-lowering agents, including insulin (16, 17)
(B rating). Most patients with T1DM should be treated with
When individualizing a patient's goals, many fac- multiple-dose insulin injections or continuous subcuta-
tors, including patient preferences and disease factors, neous insulin injection (19) (A rating). Studies have
should be considered (Appendix Figure, available at shown clear improvements in the risk for or progres-
www.annals.org) (18). sion of microvascular complications and cardiovascular
disease with intensive insulin therapy (3 injections of
insulin per day) or continuous subcutaneous insulin in-
fusion compared with 1 or 2 injections per day (6, 20).
HYPOGLYCEMIA Patients should be offered education on matching
Hypoglycemia (plasma glucose level <3.9 mmol/L prandial insulin doses to carbohydrate intake, prepran-
[<70 mg/dL]) is the major limiting factor in the glycemic dial blood glucose levels, and anticipated activity level
management of T1DM and insulin-treated T2DM. Se- (E rating). Patients with T1DM should use insulin ana-
vere hypoglycemia, characterized by cognitive impair- logues to reduce hypoglycemia risk (21, 22)
ment, is dened as that in which the patient requires (A rating).
assistance from another person. Patients at risk for se- Continuous glucose monitoring systems have re-
vere hypoglycemia should be prescribed glucagon, cently been shown to signicantly reduce severe hypo-
and their close contacts should be instructed on how to glycemia risk in patients with T1DM (23). Insulin pump
administer it (E rating). Hypoglycemia may be reversed therapy with a low blood glucose level suspend fea-
with administration of rapid-acting glucose (15 to 20 g). ture, augmented by continuous glucose monitoring, re-
Pure glucose is the preferred treatment; however, any duced nocturnal hypoglycemia without increasing
form of carbohydrate that contains glucose will in- HbA1c levels (24).
crease blood glucose level. Added fat and protein may Type 2 Diabetes
delay the acute glycemic response. Blood glucose re- A patient-centered approach should guide the
versal should be conrmed with SMBG after 15 min- choice of pharmacologic agents (18). Providers should
utes; if hypoglycemia persists, the process should be include efcacy; cost; potential side effects, including
repeated. Patients should be educated on situations effects on weight, comorbidities, and risk for hypogly-
that increase their risk for hypoglycemia, such as fasting cemia; and patient preferences when considering dif-
for tests or procedures, during or after exercise, and ferent agents (E rating).
during sleep.
Hypoglycemia unawareness is characterized by de-
cient counterregulatory hormone release and a dimin- Initial Therapy
ished autonomic response, both of which are risk fac- Newly diagnosed patients who are overweight or
tors for and caused by hypoglycemia. Patients with obese should begin lifestyle modications, including
hypoglycemia unawareness should be advised to in- physical activity, and be counseled to lose at least 5%
crease their glycemic targets for at least several weeks of their body weight.
544 Annals of Internal Medicine Vol. 164 No. 8 19 April 2016 www.annals.org
Healthy eating, weight control, increased physical activity, and diabetes education
Monotherapy
Metformin
Efficacy* High
Hypoglycemia risk Low risk
Weight Neutral/loss
Side effects GI/lactic acidosis
Costs* Low
If HbA1c target not achieved after about 3 mo of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference; choice dependent on a variety of patient- and disease-specific factors):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Dual therapy SU TZD DPP-4 inhibitor SGLT2 inhibitor GLP-1 receptor Insulin (basal)
agonist
Efficacy* High High Intermediate Intermediate High Highest
Hypoglycemia risk Moderate Low Low Low Low High
Weight Gain Gain Neutral Loss Loss Gain
Side effects Hypoglycemia Edema, HF, and Rare GU and GI Hypoglycemia
fractures dehydration
Costs* Low Low High High High Variable
If HbA1c target not achieved after about 3 mo of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference; choice dependent on a variety of patient- and disease-specific factors):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple therapy SU TZD DPP-4 inhibitor SGLT2 inhibitor GLP-1 receptor Insulin (basal)
+ + + + agonist +
+
TZD SU SU SU SU TZD
or Insulin or Insulin
If HbA1c target not achieved after about 3 mo of triple therapy and patient on oral combination therapy, move to injectables;
if patient receiving GLP-1 receptor agonist, add basal insulin; if patient receiving optimally titrated basal insulin, add
GLP-1 receptor agonist or mealtime insulin. In refractory patients, consider adding TZD or SGLT2 inhibitor:
Metformin
+
Combination
injectable Basal insulin + Mealtime insulin or GLP-1 receptor agonist
therapy
The order in the chart was determined by historical availability and the route of administration, with injectables to the right; it is not meant to denote
any specic preference. Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes mellitus are displayed, with the usual
transition moving vertically from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circum-
stances). Adapted with permission from Inzucchi and colleagues (18) and the American Diabetes Association. DPP-4 = dipeptidyl peptidase-4; GI =
gastrointestinal; GLP-1 = glucagon-like peptide-1; GU = genitourinary; HbA1c = hemoglobin A1c; HF = heart failure; SGLT2 = sodium glucose
cotransporter 2; SU = sulfonylurea; TZD = thiazolidinedione.
* See reference 18 for description of efcacy categorization.
Consider starting at this stage when the HbA1c level is 9% or greater.
Consider starting at this stage when blood glucose levels are 16.7 to 19.4 mmol/L (300 to 350 mg/dL) or greater and/or HbA1c levels are 10% to
12%, especially if symptomatic or catabolic features are present (in which case basal insulin plus mealtime insulin is the preferred initial regimen).
Usually a basal insulin (neutral protamine Hagedorn, glargine, detemir, or degludec).
improve cardiovascular outcomes, and treatment to a Lifestyle therapy for patients with diabetes and hy-
diastolic blood pressure goal of less than 70 mm Hg pertension should consist of weight loss, a reduced-
has been associated with higher mortality (36) (C rat- sodium diet, moderate alcohol intake, and increased
ing). physical activity. Pharmacologic therapy should com-
546 Annals of Internal Medicine Vol. 164 No. 8 19 April 2016 www.annals.org
www.annals.org Annals of Internal Medicine Vol. 164 No. 8 19 April 2016 549
assay into estimated average glucose values. Diabetes Care. 2008; J Med. 2008;359:1577-89. [PMID: 18784090] doi:10.1056/NEJ
31:1473-8. [PMID: 18540046] doi:10.2337/dc08-0545 Moa0806470
11. UK Prospective Diabetes Study (UKPDS) Group. Effect of inten- 26. UK Prospective Diabetes Study (UKPDS) Group. Effect of inten-
sive blood-glucose control with metformin on complications in over- sive blood-glucose control with metformin on complications in over-
weight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352: weight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:
854-65. [PMID: 9742977] 854-65. [PMID: 9742977]
12. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood- 27. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Met-
glucose control with sulphonylureas or insulin compared with con- formin in patients with type 2 diabetes and kidney disease: a system-
ventional treatment and risk of complications in patients with type 2 atic review. JAMA. 2014;312:2668-75. [PMID: 25536258] doi:10
diabetes (UKPDS 33). Lancet. 1998;352:837-53. [PMID: 9742976] .1001/jama.2014.15298
13. Pop-Busui R, Evans GW, Gerstein HC, Fonseca V, Fleg JL, Hoog- 28. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J,
werf BJ, et al; Action to Control Cardiovascular Risk in Diabetes et al; TECOS Study Group. Effect of sitagliptin on cardiovascular out-
Study Group. Effects of cardiac autonomic dysfunction on mortality comes in type 2 diabetes. N Engl J Med. 2015;373:232-42. [PMID:
risk in the Action to Control Cardiovascular Risk in Diabetes (AC- 26052984] doi:10.1056/NEJMoa1501352
CORD) trial. Diabetes Care. 2010;33:1578-84. [PMID: 20215456] doi: 29. Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like
10.2337/dc10-0125 peptide-1 receptor agonist and basal insulin combination treatment
14. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven for the management of type 2 diabetes: a systematic review and
PD, et al; VADT Investigators. Glucose control and vascular compli- meta-analysis. Lancet. 2014;384:2228-34. [PMID: 25220191] doi:10
cations in veterans with type 2 diabetes. N Engl J Med. 2009;360: .1016/S0140-6736(14)61335-0
129-39. [PMID: 19092145] doi:10.1056/NEJMoa0808431 30. MannKind Corporation. Brieng document: endocrinologic and
15. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, metabolic drug advisory committee: AFREZZA (insulin human [rDNA
et al; ADVANCE Collaborative Group. Intensive blood glucose con- origin]) inhalation powder: an ultra-rapid acting insulin treatment to
trol and vascular outcomes in patients with type 2 diabetes. N Engl J improve glycemic control in adult patients with diabetes mellitus. 1
Med. 2008;358:2560-72. [PMID: 18539916] doi:10.1056/NEJMoa April 2014. Accessed at www.fda.gov/downloads/AdvisoryCommittees
0802987 /CommitteesMeeting Materials/Drugs/EndocrinologicandMetabolic
16. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, Steinman MA. DrugsAdvisoryCommittee/UCM390865.pdf on 11 December
Potential overtreatment of diabetes mellitus in older adults with tight 2015.
glycemic control. JAMA Intern Med. 2015;175:356-62. [PMID: 31. U.S. Food and Drug Administration. FDA Drug Safety Commu-
25581565] doi:10.1001/jamainternmed.2014.7345
nication: FDA revises labels of SGLT2 inhibitors for diabetes to in-
17. Vijan S, Sussman JB, Yudkin JS, Hayward RA. Effect of patients'
clude warnings about too much acid in the blood and serious urinary
risks and preferences on health gains with plasma glucose level low-
tract infections. 15 May 2015. Accessed at www.fda.gov/Drugs
ering in type 2 diabetes mellitus. JAMA Intern Med. 2014;174:1227-
/DrugSafety/ucm475463.htm on 11 December 2015.
34. [PMID: 24979148] doi:10.1001/jamainternmed.2014.2894
32. Buse JB, Ginsberg HN, Bakris GL, Clark NG, Costa F, Eckel R,
18. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E,
et al; American Heart Association. Primary prevention of cardio-
Nauck M, et al. Management of hyperglycemia in type 2 diabetes,
vascular diseases in people with diabetes mellitus: a scientic
2015: a patient-centered approach: update to a position statement
statement from the American Heart Association and the American
of the American Diabetes Association and the European Association
Diabetes Association. Diabetes Care. 2007;30:162-72. [PMID:
for the Study of Diabetes. Diabetes Care. 2015;38:140-9. [PMID:
17192355]
25538310] doi:10.2337/dc14-2441
33. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a
19. Yeh HC, Brown TT, Maruthur N, Ranasinghe P, Berger Z, Suh YD,
multifactorial intervention on mortality in type 2 diabetes. N Engl
et al. Comparative effectiveness and safety of methods of insulin de-
livery and glucose monitoring for diabetes mellitus: a systematic re- J Med. 2008;358:580-91. [PMID: 18256393] doi:10.1056/NEJMoa
view and meta-analysis. Ann Intern Med. 2012;157:336-47. [PMID: 0706245
22777524] 34. Centers for Disease Control and Prevention, National Center for
20. Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Health Statistics, Division of Health Care Statistics. Crude and age-
Orchard TJ, et al; Diabetes Control and Complications Trial/Epide- adjusted hospital discharge rates for major cardiovascular disease as
miology of Diabetes Interventions and Complications (DCCT/EDIC) rst-listed diagnosis per 1,000 diabetic population, United States,
Study Research Group. Intensive diabetes treatment and cardiovas- 1988 2006. Atlanta, GA: Centers for Disease Control and Preven-
cular disease in patients with type 1 diabetes. N Engl J Med. 2005; tion; 2014. Accessed at www.cdc.gov/diabetes/statistics/cvdhosp
353:2643-53. [PMID: 16371630] /cvd/g3.htm on 30 November 2015.
21. DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and 35. Arguedas JA, Leiva V, Wright JM. Blood pressure targets for
type 2 diabetes mellitus: scientic review. JAMA. 2003;289:2254-64. hypertension in people with diabetes mellitus. Cochrane Database
[PMID: 12734137] Syst Rev. 2013;10:CD008277. [PMID: 24170669] doi:10.1002
22. Rosenstock J, Dailey G, Massi-Benedetti M, Fritsche A, Lin Z, /14651858.CD008277.pub2
Salzman A. Reduced hypoglycemia risk with insulin glargine: a meta- 36. McBrien K, Rabi DM, Campbell N, Barnieh L, Clement F, Hem-
analysis comparing insulin glargine with human NPH insulin in type 2 melgarn BR, et al. Intensive and standard blood pressure targets in
diabetes. Diabetes Care. 2005;28:950-5. [PMID: 15793205] patients with type 2 diabetes mellitus: systematic review and meta-
23. Chamberlain JJ, Dopita D, Gilgen E, Neuman A. Impact of fre- analysis. Arch Intern Med. 2012;172:1296-303. [PMID: 22868819]
quent and persistent use of continuous glucose monitoring (CGM) doi:10.1001/archinternmed.2012.3147
on hypoglycemia fear, frequency of emergency medical treatment, 37. Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo G,
and SMBG frequency after one year. J Diabetes Sci Technol. 2015. et al. Outcome results of the Fosinopril Versus Amlodipine
[PMID: 26353781] Cardiovascular Events Randomized Trial (FACET) in patients with hy-
24. Bergenstal RM, Klonoff DC, Garg SK, Bode BW, Meredith M, pertension and NIDDM. Diabetes Care. 1998;21:597-603. [PMID:
Slover RH, et al; ASPIRE In-Home Study Group. Threshold-based 9571349]
insulin-pump interruption for reduction of hypoglycemia. N Engl J 38. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N,
Med. 2013;369:224-32. [PMID: 23789889] doi:10.1056/NEJ Schrier RW. The effect of nisoldipine as compared with enalapril on
Moa1303576 cardiovascular outcomes in patients with non-insulin-dependent di-
25. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year abetes and hypertension. N Engl J Med. 1998;338:645-52. [PMID:
follow-up of intensive glucose control in type 2 diabetes. N Engl 9486993]
550 Annals of Internal Medicine Vol. 164 No. 8 19 April 2016 www.annals.org
www.annals.org Annals of Internal Medicine Vol. 164 No. 8 19 April 2016 551
with a combined intravenous and subcutaneous insulin glucose Technol Ther. 2011;13:121-6. [PMID: 21284478] doi:10.1089/dia
management strategy. Diabetes Care. 2007;30:823-8. [PMID: .2010.0124
17229943] 70. Shepperd S, Lannin NA, Clemson LM, McCluskey A, Cameron
69. Shomali ME, Herr DL, Hill PC, Pehlivanova M, Sharretts JM, Ma- ID, Barras SL. Discharge planning from hospital to home. Cochrane
gee MF. Conversion from intravenous insulin to subcutaneous insu- Database Syst Rev. 2013;1:CD000313. [PMID: 23440778] doi:10
lin after cardiovascular surgery: transition to target study. Diabetes .1002/14651858.CD000313.pub4
552 Annals of Internal Medicine Vol. 164 No. 8 19 April 2016 www.annals.org
Variable Value*
Hemoglobin A1c level <7.0%
Preprandial capillary plasma glucose 4.47.2 mmol/L (80130 mg/dL)
level
Peak postprandial capillary plasma <10.0 mmol/L (<180 mg/dL)
glucose level
* More or less stringent glycemic goals may be appropriate for indi-
vidual patients. Goals should be individualized on the basis of dura-
tion of diabetes, age/life expectancy, comorbid conditions, known car-
diovascular disease or advanced microvascular complications,
hypoglycemia unawareness, and individual patient considerations.
Postprandial glucose level may be targeted if hemoglobin A1c goals
are not met but preprandial glucose goals are. Postprandial glucose
measurements should be made 12 h after the beginning of the meal
(generally peak levels in patients with diabetes).
Patient/Disease Features
Disease duration
Newly diagnosed Long-standing
Usually not
modifiable
Life expectancy
Long Short
Important comorbidities
Absent Few/mild Severe
Depicted are patient and disease factors used to determine optimal HbA1c targets. Characteristics and predicaments toward the left justify more
stringent efforts to lower HbA1c level, and those toward the right suggest less stringent efforts. Adapted with permission from Inzucchi and
colleagues (18) and the American Diabetes Association. HbA1c = hemoglobin A1c.