Incretin is a gut-derived hormone released after eating that amplifies glucose-dependent insulin secretion from the pancreas. The two main human incretins are GIP (glucose-dependent insulinotropic polypeptide), secreted by the duodenum/jejunum, and GLP-1 (glucagon-like peptide-1), secreted by the ileum/colon.

GIP, in addition to stimulating glucose-dependent insulin secretion, also appears to re-tune adipose insulin sensitivity and modulate appetite circuits in the brain.

GLP-1 also stimulates glucose-dependent insulin secretion but, in addition, suppresses glucagon when glucose is high, slows gastric emptying, and dampens hunger and food-cue reward via central pathways.

The first incretins developed were for the treatment of diabetes. Eventually, incretins were approved for weight management. These early incretins were GLP-1 agonists. Semiglutide (Ozempic) is a well-known example of this. For many people, this drug is very effective for weight loss. 

Some people, however, did not respond as well. Newer drugs are now on the market that target both the GLP-1 and GIP receptors (tirzepatide under the brand names Mounjaro/Zepbound).

GLP-1 and GIP are complementary incretin targets. GLP-1 chiefly curbs appetite, slows the gut, and normalizes meal-time hormones; GIP adds central satiety and adipose metabolic benefits. Co-activating both—as with tirzepatide—has translated into larger, more durable weight loss than GLP-1-only drugs in head-to-head and obesity trials.

In comparison studies, GLP-1 targeting alone results in about 15% body weight loss in 72 weeks compared to dual therapy (trizepatide) loss of 20% body weight in non diabetic patients. 

When studied in diabetics, tirzepatide still outperformed semaglutide, but the amount lost was 8-13% vs 7% with semaglutide over 40 weeks. In addition to weight loss, these drugs have shown cardiovascular protection (fewer major cardiovascular events—even without diabetes.) Improvement in heart failure, obstructive sleep apnea, and preservation of kidney function. Even blood pressure and lipids are modestly improved.

Unfortunately, there are some issues affecting compliance with incretin treatment. 

GI side effects, especially nausea, vomiting, and constipation, are common but often can be mitigated by starting with a lower dose and gradually titrating. Smaller low-fat meals may also mitigate this. Some patients may need to use antiemetic medication and laxatives initially.

These symptoms generally improve with time.

At this time, most incretins are given by self-administered subcutaneous injection weekly. Fear of injections or overcomplicated titration schedules may not be for everyone. Oral semigutide is available for the treatment of diabetes, but is not specifically approved for obesity treatment. The dose of that medication (Rybelsus) is not as effective as the injectable version for weight loss. A larger dose oral formulation for obesity is under FDA review and holds promise.

In the past, there had been concern about a possible link to pancreatitis and pancreatic cancer, but several very large studies have shown no causal link between incretin therapy and these diseases.  

There has also been a concern about medullary thyroid cancer because it was noted in rodent studies; however, human studies are mixed with either a very modest risk or no risk.

In context, consider that medullary thyroid cancer represents only about 1-2% of thyroid cancers with an incidence of about 0.15-.018/100,000 per year in the US. Even a small relative increase would be a very small absolute increase. However, out of caution, incretins should not be used in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia syndrome type 2.

Unfortunately, like previous medications, if the therapy is stopped, the weight tends to return, especially if no other weight control strategies and meds are employed. The condition is controlled, not cured. This should not be a deterrent to its use. 

This is no different than other chronic conditions, such as diabetes or hypertension, which require ongoing treatment. It is important to combine incretin therapy with a tailored diet, exercise, and psychological support for optimal results. 

Obesity care is entering a neuro-hormonal era: incretins powerfully lower set-point pressure and cravings, but best results come when biology, behavior, and environment are addressed together. It has changed the understanding of this condition. 

We no longer overcredit willpower; if one person needs 100% effort and another only needs 20% to lose or maintain weight, the difference is biology, not virtue. Sustainable success pairs effective meds with nutrition, activity, sleep, mental health support, and policy changes that make healthier choices default.