There are many gut hormones involved in blood sugar control and weight regulation. GLP1 is one of these hormones, which has been developed into an entire class of medications for diabetes called GLP1 receptor agonists (GLP1RAs) [most commonly used in Canada are the injectable dulaglutide (Trulicity), liraglutide 1.8mg (Victoza), semaglutide (Ozempic), and oral semaglutide (Rybelsus)].
Another hormone of interest is GIP. Like GLP, GIP works to increase insulin release with meals, but people with type 2 diabetes seem to be resistant to the effect of GIP to release insulin. How GLP and GIP may work together is not well understood, but it may be that GIP is effective to improve blood sugars with the help of GLP. GIP, like GLP, also works on the brain to reduce appetite (but in different neurons) and may therefore be helpful for weight loss as well. Thus, it follows that a treatment that includes both GLP and GIP activity could be of benefit in people with type 2 diabetes.
Presented at this week’s American Diabetes Association (ADA) virtual meeting as the ADA President’s Select Abstract, and published simultaneously in The Lancet, is the SURPASS-1 trial. This was a study of the efficacy of a dual GLP1 and GIP agonist called tirzepatide in people with type 2 diabetes (the high level results were released in December 2020 as blogged previously; we now have the full paper and results).
The SURPASS-1 study included 478 adults with type 2 diabetes in India, Japan, Mexico and USA, with diabetes inadequately controlled (A1c 7-9.5%) on no diabetes medication, with a BMI ≥23. Participants were randomized to receive weekly injections of tirzepatide 5mg, 10mg, 15mg, or placebo. The primary endpoint was change in A1C at 40 weeks of treatment.
At the start of the study, the average A1C in participants was 7.9%, average age 54, and average BMI 32. As one would expect in a group of people on no diabetes medication, they were fairly early in their diabetes journey (average diabetes duration 4.7 years).
At 40 weeks, all tirzepatide doses were superior to placebo in A1c reduction (-1.9%, -1.9%, -2.1% on tirzepatide 5mg, 10mg, and 15mg respectively) vs +0.04% with placebo. Impressively, 31-52% of people in the tirzepatide groups reached a completely normal A1C (by American criteria) of less than 5.7%. Weight reduction was greater with increasing tirzepatide doses (-7kg in the 5mg group, -7.8kg in the 10mg group, -9.5kg in the 15mg group, vs -0.7kg with placebo). Also impressively, over a quarter of patients on the highest dose of tirzepatide lost ≥15% body weight. Importantly, while the A1C reduction plateaued at about 20 weeks, the weight was still going down at 40 weeks, so this study does not tell us the full capacity of tirzepatide for weight loss in this population. Liver enzymes improved with tirzepatide, suggesting that this medication may be of value in treating fatty liver disease as well (read more on fatty liver here). Improvements in blood pressure and cholesterol were also seen.
Side effects were in keeping with what we already know of GLP1RAs, with the most common side effects being gastrointestinal. This included mostly mild to moderate nausea (12-18% vs 6% in placebo), diarrhea (12-14% vs 8% placebo), and vomiting (2-6% vs 2% placebo). These symptoms decreased over time in all groups. Rates of discontinuation of medication due to gastrointestinal side effects were 2-7% with tirzepatide vs 1% with placebo. There were no cases of pancreatitis, nor clinically significant hypoglycemia (low sugar).
So what could this mean for people with type 2 diabetes? Well, people early in their diabetes journey could enjoy normalization of blood sugars and impressive weight loss with tirzepatide. While metformin is considered first line treatment in most guidelines around the world (including the Diabetes Canada guidelines), one wonders if this is a step towards a world where metformin is not first in line. We need to better understand just how tirzepatide works, and we need data on potential cardiovascular benefit of tirzepatide – the SURPASS CVOT trial is ongoing to answer this question. Note also that tirzepatide has been studied (with data presented at the ADA) in people with a longer duration of diabetes, vs semaglutide 1mg (blogged here and published here), vs insulin, and even in addition to existing insulin treatment, with impressive benefits in A1C reduction and weight loss in all of the studies.
Tirzepatide is also currently under study as an obesity treatment in people with or without diabetes.
Disclaimer: I am an investigator in the SURPASS clinical trial program. The SURPASS trials are conducted by Eli Lilly, the makers of tirzepatide. I receive honoraria as a continuing medical education speaker and consultant from the makers of tirzepatide and dulaglutide (Eli Lilly), and liraglutide and semaglutide (Novo Nordisk).
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