Some glucose-lowering drugs reduce HbA1c more than others
A recent meta-analysis supports the use of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors in patients with diabetes and elevated cardiovascular risk, but cost remains a barrier, an ACP Journal Club commentary said.
A meta-analysis of 453 diabetes drug trials found cardiovascular benefits to adding specific glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors to metformin therapy. However, for patients at low cardiovascular risk, no treatment differed from placebo for vascular outcomes. The research was funded by the European Foundation for the Study of Diabetes, supported by an unrestricted educational grant from AstraZeneca.
The review was published online June 30 by Annals of Internal Medicine and summarized in the July ACP Diabetes Monthly. The following commentary by Gunjan Y. Gandhi, MD, MSc, was published in the ACP Journal Club section of the Nov. 17 Annals of Internal Medicine.
As few head-to-head trials of diabetes treatments exist, Tsapas and colleagues used network meta-analysis to compare interventions indirectly. They included the newer GLP-1 RAs and SGLT-2 inhibitors, which herald a paradigm shift in diabetes care toward patient-important outcomes. As an add-on to metformin in patients at high cardiovascular (CV) risk, SGLT-2 inhibitors reduced all-cause and CV mortality and heart failure (HF) hospitalizations and prevented progression of renal failure. In the same population, GLP-1 RAs reduced all-cause and CV mortality and stroke. Thus, specific GLP-1 RAs or SGLT-2 inhibitors should be part of diabetes treatment in patients with, or at risk for, CV disease, independent of HbA1c levels.
However, high costs remain a barrier to widespread use of GLP-1 RAs and SGLT-2 inhibitors. GLP-1 RAs can also cause adverse gastrointestinal side effects, and most are injectable drugs. The glucose-lowering effect of SGLT-2 inhibitors is attenuated as kidney function declines, and increased risks for euglycemic ketoacidosis, infections, and amputations are potential concerns. The utility of the more affordable sulfonylureas and thiazolidinediones is fading due to increased risk for hypoglycemia and HF, respectively, while dipeptidyl peptidase-4 inhibitors have a low risk for hypoglycemia but modest HbA1c effects. However, metformin has long been the first-line monotherapy option for patients with an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 due to its affordability, low risk for hypoglycemia, and possible role in reducing the risk for CV events and death.
Tsapas and colleagues' network meta-analysis provides useful information about diabetes treatment, but questions remain due to low confidence in some results. Therefore, we need trials comparing different medication classes and assessing hard clinical outcomes as well as patient-important outcomes, such as sexual dysfunction, amputation, vision loss, and quality of life. As SGLT-2 inhibitors and GLP-1 RAs have separate mechanisms of action for reducing CV events, it would be interesting to know whether they have a synergistic effect. Until we get answers to these questions, a patient-focused approach is ideal, considering comorbid CV conditions, renal disease, hypoglycemia risk, affordability, body weight effects, side effects, and patient values and preferences.