glucagonlike peptide-1 receptor agonists (GLP1RAs) and continuous glucose monitoring (CGM) technology. I am hoping my discussion about these major advances in this edition of Highlights will be helpful to those caring for patients with diabetes.
The first GLP1RA, exenatide, was released in April 2005. Since then, numerous daily and weekly drugs of this class have been developed. We’ve learned they are effective glucose lowering drugs, and the weekly agents dulaglutide and semaglutide have shown impressive weight reduction properties as well as cardiovascular benefits.
Secondary outcomes have also shown renal benefits to these agents, and studies for primary renal efficacy are pending. Due to all of these properties, the GLP1RAs are recommended as the first injectable for the treatment of type 2 diabetes, prior to insulin initiation.1
The next generation of these agents are a combination of a GLP1RA and a glucose-dependent insulinotropic polypeptide (GIP). Glucagonlike peptide-1 (GLP-1) stimulates insulin secretion, inhibits glucagon secretion, delays gastric emptying, and has central effects inducing satiety.
We now understand that GIP is the main incretin hormone in those without diabetes, causative of most of the incretin effects. But the insulin response after GIP secretion in type 2 diabetes is strongly reduced. It is now appreciated that this poor effect of GIP can be reduced when used in combination with a GLP1RA. This combination incretin, called by some a “twincretin,” is the basis for the drug tirzepatide which was approved by the Food and Drug Administration in May of 2022.
The data supporting this agent for both diabetes and obesity are impressive. For example, in a 40-week study with a baseline HbA1c of 8.0%, those randomized to tirzepatide at 5 mg, 10 mg, and 15 mg had HbA1c reductions of 1.87%, 1.89%, and 2.07% respectively.2 Over 81% at all doses had HbA1c levels less than 6.5% at 40 weeks.
For the 5-mg, 10-mg, and 15-mg doses, weight change from baseline was 7.9%, 9.3%, and 11.0% respectively. Like older GLP1RAs, gastrointestinal side effects were the main problem. For the three doses, 3%, 5%, and 7%, respectively, had to stop the drug, compared with the 3% who stopped taking the placebo. In another study, tirzepatide was noninferior or superior at all three doses compared with semaglutide 1 mg weekly.3
In a population without diabetes, with 40% of patients having prediabetes, weight loss percentages for the three doses were 15.0%, 19.5%, and 20.9% respectively.4 Discontinuation percentages due to side effects were 4%-7%. The exciting part is we now have a drug that approaches weight loss from bariatric surgery. The cardiovascular and renal outcome trials are now underway, but the enthusiasm for this drug is clear from the data.
Like other GLP1RAs, the key is to start low and go slowly. It is recommended to start tirzepatide at 2.5 mg four times a week, then increase to 5 mg. Due to gastrointestinal side effects, some patients will do better at the lower dose before increasing. For those switching from another GLP1RA, there are no data to guide us but, in my practice, I start those patients at 5 mg weekly.