Are two incretins better than one?
The normal regulation of post-prandial glucose metabolism is dependent on the incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide (GIP), which are secreted by the intestinal L‑cells and K‑cells, respectively. These hormones both enhance glucose-dependent insulin secretion and are part of normal post-meal satiety signaling. GIP may also play a role in fat metabolism in adipose tissue.
In people with type 2 diabetes, there appears to be a reduction in secretion of GLP‑1 and responses to GIP are diminished, which may contribute to hyperglycemia. Long-acting GLP‑1 receptor agonists, such as exenatide, liraglutide, dulaglutide, and semaglutide, were developed on the basis of experimental studies with GLP‑1 infusions which showed that it helps to lower glucose in type 2 diabetes. Interest in GIP agonists has been limited, however, as it was thought that GIP is relatively ineffective at lowering glucose in type 2 diabetes.
‘Mind the GIP’
Recent research has challenged previously held views on GIP, with suggestions that, in the presence of higher GLP‑1 levels, GIP sensitivity can be restored in type 2 diabetes. There is also new experimental evidence to suggest that GIP, like GLP‑1, may help lower bodyweight in animal models of obesity, and could have favorable effects on lipid metabolism and liver fat, due to direct effects on adipocytes that promote lipid clearance. Hence, although GIP may be ineffective when given alone, a combination with GLP‑1 (with the right balance) may prove to be an even more effective treatment for diabetes than current GLP‑1 analogs. It has also been suggested that the combination may be useful for treatment of obesity and fatty liver disease.
One of the first of the dual GIP/GLP-1 agonists developed, tirzepatide, is currently undergoing phase 3 clinical trials.
The story so far with tirzepatide
Tirzepatide can be considered an imbalanced and biased (more active against GIP receptor) dual GLP-1/GIP agonist. A phase 2 trial looked at four doses of tirzepatide (given subcutaneously, once weekly for 26 weeks) compared with placebo and the GLP‑1 analog dulaglutide. In this trial, the highest dose used (15 mg) resulted in a glycated hemoglobin (HbA1c) reduction of 1.89%, compared with 1.26% for dulaglutide. Weight loss was 11.3 kg compared with 2.7 kg for dulaglutide. Adverse effects of tirzepatide were similar to dulaglutide, with gastrointestinal side effects being most prominent.
Of interest, an analysis from the same trial showed reductions in triglycerides that were greater than were seen with dulaglutide treatment (a 37% fall at the highest dose), and also reductions in the atherogenic lipoproteins APO-CIII and APO-B. Statistical analysis suggested these improvements were independent of the greater weight loss seen with tirzepatide. It is therefore interesting to speculate whether this may translate into a greater effect on cardiovascular disease in an outcome trial.
What data can we expect in the near future?
At present, limited long-term data are available, but the ongoing SURPASS program of phase 3 trials with tirzepatide in type 2 diabetes will soon provide a wealth of information about the efficacy and safety of this novel treatment. The question of whether the aforementioned improvements in triglycerides and lipoprotein markers of cardiovascular risk will translate into greater reductions in cardiovascular events than with a GLP‑1 analog is being tested in the SURPASS-CVOT cardiovascular outcomes trial. This head-to-head trial compares dulaglutide with tirzepatide and includes 12,500 people with diabetes and cardiovascular disease; SURPASS-CVOT is expected to report in 2024. The related SURMOUNT and SYNERGY trial programs are evaluating tirzepatide in obesity and non-alcoholic fatty liver disease, respectively.
In summary, the idea of dual GIP/GLP-1 agonism for treatment of diabetes and obesity seems close to being realized. It remains to be seen whether the promising data from preclinical work and early clinical trials will translate into better outcomes for people with diabetes than existing GLP‑1 receptor analogs.
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