The lecture focuses on the concept of incretin hormones- Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), their clinical history and therapeutic role in the future for patients with type 2 diabetes supported by abundant evidence over the years. 

Incretin mimetics such as GLP 1 were approved for use in 2006. The earlier molecules were in a short acting form and later progressed to long-acting forms indicating a step up in their efficacy. With respect to efficacy, the one exception to this class was albiglutide which was not a potent molecule for HbA1c reduction. Semaglutide was introduced some years later which was administered as an oral tablet with some precautions but is now available in a once-weekly injectable form. Tirzepatide is the newest addition to this class of drugs which is a GIP/GLP1 dual agonist and currently approved by the European Union.

GLP1 agonists have a unique mechanism of action which results in a remarkable impact on gastric emptying, reduction in body weight, blood glucose reduction, and a low risk of cardiovascular events. A study on patients who were administered meals along with saline infusion or a GLP1 have demonstrated that patients ate 12% fewer meals in the GLP1 group. The reduced meal size translates into a loss of body weight. It has been observed that GLP1 can access the circumscribed areas of the brain such as the hypothalamus and the brain stem which control the desire to eat and meal termination. Among the injectable forms, semaglutide has a greater weight reduction than dulaglutide (an average of 3kg). On the other hand, Tirzepatide produces weight loss of more than10kg on an average. 

The GLP1 receptor stimulation has a considerable effect on gastric emptying which leads to a delayed the absorption of nutrients, including carbohydrates, and reductions in glycemic excursions following meals which can have a potential impact on postprandial gastric glycemic excursions.

A meta-analysis on GLP1 receptor agonists (excluding ELIXA results on lixisenatide) has demonstrated 15% reduction in Major adverse cardiac events (MACE) and its components (myocardial infarction, stroke, CV mortality also of all-cause mortality, hospitalization for heart failure) and kidney related outcomes. When compared to SGLT2is, SGLT2is seem to have more benefits on hospitalisation for heart failure and kidney outcomes based on no-overlapping confidence interval. Cardiovascular outcome studies have also established that GLP1 receptor agonists are not associated with pancreatic cancer/pancreatitis as seen in the hazard ratio being close to 1.

Studies on patients with nonalcoholic steatohepatitis (NASH) have reported that GLP1 receptor agonists, like semaglutide, can stop the progression of fibrosis in a significant number of patients making a suitable option in individuals with fatty liver disease. 

In a study comparing Semaglutide and Tirzepatide, once weekly semaglutide can reduce HbA1c by 1.9% (baseline 8.3%) with an overall mean HbA1c reduction to 6.4%.  Tirzapatide reduces HbA1c in a dose dependent manner, as seen by 2.3% reduction to below 6%. Thus, up to 86% patients achieved HbA1c <7%, up to 80% patients achieved HbA1c below 6.5% and even a normal b1c below 5.7 in almost half of the patients with this high dose. Semaglutide produced body weight reduction of -6 kg while Tirzapatide reduced around 11kg on an average.

In summary, the indications for GLP1 receptor agonists are novel owing to their effects on weight reduction, cardiovascular safety, meaningful reductions in HbA1c, negligible risk of hypoglycaemia and better glucose lowering effect which is similar or even better than that of basal insulin.

S 02, European Association for the Study of Diabetes (EASD) International Congress 2022, 19^th – 23^rd Sept. 2022, Stockholm