For updates on the diagnosis and management of coexisting conditions during the coronavirus disease 2019 (COVID-19) pandemic, please see our topic "Management of coexisting conditions in the context of COVID-19".
The cornerstone of therapy for all patients with type 2 diabetes is a personalized management program that includes pharmacotherapy and ongoing self-management education by a diabetes education nurse or dietician.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
[70]Powers MA, Bardsley JK, Cypress M, et al. Diabetes self-management education and support in adults with type 2 diabetes: a consensus report of the American Diabetes Association, the Association of Diabetes Care & Education Specialists, the Academy of Nutrition and Dietetics, the American Academy of Family Physicians, the American Academy of PAs, the American Association of Nurse Practitioners, and the American Pharmacists Association. Diabetes Care. 2020 Jul;43(7):1636-49.
https://care.diabetesjournals.org/content/43/7/1636.long
http://www.ncbi.nlm.nih.gov/pubmed/32513817?tool=bestpractice.com
Diabetes self-management education promotes diabetes self-care and supports beneficial lifestyle changes on an ongoing basis.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
This requires general nutrition and health lifestyle knowledge and an individualized nutrition and exercise plan based on an initial assessment and treatment goals. Interventions that enhance self-management can significantly reduce diabetes distress.[71]Fisher L, Hessler D, Glasgow RE, et al. REDEEM: a pragmatic trial to reduce diabetes distress. Diabetes Care. 2013 Sep;36(9):2551-8.
https://care.diabetesjournals.org/content/36/9/2551.long
http://www.ncbi.nlm.nih.gov/pubmed/23735726?tool=bestpractice.com
If antihyperglycemic pharmacotherapy is required, the choice of agents should be individualized, taking into account patient values and preferences, the likelihood that an agent reduces all-cause or cardiovascular mortality, renal effects, adverse effects, costs, and other factors.
About 80% of adults with type 2 diabetes have concurrent dyslipidemias or hypertension, 70% are overweight or obese, and around 15% are current smokers.[12]Preis SR, Pencina MJ, Hwang SJ, et al. Trends in cardiovascular disease risk factors in individuals with and without diabetes mellitus in the Framingham Heart Study. Circulation. 2009 Jul 6;120(3):212-20.
https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.108.846519
http://www.ncbi.nlm.nih.gov/pubmed/19581493?tool=bestpractice.com
On average, adults with type 2 diabetes are up to twice as likely to die of stroke or myocardial infarction compared with those without diabetes, and they are more than 40 times more likely to die of macrovascular than microvascular complications of diabetes.[72]Hansen MB, Jensen ML, Carstensen B. Causes of death among diabetic patients in Denmark. Diabetologia. 2012 Feb;55(2):294-302.
http://www.ncbi.nlm.nih.gov/pubmed/22127411?tool=bestpractice.com
[73]Tancredi M, Rosengren A, Svensson AM, et al. Excess mortality among persons with type 2 diabetes. N Engl J Med. 2015 Oct 29;373(18):1720-32.
https://www.nejm.org/doi/full/10.1056/NEJMoa1504347
http://www.ncbi.nlm.nih.gov/pubmed/26510021?tool=bestpractice.com
[74]Desai JR, Vazquez-Benitez G, Xu Z, et al. Who must we target now to minimize future cardiovascular events and total mortality? Lessons from the surveillance, prevention and management of diabetes mellitus (SUPREME-DM) cohort study. Circ Cardiovasc Qual Outcomes. 2015 Sep;8(5):508-16.
https://www.ahajournals.org/doi/full/10.1161/circoutcomes.115.001717
http://www.ncbi.nlm.nih.gov/pubmed/26307132?tool=bestpractice.com
However, data indicate that adults with type 2 diabetes who optimally manage glucose, blood pressure (BP), lipids, smoking, and weight have a risk of major cardiovascular events that is not significantly above the risk of age and sex-matched non-diabetes peers.[75]Rawshani A, Rawshani A, Franzén S, et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2018 Aug 16;379(7):633-44.
https://www.nejm.org/doi/10.1056/NEJMoa1800256
http://www.ncbi.nlm.nih.gov/pubmed/30110583?tool=bestpractice.com
[76]Berkelmans GF, Gudbjörnsdottir S, Visseren FL, et al. Prediction of individual life-years gained without cardiovascular events from lipid, blood pressure, glucose, and aspirin treatment based on data of more than 500 000 patients with type 2 diabetes mellitus. Eur Heart J. 2019 Sep 7;40(34):2899-906.
http://www.ncbi.nlm.nih.gov/pubmed/30629157?tool=bestpractice.com
Therefore, care of adults with type 2 diabetes must include management of all major cardiovascular risk factors to individualized targets. In addition to glucose control, this includes smoking cessation, BP control, lipid control, antiplatelet use for patients with known coronary heart disease, and ACE inhibitors or angiotensin-II receptor antagonists for patients with chronic kidney disease (CKD) or proteinuria.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
[44]Cosentino F, Grant PJ, Aboyans V, et al; Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD). 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020 Jan 7;41(2):255-323. [Erratum in: Eur Heart J. 2020 December 1;41(45):4317.]
https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehz486/5556890
http://www.ncbi.nlm.nih.gov/pubmed/31497854?tool=bestpractice.com
[77]Cheng J, Zhang W, Zhang X, et al. Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis. JAMA Intern Med. 2014 May;174(5):773-85.
http://www.ncbi.nlm.nih.gov/pubmed/24687000?tool=bestpractice.com
In addition, use of antihyperglycemic agents such as sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists, which reduce cardiovascular or overall mortality, cardiovascular events, or CKD progression, may be especially beneficial in those with type 2 diabetes and at risk of/with established cardiovascular disease (CVD) or CKD regardless of the level of glucose management.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
[44]Cosentino F, Grant PJ, Aboyans V, et al; Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD). 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020 Jan 7;41(2):255-323. [Erratum in: Eur Heart J. 2020 December 1;41(45):4317.]
https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehz486/5556890
http://www.ncbi.nlm.nih.gov/pubmed/31497854?tool=bestpractice.com
[78]Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669-701.
https://care.diabetesjournals.org/content/41/12/2669.long
http://www.ncbi.nlm.nih.gov/pubmed/30291106?tool=bestpractice.com
[79]Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2020 Feb;43(2):487-93.
https://care.diabetesjournals.org/content/43/2/487.long
http://www.ncbi.nlm.nih.gov/pubmed/31857443?tool=bestpractice.com
[80]Rangaswami J, Bhalla V, de Boer IH, et al. Cardiorenal protection with the newer antidiabetic agents in patients with diabetes and chronic kidney disease: a scientific statement from the American Heart Association. Circulation. 2020 Oct 27;142(17):e265-86.
https://www.ahajournals.org/doi/10.1161/CIR.0000000000000920?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
http://www.ncbi.nlm.nih.gov/pubmed/32981345?tool=bestpractice.com
Diet
Nutrition therapy involves limiting caloric intake to achieve recommended weight, while offering a diversified and appealing menu of food choices.[81]Cradock KA, ÓLaighin G, Finucane FM, et al. Diet behavior change techniques in type 2 diabetes: a systematic review and meta-analysis. Diabetes Care. 2017 Dec;40(12):1800-10.
https://care.diabetesjournals.org/content/40/12/1800.long
http://www.ncbi.nlm.nih.gov/pubmed/29162585?tool=bestpractice.com
Nutrition advice needs to be tailored to the needs of each individual patient, preferably by a nutritionist.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
[33]Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 2019 May;42(5):731-54.
https://care.diabetesjournals.org/content/42/5/731.long
http://www.ncbi.nlm.nih.gov/pubmed/31000505?tool=bestpractice.com
The American Diabetes Association stresses that there is no ideal dietary macronutrient (carbohydrate, protein, and fat) distribution for people with diabetes, and that food plans should be individualized taking into account preferences and metabolic goals.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
Low-carbohydrate diets appear to be beneficial for glycemic control in type 2 diabetes management.[82]Ojo O, Ojo OO, Adebowale F, et al. The effect of dietary glycaemic index on glycaemia in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Nutrients. 2018 Mar 19;10(3):E373.
https://www.mdpi.com/2072-6643/10/3/373/htm
http://www.ncbi.nlm.nih.gov/pubmed/29562676?tool=bestpractice.com
Mediterranean diet and Dietary Approaches to Stop Hypertension (DASH) diets for people with hypertension have the best supporting evidence for use in patients with type 2 diabetes.[33]Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 2019 May;42(5):731-54.
https://care.diabetesjournals.org/content/42/5/731.long
http://www.ncbi.nlm.nih.gov/pubmed/31000505?tool=bestpractice.com
Saturated fat should be limited to <10% of calories.[33]Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 2019 May;42(5):731-54.
https://care.diabetesjournals.org/content/42/5/731.long
http://www.ncbi.nlm.nih.gov/pubmed/31000505?tool=bestpractice.com
Reducing sugary beverage consumption (including soda, energy drinks, and fruit juice) is of benefit to many patients.[33]Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 2019 May;42(5):731-54.
https://care.diabetesjournals.org/content/42/5/731.long
http://www.ncbi.nlm.nih.gov/pubmed/31000505?tool=bestpractice.com
Weight loss management programs with a healthy eating and physical activity plan resulting in an energy deficit have the potential for type 2 diabetes remission.[33]Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 2019 May;42(5):731-54.
https://care.diabetesjournals.org/content/42/5/731.long
http://www.ncbi.nlm.nih.gov/pubmed/31000505?tool=bestpractice.com
[83]Lean ME, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2018 Feb 10;391(10120):541-51.
http://www.ncbi.nlm.nih.gov/pubmed/29221645?tool=bestpractice.com
[84]Gregg EW, Chen H, Wagenknecht LE, et al; Look AHEAD Research Group. Association of an intensive lifestyle intervention with remission of type 2 diabetes. JAMA. 2012 Dec 19;308(23):2489-96.
https://jamanetwork.com/journals/jama/fullarticle/1486829
http://www.ncbi.nlm.nih.gov/pubmed/23288372?tool=bestpractice.com
The Diabetes Remission Clinical Trial (DiRECT) of supported weight loss management for people diagnosed with type 2 diabetes within the previous 6 years, and a body mass index (BMI) of 27 kg/m² to 45 kg/m², found that almost half of participants achieved remission to a non-diabetic state and off antidiabetic drugs at 12 months.[83]Lean ME, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2018 Feb 10;391(10120):541-51.
http://www.ncbi.nlm.nih.gov/pubmed/29221645?tool=bestpractice.com
At 2 years, more than a third of people with type 2 diabetes had sustained remission.[85]Lean ME, Leslie WS, Barnes AC, et al. Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial. Lancet Diabetes Endocrinol. 2019 May;7(5):344-55.
http://www.ncbi.nlm.nih.gov/pubmed/30852132?tool=bestpractice.com
Exercise and sleep
To improve glycemic control, assist with weight maintenance, and reduce cardiovascular risk, moderate physical activity is recommended as tolerated. The American College of Cardiology/American Heart Association has recommended that, in general, adults should engage in 3 to 4 sessions of aerobic physical activity per week, with each session lasting on average 40 minutes, and involving moderate- to vigorous-intensity physical activity.[86]Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):2960-84.
http://www.onlinejacc.org/content/63/25_Part_B/2960
http://www.ncbi.nlm.nih.gov/pubmed/24239922?tool=bestpractice.com
Walking frequently in proper footwear is a recommended activity.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
In addition, gentle strength training that targets all major muscle groups may be beneficial if done for 20 minutes 2 to 3 times per week on nonconsecutive days. Patients with severe or symptomatic heart disease may require evaluation before increasing levels of physical activity.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
People should be encouraged to limit the amount of time they spend being sedentary by avoiding extended amounts of time spent sitting.[87]Bull FC, Al-Ansari SS, Biddle S, et al. World Health Organization 2020 guidelines on physical activity and sedentary behaviour. Br J Sports Med. 2020 Dec;54(24):1451-62.
https://bjsm.bmj.com/content/54/24/1451.long
http://www.ncbi.nlm.nih.gov/pubmed/33239350?tool=bestpractice.com
Older adults may benefit from flexibility training and balance training 2 to 3 times/week (e.g., with yoga or tai chi).
An assessment of sleep duration and quality should be considered. Obesity, diabetes, hypertension, atrial fibrillation, and male sex are risk factors for sleep apnea, and inadequate sleep may affect glycemic control.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
Antihyperglycemic pharmacotherapy: initial considerations
HbA1c goals should be individualized.[88]Laiteerapong N, Cooper JM, Skandari MR, et al. Individualized glycemic control for US adults with type 2 diabetes: a cost-effectiveness analysis. Ann Intern Med. 2018 Feb 6;168(3):170-8.
http://www.ncbi.nlm.nih.gov/pubmed/29230472?tool=bestpractice.com
[89]Ismail-Beigi F, Moghissi E, Tiktin M, et al. Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials. Ann Intern Med. 2011 Apr 19;154(8):554-9.
http://www.ncbi.nlm.nih.gov/pubmed/21502652?tool=bestpractice.com
For many patients, the goal HbA1c <7% is appropriate. However, HbA1c 7.0% to 7.9% may be more appropriate in some patients, such as those with advanced age, limited life expectancy, known CVD, high risk of severe hypoglycemia, or difficulty achieving lower HbA1c goals despite use of multiple antihyperglycemic medications and insulin.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
Individualized HbA1c goals improve quality of life compared with uniform tight control.[89]Ismail-Beigi F, Moghissi E, Tiktin M, et al. Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials. Ann Intern Med. 2011 Apr 19;154(8):554-9.
http://www.ncbi.nlm.nih.gov/pubmed/21502652?tool=bestpractice.com
Pharmacotherapy is recommended to reduce risk of both microvascular (nephropathy, retinopathy, neuropathy) and macrovascular (myocardial infarction, stroke, peripheral vascular disease) complications, and is guided by HbA1c goals or a unique indication (presence of atherosclerotic CVD, heart failure, CKD).[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
[78]Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669-701.
https://care.diabetesjournals.org/content/41/12/2669.long
http://www.ncbi.nlm.nih.gov/pubmed/30291106?tool=bestpractice.com
[79]Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2020 Feb;43(2):487-93.
https://care.diabetesjournals.org/content/43/2/487.long
http://www.ncbi.nlm.nih.gov/pubmed/31857443?tool=bestpractice.com
[80]Rangaswami J, Bhalla V, de Boer IH, et al. Cardiorenal protection with the newer antidiabetic agents in patients with diabetes and chronic kidney disease: a scientific statement from the American Heart Association. Circulation. 2020 Oct 27;142(17):e265-86.
https://www.ahajournals.org/doi/10.1161/CIR.0000000000000920?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
http://www.ncbi.nlm.nih.gov/pubmed/32981345?tool=bestpractice.com
[90]UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998 Sep 12;352(9131):854-65.
http://www.ncbi.nlm.nih.gov/pubmed/9742977?tool=bestpractice.com
[91]Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008 Oct 9;359(15):1577-89.
https://www.nejm.org/doi/full/10.1056/NEJMoa0806470
http://www.ncbi.nlm.nih.gov/pubmed/18784090?tool=bestpractice.com
Antihyperglycemic medications that reduce all-cause or cardiovascular mortality, or major cardiovascular events or renal complications in some patient subgroups are metformin, SGLT2 inhibitors, and GLP-1 agonists.[92]Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia. 2017 Sep;60(9):1620-9.
https://link.springer.com/article/10.1007%2Fs00125-017-4337-9
http://www.ncbi.nlm.nih.gov/pubmed/28770324?tool=bestpractice.com
[93]Zelniker TA, Wiviott SD, Raz I, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation. 2019 Apr 23;139(17):2022-31.
http://www.ncbi.nlm.nih.gov/pubmed/30786725?tool=bestpractice.com
[94]Mahaffey KW, Jardine MJ, Bompoint S, et al. Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups. Circulation. 2019 Aug 27;140(9):739-50.
https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.119.042007
http://www.ncbi.nlm.nih.gov/pubmed/31291786?tool=bestpractice.com
[95]Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019 Oct;7(10):776-85.
http://www.ncbi.nlm.nih.gov/pubmed/31422062?tool=bestpractice.com
In older studies such as ACCORD, ADVANCE, and the Veterans Affairs Diabetes Trial (VADT), use of multiple drugs to achieve near-normal HbA1c was either not beneficial or increased mortality in type 2 diabetes patients with CVD or high CVD risk.[96]Gerstein HC, Miller ME, Genuth S, et al; ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011 Mar 3;364(9):818-28.
http://www.ncbi.nlm.nih.gov/pubmed/21366473?tool=bestpractice.com
[97]Patel A, MacMahon S, et al; ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008 Jun 6;358(24):2560-72.
https://www.nejm.org/doi/full/10.1056/NEJMoa0802987
http://www.ncbi.nlm.nih.gov/pubmed/18539916?tool=bestpractice.com
[98]Reaven PD, Emanuele NV, Wiitala WL, et al; VADT Investigators. Intensive glucose control in patients with type 2 diabetes - 15-year follow-up. N Engl J Med. 2019 Jun 6;380(23):2215-24.
http://www.ncbi.nlm.nih.gov/pubmed/31167051?tool=bestpractice.com
[99]Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009 Jan 8;360(2):129-39.
https://www.nejm.org/doi/full/10.1056/NEJMoa0808431
http://www.ncbi.nlm.nih.gov/pubmed/19092145?tool=bestpractice.com
[100]Gerstein HC, Miller ME, Byington RP, et al; Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2545-59.
https://www.nejm.org/doi/full/10.1056/NEJMoa0802743
http://www.ncbi.nlm.nih.gov/pubmed/18539917?tool=bestpractice.com
However, SGLT2 inhibitors were not available and GLP-1 agonists were infrequently used in those studies.
Metformin is the recommended first-choice therapy at diagnosis in the absence of contraindications because of its safety profile and likely cardiovascular benefit.[90]UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998 Sep 12;352(9131):854-65.
http://www.ncbi.nlm.nih.gov/pubmed/9742977?tool=bestpractice.com
[92]Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia. 2017 Sep;60(9):1620-9.
https://link.springer.com/article/10.1007%2Fs00125-017-4337-9
http://www.ncbi.nlm.nih.gov/pubmed/28770324?tool=bestpractice.com
Metformin may be safely used in patients with reduced estimated glomerular filtration rates (eGFRs), but it is contraindicated if eGFR <30 mL/minute/1.73 m².[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
[78]Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669-701.
https://care.diabetesjournals.org/content/41/12/2669.long
http://www.ncbi.nlm.nih.gov/pubmed/30291106?tool=bestpractice.com
Metformin should not be initiated if the eGFR is <45 mL/minute/1.73 m², and, for patients taking metformin whose eGFR falls to within the 30-45 mL/minute/1.73 m² range, continued use can be considered with close monitoring of renal function and a dose reduction.[78]Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669-701.
https://care.diabetesjournals.org/content/41/12/2669.long
http://www.ncbi.nlm.nih.gov/pubmed/30291106?tool=bestpractice.com
People who are unable to take metformin due to contraindications or intolerance can either use an alternative noninsulin agent or start insulin therapy. Basal-bolus insulin is used as initial treatment (without metformin) for those with type 2 diabetes and very high initial glucose levels (>300 mg/dL).
In patients with diabetes without diagnosed CVD, if metformin is used as initial treatment and fails to achieve goals after 3 months, a second agent may be added based on individualized assessment of necessary clinical benefit, safety considerations, costs, and patient preference:[78]Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669-701.
https://care.diabetesjournals.org/content/41/12/2669.long
http://www.ncbi.nlm.nih.gov/pubmed/30291106?tool=bestpractice.com
SGLT2 inhibitor: canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin
GLP-1 agonist: liraglutide, exenatide, lixisenatide, semaglutide, or dulaglutide
Dipeptidyl peptidase-4 (DPP-4) inhibitor: sitagliptin, saxagliptin, linagliptin, or alogliptin
Sulfonylurea: glimepiride or glipizide; meglitinides (e.g., repaglinide, nateglinide) are an alternative
Alpha-glucosidase inhibitor: acarbose or miglitol
Thiazolidinedione: pioglitazone or rosiglitazone
Insulin.
In patients with diabetes and with diagnosed CVD, heart failure, or CKD, metformin is used as initial treatment. Addition of a SGLT2 inhibitor or GLP-1 agonist is also recommended if not contraindicated, regardless of HbA1c and glycemic status, with choice of class dependent on comorbidity.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
Diagnosed atherosclerotic CVD favors either SGLT2 or GLP-1 therapy, while heart failure favors SGLT2 therapy and CKD favors SGLT2 therapy, with some benefit being demonstrated for GLP-1 therapy.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
[78]Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669-701.
https://care.diabetesjournals.org/content/41/12/2669.long
http://www.ncbi.nlm.nih.gov/pubmed/30291106?tool=bestpractice.com
[79]Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2020 Feb;43(2):487-93.
https://care.diabetesjournals.org/content/43/2/487.long
http://www.ncbi.nlm.nih.gov/pubmed/31857443?tool=bestpractice.com
[101]Das SR, Everett BM, Birtcher KK, et al. 2020 expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020 Sep 1;76(9):1117-45.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545583/
http://www.ncbi.nlm.nih.gov/pubmed/32771263?tool=bestpractice.com
SGLT2 inhibitor: canagliflozin, empagliflozin, or dapagliflozin may be preferred.
GLP-1 agonist: liraglutide, semaglutide, or dulaglutide may be preferred.
There are many appropriate 3-agent combinations of glucose-lowering therapy that do not involve insulin. Choice of second and third antihyperglycemic medications may differ depending on cardiovascular comorbidities.[78]Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669-701.
https://care.diabetesjournals.org/content/41/12/2669.long
http://www.ncbi.nlm.nih.gov/pubmed/30291106?tool=bestpractice.com
[79]Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2020 Feb;43(2):487-93.
https://care.diabetesjournals.org/content/43/2/487.long
http://www.ncbi.nlm.nih.gov/pubmed/31857443?tool=bestpractice.com
When 2- or 3-drug noninsulin regimens fail, basal insulin can be added. Bolus insulin can be subsequently added if needed to achieve or maintain adequate glucose control. To reduce the risk of hypoglycemia, a sulfonylurea is usually tapered if insulin is started.
Clinical properties of specific oral antihyperglycemic agents
Agents are often selected based on a discussion with the patient of the pros and cons of the agents. Agents that reduce all-cause or cardiovascular mortality may be preferred.[44]Cosentino F, Grant PJ, Aboyans V, et al; Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD). 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020 Jan 7;41(2):255-323. [Erratum in: Eur Heart J. 2020 December 1;41(45):4317.]
https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehz486/5556890
http://www.ncbi.nlm.nih.gov/pubmed/31497854?tool=bestpractice.com
Metformin can promote weight loss and may reduce cardiovascular events and mortality.[90]UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998 Sep 12;352(9131):854-65.
http://www.ncbi.nlm.nih.gov/pubmed/9742977?tool=bestpractice.com
[92]Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia. 2017 Sep;60(9):1620-9.
https://link.springer.com/article/10.1007%2Fs00125-017-4337-9
http://www.ncbi.nlm.nih.gov/pubmed/28770324?tool=bestpractice.com
SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin) inhibit renal glucose reabsorption. The resulting increase in glycosuria improves glycemic control, promotes weight loss, and has a diuretic effect that reduces BP.[102]Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015 Jan;75(1):33-59.
http://www.ncbi.nlm.nih.gov/pubmed/25488697?tool=bestpractice.com
There is evidence that use of SGLT2 inhibitors prevents major kidney outcomes (dialysis, transplantation, or death due to kidney disease) in people with type 2 diabetes.[103]Neuen BL, Young T, Heerspink HJL, et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2019 Nov;7(11):845-54.
http://www.ncbi.nlm.nih.gov/pubmed/31495651?tool=bestpractice.com
Empagliflozin and canagliflozin have been shown to reduce cardiovascular risk in people with CVD and type 2 diabetes, and may have renal benefits.[93]Zelniker TA, Wiviott SD, Raz I, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation. 2019 Apr 23;139(17):2022-31.
http://www.ncbi.nlm.nih.gov/pubmed/30786725?tool=bestpractice.com
[104]Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017 Aug 17;377(7):644-57.
https://www.nejm.org/doi/full/10.1056/NEJMoa1611925
http://www.ncbi.nlm.nih.gov/pubmed/28605608?tool=bestpractice.com
[105]Cherney DZ, Zinman B, Inzucchi SE, et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017 Aug;5(8):610-21.
http://www.ncbi.nlm.nih.gov/pubmed/28666775?tool=bestpractice.com
[94]Mahaffey KW, Jardine MJ, Bompoint S, et al. Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups. Circulation. 2019 Aug 27;140(9):739-50.
https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.119.042007
http://www.ncbi.nlm.nih.gov/pubmed/31291786?tool=bestpractice.com
[106]Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019 Jan 5;393(10166):31-39.
http://www.ncbi.nlm.nih.gov/pubmed/30424892?tool=bestpractice.com
Empagliflozin and canagliflozin have been shown to significantly reduce cardiovascular or all-cause mortality in those with diabetes and established CVD.[107]Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28.
https://www.nejm.org/doi/10.1056/NEJMoa1504720
http://www.ncbi.nlm.nih.gov/pubmed/26378978?tool=bestpractice.com
[108]Mahaffey KW, Neal B, Perkovic V, et al; CANVAS Program Collaborative Group. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2018 Jan 23;137(4):323-34.
https://www.ahajournals.org/doi/full/10.1161/circulationaha.117.032038
http://www.ncbi.nlm.nih.gov/pubmed/29133604?tool=bestpractice.com
[109]Rådholm K, Figtree G, Perkovic V, et al. Canagliflozin and heart failure in type 2 diabetes mellitus. Circulation. 2018 Jul 31;138(5):458-68.
https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.118.034222
http://www.ncbi.nlm.nih.gov/pubmed/29526832?tool=bestpractice.com
In one trial, treatment with dapaglifozin in patients with type 2 diabetes who had, or were at risk for, atherosclerotic CVD did not result in a lower rate of major adverse cardiovascular events, but did report a lower rate of cardiovascular death or hospitalization for heart failure.[110]Wiviott SD, Raz I, Bonaca MP, et al; DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019 Jan 24;380(4):347-57.
http://www.ncbi.nlm.nih.gov/pubmed/30415602?tool=bestpractice.com
Dapagliflozin also improves renal outcomes in patients with, and without, diabetes.[111]Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020 Oct 8;383(15):1436-46.
http://www.ncbi.nlm.nih.gov/pubmed/32970396?tool=bestpractice.com
One published trial on the CVD benefits of ertugliflozin supports its use in patients with diabetes and heart failure.[112]ClinicalTrials.gov. ERtugliflozin triAl in DIabetes With Preserved or Reduced ejeCtion FrAcTion mEchanistic Evaluation in Heart Failure (ERADICATE-HF). NCT03416270. May 2018 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03416270
[113]Cosentino F, Cannon CP, Cherney DZI, et al. Efficacy of ertugliflozin on heart failure-related events in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease: results of the VERTIS CV trial. Circulation. 2020 Dec 8;142(23):2205-15.
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.050255?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
http://www.ncbi.nlm.nih.gov/pubmed/33026243?tool=bestpractice.com
[114]Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020 Oct 8;383(15):1425-35.
https://www.nejm.org/doi/10.1056/NEJMoa2004967?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
http://www.ncbi.nlm.nih.gov/pubmed/32966714?tool=bestpractice.com
Adverse effects for different agents have included a higher rate of genital infections, diabetic ketoacidosis, acute kidney injury, fracture, and/or amputation.[115]US Food and Drug Administration (FDA). FDA drug safety communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. March 2020 [internet publication].
https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about
[116]US Food and Drug Administration (FDA). FDA drug safety communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). Jun 2016 [internet publication].
https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-kidney-warnings-diabetes-medicines-canagliflozin
[117]Ueda P, Svanström H, Melbye M, et al. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ. 2018 Nov 14;363:k4365.
https://www.bmj.com/content/363/bmj.k4365.long
http://www.ncbi.nlm.nih.gov/pubmed/30429124?tool=bestpractice.com
[118]McGill JB, Subramanian S. Safety of sodium-glucose co-transporter 2 inhibitors. Am J Cardiol. 2019 Dec 15;124(suppl 1):S45-52.
https://www.ajconline.org/article/S0002-9149(19)31179-8/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/31741440?tool=bestpractice.com
The Food and Drug Administration (FDA) and European Medicines Agency (EMA) warn of the potential increased risk of toe amputation with SGLT2 inhibitors and the need for appropriate monitoring.[119]European Medicines Agency (EMA). SGLT2 inhibitors: information on potential risk of toe amputation to be included in prescribing information. Feb 2017 [internet publication].
https://www.ema.europa.eu/en/documents/referral/sglt2-inhibitors-previously-canagliflozin-article-20-procedure-sglt2-inhibitors-information_en-0.pdf
[120]US Food and Drug Administration (FDA). FDA removes boxed warning about risk of leg and foot amputations for the diabetes medicine canagliflozin (invokana, invokamet, invokamet XR). 26 August 2020 [internet publication].
https://www.fda.gov/drugs/drug-safety-and-availability/fda-removes-boxed-warning-about-risk-leg-and-foot-amputations-diabetes-medicine-canagliflozin
[121]Heyward J, Mansour O, Olson L, et al. Association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and lower extremity amputation: a systematic review and meta-analysis. PLoS One. 2020;15(6):e0234065.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234065
http://www.ncbi.nlm.nih.gov/pubmed/32502190?tool=bestpractice.com
The FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA) warn of cases of necrotizing fasciitis of the perineum (also known as Fournier gangrene) observed in post-marketing surveillance of SGLT2 inhibitors.[122]US Food and Drug Administration (FDA). FDA drug safety communication: FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. Aug 2018 [internet publication].
https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrences-serious-infection-genital-area-sglt2-inhibitors-diabetes
[123]Medicines and Healthcare products Regulatory Agency (UK). SGLT2 inhibitors: reports of Fournier’s gangrene (necrotising fasciitis of the genitalia or perineum). Feb 2019 [internet publication].
https://www.gov.uk/drug-safety-update/sglt2-inhibitors-reports-of-fournier-s-gangrene-necrotising-fasciitis-of-the-genitalia-or-perineum
Thus, SGLT2 inhibitors should be avoided in patients with conditions that increase the risk for limb amputations, and in patients prone to urinary tract or genital infections.
GLP-1 agonists (liraglutide, exenatide, lixisenatide, semaglutide, dulaglutide) are suitable for obese patients without gastroparesis who desire weight loss, are willing to take injections, and can tolerate the common adverse effect of initial nausea.[124]Htike ZZ, Zaccardi F, Papamargaritis D, et al. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a systematic review and mixed-treatment comparison analysis. Diabetes Obes Metab. 2017 Apr;19(4):524-36.
http://www.ncbi.nlm.nih.gov/pubmed/27981757?tool=bestpractice.com
As a class of drugs, GLP-1 agonist treatment has beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes.[95]Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019 Oct;7(10):776-85.
http://www.ncbi.nlm.nih.gov/pubmed/31422062?tool=bestpractice.com
Liraglutide significantly reduced cardiovascular mortality and all-cause mortality in those with diabetes and CVD or high CVD risk in one randomized trial.[125]Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee on behalf of the LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016 Jul 28;375(4):311-22.
https://www.nejm.org/doi/full/10.1056/NEJMoa1603827
http://www.ncbi.nlm.nih.gov/pubmed/27295427?tool=bestpractice.com
Dulaglutide and semaglutide have both been shown to reduce major cardiovascular events, but not all-cause or cardiovascular mortality.[126]Gerstein HC, Colhoun HM, Dagenais GR, et al; REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019 Jul 13;394(10193):121-30.
http://www.ncbi.nlm.nih.gov/pubmed/31189511?tool=bestpractice.com
[127]Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016 Nov 10;375(19):1834-44.
https://www.nejm.org/doi/full/10.1056/NEJMoa1607141
http://www.ncbi.nlm.nih.gov/pubmed/27633186?tool=bestpractice.com
[128]Kaul S. Mitigating cardiovascular risk in type 2 diabetes with antidiabetes drugs: a review of principal cardiovascular outcome results of EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 trials. Diabetes Care. 2017 Jul;40(7):821-31.
https://care.diabetesjournals.org/content/40/7/821.long
http://www.ncbi.nlm.nih.gov/pubmed/28637887?tool=bestpractice.com
Semaglutide is the only GLP-1 agonist to also be available in an oral form.[129]Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019 Aug 29;381(9):841-51.
https://www.nejm.org/doi/10.1056/NEJMoa1901118?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
http://www.ncbi.nlm.nih.gov/pubmed/31185157?tool=bestpractice.com
Exenatide and lixisenatide have both been shown not to reduce major cardiovascular events.[130]Hu Y. Advances in reducing cardiovascular risk in the management of patients with type 2 diabetes mellitus. Chronic Dis Transl Med. 2019 Mar 15;5(1):25-36.
https://www.sciencedirect.com/science/article/pii/S2095882X18300653
http://www.ncbi.nlm.nih.gov/pubmed/30993261?tool=bestpractice.com
The MHRA warns of cases of diabetic ketoacidosis in patients with type 2 diabetes on a combination of a GLP-1 receptor agonist and insulin who had doses of concomitant insulin rapidly reduced or discontinued.[131]Medicines and Healthcare products Regulatory Agency (UK). GLP-1 receptor agonists: reports of diabetic ketoacidosis when concomitant insulin was rapidly reduced or discontinued. Jun 2019 [internet publication].
https://www.gov.uk/drug-safety-update/glp-1-receptor-agonists-reports-of-diabetic-ketoacidosis-when-concomitant-insulin-was-rapidly-reduced-or-discontinued
DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, alogliptin) are well tolerated, weight-neutral, but confer no mortality benefit.
Sulfonylureas (glipizide, glimepiride, glyburide) are the subject of long clinical experience and may reduce microvascular complications, but confer no mortality benefit and may cause weight gain and hypoglycemia.[78]Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669-701.
https://care.diabetesjournals.org/content/41/12/2669.long
http://www.ncbi.nlm.nih.gov/pubmed/30291106?tool=bestpractice.com
Along with metformin and human insulin, these are among the more affordable antihyperglycemic medications.[132]World Health Organization. Guidelines on second- and third-line medicines and type of insulin for the control of blood glucose levels in non-pregnant adults with diabetes mellitus. 2018 [internet publication].
https://apps.who.int/iris/bitstream/handle/10665/272433/9789241550284-eng.pdf?ua=1
Alpha-glucosidase inhibitors (acarbose, miglitol) can be added to metformin in people with large postprandial glucose excursions, but increased flatus and gastrointestinal side effects are common. There is no strong evidence of a benefit on all-cause or cardiovascular mortality.
Thiazolidinediones (pioglitazone, rosiglitazone) lower blood sugar effectively but more than double the risk of congestive heart failure, often causing weight gain and edema.[78]Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669-701.
https://care.diabetesjournals.org/content/41/12/2669.long
http://www.ncbi.nlm.nih.gov/pubmed/30291106?tool=bestpractice.com
They may cause anemia and increase fracture rates in both women and men. In addition, rosiglitazone raises low-density lipoprotein (LDL)-cholesterol and mixed evidence suggests rosiglitazone may increase the risk of cardiovascular events.[133]Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007 Jun 14;356(24):2457-71.
https://www.nejm.org/doi/full/10.1056/NEJMoa072761
http://www.ncbi.nlm.nih.gov/pubmed/17517853?tool=bestpractice.com
Rosiglitazone has been removed from the European market due to persistent safety concerns.[134]European Medicines Agency (EMA). Questions and answers on the suspension of rosiglitazone-containing medicines (Avandia, Avandamet and Avaglim). Sep 2010 [internet publication].
https://www.ema.europa.eu/en/documents/medicine-qa/questions-answers-suspension-rosiglitazone-containing-medicines-avandia-avandamet-avaglim_en.pdf
However, in 2013, the FDA lifted previous restrictions applied to rosiglitazone in the US, based on newer data.[135]Bach RG, Brooks MM, Lombardero M, et al; BARI 2D Investigators. Rosiglitazone and outcomes for patients with diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Circulation. 2013 Aug 20;128(8):785-94.
https://ahajournals.org/doi/full/10.1161/circulationaha.112.000678
http://www.ncbi.nlm.nih.gov/pubmed/23857320?tool=bestpractice.com
As a result of an updated review, the FDA has concluded that use of pioglitazone may be linked to an increased risk of bladder cancer.[136]US Food and Drug Administration (FDA). FDA drug safety communication: updated FDA review concludes that use of type 2 diabetes medicine pioglitazone may be linked to an increased risk of bladder cancer. Dec 2016 [internet publication].
https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-updated-fda-review-concludes-use-type-2-diabetes-medicine-pioglitazone
Bromocriptine and colesevelam are oral agents approved by the FDA for glucose-lowering. They have limited impact on blood glucose in many patients.
[
]
In people with type 2 diabetes mellitus, what are the effects of adding colesevelam to other antidiabetic agents?/cca.html?targetUrl=https://cochranelibrary.com/cca/doi/10.1002/cca.170/fullShow me the answer Bromocriptine may cause gastrointestinal side effects. Colesevelam, originally approved as a bile-acid sequestrant, requires multiple doses per day, and may bind other medications. Neither of these agents is widely used for glucose control at present.
Insulin therapy
Insulin therapy is required for severe hyperglycemia and is an option when metformin monotherapy or multidrug regimens are inadequate.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
Because of the progressive loss of beta-cell function that characterizes the natural history of type 2 diabetes, insulin therapy is often required over time to overcome the insulin deficiency that accompanies progressive beta-cell loss in longer-standing type 2 diabetes.
Insulin treatment should be considered at the time of diagnosis if glucose level is ≥300 mg/dL or if HbA1c is ≥10%. Metformin is typically used adjunctively, in the absence of nausea, vomiting, or volume depletion.
For individuals with severe hyperglycemia (HbA1c ≥11%; or fasting or postprandial glucose >350 mg/dL), or individuals with metabolic compromise related to hyperglycemia (polyuria, polydipsia, ongoing weight loss) but without ketonuria or dehydration, both basal (background) and bolus (mealtime/prandial) insulin are typically recommended to reverse symptoms rapidly.[78]Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669-701.
https://care.diabetesjournals.org/content/41/12/2669.long
http://www.ncbi.nlm.nih.gov/pubmed/30291106?tool=bestpractice.com
For individuals with less dramatic hyperglycemia, insulin can often be initiated with long-acting basal insulin at bedtime.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
Some patients' blood sugars can be well controlled with a combination of noninsulin therapy and one injection of basal insulin. However, some patients will need to use both a long-acting basal insulin (e.g., detemir, glargine, or degludec) injection once daily and rapid-acting insulin (e.g., lispro, aspart, or glulisine) injected before each meal.
Intermediate (NPH) and short-acting (regular) insulins are other choices for basal-bolus regimens. For patients with type 2 diabetes, observational studies suggest human insulins can be as effective as analog insulins for glucose control, serious hypoglycemia risk, and mortality and cardiovascular events.[137]Fullerton B, Siebenhofer A, Jeitler K, et al. Short-acting insulin analogues versus regular human insulin for adult, non-pregnant persons with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2018 Dec 17;(12):CD013228.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013228/full
http://www.ncbi.nlm.nih.gov/pubmed/30556900?tool=bestpractice.com
[
]
How do short‐acting insulin analogues compare with regular human insulin for adults with type 2 diabetes mellitus?/cca.html?targetUrl=https://www.cochranelibrary.com/cca/doi/10.1002/cca.2514/fullShow me the answer Human insulins are significantly less expensive than analog insulins. For individuals with relaxed HbA1c goals, low rates of hypoglycemia, and prominent insulin resistance, as well as those with cost concerns, human insulin (NPH and regular) may be the appropriate choice of therapy.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
Premixed insulin is available in various ratios of rapid-acting/NPH and regular/NPH insulin combinations. When injected before (typically) breakfast and dinner meals, premixed insulin can sometimes be used effectively to cover both basal and prandial insulin needs in appropriate individuals (desire for no more than 2 injections per day, less insulin-sensitive and hypoglycemia-prone, and willing to eat consistent meals on a reasonably consistent schedule). For many, the greater flexibility and adaptability of a basal (background) and bolus (mealtime) regimen outweighs the potential convenience of premixed insulin.
Regimens should be individualized. Insulin delivery devices (insulin pens) that can be adjusted to administer set doses of insulin are widely available, and offer increased convenience and accuracy in insulin dosing. Less frequently, insulin pumps and patch pump systems are used in individuals with type 2 diabetes requiring multiple daily dose insulin. While allowing improved precision in insulin administration and dosing, insulin pump systems require significant engagement and involvement by the individuals using the systems to achieve clinical benefits beyond multiple daily dose injection-based therapy.
Metformin therapy is typically started or continued at the time of initiation of insulin in type 2 diabetes, unless contraindicated. While consideration should be given to discontinuing sulfonylurea therapy in individuals initiating insulin therapy because of additive hypoglycemia risk, other noninsulin therapies can often be continued if an individual is benefiting.[138]DeVries JH, Meneghini L, Barnett AH, et al. A patient-level analysis of efficacy and hypoglycaemia outcomes across treat-to-target trials with insulin glargine added to oral antidiabetes agents in people with type 2 diabetes. Eur Endocrinol. 2014 Feb;10(1):23-30.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983093/
http://www.ncbi.nlm.nih.gov/pubmed/29872460?tool=bestpractice.com
In particular, individuals on SGLT2 or GLP-1 therapy because of unique indications (atherosclerotic cardiovascular disease [ASCVD], heart failure, CKD) can be continued on those therapies when initiating insulin.
Exogenous insulin is a very effective way to lower serum glucose and lower HbA1c, but its use must be guided in most patients by regular self-monitored blood glucose testing (fingerstick blood glucose testing) or continuous glucose monitoring. Hypoglycemia (glucose ≤70 mg/dL) is the most serious potential complication of insulin therapy. Another significant side effect is weight gain. Less common side effects may include hunger, nausea, diaphoresis, injection site irritation, or anaphylaxis.
Correction doses of insulin
When basal-bolus insulin is used by motivated and knowledgeable patients, the dose of rapid-acting insulin that is administered before each meal can be based on anticipated carbohydrate content of the upcoming meal and sometimes adjusted for anticipated physical activity (carbohydrate-based dosing, sometimes called “carb-counting”), rather than administered as a fixed mealtime dose. Correctional doses of rapid-acting insulin can also be applied based on premeal blood sugar readings (correctional algorithms). One acceptable method of determining a correction algorithm is to divide 1800 by the total daily dose of insulin to yield the expected blood sugar reduction per unit of insulin. For example, for a patient taking 60 units of insulin per day, the expected blood sugar lowering of 1 additional unit of insulin would be 1800/60=30 mg/dL.
Cardiovascular risk management
Blood pressure
Blood pressure (BP) guidelines differ regarding recommended targets for those with diabetes.
The 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guideline for management of high BP in adults recommends BP <130/80 mmHg for people with diabetes, and classifies BP using the following categories:[69]Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018 May 15;71(19):e127-248.
http://www.onlinejacc.org/content/71/19/e127
http://www.ncbi.nlm.nih.gov/pubmed/29146535?tool=bestpractice.com
normal (<120/80 mmHg)
elevated (120-129/<80 mmHg)
stage 1 (130-139/80-89 mmHg)
stage 2 hypertension (≥140/90 mmHg).
The American Diabetes Association (ADA) Standards of Medical Care in Diabetes recommends goal BP <140/90 mmHg for people with diabetes, with consideration of a goal BP <130/80 mmHg for those with established hypertension and diabetes and who have established CVD or 10-year cardiovascular risk greater than 15%.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
[139]James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5;311(5):507-20.
https://jamanetwork.com/journals/jama/fullarticle/1791497
http://www.ncbi.nlm.nih.gov/pubmed/24352797?tool=bestpractice.com
Regardless of specific BP goal, initial treatment with an ACE inhibitor, an angiotensin-II receptor antagonist, a calcium-channel blocker, or a thiazide (or thiazide-like) diuretic is preferred. Black people may benefit most from a thiazide diuretic or a calcium-channel blocker.[139]James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5;311(5):507-20.
https://jamanetwork.com/journals/jama/fullarticle/1791497
http://www.ncbi.nlm.nih.gov/pubmed/24352797?tool=bestpractice.com
ACE inhibitors may reduce mortality and cardiovascular events more than angiotensin-II receptor antagonists.[77]Cheng J, Zhang W, Zhang X, et al. Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis. JAMA Intern Med. 2014 May;174(5):773-85.
http://www.ncbi.nlm.nih.gov/pubmed/24687000?tool=bestpractice.com
Combination drug therapy (with ACE inhibitor/angiotensin-II receptor antagonist, calcium-channel blocker, thiazide diuretic) is often required to reach BP goals. Combined use of an ACE inhibitor and an angiotensin-II receptor antagonist is not recommended due to increased risk of adverse events.[140]Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013 Nov 14;369(20):1892-903.
https://www.nejm.org/doi/full/10.1056/NEJMoa1303154
http://www.ncbi.nlm.nih.gov/pubmed/24206457?tool=bestpractice.com
However, most people with chronic kidney disease (CKD) should receive an ACE inhibitor or an angiotensin-II receptor antagonist as part of their antihypertensive regimen.[139]James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5;311(5):507-20.
https://jamanetwork.com/journals/jama/fullarticle/1791497
http://www.ncbi.nlm.nih.gov/pubmed/24352797?tool=bestpractice.com
CKD is defined as (a) age <70 years with glomerular filtration rate (GFR) <60 mL/minute/1.73 m², or (b) people of any age with albuminuria >30 mg albumin/g of creatinine at any level of GFR.
Consider initiation and titration of two antihypertensive medications along with lifestyle therapy if BP ≥160/100 mmHg.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
Beta-blockers are not contraindicated in people with diabetes but are less-preferred antihypertensive agents[139]James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5;311(5):507-20.
https://jamanetwork.com/journals/jama/fullarticle/1791497
http://www.ncbi.nlm.nih.gov/pubmed/24352797?tool=bestpractice.com
and may mask symptoms of hypoglycemia.
If BP remains uncontrolled on first-line therapies, discontinue or minimize interfering substances such as nonsteroidal anti-inflammatory drugs (NSAIDs), evaluate for secondary causes of hypertension (including obstructive sleep apnea), and consider the addition of a mineralocorticoid receptor agonist,[141]Williams B, MacDonald TM, Morant S, et al; British Hypertension Society's PATHWAY Studies Group. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015 Nov 21;386(10008):2059-68.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00257-3/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/26414968?tool=bestpractice.com
and/or refer to a hypertension specialist.
BP goals and guidelines are evolving as more studies are carried out. The Systolic Blood Pressure Intervention Trial (SPRINT) was terminated early, as it found that a lower systolic target of 120 mmHg reduced cardiovascular complications and deaths in people over age 50 years with high BP and at least one additional risk factor for heart disease.[142]Wright JT Jr, Williamson JD, et al; SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015 Nov 9;373(22):2103-16.
https://www.nejm.org/doi/10.1056/NEJMoa1511939
http://www.ncbi.nlm.nih.gov/pubmed/26551272?tool=bestpractice.com
However, people with diabetes were excluded from this trial.
There is an increasing emphasis to incorporate the use of home BP monitoring into the diagnosis and management of hypertension in adults, including those with diabetes.[143]Margolis KL, Asche SE, Bergdall AR, et al. Effect of home blood pressure telemonitoring and pharmacist management on blood pressure control: a cluster randomized clinical trial. JAMA. 2013 Jul 3;310(1):46-56.
https://jamanetwork.com/journals/jama/fullarticle/1707720
http://www.ncbi.nlm.nih.gov/pubmed/23821088?tool=bestpractice.com
Lipids
The ACC/AHA guidelines recommend high-intensity statin therapy if tolerated in adults aged over 21 years if the patient has clinical ASCVD or LDL-cholesterol ≥190 mg/dL.[68]Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139(25):e1082-1143.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000625
http://www.ncbi.nlm.nih.gov/pubmed/30586774?tool=bestpractice.com
In those ages 40 to 75 years with diabetes but no ASCVD, moderate-intensity statin therapy should be considered.
[
]
Is there randomized controlled trial evidence to support the use of statins for the primary prevention of cardiovascular disease?/cca.html?targetUrl=https://cochranelibrary.com/cca/doi/10.1002/cca.334/fullShow me the answer In those with diabetes and 10-year ACC/AHA cardiovascular risk greater than 20%, consider adding ezetimibe to maximally-tolerated statin therapy to reduce LDL by 50% or more.[68]Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139(25):e1082-1143.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000625
http://www.ncbi.nlm.nih.gov/pubmed/30586774?tool=bestpractice.com
In diabetes patients over age 75 years, it is reasonable to consider and discuss with the patient advantages and disadvantages of initiation or continuation of statin therapy.[68]Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139(25):e1082-1143.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000625
http://www.ncbi.nlm.nih.gov/pubmed/30586774?tool=bestpractice.com
In those ages 20 to 39 years with diabetes, it may be reasonable to initiate statin therapy in the presence of albuminuria, estimated GFR <60 mL/minute/1.73 m², retinopathy, or neuropathy.[68]Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139(25):e1082-1143.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000625
http://www.ncbi.nlm.nih.gov/pubmed/30586774?tool=bestpractice.com
Statins are contraindicated in pregnancy.
The ADA recommends that management of lipid abnormalities is driven by risk status rather than LDL cholesterol level.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
Risk factors for CVD include LDL-cholesterol >100 mg/dL, high BP, smoking, and overweight and obesity. Lifestyle therapy is recommended for all people. For people with diabetes and overt CVD, high-intensity statin therapy is added to lifestyle therapy, regardless of baseline lipid values. High-intensity statin therapy is also considered for those over age 40 years without overt CVD, but with one or more CVD risk factors. For people with diabetes over age 40 years without additional CVD risk factors, moderate-intensity statin therapy is still considered. For some people with diabetes and established coronary heart disease who have persistently elevated LDL despite maximally-tolerated statin therapy, addition of ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (e.g., alirocumab, evolocumab) may confer clinical benefit.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
[144]Giugliano RP, Cannon CP, Blazing MA, et al; IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) Investigators. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation. 2018 Apr 10;137(15):1571-82.
http://www.ncbi.nlm.nih.gov/pubmed/29263150?tool=bestpractice.com
[145]Sabatine MS, Giugliano RP, Keech AC, et al; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017 May 4;376(18):1713-22.
https://www.nejm.org/doi/10.1056/NEJMoa1615664
http://www.ncbi.nlm.nih.gov/pubmed/28304224?tool=bestpractice.com
[146]Squizzato A, Suter MB, Nerone M, et al. PCSK9 inhibitors for treating dyslipidemia in patients at different cardiovascular risk: a systematic review and a meta-analysis. Intern Emerg Med. 2017 Oct;12(7):1043-53.
http://www.ncbi.nlm.nih.gov/pubmed/28695455?tool=bestpractice.com
In individuals with established CVD, or high cardiovascular risk on a statin with controlled LDL cholesterol but elevated triglycerides, the addition of icosapent ethyl has been shown to modestly reduce cardiovascular events.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
[147]Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22.
https://www.nejm.org/doi/10.1056/NEJMoa1812792?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
http://www.ncbi.nlm.nih.gov/pubmed/30415628?tool=bestpractice.com
Smoking cessation
Patients who smoke should be provided with smoking cessation resources, and be provided with smoking cessation assistance such as medications and counseling as appropriate. Varenicline combined with nicotine replacement therapy may be more effective than varenicline alone.[148]Koegelenberg CF, Noor F, Bateman ED, et al. Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized clinical trial. JAMA. 2014 Jul;312(2):155-61.
http://www.ncbi.nlm.nih.gov/pubmed/25005652?tool=bestpractice.com
The ADA does not support e-cigarettes as an alternative to smoking or to facilitate smoking cessation.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
Antiplatelet therapy
Adults with CVD should receive aspirin for secondary prevention. Clopidogrel is an alternative for patients with aspirin allergy or intolerance. Dual antiplatelet therapy is reasonable for up to 12 months after an acute coronary syndrome. The main adverse effect is an increased risk of gastrointestinal bleeding.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
[149]Squizzato A, Bellesini M, Takeda A, et al. Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular events. Cochrane Database Syst Rev. 2017 Dec 14;(12):CD005158.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD005158.pub4/full
http://www.ncbi.nlm.nih.gov/pubmed/29240976?tool=bestpractice.com
The ADA recommends that aspirin therapy be considered for primary prevention in adults with type 2 diabetes ages 50 to 70 years who are at increased cardiovascular risk (family history of premature CVD, hypertension, dyslipidemias, smoking, CKD/albuminuria), unless they are at high risk of serious bleeding.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
For patients aged over 70 years, the risk of bleeding increases and aspirin is generally not recommended for primary prevention in this population.[150]Patel NJ, Baliga RR. Role of aspirin for primary prevention in persons with diabetes mellitus and in the elderly. Curr Cardiol Rep. 2020 May 29;22(7):48.
http://www.ncbi.nlm.nih.gov/pubmed/32472363?tool=bestpractice.com
US Preventive Services Task Force (USPSTF) recommendations for primary prevention of heart attack or stroke in those ages 50 to 70 years are similar.[151]Bibbins-Domingo K; US Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2016 Jun 21;164(12):836-45.
https://annals.org/aim/fullarticle/2513179/aspirin-use-primary-prevention-cardiovascular-disease-colorectal-cancer-u-s
http://www.ncbi.nlm.nih.gov/pubmed/27064677?tool=bestpractice.com
Bariatric surgery for treatment of diabetes in patients with obesity
Randomized clinical trials have shown a benefit from bariatric surgery (also referred to as metabolic surgery) with regard to diabetes remission, glycemic control, need for glucose-lowering medications, quality of life, and reduction in cardiovascular risk factor markers over the short term (e.g., 1-3 years) in people with type 2 diabetes compared with medical therapy alone,[152]Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012 Apr 26;366(17):1567-76.
https://www.nejm.org/doi/10.1056/NEJMoa1200225
http://www.ncbi.nlm.nih.gov/pubmed/22449319?tool=bestpractice.com
[153]Schauer PR, Bhatt DL, Kirwan JP, et al; STAMPEDE Investigators. Bariatric surgery versus intensive medical therapy for diabetes - 5-year outcomes. N Engl J Med. 2017 Feb 16;376(7):641-51.
https://www.nejm.org/doi/10.1056/NEJMoa1600869
http://www.ncbi.nlm.nih.gov/pubmed/28199805?tool=bestpractice.com
[154]Kashyap SR, Bhatt DL, Wolski K, et al. Metabolic effects of bariatric surgery in patients with moderate obesity and type 2 diabetes: analysis of a randomized control trial comparing surgery with intensive medical treatment. Diabetes Care. 2013 Aug;36(8):2175-82.
https://care.diabetesjournals.org/content/36/8/2175.long
http://www.ncbi.nlm.nih.gov/pubmed/23439632?tool=bestpractice.com
[155]Ikramuddin S, Korner J, Lee WJ, et al. Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial. JAMA. 2013 Jun 5;309(21):2240-9.
https://jamanetwork.com/journals/jama/fullarticle/1693889
http://www.ncbi.nlm.nih.gov/pubmed/23736733?tool=bestpractice.com
[156]Halperin F, Ding SA, Simonson DC, et al. Roux-en-Y gastric bypass surgery or lifestyle with intensive medical management in patients with type 2 diabetes: feasibility and 1-year results of a randomized clinical trial. JAMA Surg. 2014 Jul;149(7):716-26.
https://jamanetwork.com/journals/jamasurgery/fullarticle/1876617
http://www.ncbi.nlm.nih.gov/pubmed/24899464?tool=bestpractice.com
as well as for possible prevention of type 2 diabetes.[157]Carlsson LM, Peltonen M, Ahlin S, et al. Bariatric surgery and prevention of type 2 diabetes in Swedish obese subjects. N Engl J Med. 2012 Aug 23;367(8):695-704.
https://www.nejm.org/doi/10.1056/NEJMoa1112082
http://www.ncbi.nlm.nih.gov/pubmed/22913680?tool=bestpractice.com
Cohort studies suggest that both Roux en Y bypass and sleeve gastrectomy procedures lead to diabetes remission that lasts a mean of about 5 years in more than half of patients, and significantly reduce mortality, stroke, myocardial infarction, and microvascular complications in those with type 2 diabetes.[158]Yska JP, van Roon EN, de Boer A, et al. Remission of type 2 diabetes mellitus in patients after different types of bariatric surgery: a population-based cohort study in the United Kingdom. JAMA Surg. 2015 Dec;150(12):1126-33.
https://jamanetwork.com/journals/jamasurgery/fullarticle/2446843
http://www.ncbi.nlm.nih.gov/pubmed/26422580?tool=bestpractice.com
[159]Fisher DP, Johnson E, Haneuse S, et al. Association between bariatric surgery and macrovascular disease outcomes in patients with type 2 diabetes and severe obesity. JAMA. 2018 Oct 16;320(15):1570-82.
https://jamanetwork.com/journals/jama/fullarticle/2707461
http://www.ncbi.nlm.nih.gov/pubmed/30326126?tool=bestpractice.com
[160]O'Brien R, Johnson E, Haneuse S, et al. Microvascular outcomes in patients with diabetes after bariatric surgery versus usual care: a matched cohort study. Ann Intern Med. 2018 Sep 4;169(5):300-10.
http://www.ncbi.nlm.nih.gov/pubmed/30083761?tool=bestpractice.com
Compared with sleeve gastrectomy, Roux en Y leads to somewhat greater weight loss and other benefits, but is a more technically challenging operation with higher reoperation and readmission rates, and more of a tendency to malabsorption of vitamins and minerals postoperatively. The benefits and risks of bariatric surgery also vary substantially across type 2 diabetes patient subgroups. In observational studies, average benefits appeared to be highest in those who are younger (age 40-50 years), those with more recent onset of type 2 diabetes, and those not on insulin therapy.[161]Park JY. Prediction of type 2 diabetes remission after bariatric or metabolic surgery. J Obes Metab Syndr. 2018 Dec 30;27(4):213-22.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513303/
http://www.ncbi.nlm.nih.gov/pubmed/31089566?tool=bestpractice.com
Health insurers in the US generally restrict payment for bariatric surgery, but the eligibility criteria have been slowly expanding over time. Bariatric surgery may be considered for adults with BMI ≥40 kg/m² (≥37.5 kg/m² for Asian-Americans) with any level of glycemic control/any complexity of glucose-lowering regimen.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
Surgery may also be considered for adults with BMI 35.0 to 39.9 kg/m² (32.5 to 37.4 kg/m² for Asian-Americans) with hyperglycemia inadequately controlled despite lifestyle and optimal medical management, and may be considered for those with BMI 30.0 to 34.9 kg/m² (27.5 to 32.4 kg/m² for Asian-Americans) with hyperglycemia inadequately controlled despite optimal use of oral or injectable medications (including insulin).[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
Bariatric surgery is best done in a high-volume, specialized center.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
Treatment of diabetes in pregnancy
Good glucose control with HbA1c as close to normal as is safely possible (ideally HbA1c <6.5% [48 mmol/mol]) before conception and during pregnancy optimizes maternal and fetal health outcomes.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
[162]Tieu J, Middleton P, Crowther CA, et al. Preconception care for diabetic women for improving maternal and infant health. Cochrane Database Syst Rev. 2017 Aug 11;(8):CD007776.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007776.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/28799164?tool=bestpractice.com
American Diabetes Association guidelines recommend the following blood glucose targets in pregnant women with preexisting type 2 diabetes (the same as for gestational diabetes): <95 mg/dL fasting, and either ≤140 mg/dL 1-hour postprandially or ≤120 mg/dL 2-hour postprandially, with HbA1c goal individualized between <6% and <6.5% or up to <7% as necessary to prevent hypoglycemia.[2]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. January 2020;43(suppl 1):S1-207.
https://care.diabetesjournals.org/content/43/Supplement_1
In clinical practice, insulin is usually used when nutrition therapy fails to achieve these goals. NPH insulin may be combined with human short-acting or analog rapid-acting insulin. Long-acting analog insulins (glargine, detemir, or degludec) are not FDA-approved in pregnancy. ACE inhibitors, angiotensin-II receptor antagonists, and beta-blockers are not recommended in pregnancy and should be avoided. Statins are contraindicated in pregnancy. Retinal exam in those with diabetes prior to pregnancy should be performed prior to, during, and after pregnancy. Women with diabetes who anticipate pregnancy or who are pregnant benefit from care supervision by a specialized center whenever possible.
Care delivery models
Diabetes care in the US has, on average, dramatically improved in the past 20 years, with a 50% reduction in mortality rates, cardiovascular mortality rates, and cardiovascular event rates in adults with diabetes.[20]National Institute of Diabetes and Digestive and Kidney Diseases. Diabetes in America. 3rd edition. Bethesda, MD: National Institutes of Health, NIH Pub No. 17-1468; 2018.
https://www.niddk.nih.gov/about-niddk/strategic-plans-reports/diabetes-in-america-3rd-edition
Many factors have contributed to diabetes care improvement and better clinical outcomes for patients.[163]Ali MK, Bullard KM, Saaddine JB, et al. Achievement of goals in US diabetes care, 1999-2010. N Engl J Med. 2013 Apr 25;368(17):1613-24.
https://www.nejm.org/doi/full/10.1056/NEJMsa1213829
http://www.ncbi.nlm.nih.gov/pubmed/23614587?tool=bestpractice.com
The principal model used to frame these strategies is the Chronic Care Model.[164]Bodenheimer T, Wagner E, Grumbach K. Improving primary care for patients with chronic illness: the chronic care model. JAMA. 2002 Oct 9;288(14):1775-9.
http://www.ncbi.nlm.nih.gov/pubmed/12365965?tool=bestpractice.com
The model includes 6 core elements: delivery system design, self-management support, decision support, clinical information systems, community resources and policies, and health systems.
Evidence is generally supportive of the following care improvement strategies.
A multidisciplinary team approach to patient care, including the involvement of trained diabetes self-management educators, pharmacists, and case managers[165]Bongaerts BW, Müssig K, Wens J, et al. Effectiveness of chronic care models for the management of type 2 diabetes mellitus in Europe: a systematic review and meta-analysis. BMJ Open. 2017 Mar 20;7(3):e013076.
https://bmjopen.bmj.com/content/7/3/e013076.long
http://www.ncbi.nlm.nih.gov/pubmed/28320788?tool=bestpractice.com
[166]McLean DL, McAlister FA, Johnson JA, et al. A randomized controlled trial of the effect of community pharmacist and nurse care on improving blood pressure management in patients with diabetes mellitus: study of cardiovascular risk intervention by pharmacists - hypertension (SCRIP-HTN). Arch Intern Med. 2008 Nov 24;168(21):2355-61.
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/414649
http://www.ncbi.nlm.nih.gov/pubmed/19029501?tool=bestpractice.com
Advanced and integrated electronic medical record clinical decision support beyond simple reminder systems and alerts[167]Sperl-Hillen JM, Crain AL, Margolis KL, et al. Clinical decision support directed to primary care patients and providers reduces cardiovascular risk: a randomized trial. J Am Med Inform Assoc. 2018 Sep 1;25(9):1137-46.
https://academic.oup.com/jamia/article/25/9/1137/5048778
http://www.ncbi.nlm.nih.gov/pubmed/29982627?tool=bestpractice.com
[168]O’Connor PJ, Sperl-Hillen JM, Rush WA, et al. Impact of electronic health record clinical decision support on diabetes care: a randomized trial. Ann Fam Med. 2011 Jan-Feb;9(1):12-21.
http://www.annfammed.org/content/9/1/12.full
http://www.ncbi.nlm.nih.gov/pubmed/21242556?tool=bestpractice.com
Simulated case-based learning interventions for clinicians.[169]Sperl-Hillen J, O'Connor P, Ekstrom H, et al. Using simulation technology to teach diabetes care management skills to resident physicians. J Diabetes Sci Technol. 2013 Sep 1;7(5):1243-54.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876368/
http://www.ncbi.nlm.nih.gov/pubmed/24124951?tool=bestpractice.com
[170]Sperl-Hillen JM, O'Connor PJ, Rush WA, et al. Simulated physician learning program improves glucose control in adults with diabetes. Diabetes Care. 2010 Aug;33(8):1727-33.
https://care.diabetesjournals.org/content/33/8/1727.long
http://www.ncbi.nlm.nih.gov/pubmed/20668151?tool=bestpractice.com
[171]O'Connor PJ, Sperl-Hillen JM, Johnson PE, et al. Simulated physician learning intervention to improve safety and quality of diabetes care: a randomized trial. Diabetes Care. 2009 Apr;32(4):585-90.
https://care.diabetesjournals.org/content/32/4/585.long
http://www.ncbi.nlm.nih.gov/pubmed/19171723?tool=bestpractice.com
Other redesigns to the care delivery system such as alternative reimbursement methods, public policy changes to support healthier lifestyles, the patient-centered medical home, and mobile health (mHealth) technology may provide additional opportunities to improve care and are currently being evaluated.[172]Kim EK, Kwak SH, Jung HS, et al. The effect of a smartphone-based, patient-centered diabetes care system in patients with type 2 diabetes: a randomized, controlled trial for 24 weeks. Diabetes Care. 2019 Jan;42(1):3-9.
https://care.diabetesjournals.org/content/42/1/3.long
http://www.ncbi.nlm.nih.gov/pubmed/30377185?tool=bestpractice.com
[173]Fu H, McMahon SK, Gross CR, et al. Usability and clinical efficacy of diabetes mobile applications for adults with type 2 diabetes: a systematic review. Diabetes Res Clin Pract. 2017 Sep;131:70-81.
http://www.ncbi.nlm.nih.gov/pubmed/28692830?tool=bestpractice.com
Diabetes management decisions should be timely, rely on evidence-based guidelines, and be made collaboratively with the patient.