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

  • Acarbose (e.g., Precose [U.S.], Glucobay [Canada])
  • Miglitol (e.g., Glyset [U.S.])

Unknown:

  • Miglitol

Neutral:

  • Acarbose
  • Acarbose (ACE trial [Evidence Level A-1]): use in patients with established coronary heart disease and impaired glucose tolerance had a neutral CV effect.18
  • Miglitol: Unable to identify published or ongoing trials evaluating CV impact.

Amylin analog

  • Pramlintide (SymlinPen [U.S.])

Unknown:

  • Pramlintide
  • Pramlintide: Unable to identify published or ongoing trials evaluating CV impact.

Biguanide

  • Metformin (e.g., Glucophage)

Improves Outcomes:

  • Metformin
  • Metformin (UKPDS trial subanalysis [Evidence Level A-1]): good glycemic control with metformin for ~10 years may reduce CV mortality, especially in obese patients, NNT = 14.21
    • Pooled data demonstrate possible reduced CV mortality (NNT = 56), compared to other DM medications or placebo [Evidence Level A-1].15

Dipeptidyl peptidase-4 (DPP-4) inhibitors

  • Alogliptin (e.g., Nesina)
  • Linagliptin (e.g., Tradjenta [U.S.]; Trajenta [Canada])
  • Saxagliptin (e.g., Onglyza)
  • Sitagliptin (e.g., Januvia)

Neutral:

  • Alogliptin*
  • Linagliptin
  • Saxagliptin*
  • Sitagliptin

*based on CV morbidity and mortality outcomes, but note increased risk of heart failure-related admissions.
  • Alogliptin (EXAMINE trial [Evidence Level A-1]): use in patients with type 2 DM and a recent ACS, did not increase major adverse CV events, compared to placebo,but was associated with an increased risk of HF-related admissions, NNH = 167.10,22
  • Saxagliptin (SAVOR-TIMI 53 trial [Evidence Level A-1]): use in patients with type 2 DM at high risk for CV events; neither reduced nor increased the risk of CV death, MI, or ischemic stroke, compared to standard therapy, but was associated with an increased risk of HF-related admissions, NNH = 143.11,22
  • Sitagliptin (TECOS trial [Evidence Level A-1]): added to existing DM therapy did not increase the major adverse CV events, hospitalization for HF, or other adverse events compared to placebo.12
  • Linagliptin:
    • CARMELINA trial [Evidence Level A-1]: use in patients with type 2 DM did not increase the risk of hospitalization for HF or the composite outcome of CV death, nonfatal MI, or nonfatal stroke compared to placebo.32
    • CAROLINA trial [Evidence Level A-1]: adding glimepiride or linagliptin to metformin for ~6.3 years in patients with type 2 DM and risk factors for or established CV disease had a similar impact on the combined outcome of CV death, nonfatal MI, or nonfatal stroke.14

Glucagon-like peptide-1 (GLP-1) receptor agonists

  • Dulaglutide (e.g., Trulicity)
  • Exenatide (e.g., Byetta, Bydureon, Bydureon BCise [approved, but not yet marketed in Canada])
  • Liraglutide (e.g., Victoza, Saxendab)
  • Lixisenatide (Adlyxin [U.S.]; Adlyxine [Canada])
  • Semaglutide (e.g., Ozempic)

Improves Outcomes:

  • Dulaglutide
  • Liraglutide
  • Semaglutide

Neutral:

  • Exenatide*
  • Lixisenatide

*based on CV morbidity and mortality outcomes, but note reduced risk of death from any cause.
  • Dulaglutide (REWIND trial [Evidence Level A-1]): added to standard DM therapy in patients with type 2 DM and CV disease or CV risk factors over ~5.4 years may reduce the composite endpoint of nonfatal MI, nonfatal stroke, and death from CV or unknown causes (NNT = 71).23 Of the individual endpoints, only reduction in nonfatal stroke was significant.23
  • Exenatide:
    • EXSCEL trial [Evidence Level A-1]: once-weekly exenatide added to standard DM therapy in patients with or without CV disease had a neutral CV effect, but was associated with a reduction in death from any cause compared to placebo (NNT = 341).24
    • Awaiting results of FREEDOM CVO (NCT01455896) evaluating CV outcomes in patients with type 2 DM treated with ITCA 650. ITCA 650 delivers exenatide through a minipump.33,34
  • Liraglutide (LEADER trial [Evidence Level A-1]): added to standard care in patients with type 2 DM with CV disease or at high CV risk over ~4 years may reduce:13
    • death from CV causes, nonfatal MI, or nonfatal stroke, NNT = 53.
    • death from CV causes, NNT = 77.
    • death from any cause, NNT = 71.
    • Did not reduce the individual rates of MI, nonfatal stroke, or HF-related hospitalizations.
  • Lixisenatide (ELIXA trial [Evidence Level A-1]): added to conventional therapy in type 2 DM patients with a recent ACS had a neutral CV effect.29
  • Semaglutide:
    • SUSTAIN-6 trial [Evidence Level A-1]: added to conventional therapy in type 2 DM patients with CV disease, CKD, or CV risk factors for ~2 years may reduce the combined endpoint of CV death, nonfatal MI, or nonfatal stroke (NNT = 44).Of the individual endpoints, only nonfatal stroke was significant.30
    • PIONEER 6 trial [Evidence Level A-1]: found ORAL semaglutide in patients with type 2 DM and CV disease, CKD, or CV risk factors had a neutral CV effect.35

Insulin

Neutral:

  • Glargine
  • Glargine (ORIGIN trial [Evidence Level A-1]): use over ~6 years had a neutral CV effect.6

Meglitinides

  • Nateglinide (e.g., Starlix [U.S.])
  • Repaglinide (e.g., Prandin [U.S.], GlucoNorm [Canada])

Unknown:

  • Nateglinide
  • Repaglinide
  • Nateglinide (NAVIGATOR trial [Evidence Level A-1]): use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on CV outcomes.25 No outcomes data in patients with type 2 DM.
  • Repaglinide: Unable to identify any published or ongoing trials evaluating CV impact.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors

  • Canagliflozin (e.g., Invokana)
  • Dapagliflozin (e.g., Farxiga [U.S.], Forxiga [Canada])
  • Empagliflozin (e.g., Jardiance)
  • Ertugliflozin (e.g., Steglatro [U.S. only])

Neutral:

  • Ertugliflozin**

Improves Outcomes:

  • Canagliflozin
  • Dapagliflozin*
  • Empagliflozin

*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
  • Canagliflozin:
    • CANVAS trial [Evidence Level A-1]: added to standard DM therapy in patients with type 2 DM and very high CV risk for ~3.5 years may reduce the combined endpoint of CV mortality, nonfatal MI, or nonfatal stroke. (The composite endpoint occurred in 26.9 [canagliflozin] versus 31.5 [placebo] participants per 1,000 patient-years. Unable to reliably calculate NNT based on the available data.) When evaluated individually, improvement in these endpoints were no longer significantly different.20
    • CREDENCE trial [Evidence Level A-1]: use for ~2.6 years in patients with type 2 DM and CKD (i.e., eGFR ≥30 and <90 mL/min/1.73m2) may reduce the composite of endpoint of end-stage kidney disease (dialysis, transplantation, or a sustained eGFR of <15 mL/min/1.73 m2), doubling of SCr, or death from renal or CV causes (NNT = 23) (mostly driven by the doubling of SCr; death from CV causes was not significantly different).36
      • Secondary endpoint: use for ~2.6 years in patients with type 2 DM and CKD may reduce the risk of CV death or hospitalization for HF
        (NNT = 30); CV death, MI, or stroke (NNT = 42); or hospitalization for HF (NNT = 42).36
  • Dapagliflozin:
    • DECLARE-TIMI58 trial [Evidence Level A-1]: use for ~4.2 years when added to DM therapy in patients with type 2 DM and CV disease or at high-risk for CV disease had a neutral effect on the composite endpoint of CV death, MI, or ischemic stroke.26
      • Reduced the combined endpoint of CV death or hospitalization for HF (NNT = 438) [Evidence Level A-1]. Of the individual endpoints, only hospitalization for HF was significant.26
    • Dapa-CKD trial [Evidence Level A-1]: use for ~2.4 years when added to standard renal-protective therapy in patients with CKD (with or without DM) may reduce the composite endpoint of sustained decline in eGFR of at least 50%, progression to end-stage kidney disease, or death from renal or CV causes (NNT = 19 [patients with or without DM], NNT ~19 [patients with DM], NNT ~25 [patients without DM]). Of the individual endpoints, only reduced decline in eGFR of at least 50% and delayed progression to end-stage kidney disease were significant.37
  • Dapagliflozin:
    • Dapa-HF trial [Evidence Level A-1]: use for ~1.5 years when added to standard HF therapy in patients with class II, III, or IV HF with reduced ejection fraction (HFrEF), with or without type 2 DM, may reduce the composite endpoint of worsening HF (hospitalization or urgent visit requiring intravenous HF therapy) or CV death (NNT = 21 [patients with and without DM], NNT ~18 [patients with DM], or NNT ~22 [patients without DM]).38
  • Empagliflozin:
    • The EMPA-REG OUTCOME trial [Evidence Level A-1] found empagliflozin use for ~3 years, when added to standard DM therapy in patients with type 2 DM and underlying CV disease, may reduce:7
      • Hospitalization due to HF (NNT = 71).
      • CV death rates (NNT = 45).
      • Overall death rates (NNT = 39).
      • Empagliflozin did not reduce the individual rates of MI or stroke.
    • EMPEROR-Reduced trial [Evidence Level A-1] found empagliflozin use for about 16 months, when added to standard HF therapy in patients with class II, III, or IV HFrEF with or without type 2 DM may reduce the composite endpoint of hospitalizations for HF or CV death (NNT = 19 [patients with and without DM], NNT ~14 [patients with DM], NNT ~26 [patients without DM]).19 Composite endpoint mostly driven by hospitalizations (death from CV causes was not significantly different).19
    • EMPEROR-Preserved trial [Evidence Level A-1]: use for ~2 years when added to usual therapy in patients with class II, III, or IV HFpEF, with or without type 2 DM, may reduce the composite endpoint of CV death or HF-related hospitalizations (NNT = 31 [patients with and without DM],
      NNT ~29 [patients with DM], or NNT ~33 [patients without DM]). Composite endpoint mostly driven by reduction in HF-related hospitalizations (death from CV causes was not significantly different).39
  • Ertugliflozin (VERTIS CV trial [Evidence Level A-1]): use for ~3.5 years when added to standard DM therapy in patients with type 2 DM and CV disease had a neutral CV effect (composite of death from CV causes, nonfatal MI, or nonfatal stroke) compared to placebo. The secondary endpoint found use may reduce the risk of HF-related hospitalizations (NNT ~29).31

Sulfonylureas
(first generation)

  • Chlorpropamide
  • Tolazamide
  • Tolbutamide

Unknown:

  • Chlorpropamide
  • Tolazamide

Worsens Outcomes:

  • Tolbutamide
  • Chlorpropamide and tolazamide: Unable to identify any published or ongoing trials evaluating CV impact.
  • Tolbutamide: Use has been associated with increased CV mortality compared to diet alone or diet plus insulin.16

Sulfonylureas
(second generation)

  • Gliclazide (Canada)
  • Glipizide
  • Glimepiride
  • Glyburide

Unknown:

  • Gliclazide
  • Glipizide
  • Glyburide

Neutral:

  • Glimepiride
  • Gliclazide, glipizide, and glyburide: Unable to identify any published or ongoing trials evaluating CV impact.
  • Glimepiride (CAROLINA trial [Evidence Level A-1]): adding glimepiride or linagliptin (considered CV neutral) to metformin for ~6.3 years in patients with type 2 DM and risk factors for or established CV disease had a similar impact on the combined outcome of CV death, nonfatal MI, or nonfatal stroke.14

Thiazolidinediones

  • Pioglitazone (e.g., Actos)
  • Rosiglitazone (e.g., Avandia)

Improves Outcomes:*

  • Pioglitazone

Neutral:*

  • Rosiglitazone

*based on CV morbidity and mortality outcomes, but note increased risk of HF associated with use.
  • Pioglitazone:
    • IRIS trial [Evidence Level A-1]: use for ~5 years in patients with prediabetes and a history of stroke (with mild impairment) or transient ischemic attack may reduce the risk of a future stroke or MI (NNT = 36).8
    • PROactive trial [Evidence Level A-1]: No improvement in primary endpoint. A secondary endpoint found use ~3 years in patients with type 2 DM and macrovascular disease (e.g., MI, stroke, PCI) may reduce the risk of all-cause mortality, non-fatal MI, and stroke (NNT = 50).27
    • Subgroup analysis [Evidence Level A-1]: use for ~3 years in patients with type 2 DM and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22).28
  • Rosiglitazone (RECORD trial [Evidence Level A-1]): added to metformin or a sulfonylurea for ≥5 years did not impact overall CV morbidity or mortality.9
  • Pioglitazone and rosiglitazone are known for their associated risk of HF
    (NNH ~50 patients treated with either agent for ~2 years) [Evidence Level A-2].17
  1. Many of these are also available as combination products with other medications like metformin or pioglitazone with different brand names.
  2. 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.*
  1. High-quality RCT
  2. SR/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*
  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

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

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  2. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002;287:2570-81.
  3. Di Angelantonio E, Kaptoge S, Wormser D, et al. Association of cardiometabolic multimorbidity with mortality. JAMA 2015;314:52-60.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374:1321-31.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. Singh S, Loke YK, Furberg CD. Thiazolidinediones and heart failure: a teleo-analysis. Diabetes Care 2007;30:2148-53.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
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  23. 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.
  24. 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.
  25. 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.
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  28. 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.
  29. 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.
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  31. 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.
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  33. 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).
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  39. 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]

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