Treating CVD with DPP-4 Inhibitors vs. Sulphonylureas Plus Metformin

New retrospective study results compare the two most primarily prescribed antidiabetic medication classes, DPP-4i & sulphonylureas, in addition to metformin to determine the impact on the incidence of CV events in patients with T2DM.

Dipeptidyl-peptidase-4 inhibitors (DPP-4i) and sulphonylureas (sulfonylureas in the US) (SU) are two of the most prescribed medications to date for the treatment of type 2 diabetes mellitus (T2DM) in addition to metformin, despite the introduction of newer medications. Previous studies have compared the two for glycemic reduction, which has shown to be around the same, and for incidence of hypoglycemia, where SU was higher. However, limited information looks at the long-term cardiovascular (CV) safety of DPP-4i outside of randomized control trials (RCTs). In addition, there are currently uncertainties around SU because previous studies have shown conflicting results where some have noted benefit, while others have shown increased risk. This study served to assess this outcome because, in T2DM patients, approximately 70% of deaths are related to CV events, and was done using a retrospective study design to limit selection biases that may have been present in the RCTs, which can compromise the validity of the study.

This retrospective cohort study included 23,287 patients prescribed metformin plus a DPP-4i (6,267) or SU (17,570) and were followed between 2008-2017. These patients were pulled from QVIA Medical Research Data (IMRD) UK primary care database that included over 700 general practices in the United Kingdom (UK). The primary outcome was the incidence of major adverse cardiovascular events (MACE), including stroke, myocardial infarction (MI), or significant CV surgery. This was expanded to include those that had already had one existing MACE (primary and secondary MACE). In addition, a secondary outcome of all-cause mortality was also assessed. Cox proportional-hazard regression models were used to determine the association of use of these medications in both cohorts with an adjusted hazard ratio (aHR) for the covariates. In addition, sensitivity analysis was done to evaluate if including mortality in the primary outcome impacted the results.

The results of the study showed that both cohorts (metformin + DDP-4i or SU) had a similar incidence of primary MACE both when adjusted for confounding variates and when not (unadjHR:0.84, 95% CI 0.71-1.00, p-value 0.0505) (10.3 vs. 8.5 events per 1000 person-years; aHR: 0.94; 95% CI 0.80–1.14, p-value 0.6053) and while the incidence of MACE was higher in those who had already had a MACE (secondary) the occurrence was similar between both cohorts as well, both in the unadjusted and adjusted. (unadjHR: 0.78 95% CI 0.59-1.04, p-value 0.0940) (21.8 vs 17.2 events per 1000 person-years; aHR: 0.93; 95% CI 0.69–1.24, p-value 0.5993). When both populations were combined into an overall assessment, the adjusted again revealed no difference in the incidence of MACE between the use of DPP-4i and SU with metformin (aHR: 0.94 95% CI 0.81-1.10, p-value 0.4411). Additionally, when all-cause mortality was combined as part of the MACE definition, the sensitivity analysis revealed no change in outcome (aHR: 0.95 95% CI 0.85-1.07, p-value 0.4137. This was also true when looked at alone as the secondary outcome (aHR: 0.97 95% CI 0.81-1.16, p-value 0.728).

The findings of this study show that when it comes to the risk of cardiovascular events (MACE), there is no difference in the occurrence between the use of DPP-4i and SU with metformin; this was true for patients with and without a history of MACE. Therefore, the clinicians mustn’t base prescribing one over the other on that indication alone. Instead, additional factors can be considered, such as cost, weight issues, and risk of hypoglycemia. Sulphonylureas tend to cost less, but previous studies have shown that they are associated with weight gain and increased risk of hypoglycemia, whereas the dipeptidyl-peptidase-4 inhibitors are not. While there were strengths of this study, including the elimination of selection basis due to study design, reduction of confounding to indication by ensuring all patients were on metformin and were at similar stages in their disease progression, and that the data was obtained in UK primary cares where the T2DM and therapies were being managed, which ensured that the data was reflecting actual clinical practice and was comprehensive. The authors note that no limitations were present. Still, because this study only included one country, it would be essential to have a future study that broadened the patient population to increase generalizability.

Practice Pearls:

• Patients with type 2 diabetes mellitus taking metformin have the same cardiovascular risk whether they are placed on dipeptidyl-peptidase-4 inhibitors (DPP-4i) or sulphonylureas (SU) when prescribed add-on therapy.
• Whether a patient with T2DM and is on metformin and either a DPP-4i or SU has already experienced a major adverse cardiovascular event or not, their risk of a MACE does not differ.
• The risk of the cardiovascular event should not affect the choice of whether to prescribe a DPP-4i or SU as an addition to metformin. Instead, it should be decided based on other factors, such as cost, weight issues, and risk of hypoglycemia.

Bazo-Alvarez, Juan Carlos et al. “Cardiovascular outcomes of type 2 diabetic patients treated with DPP‑4 inhibitors versus sulphonylureas as an add-on to metformin in clinical practice.” Scientific Reports vol. 11,1 23826. 13 Dec. 2021, doi:10.1038/s41598-021-02670-9

Alexa Rodriguez, PharmD Candidate 2022, University of South Florida, Taneja College of Pharmacy

See more about DPP-4i and sulphonylureas.