GLP-1 RA plus SGLT-2 inhibitor vs. either drug alone reduces HbA1c and SBP
The finding that combining glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors improves glycemic control and systolic blood pressure (SBP) without increasing hypoglycemia is important, but additional cost-effectiveness research on the drugs is needed, an ACP Journal Club commentary said.
A systematic review and meta-analysis looked at randomized controlled trials (RCTs) that compared combined therapy with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors to treatment with each of the drug classes individually. It found improved glycemic and blood pressure control with no increase in severe hyperglycemia.
The review was published on June 1 by Diabetes, Obesity and Metabolism. The following commentary by Michael Tanner, MD, FACP, was published in the ACP Journal Club section of the Nov. 17 Annals of Internal Medicine.
The U.S. Food and Drug Administration approval of the first GLP-1 RA (exenatide) in 2005 and the first SGLT-2 inhibitor (canagliflozin) in 2013 are important milestones in 21st-century diabetes pharmacotherapy. A recent systematic review and network meta-analysis by Tsapas and colleagues (see previous article) found that, in patients at increased cardiovascular (CV) risk, GLP-1 RAs and SGLT-2 inhibitors each had favorable effects on important CV outcomes and all-cause mortality. Simultaneous or sequential combination of agents from these 2 drug classes with markedly different mechanisms makes good therapeutic sense.
Mantsiou and colleagues' systematic review of 7 RCTs with 1,913 patients found that, compared with monotherapy, the GLP-1 RA plus SGLT-2 inhibitor combination improved HbA1c (primary outcome), SBP, and body weight. Improvements were not seen in other secondary outcomes (diastolic BP, stroke, myocardial infarction, or CV mortality), and no data were reported for estimated glomerular filtration rate and hospitalization for heart failure. Given that 6 of the 7 trials had duration of only 12 to 30 weeks, between-group differences in mortality and CV events would not be expected. However, combining the 2 classes of medications was not associated with severe hypoglycemia, which is an important finding.
The authors acknowledge the limited quality of evidence in this relatively new area of inquiry. The trials had very low GRADE assessments for HbA1c, body weight, and SBP due to serious or very serious risk for bias, inconsistency, and indirectness. Clinical and statistical heterogeneity between the studies was marked. If the 7 trials were cards in a hand of “Texas hold ‘em,” there wouldn't be a pair—each trial examined a different GLP-1 RA plus SGLT-2 inhibitor combination.
Will GLP-1 RAs and SGLT-2 inhibitors, alone or in combination, supplant metformin as initial therapy in treatment-naive patients with type 2 diabetes? The high price of the drugs is a serious concern that cost-effectiveness analyses will need to address.