So what’s the big deal about Mounjaro?

Background Context

Per a News Release in September 2022 (link below), “More than 30 million Americans have T2D, but despite the availability of many medications to treat diabetes, only around half of US adults with T2D achieve target haemoglobin A1c (HbA1c; a measure of blood sugar control) of less than 7% [2]. Higher HbA1c levels are associated with complications like heart disease, stroke, kidney disease (nephropathy), eye disease (retinopathy) and nerve disease (neuropathy).” Diabetes patients taking  Mounjaro (chemical name: Tirzepatide) reached the standard T2D treatment goal of under-7 A1C faster than other traditional diabetes drugs. Unlike Insulin, it conveys weight loss instead of weight gain and reverses insulin resistance (whereas the administration of insulin increases insulin resistance). ADA recommends GLP-1RA drugs prior to insulin as first step for injection therapy naive T2D patients failing to reach under-7 A1C goal using traditional therapies.

Latest type 2 diabetes drug achieves blood sugar and weight targets faster

https://www.eurekalert.org/news-releases/964588

Mounjaro is the brand name for the molecule Tirzepatide, created by Eli Lilly. It is part of the class of drugs that activate at least one of the body’s digestive (incretin) hormone receptors to initiate optimal metabolic handling of food eaten. This class of drugs or therapeutic approach was pursued because research showed that the endocrine system of diabetics have dysregulations in the body’s handling of food eaten. Molecules in this class of drugs are referred to as incretin mimetics: they mimic the behavior of hormones that work more optimally in non-diabetic people’s metabolisms.

 

Specifically, drugs in this class have some or all of the following features in common:

• Help the pancreas produce more insulin by making the beta cells more robust,
• Encourage the body’s cells to uptake glucose from the bloodstream so it’s used efficiently as fuel (decreasing insulin resistance),
• Discourage the liver from releasing too much glucose,
• Reduce appetite/increase satiety (decreasing food intake),
• Alter taste sensations to encourage better dietary intake,
• Slow the amount of sugar the body has to process so it’s easier to handle,
• Don’t typically result in hypoglycemia events (unless taken concurrently with sulfonylureas or insulin),
• GLP-1RAs can potentially reset a patient’s entire metabolic system

 

Drugs in this class are typically delivered via injections at routine intervals, and are frequently available in multiple doses for various strengths, based on the patients’ needs, results and tolerance. Prior to Mounjaro, they were referred to as “GLP-1 analogues,” (GLP-1 stands for glucagon-like peptide 1). In peer-reviewed journal articles, these are sometimes referred to as “GLP-1RA drugs” (RA stands for Receptor Agonist). One downside of these GLP-1 drugs has been the frequency of gastrointestinal adverse events or side effects, in particular, nausea, vomiting or diarrhea. While these GI-related side effects are not life-threatening, one who experiences these side effects is less likely to continue the drug and successfully achieve therapeutic benefits.

Examples of other drugs in this class that pre-date Mounjaro:

 

Brand Name Molecule Name Prescribed on-label for Injection Timing

Ozempic Semaglutide Type 2 Diabetes Weekly

WeGovy Semaglutide Weight Loss Weekly

Trulicity Dulaglutide Type 2 Diabetes Weekly

Byetta Exenatide Type 2 Diabetes Weekly

Victoza Liraglutide Type 2 Diabetes Daily

Saxenda Liraglutide Weight Loss Daily

 

Why’s Mounjaro a Big Deal?

Mounjaro is the first dual-receptor agonist drug to hit the market. Dual-receptor means that instead of only acting on the GLP-1 hormone receptor, it also acts on a second incretin hormone receptor, the GIP hormone receptor. Combined activation of both receptors was found to act synergistically, providing additive effects, enhancing glucose control and weight loss compared to just GLP-1 analogues alone.

In trial studies, Mounjaro (tirzepatide)’s effectiveness exceeded all prior-generation medications and also insulin, for reducing A1C, reducing triglycerides, and weight reduction, including intra-abdominal fat and liver fat. The results were significantly greater than last generation medications, both in results and time to achieve results. Trial participants remarked that exercising caloric restriction, which usually is an obstacle to weight loss and results in increased hunger, instead came easily, and the GI-related side effect of nausea is reduced due to the GIP-RA being activated. Research was done to investigate use of Mounjaro as an add-on to other treatments such as metformin and insulin, but also to investigate its use as a monotherapy, which would enable patients to drop other medications altogether. Weight loss results are similar to bariatric surgery, but unlike bariatric surgery, Mounjaro doesn’t generate increased hunger long-term due to the reduced absorption of calories.

 

Mechanisms underlying tirzepatide efficacy revealed

Medicine Matters, 4/28/2022

https://diabetes.medicinematters.com/tirzepatide/type-2-diabetes/mechanisms-tirzepatide-type-2-diabetes-beta-cell-function/20352860

 

Tirzepatide, a New Era of Dual-Targeted Treatment for Diabetes and Obesity: A Mini-Review

Molecules, July 2022

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268041/

 

Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction

Cardiovasc Diabetol. 2022 Sep

https://pubmed.ncbi.nlm.nih.gov/36050763/

 

Tirzepatide generated extra weight loss compared to semaglutide and they are not sure why, as both drugs decreased appetite and food intake equally. Data on the results from one study are below. It’s believed that the coadministration of an agonist fit GLP-1 and GIP receptors gives greater results than the administration of one alone.

 

“At 28 weeks, reductions in body weight from baseline were observed with TZP 15 mg (-11.2 kg) and SEMA 1 mg (-6.9 kg) , and significantly differed between treatment groups (-4.3 kg [95% confidence interval [CI]: -6.8, -1.9]; p<0.001) . Reductions in fat mass from baseline were also observed with TZP 15 mg (-9.7 kg) and SEMA 1 mg (-5.9 kg) , and significantly differed between treatment groups (-3.8 kg [95% CI: -6.2, -1.4]; p=0.002) . Energy intake reductions from baseline observed with TZP 15 mg (-348.4 kcal) and SEMA 1 mg (-284.1 kcal) did not differ between treatment groups (-64.3 kcal [95% CI: -160.3, 31.7]; p=0.187) . TZP reduced overall appetite by increasing satiety with decreased PFC (all p<0.05) . Appetite ratings did not differ between TZP and SEMA. In conclusion, TZP achieved greater weight loss than selective GLP-1 RA, mostly driven by fat mass loss. Significant and clinically meaningful reductions in appetite and energy intake were observed with both TZP and selective GLP-1 RA. However, these effects could not totally explain the additional weight loss with TZP. As appetite and energy intake reduction were not significantly different between treatments; additional mechanisms might contribute to the weight loss with TZP. Ongoing studies will further elucidate the mechanism of weight loss with TZP.”
Tirzepatide Reduces Appetite, Energy Intake, and Fat Mass in People with T2D

Diabetes, June 2022

https://diabetesjournals.org/diabetes/article/71/Supplement_1/338-OR/145167/338-OR-Tirzepatide-Reduces-Appetite-Energy-Intake?searchresult=1

 

“Both GLP-1 and GIP are classified as incretins and are expressed throughout the body, including pancreatic beta cells and the gastrointestinal tract. These stimulate insulin secretion in a glucose-dependent manner.

 

Incretins are a group of metabolic hormones that are released from the enteroendocrine cells into the bloodstream after eating and stimulate a decrease in blood glucose levels. There are 2 incretins produced: GIP and GLP-1.

 

GLP-1 and GIP increase insulin from beta cells and glucose uptake by muscles and decrease blood glucose. GLP-1 stimulates glucose dependent decrease of glucagon from alpha cells, lowering glucose production from the liver and decreasing blood glucose.

 

GIP promotes the growth and survival of the pancreatic beta cell and stimulation of adipogenesis. Dipeptidyl peptidase-4 (DPP-4) is a serine protease responsible for the inactivation of GLP-1 and GIP. In patients with type 2 diabetes, there is decreased GLP-1 and GIP production.3

 

Tirzepatide’s protein sequence was based on the sequence of endogenous GIP and its pharmacological action on GLP-1 receptors is comparable to endogenous GIP. It is a 39 amino acid linear synthetic peptide conjugated to a C20 fatty diacid moiety.

 

The drug is also highly bound to albumin in the plasma, which prolongs its half-life.4 The long half-life of tirzepatide allows for a once-weekly dosing via subcutaneous administration. It is available in 6 doses: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg.1

 

The mechanisms of action for tirzepatide include stimulation of first- and second-phase insulin secretion, as well reduced glucagon levels, both in a glucose-dependent manner. The drug delays gastric emptying, lowers fasting and postprandial glucose concentration, decreases food intake, and reduces body weight in patients with type 2 diabetes. In addition, tirzepatide increases insulin sensitivity.

 

The glycemic and weight control effects of this drug are believed to arise from dual agonism at GIP and GLP-1R. Studies have demonstrated that coadministration of a GIP and GLP-1R agonist significantly increases insulin response and suppresses glucagon secretion compared to separate administration of either hormone alone.2

 

In clinical trials, tirzepatide was compared to semaglutide (GLP-1), insulin glargine and insulin degludec. Participants in the SURPASS-2 program achieved better average hemoglobin A1C reductions with tirzepatide than semaglutide.4

 

In the SURPASS-3 program, tirzepatide was superior to titrated insulin degludec, with greater reductions in HbA1c and body weight at week 52 and a lower risk of hypoglycemia.5 SURPASS-4 study evaluated patients with type 2 diabetes and elevated cardiovascular risk. Compared with glargine, tirzepatide demonstrated a greater and clinically meaningful HbA1c reduction with a lower incidence of hypoglycemia at week 52. Tirzepatide treatment was not associated with excess cardiovascular risk.”

Clinical Overview: Tirzepatide for Type 2 Diabetes

Pharmacy Times, September 2022

https://www.pharmacytimes.com/view/clinical-overview-tirzepatide-for-type-2-diabetes

Mounjaro’s Relevance to Diabetes

• In SURPASS-1, all three tirzepatide doses demonstrated statistically significant and clinically meaningful improvements in A1C and body weight reductions compared to placebo. Up to 92% of participants on tirzepatide achieved an A1C of less than 7%—the ADA’s recommended target for most people with diabetes. Up to 52% achieved an A1C of less than 5.7%—the level for people without diabetes.
• In SURPASS-2, all three tirzepatide doses delivered superior A1C and body weight reductions from baseline compared to semaglutide. Up to 92% of participants on tirzepatide achieved an A1C of less than 7% and up to 51% achieved an A1C less than 5.7%. 
• In SURPASS-3, all three tirzepatide doses delivered superior A1C and body weight reductions from baseline compared to titrated insulin degludec. Up to 93% of participants on tirzepatide achieved an A1C of less than 7% and up to 48% achieved an A1C of less than 5.7%.
• In SURPASS-5, all three tirzepatide doses delivered superior A1C reductions and weight reductions compared to placebo both added to titrated insulin glargine. Up to 97% of participants on tirzepatide achieved an A1C of less than 7% and up to 62% of participants on tirzepatide achieved an A1C of less than 5.7%.

 

Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial

The Lancet, June 2021

https://pubmed.ncbi.nlm.nih.gov/34186022/ 

 

Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial

The Lancet, August 2021

https://pubmed.ncbi.nlm.nih.gov/34370970/ 

 

Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial

The Lancet, April 2022 (paywall)

https://www.thelancet.com/journals/landia/article/PIIS2213-8587(22)00070-5/fulltext 

 

Efficacy of once-weekly tirzepatide versus once-daily insulin degludec on glycaemic control measured by continuous glucose monitoring in adults with type 2 diabetes (SURPASS-3 CGM): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial

The Lancet, April 2022 (paywall)

https://www.thelancet.com/journals/landia/article/PIIS2213-8587(22)00077-8/fulltext 

 

Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial

JAMA, February 2022

https://pubmed.ncbi.nlm.nih.gov/35133415/ 

 

Mounjaro’s Relevance to Weight Loss

Goal for weight loss medications is to reach an endpoint of 5% weight loss. In the SURMOUNT-1 trial, there were 2,539 participants. Tirzepatide trial participants lost 20.9% of overall body weight in 72 weeks. About a third of people on the highest two tirzepatide doses lost at least a quarter of their bodyweight during 72 weeks of treatment. All participants received regular lifestyle counseling over the course of the trial, promoting healthy, balanced meals, a 500 calorie per day deficit, and 150 recommended minutes of exercise per week, but the placebo group only lost an average of 3.1% of their bodyweight.

 

Can New Weight-Loss Drugs Really Treat Obesity?

Yale Medicine, June 2022

https://www.yalemedicine.org/news/new-medications-treat-obesity 

 

“GLP-1 is of relevance to appetite and weight maintenance because it has actions on the gastrointestinal tract as well as the direct regulation of appetite. It delays gastric emptying and gut motility in humans. In addition, interventricular injections of GLP-1 inhibit food intake, independent of the presence of food in the stomach or gastric emptying. Peripherally administered GLP-1 also affects the central regulation of feeding. It is therefore the synergistic actions of GLP-1 in the gut and brain, acting on both central and peripheral receptors that seem responsible for the effects of the hormone on satiety.

…unlike pure dietary measures, weight loss may be sustained for up to a period of 3 years in the presence of GLP-1 agonist therapy [67, 68]. However, once therapy is discontinued, there is some regain of weight [69]. There seems to be minimal effect of GLP-1 on energy expenditure per se and thus the overall negative energy balance seen with GLP-1 therapy is largely a result of decreased energy intake [70].”

Effects of GLP-1 on appetite and weight

Reviews in Endocrine and Metabolic Disorders, 2014

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119845/ 

 

Below, some info about how semaglutide works (which is a GLP-1RA drug that was released before Mounjaro under the brand names Ozempic & WeGovy):

How a lizard’s venom inspired the promising weight loss drug Wegovy

Vox, July 2021

https://www.vox.com/22553793/gila-monster-lizard-venom-inspired-obesity-drug-semaglutide 

 

Below is a screencap and a link to a video presentation of key results from a STEP 2 Trial on Ozempic, where they did research for 68 weeks on 2.4mg of Semaglutide (Ozempic/WeGovy) on T2D weight loss.They saw more vomiting at 2.4mg (20% vs 13% vomiting at the 1mg). Most of the A1C benefits are reached with Ozempic at 1mg, and the difference at higher doses is seen in weight loss. There are links to other video presentations about Tirzepatide (Mounjaro) results in the SURPASS-2 and SURPASS-5 trials as well on this page.