Review of the Cardiovascular Safety of Dipeptidyl peptidase-4 Inhibitors and the Clinical Relevance of the CAROLINA Trial

BMC Cardiovasc Disord. 2019 Mar 15;19(1):60. doi: 10.1186/s12872-019-1036-0.


Background: Cardiovascular (CV) disease (CVD) is a well-recognized complication of type 2 diabetes mellitus (T2DM) and there is a clinical need for glucose-lowering therapies that do not further increase CV risk in this population. Although sulfonylureas (SUs) may be used as second-line therapy for patients requiring additional therapy after first-line metformin to improve glycemic control, their long-term effects on CV outcomes remain uncertain, and a wide range of alternative agents exist including dipeptidyl peptidase-4 (DPP-4) inhibitors.

Methods: Literature searches in PubMed (2013-2018) were conducted with terms for DPP-4 inhibitors combined with CV terms, with preference given to cardiovascular outcomes trials (CVOTs). Reference lists from retrieved articles and diabetes guidelines were also considered.

Results: This narrative review discusses current evidence for the CV safety of these agents, describes the long-term CV effects of DPP-4 inhibitors, including effects on CV events, mortality, the risk for heart failure hospitalization, and highlights the need for further research into the CV effects of SU therapy. Although SUs remain a treatment option for T2DM, the long-term effects of these agents on CV outcomes are unclear, and further long-term studies are required. For DPP-4 inhibitors, uncertainties have been raised about their long-term effect on hospitalization for heart failure in light of the results of SAVOR-TIMI 53, although the findings of other DPP-4 inhibitor CVOTs in T2DM and data analyses have suggested these agents do not increase the occurrence of adverse CV outcomes.

Conclusions: Based on recent CVOTs and guideline updates, the choice of add-on to metformin therapy for patients with T2DM and established CV disease should be a sodium-glucose co-transporter-2 inhibitor or a glucagon-like peptide-1 agonist with proven CV benefit. Additional treatment options for those individuals who require therapy intensification, as well as in patients with T2DM and without established CVD include DPP-4 inhibitors and SUs. Since few head-to-head trials have compared the effects of different oral glucose-lowering agents on CV outcomes in T2DM, with most CVOTs using placebo as a comparator, the CAROLINA trial will provide important information on the comparative CV safety of a commonly prescribed SU and a DPP-4 inhibitor.

Keywords: Cardiovascular diseases; DPP-4 inhibitors; Linagliptin; Sulfonylureas; Type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Biomarkers / blood
  • Blood Glucose / drug effects*
  • Blood Glucose / metabolism
  • Cardiovascular Diseases / diagnosis
  • Cardiovascular Diseases / epidemiology*
  • Cardiovascular Diseases / mortality
  • Cardiovascular Diseases / therapy
  • Clinical Trials as Topic
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / diagnosis
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / mortality
  • Dipeptidyl-Peptidase IV Inhibitors / adverse effects
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
  • Disease Progression
  • Hospitalization
  • Humans
  • Risk Assessment
  • Risk Factors
  • Sulfonylurea Compounds / adverse effects
  • Sulfonylurea Compounds / therapeutic use*
  • Time Factors
  • Treatment Outcome


  • Biomarkers
  • Blood Glucose
  • Dipeptidyl-Peptidase IV Inhibitors
  • Sulfonylurea Compounds