Observational Analyses of Second-Line Pharmacological Agents in Type 2 Diabetes – Cycle 2 2020

Through this initiative, PCORI seeks to fund high-quality studies using observational designs that compare the effectiveness of newer versus older second-line pharmacological agents in type 2 diabetes mellitus (T2DM) among individuals at moderate cardiovascular risk (2-3 percent risk of events per year).

Findings from the EMPA-REG OUTCOME trial (empagliflozin; sodium glucose cotransporter 2 (SGLT2) inhibitor) in late 2015 indicate that empagliflozin may have a cardiovascular protective effect in patients with T2DM at high-risk for cardiovascular events.^[1] Subsequently, the LEADER (liraglutide; glucagon-like peptide-1 (GLP-1) receptor agonist)^[2], SUSTAIN-6 (semaglutide; GLP-1 receptor agonist)^[3], CANVAS (canagliflozin; SGLT2 inhibitor)^[4], and REWIND (dulaglutide; GLP-1 receptor agonist)^[5] trials all found an apparent cardiovascular benefit of either an SGLT2 inhibitor or a GLP-1 receptor agonist relative to placebo. These results have led to challenges for clinicians in choosing among an expanded range of medication choices for T2DM patients who no longer have acceptable metabolic control with metformin monotherapy. The available agents vary in both their associated side effect profiles and their costs to patients.

PCORI is interested in studies that compare newer medication classes (SGLT2 inhibitors and GLP-1 receptor agonists) to older, lower-cost treatments (sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors). These studies should address whether the newer agents offer true benefits in terms of cardiovascular disease endpoints and how large any benefits may be. PCORI is particularly interested in medication comparisons for patients whose baseline cardiovascular risk is lower than among those who participated in the published clinical trials. 

While a large-scale randomized controlled trial on this topic would be desirable, such a trial would require many years and substantial resources. Well-designed, methodologically robust observational studies that emulate a randomized trial, while not a substitute for clinical trials, have the potential to provide real-world evidence to inform clinical decision-making over the short term. In addition, observational studies in this space may help to inform the design of future trials.

The potential observational study would focus on the comparative risks and benefits of the classes of drugs (and individual drugs within those classes), with a primary focus on cardiovascular outcomes. The envisioned primary endpoints of the study include 3-point major adverse cardiovascular events (MACE): non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the potential addition of a fourth point to include revascularization or hospitalization for heart failure. Other endpoints of interest include the individual components of MACE, all-cause mortality, renal function, medication side effects, renal function, changes in body weight, and additional patient centered outcomes (e.g., hypoglycemia). The potential observational study may also look at the incidence of microvascular complications (including new onset of diabetic retinopathy or early renal disease), the time to the introduction of second- and third-line agents, and the clinical events that precede drug switching.