Diabetes Medications and Cardiovascular Impact
Full update October 2021
Type 2 DM is a known CV disease risk factor.1,2 In addition, concomitant DM and CV disease increases the risk of death.3 Metformin remains the optimal first-line oral med for most patients with type 2 DM.4,5 For available DM meds including expected A1C lowering and adverse effects see our charts, Drugs for Type 2 Diabetes (U.S.) and Stepwise Treatment of Type 2 Diabetes (Canada). The chart below reviews CV outcome data for meds used to treat type 2 DM.
Cardiovascular impact definitions listed in the chart below include:
- Improves outcomes = published data demonstrate CV benefit with use in the treatment of type 2 DM.
- Neutral = published data demonstrate neither benefit nor harm in CV endpoints with use in the treatment of type 2 DM.
- Unknown = CV outcome data is currently unavailable.
- Worsens outcomes = published data demonstrates CV harm with use in the treatment of type 2 DM.
Medicationsa |
Cardiovascular Impact |
Cardiovascular Outcomes Data |
||||||||||||
Alpha-glucosidase inhibitors
|
Unknown:
Neutral:
|
|
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Amylin analog
|
Unknown:
|
|
||||||||||||
Biguanide
|
Improves Outcomes:
|
|
||||||||||||
Dipeptidyl peptidase-4 (DPP-4) inhibitors
|
Neutral:
*based on CV morbidity and mortality outcomes, but note increased risk of heart failure-related admissions. |
|
||||||||||||
Glucagon-like peptide-1 (GLP-1) receptor agonists
|
Improves Outcomes:
Neutral:
*based on CV morbidity and mortality outcomes, but note reduced risk of death from any cause. |
|
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Insulin |
Neutral:
|
|
||||||||||||
Meglitinides
|
Unknown:
|
|
||||||||||||
Sodium-glucose co-transporter 2 (SGLT2) inhibitors
|
Neutral:
Improves Outcomes:
*Note that some data suggest a neutral effect on the composite of CV death, MI, or ischemic stroke. **based on death from CV causes, nonfatal MI, or nonfatal stroke, but note reduced risk of HF-related admissions.31 |
|
||||||||||||
Sulfonylureas
|
Unknown:
Worsens Outcomes:
|
|
||||||||||||
Sulfonylureas
|
Unknown:
Neutral:
|
|
||||||||||||
Thiazolidinediones
|
Improves Outcomes:*
Neutral:*
*based on CV morbidity and mortality outcomes, but note increased risk of HF associated with use. |
|
- Many of these are also available as combination products with other medications like metformin or pioglitazone with different brand names.
- Saxenda contains the same active ingredient as Victoza, but at higher doses and is indicated for weight loss, NOT the treatment of DM.
Abbreviations: ACS = acute coronary syndrome; CKD = chronic kidney disease; CV = cardiovascular; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; HF = heart failure; MI = myocardial infarction; NNH = number needed to harm; NNT = number needed to treat; SCr = serum creatinine.
Levels of Evidence
In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.
Level |
Definition |
Study Quality |
A |
Good-quality patient-oriented evidence.* |
|
B |
Inconsistent or limited-quality patient-oriented evidence.* |
|
C |
Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening. |
*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).
RCT = randomized controlled trial; SR = systematic review [Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. http://www.aafp.org/afp/2004/0201/p548.pdf.]
References
- Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375:2215-22.
- Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002;287:2570-81.
- Di Angelantonio E, Kaptoge S, Wormser D, et al. Association of cardiometabolic multimorbidity with mortality. JAMA 2015;314:52-60.
- Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140-9.
- Diabetes Canada Clinical Practice Guideline Expert Committee, Lipscombe L, Butalia S, et al. Pharmacologic glycemic management of type 2 diabetes in adults: 2020 update. Can J Diabetes 2020;44:575-91.
- ORIGIN trial investigators, Gerstein HC, Bosch J, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012;367:319-28.
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
- Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374:1321-31.
- Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in an oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomized, open-label trial. Lancet 2009;373:2125-35.
- White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35.
- Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26.
- Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232-42.
- Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.
- Rosenstock J, Kahn SE, Johansen OE, et al. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial. JAMA 2019;322:1155-66.
- Selvin E, Bolen S, Yeh HC, et al. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med 2008;168:2070-80.
- Meinert CL, Knatterud GL, Prout TE, Klimt CR. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. mortality results. Diabetes 1970;19:S789-830.
- Singh S, Loke YK, Furberg CD. Thiazolidinediones and heart failure: a teleo-analysis. Diabetes Care 2007;30:2148-53.
- Holman RR, Coleman RL, Chan JCN, et al. Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomized, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2017;5:877-86.
- Packer M, Anker S, Butler AJ, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383;1413-24.
- Neal B, Perkovic V, Matthews DR, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:2099.
- Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854-65.
- FDA. FDA drug safety communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin. Updated March 7, 2018. https://www.fda.gov/drugs/drugsafety/ucm486096.htm. (Accessed September 2, 2021).
- Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomized placebo-controlled trial. Lancet 2019;394:121-30.
- Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228-39.
- Holman RR, Haffner SM, McMurray JJ, et al. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med 2010;362:1463-76.
- Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-57.
- Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279-89.
- Wilcox R, Bousser MG, Betteridge DJ, et al. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke 2007;38:865-73.
- Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247-57.
- Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-44.
- Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 2020;383;1425-35.
- Rosentock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk. The CARMELINA randomized clinical trial. JAMA 2019;321:69-79.
- ClinicalTrials.gov. A study to evaluate cardiovascular outcomes in patients with type 2 diabetes treated with ITCA 650. January 27, 2017. https://clinicaltrials.gov/ct2/show/NCT01455896. (Accessed September 2, 2021).
- Marx N, McGuire DK, Perkovic V, et al. Composite primary end points in cardiovascular outcomes trials involving type 2 diabetes patients: should unstable angina be included in the primary end point? Diabetes Care 2017;40:1144-51.
- Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019;381:841-51.
- Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-306.
- Heerspink HJL, Stefansson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383;1436-46.
- McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381;1195-2008.
- Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021 Aug 27. doi: 10.1056/NEJMoa2107038.
Cite this document as follows: Clinical Resource, Diabetes Medications and Cardiovascular Impact. Pharmacist’s Letter/Prescriber’s Letter. October 2021. [371008]