A new kind of diabetes medication approved by the FDA: is there hope for obesity?

Globally, the percentage of people suffering from obesity and type 2 diabetes is constantly increasing. Several epidemiological studies have proven the tight association between diabetes and obesity; it is estimated that more than 80% of type 2 diabetes patients are overweight or obese. Obese individuals with diabetes must be managed with large and persistent weight reduction. The American Diabetes Association recommends an A1C goal of less than 7%. According to research by the Diabetes Prevention Program, every kilogram lost is associatedwith a 16%decrease in the development of type 2 diabetes. Moderate weight loss has been associated with decreased insulin resistance, alleviated diabetic complications, reduced cardiovascular disease risk factors, and better glycemic parameters. However, many people with type 2 diabetes find it challenging to reach their blood sugar goals through diet and exercise alone. On May 13, 2022, the US Food and Drug Administration (FDA) approved a unique, first-in-class medication for the treatment of type 2 diabetes, known as tirzepatide (Mounjaro). It is administered as a once-weekly injection under the skin and has a dual impact, decreasing blood sugar and promoting weight reduction more effectively than the existing treatments for this illness. Tirzepatide is a dual incretin agonist. Following a meal, the gut releases hormones called incretins, notably glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Incretins stimulate the pancreas to release the glucose-lowering hormone insulin and block the hormone glucagon, which would cause the liver to release stored glucose, hence raising blood glucose levels. Additionally, incretins postpone stomach emptying, which delays the release of glucose into the bloodstream and encourages satiety. Type 2 diabetes patients do not respond, as intensely, to incretin hormones as normal people would. Tirzepatide compensates for this deficiency by activating the GLP-1 and GIP receptors in the body. Both hormones are rapidly released after consumption and appear to be controlled by the nervous system. They stimulate insulin synthesis in pancreatic cells in a glucosedependent way. Furthermore, GLP-1 inhibits pancreatic glucagon release and has extrapancreatic effects such as direct suppressive action on appetite centers and a delay in stomach emptying, boosting the sense of fullness. Tirzepatide engages with the GIP receptor more than the GLP-1 receptor, indicating an unbalanced mode of action. Pharmacological investigations suggest that tirzepatide resembles the activities of natural GIP at the GIP receptor but favors cAMP production over arrestin recruitment at the GLP-1 receptor, which coincides with a reduced capacity to induce GLP-1 receptor internalization compared to GLP-1. Experiments in primary islets show that arrestin1 reduces the insulin response to GLP-1 but not to GIP or tirzepatide, implying that tirzepatide’s biased agonism increases insulin production. In five clinical studies, three distinct dosages of tirzepatide (5, 10, and 15 mg) were studied as either stand-alone treatments or as add-ons to existing diabetic medications. Tirzepatide’s effectiveness was compared with that of a placebo, a GLP-1 receptor agonist (semaglutide), and two long-acting insulin analogs. When used as a stand-alone therapy, patients randomized to receive the recommended dose of tirzepatide (15 mg) had their hemoglobin A1c level lowered by 1.6% more than placebo, and 1.5% more than placebo, when used in combination with longacting insulin. In trials comparing tirzepatide with other diabetic drugs, individuals who got the highest recommended dose of tirzepatide had a 0.5% lower HbA1c than semaglutide, a 0.9% lower HbA1c than insulin degludec, and a 1.0% lower HbA1c than insulin glargine. Obesity was prevalent among participants, with an average BMI of 32–34 kg/height in m reported at enrollment. The average weight reduction with tirzepatide was 15 pounds greater than placebo when neither was taken with insulin and 23 pounds greater than placebo when both were used with insulin among participants, randomized to the highest indicated dosage. With the highest prescribed dose of tirzepatide, the average weight reduction was 12 pounds greater than with semaglutide, 29 pounds greater than with insulin degludec, and 27 pounds greater than with insulin glargine. Patients who received insulin without tirzepatide gained weight during the trial. Moreover, ascertaining the weight loss, another recent doubleblinded randomized controlled trial was published in NEJM where all patients intervened for Tirzepatide showed a greater tendency to lose weight when compared with patients taking placebo. However, there were complications with the methodology of the trial; participants involved were more committed to losing weight, thus requiring a change in lifestyle; changes in cardiometabolic variables were not inspected due to insufficient time span; and, lastly, there was a lack of diversity; the study involved fewer patients who were suffering from obesity and an obesity-induced disease simultaneously. The above-stated reasons contributed to imprecise results. aDow University of Health Sciences, Karachi and bMaroof International Hospital, Public Health Scholar: Health Services Academy, Islamabad, Pakistan