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Martin J. Abrahamson, MD, FACP:
At ADA 2021, we saw the preliminary results of the first head-to-head comparative effectiveness study for people with type 2 diabetes (T2D), new phase III data on a dual incretin, and more data on drugs for the treatment of T2D and obesity. Here’s my take on the most clinically relevant data with agents such as liraglutide, semaglutide, and tirzepatide.
The phase III GRADE trial is the first head-to-head study comparing the effectiveness of 4 common diabetes medications—sitagliptin, glimepiride, liraglutide, and insulin glargine—as add-on therapy to metformin in people with T2D. The primary outcome was time to A1C ≥7.0%. The results showed that both liraglutide and basal insulin had a lower incidence of patients exceeding an A1C of 7.0% and a longer mean duration until onset of A1C ≥7.0% compared with sitagliptin and glimepiride. Although these findings demonstrate that T2D remains a progressive disease, and there is no medication that has an indefinite, durable effect on glycemic control, the GLP-1 receptor agonist liraglutide and basal insulin offer an advantage in durability compared with the other 2 drugs studied. Indeed, the metabolic benefit of liraglutide and insulin lasted approximately 6 months longer than sitagliptin and glimepiride.
The GRADE trial results confirm that GLP-1 receptor agonists should be the first choice of medication to add to metformin unless cost is an issue. Given the advantages of GLP‑1 receptor agonists and SGLT2 inhibitors (which were not studied in GRADE since they were not approved for clinical use when the study was being designed) in terms of weight loss and low risk of hypoglycemia, I think these are better options for second-line therapy. The GRADE trial also demonstrated the cardiovascular benefit of liraglutide—another compelling reason to choose this type of medication to add to metformin.
At ADA, we saw phase III results from the SURPASS trial evaluating the dual incretin tirzepatide, which is both a glucose-dependent insulinotropic polypeptide (GIP) and a GLP-1 receptor agonist, in persons with T2D. SURPASS studied 3 doses—5 mg, 10 mg, and 15 mg—of tirzepatide, and the comparators were placebo (SUPRASS-1), semaglutide 1 mg (SURPASS-2), and insulin degludec (SURPASS-3). SURPASS-5 evaluated the 3 doses of tirzepatide vs placebo as add-on therapy to insulin glargine.
The consistent finding across these trials was that tirzepatide has superior glucose‑lowering and weight loss effects vs all evaluated comparators, including semaglutide 1 mg. For example, in SURPASS-1, tirzepatide 15 mg monotherapy led to a mean A1C change from baseline of -2.07% vs +0.04% with placebo; the mean change in bodyweight was -9.5 kg vs -0.7 kg with placebo. Moreover, the proportion of people achieving A1C <7.0% with tirzepatide is noteworthy at approximately 90% across these studies, including approximately one third of individuals who achieved an A1C <5.7%. Tirzepatide also had a beneficial effect on lipids, which distinguishes it from GLP‑1 receptor agonists. I think this could be related to the fact that GIP receptors are present on adipocytes.
The safety profile of tirzepatide was dose dependent and included mainly gastrointestinal adverse events, primarily nausea. As we see with GLP‑1 receptor agonists, these adverse events appeared to diminish with continued use.
Of importance, with tirzepatide, we now have 2 incretins combined into one peptide with a long half-life that can be given on a weekly basis. The addition of GIP seems to have a greater effect on weight loss and A1C reduction, as well as a more beneficial effect on lipids. We will have to wait for the cardiovascular outcome data, but we will eagerly await the approval of this new class.
The phase III STEP trial focused on the weight loss effects of semaglutide in people with obesity (with or without diabetes). This trial used doses of semaglutide up to 2.4 mg/week. This dose was associated with an average weight loss of 15% (vs 2% with placebo). In addition, 32% of patients lost ≥20% of their baseline bodyweight. Based on these results, semaglutide 2.4 mg was approved for chronic weight management in persons with body mass index ≥30 kg/m2 or in patients with body mass index ≥27 kg/m2 and ≥1 weight-associated comorbidity.
In semaglutide, we now have a drug that is approved to treat people with obesity that has the potential to promote as much weight loss as metabolic surgery. I think this is a game changer for the management of people with obesity.