Comparing the Effectiveness of Second-line Antidiabetic Medications on Cardiovascular Events in Patients with Type 2 Diabetes Mellitus

By Mary R Dicklin, PhD and Kevin C Maki, PhD, CLS, FNLA


Cardiovascular disease is the leading cause of morbidity and mortality among patients with type 2 diabetes (T2D).1  Metformin is widely recommended as first-line therapy, but metformin alone may be inadequate for achieving glycemic control, or may not be tolerated, in which case clinicians have several second-line antidiabetic medication (ADM) prescription options.2  The second-line ADMs include sulfonylureas (SFUs), thiazolidinediones (TZDs), insulin, glucagon-like peptide 1 (GLP-1) receptor agonists, sodium-glucose-cotransporter 2 (SGLT-2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors.3  Understanding how these ADMs differ in their effects on cardiovascular outcomes may assist clinicians in preventing comorbidities in patients with diabetes.


Results were recently published from a large, retrospective cohort study that examined major adverse cardiovascular events among insured adults with T2D who had recently started therapy with a second-line ADM after either taking metformin alone or not having received prior ADM.4  Nationwide U.S. administrative claims data were used from 2011-2015.  The primary outcome of the study was time to first cardiovascular event (defined as the composite of hospitalization for congestive heart failure, stroke, ischemic heart disease or peripheral artery disease) after starting a second-line ADM.  Patients were censored after either their first cardiovascular event, discontinuation of insurance coverage, transition of medical claims data coding from the International Classification of Diseases 9th revision to the 10th revision, or two years of follow up.


Among the 132,737 adults evaluated in this study, SFUs were used by 47.6%, DPP-4 inhibitors by 21.8%, basal insulin by 12.2%, GLP-1 receptor agonists by 8.6%, TZDs by 5.6% and SGLT-2 inhibitors by 4.3%.4  During the 169,384 person-years of follow-up there were 3480 incident cardiovascular events.  After adjusting for patient, prescriber and health plan characteristics, the risk of composite cardiovascular events according to second-line ADM was determined.  DPP-4 inhibitors were considered to have a neutral effect on cardiovascular outcomes, based on previous clinical trial evidence.5-7  Thus, DPP-4 inhibitor use was the referent (1.0) in the Cox proportional hazard regression analysis.4  The hazard ratios (95% confidence intervals) were:

  • DPP-4 inhibitors: 1.00 (reference)
  • GLP-1 receptor agonists: 0.78 (0.63-0.96)
  • SGLT-2 inhibitors: 0.81 (0.57-1.53)
  • TZDs: 0.92 (0.76-1.11)
  • SFUs: 1.36 (1.23-1.49)
  • Basal insulin: 2.03 (1.81-2.27)


Higher cardiovascular risk was associated with use of SFUs or basal insulin.  The risk associated with GLP-1 receptor agonist use was lower than with DPP-4 inhibitor use, but this finding was not statistically significant in all of the sensitivity analyses.  The risks associated with SGLT-2 inhibitors and TZDs were not significantly different from DPP-4 inhibitors.


Recent randomized clinical trials that have evaluated the cardiovascular risk associated with newer ADMs have also suggested reduced cardiovascular events.8,9  Unlike those randomized trials, in which most of the participants already had cardiovascular disease, just 5.5% of participants in this observational study had a history of prior cardiovascular events, although cardiovascular risk factors, such as dyslipidemia (61.6%) and hypertension (70.1%), were present in the majority of subjects.


In summary, these results suggest that, with regard to managing cardiovascular comorbidity in their patients with T2D, after metformin, clinicians may consider prescribing any of the newer ADMs (i.e., GLP-1 receptor agonists, SGLT-2 inhibitors and DPP-4 inhibitors) that were shown to be similarly associated with lower cardiovascular risk, instead of SFUs or basal insulin, which were associated with greater cardiovascular risk.



  1. American Diabetes Association. 10. Cardiovascular disease and risk management: Standard of medical care in diabetes – 2019. Diabetes Care. 2019;42(Suppl 1):S102-S123.
  2. American Diabetes Association. 3. Prevention or delay of type 2 diabetes: Standards of medical care in diabetes – 2019. Diabetes Care. 2019;42(Suppl 1):S29-S33.
  3. Thrasher J. Pharmacologic management of type 2 diabetes mellitus: available therapies. Am J Cardiol. 2017;120:S4-S16.
  4. O’Brien MJ, Karam SL, Wallia A, et al. Association of second-line antidiabetic medications with cardiovascular events among insured adults with type 2 diabetes. JAMA Network Open. 2018;1:e1816125.
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  6. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232-242.
  7. White WB, Kupfer S, Zannad F, et al. Cardiovascular mortality in patients with type 2 diabetes and recent acute coronary syndromes from the EXAMINE trial. Diabetes Care. 2016;39:1267-1273.
  8. 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. 2018; Epub ahead of print.
  9. Sposito AC, Berwanger O, de Carvalho LSG, Saraiva JFK. GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data. Cardiovasc Diabetol. 2018;17:157.
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