Ronald M. Goldenberg, MD, FRCPC, FACE
Research continues to demonstrate the benefits of glucagon-like peptide-1 receptor (GLP-1R) agonists or co-agonists for type 2 diabetes (T2D). Arslanian and the AWARD-PEDS investigators have published the results of a randomized controlled trial comparing once-weekly dulaglutide vs.placebo in youths between 10 and17 years of age with T2D. A1c was reduced by 1.2% with 0.75 mg dulaglutide and by 1.5% with a 1.5 mg dose, compared with placebo. Of note, there was no significant weight difference between dulaglutide and placebo, similar to what has been found with liraglutide and extended-release exenatide in similar populations. This is also contrary to the weight loss that is found with GLP-1R agonists in adult studies. While the GLP-1R agonist class provides a nice glycemic benefit in youth with T2D, it remains perplexing as to why weight loss has not been demonstrated in clinical trials.
In the SURPASS trials of the GLP-1/gastric inhibitory polypeptide (GIP) receptor co-agonist tirzepatide, there was robust A1c lowering and weight loss among individuals with T2D. A meta-analysis published by Karagiannis and colleagues of seven tirzepatide trials has shown dose-dependent superiority for A1c and weight compared withplacebo, GLP-1R agonists, and basal insulin. Gastrointestinal side effects were similar to what we have come to expect with GLP-1R agonist–based therapies. Tirzepatide, recently approved by the US Food and Drug Administration (FDA) for the treatment of T2D, is a welcome addition to the pharmacotherapy toolkit.
In the SURPASS-2 study, all doses of tirzepatide were superior to 1 mg semaglutide for both A1c and body weight reduction. Following the recent approval of 2 mg semaglutide by the FDA for the management of T2D, Vadher and colleagues explored how tirzepatide compares with 2 mg semaglutide via an indirect treatment comparison. Using data from the SUSTAIN-FORTE and SURPASS-2 trials, these authors found that A1c and weight reductions were significantly greater for 10 and 15 mg tirzepatide vs 2 mg semaglutide and similar for 5 mg tirzepatide vs 2 mg semaglutide. In the absence of a head-to-head trial, this analysis suggests greater efficacy with tirzepatide compared with high-dose semaglutide in T2D.
Continuous glucose monitoring (CGM) provides information about glycemia that is not available with A1c and capillary glucose monitoring. The coefficient of variation (CV) calculated from CGM is a good measure of glycemic variability, with a goal of ≤36%. There are inconsistent data for the association of CV with microvascular or macrovascular complications and very little study of the relationship between CV and long-term mortality. Mo and colleagues investigated the association between short-term glycemic variability measured by CV and all-cause mortality in a prospective study of 1839 individuals with T2D and a well-controlled glucose profile monitored by CGM. After about 7 years of follow-up, a greater baseline CV was associated with an increased risk for all-cause mortality, with a greater than twofold risk fo rmortality with a baseline CV of >35% compared witha baseline CV of ≤20%. This study suggests that clinicians should pay attention when CV is high, even with otherwise good glycemic control. With the expanding use of CGM, long-term intervention studies are needed to determine the role of glycemic variability(CV) in the development of complications and hard outcomes.