Combining GLP-1 Receptor Agonists and SGLT2 Inhibitors for Cardiorenal Prevention

D rugs that are analogs for native glucagon- like peptide-1 (glucagon-like peptide-1 receptor agonists [GLP-1RAs]) and those that inhibit sodium-glucose-linked transporters in the kidney (the sodium-glucose cotransporter 2 inhibitor [SGLT2i] drugs) were originally developed to lower glucose in people with type 2 diabetes (T2D).When drugs from both these classes were tested in long-term, large randomized and placebo-controlled outcomes trials to establish their cardiovascular and cerebrovascular (CV) safety in people with T2D, they reduced the incidence of serious, lifethreatening CV and kidney outcomes.1 Subsequent large outcomes trials demonstrated similar effects in people without diabetes who were overweight or living with obesity and who had evidence of prior CV disease.2,3 As a result, representatives of these 2 drug classes are quickly becoming mainstays of preventive therapy for a variety of serious health outcomes, and are being increasingly prescribed by generalists, cardiologists, and nephrologists in addition to endocrinologists and diabetologists.Indeed, a recent analysis of a large American health network reported that the proportions of 121,508 people with T2D who were at high risk of CV or kidney disease and who were taking a GLP-1RA, SGLT2i, or both together were 22%, 17%, and 6%, respectively.4Differences in the structure and proposed mechanisms of actions of these 2 classes support the hypothesis that combining them could potentially magnify their cardiovascular and kidney benefits.Unfortunately, no randomized controlled outcomes trials of combination therapy have been reported to date.Nevertheless, several of the completed trials using a representative of either one or the other class permitted participants to take the alternate drug class as background therapy.The researchers then analyzed whether the CV or kidney effects of the tested drug differed according to this background therapy.Syntheses and scrutiny of these analyses provide potential insights regarding the CV and kidney efficacy of using both in combination.The relevant data are reviewed and summarized herein, along with a worked estimate of the potential impact of the combination use to help inform clinical practice.As noted previously, several drugs with GLP-1RA properties reduce the hazard of both CV and kidney outcomes in middle aged and older overweight or obese participants with T2D and additional CV risk factors.A meta-analysis that synthesized the observed findings from 10 large outcomes trials comprising 77,419 participants followed for a mean of 3.3 years 1 reported significant reductions (i.e., HR: 0.86; 95% CI: 0.81-0.90) in major adverse cardiovascular events (MACE) (ie, a myocardial infarction, stroke, or cardiovascular death), each component of this composite (HR: 0.86 for all), all-cause mortality (HR: 0.88; 95% CI: 0.82-0.93),heart failure hospitalization (HR: 0.86; 95% CI: 0.79-0.93),and worsening kidney function (HR: 0.78; 95% CI: 0.69-0.88).