Highlights

Mounjaro (tirzepatide) is a new drug indicated for treating type 2 diabetes in adult patients.

Mounjaro, developed by Eli Lilly to improve glycemic control, works best, as with all antidiabetic medications, with diet and exercise.

Mounjaro is approved by the U.S. Food and Drug Administration (FDA) in mid-May 2022.

Regulators in other countries and territories, including the European Union and Japan, continue to review Mounjaro’s application.

Mounjaro is prescribed as a subcutaneous injection once a week.

Mounjaro administration provided proper glycemic control in almost 90% of patients whose glycated hemoglobin level (HbA1c) dropped below 7.0% as the American Diabetes Association (ADA) recommended target for type 2 diabetes. At the same time, more than half of the patients who received the maximum dose of Mounjaro and strictly followed the therapeutic regimen had their HbA1c level lowered to less than 5.7%, a level fair for individuals without diabetes.

Additionally, Mounjaro was successful in getting patients off the excess weight and reducing the risk of cardiovascular complications quite well.

Mounjaro was more than successful in direct comparison with Ozempic (semaglutide) from Novo Nordisk and the insulins Tresiba (insulin degludec) and Lantus (insulin glargine), which were developed by Novo Nordisk and Sanofi, respectively.

Tirzepatide is the first dual agonist of glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP-1R) on the market.

Mounjaro’s impressive therapeutic efficacy, outperforming all existing antidiabetic drugs, will shake up the global type 2 diabetes market.

Eli Lilly is concurrently studying the applicability of Mounjaro in the task of reducing overweight and for the treatment of non-alcoholic steatohepatitis (NASH). Thus, tirzepatide was the first drug to provide weight loss of more than 20% among obese patients.

obesity

Tirzepatide: Strong Weight-Loss Drug

Minus 24 kilograms in a year and a half.

Eli Lilly has not yet announced the price of Mounjaro, but this does not deter industry observers who speculate the highest demand for the drug. Thus, Mounjaro could earn at least $4 billion per year on obesity alone, while diabetes will allow Eli Lilly to eventually add $10 billion to its account each year. According to optimistic forecasts, Mounjaro’s peak sales could well reach $20 billion per year.

 

Mounjaro: Efficacy and Safety of Tirzepatide in Treating Type 2 Diabetes Mellitus

Mounjaro received regulatory approval based on the results of five phase 3 clinical trials that formed the basis of the New Drug Application (NDA):

  • SURPASS-1 (NCT03954834): tirzepatide versus placebo
  • SURPASS-2 (NCT03987919): tirzepatide vs. Ozempic (semaglutide), Novo Nordisk’s GLP-1R agonist, — on background metformin
  • SURPASS-3 (NCT03882970): tirzepatide vs. Novo Nordisk’s Tresiba (insulin degludec)
  • SURPASS-4 (NCT03730662): tirzepatide vs. Lantus (insulin glargine) [original developed by Sanofi, biosimilars already available] — among diabetics with increased cardiovascular risk
  • SURPASS-5 (NCT04039503): tirzepatide vs. placebo — among diabetics following a course of insulin glargine (with or without metformin).

 

Efficacy of Mounjaro

The efficacy of tirzepatide during experimental therapy of type 2 diabetes mellitus was analyzed by two methods. First, efficacy was assessed by efficacy up to the time of discontinuation of tirzepatide or administration of rescue therapy for persistent severe hyperglycemia. Second, efficacy was assessed independently of the pattern of adherence to therapy or prescription of rescue therapy, throughout the entire clinical trial.

In other words, the first method established the efficacy of tirzepatide when the treatment regimen was strictly followed, whereas the second method, which was closer to the real world, assumed that patients might not be particularly committed to treatment, for example, by skipping the next dose of the drug. Conditionally, we can say that the first method is fair for “ideal” patients, and the second method is fair for patients with some connivance with their health.

 

SURPASS-1 Results

The SURPASS-1 (NCT03954834) phase 3 clinical trial (randomized, double-blind, placebo-controlled, multicenter, international) enrolled adult patients (n=478) with type 2 diabetes that was not adequately controlled with diet and exercise alone.

The main criteria for inclusion in the trial were: naïve to diabetes injectable therapies and no any oral antidiabetic drugs for at least 3 months before screening; glycated hemoglobin (HbA1c) levels in the 7.0–9.5% range; body mass index (BMI) ≥23 kg/m2.

For 40 weeks, participants were given placebo or tirzepatide at a dose of 5, 10, or 15 mg by subcutaneous injection once a week.

Tirzepatide was administered in a stepwise manner. All patients started with a dose of 2.5 mg, which was increased by an additional 2.5 mg every 4 weeks until the required maintenance dose was reached.

Regardless of the methods used to evaluate the effectiveness of tirzepatide, it provided statistically significant reductions in glycated hemoglobin and body weight compared with placebo.

Tirzepatide: results of treating type 2 diabetes in SURPASS-1 (NCT03954834) phase 3 clinical trial [first evaluation method]

 Tirzepatide 5 mgTirzepatide 10 mgTirzepatide 15 mgPlacebo
Absolute HbA1c reduction from baseline of 7.9%−1.87%−1.89%−2.07%+0.04%
Placebo-adjusted HbA1c reduction−1.91%−1.93%−2.11%
Absolute weight reduction from baseline of 85.9 kg−7.0 kg (−7.9%)−7.8 kg (−9.3%)−9.5 kg (−11.0%)−0.7 kg (−0.9%)
Placebo-adjusted weight reduction−6.3 kg−7.1 kg−8.8 kg
Percent of participants achieving HbA1c <7.0%86.8%91.5%87.9%19.6%
Percent of participants achieving HbA1c <5.7%33.9%30.5%51.7%0.9%

Tirzepatide: results of treating type 2 diabetes in SURPASS-1 (NCT03954834) phase 3 clinical trial [second evaluation method]

 Tirzepatide 5 mgTirzepatide 10 mgTirzepatide 15 mgPlacebo
Absolute HbA1c reduction from baseline of 7.9%−1.75%−1.71%−1.69%−0.09%
Placebo-adjusted HbA1c reduction−1.66%−1.62%−1.60%
Absolute weight reduction from baseline of 85.9 kg−6.3 kg−7.0 kg−7.8 kg−1.0 kg
Placebo-adjusted weight reduction−5.3 kg−6.0 kg−6.8 kg
Percent of participants achieving HbA1c <7.0%81.8%84.5%78.3%23.0%
Percent of participants achieving HbA1c <5.7%30.9%26.8%38.4%1.4%

The overall safety profile of tirzepatide is similar to that of drugs in the GLP-1R agonist class. The most common adverse reactions to the therapy with tirzepatide occurred in the gastrointestinal tract. In most cases they were mildly-moderate, detected during dose escalation and decreased during treatment: nausea (11.6%, 13.2%, and 18.2% of patients in 5, 10, and 15 mg tirzepatide groups), diarrhea (11.6%, 14.0%, and 11.6%), vomiting (3.3%, 2.5%, and 5.8%), constipation (5.8%, 5.0%, and 6.6%). In the placebo group: nausea (6.1%), diarrhea (7.8%), vomiting (1.7%), constipation (0.9%).

No events of severe hypoglycemia or hypoglycemia with glucose levels below 54 mg/dL were observed.

Treatment discontinuation due to adverse events was noted among less than 7% of patients in each tirzepatide dose group.

The overall rates of treatment discontinuation were as follows: 9.1% of patients in the 5-mg dose group of tirzepatide, 9.9% (10-mg), 21.5% (15-mg), and 14.8% (placebo). Most refusals in the 15-mg dose of tirzepatide and placebo were for reasons other than adverse reactions: for example, because of fears in the context of a coronavirus pandemic, family or work factors.

 

SURPASS-2 Results

The SURPASS-2 (NCT03987919) phase 3 clinical trial (randomized, open-label, active-control, multicenter, international) invited adult patients (n=1879) with type 2 diabetes that was not adequately controlled with stable metformin therapy.

The main criteria for inclusion in the trial were: adherence to a stable course of metformin at a dose greater than 1500 mg/day for at least 3 months before screening; glycated hemoglobin (HbA1c) levels in the 7.0–10.5% range; body mass index (BMI) ≥25 kg/m2.

For 40 weeks, participants received subcutaneous injections once weekly of either Ozempic (semaglutide), a Novo Nordisk GLP-1R agonist, in a dose of 1 mg, or tirzepatide in doses of 5, 10, or 15 mg. Patients continued on metformin therapy.

Tirzepatide was administered in a stepwise manner. All patients started with a dose of 2.5 mg, which was increased by an additional 2.5 mg every 4 weeks until the required maintenance dose was reached. A similar regimen was established for semaglutide: initially 0.25 mg every 4 weeks, then 0.5 mg every 4 weeks, and finally 1 mg for the remainder of the trial.

Regardless of the methods used to evaluate the effectiveness of tirzepatide, it provided statistically significant reductions in glycated hemoglobin and body weight compared with semaglutide.

Tirzepatide: results of treating type 2 diabetes in SURPASS-2 (NCT03987919) phase 3 clinical trial [first evaluation method]

 Tirzepatide 5 mgTirzepatide 10 mgTirzepatide 15 mgSemaglutide 1 mg
Absolute HbA1c reduction from baseline of 8.28%−2.09%−2.37%−2.46%−1.86%
Absolute weight reduction from baseline of 93.7 kg−7.8 kg (−8.5%)−10.3 kg (−11.0%)−12.4 kg (−13.1%)−6.2 kg (−6.7%)
Percent of participants achieving HbA1c <7.0%85.5%88.9%92.2%81.1%
Percent of participants achieving HbA1c <5.7%29.3%44.7%50.9%19.7%

Tirzepatide: results of treating type 2 diabetes in SURPASS-2 (NCT03987919) phase 3 clinical trial [second evaluation method]

 Tirzepatide 5 mgTirzepatide 10 mgTirzepatide 15 mgSemaglutide 1 mg
Absolute HbA1c reduction from baseline of 8.28%−2.01%−2.24%−2.30%−1.86%
Absolute weight reduction from baseline of 93.7 kg−7.6 kg−9.3 kg−11.2 kg−5.7 kg
Percent of participants achieving HbA1c <7.0%82.0%85.6%86.2%79.0%
Percent of participants achieving HbA1c <5.7%27.1%39.8%45.7%18.9%

The overall safety profile of tirzepatide is similar to that of drugs in the GLP-1R agonist class. The most common adverse reactions to the therapy with tirzepatide occurred in the gastrointestinal tract. In most cases they were mildly-moderate, detected during dose escalation and decreased during treatment: nausea (in 17.4%, 19.2%, and 22.1% of patients in 5, 10, and 15 mg tirzepatide groups) — versus 17.9% of patients in semaglutide group; diarrhea (13.2%, 16.4%, and 13.8%) — versus 11.5%; vomiting (5.7%, 8.5%, and 9.8%) — versus 8.3%.

Hypoglycemic events with glucose levels below 54 mg/dL were reported in 0.6% of patients in the 5-mg dose tirzepatide group, 0.2% (10-mg), and 1.7% (15-mg). 0.4% of patients treated with semaglutide experienced hypoglycemic events.

Treatment discontinuation due to adverse events was noted among 5.1%, 7.7%, and 7.9% of participants in the respective tirzepatide dose groups — versus 3.8% in the control group.

 

SURPASS-3 Results

The SURPASS-3 (NCT03882970) phase 3 clinical trial (randomized, open-label, active-control, multicenter, international) enrolled adult patients (n=1444) with type 2 diabetes that was not adequately controlled with stable metformin therapy (or its combination with an SGLT2 inhibitor).

The main criteria for inclusion in the trial were: adherence to a stable course of either metformin or metformin combined with a sodium/glucose cotransporter 2 (SGLT2) inhibitor for at least 3 months before screening; glycated hemoglobin (HbA1c) levels in the 7.0–10.5% range; body mass index (BMI) ≥25 kg/m2.

For 52 weeks, participants received subcutaneous injections either once weekly of 5, 10, or 15 mg of tirzepatide or daily of Tresiba (insulin degludec) from Novo Nordisk.

Tirzepatide was administered in a stepwise manner. All patients started with a dose of 2.5 mg, which was increased by an additional 2.5 mg every 4 weeks until the required maintenance dose was reached. The starting dose in the insulin degludec group was 10 units/day, then it could be increased until reaching the target fasting glucose level below 90 mg/dL (the average dose at week 52 was 48.8 units/day).

Regardless of the methods used to evaluate the effectiveness of tirzepatide, it provided statistically significant reductions in glycated hemoglobin and body weight compared with insulin degludec.

Tirzepatide: results of treating type 2 diabetes in SURPASS-3 (NCT03882970) phase 3 clinical trial [first evaluation method]

 Tirzepatide 5 mgTirzepatide 10 mgTirzepatide 15 mgInsulin degludec
Absolute HbA1c reduction from baseline of 8.17%−1.93%−2.20%−2.37%−1.34%
Absolute weight reduction from baseline of 94.3 kg−7.5 kg (−8.1%)−10.7 kg (−11.4%)−12.9 kg (−13.9%)+2.3 kg (+2.7%)
Percent of participants achieving HbA1c <7.0%82.4%89.7%92.6%61.3%
Percent of participants achieving HbA1c <5.7%25.8%38.6%48.4%5.4%

Tirzepatide: results of treating type 2 diabetes in SURPASS-3 (NCT03882970) phase 3 clinical trial [second evaluation method]

 Tirzepatide 5 mgTirzepatide 10 mgTirzepatide 15 mgInsulin degludec  
Absolute HbA1c reduction from baseline of 8.17%−1.85%−2.01%−2.14%−1.25%
Absolute weight reduction from baseline of 94.3 kg−7.0 kg−9.6 kg−11.3 kg+1.9 kg
Percent of participants achieving HbA1c <7.0%79.2%81.5%83.5%58.0%

The overall safety profile of tirzepatide is similar to that of drugs in the GLP-1R agonist class. The most common adverse reactions to the therapy with tirzepatide occurred in the gastrointestinal tract. In most cases they were mildly-moderate, detected during dose escalation and decreased during treatment: nausea (in 11.5%, 22.5% and 23.7% of patients in 5, 10, and 15 mg tirzepatide groups) — versus 1.7% of patients in insulin degludec group; diarrhea (15.4%, 16.7%, and 15.6%) — vs. 3.9%; vomiting (5.9%, 9.4%, and 10.0%) — vs. 1.1%.

Hypoglycemic events with glucose levels below 54 mg/dL were reported in 1.4% of patients in the 5-mg dose tirzepatide group, 1.1% (10-mg), and 2.2% (15-mg). 7.3% of patients treated with insulin degludec experienced hypoglycemic events.

Treatment discontinuation due to adverse events was noted among 7.2%, 9.7%, and 10.9% of participants in the respective tirzepatide dose groups — versus 1.4% in the control group.

 

SURPASS-4 Results

The SURPASS-4 (NCT03730662) phase 3 clinical trial (randomized, open-label, active-control, multicenter, international) enrolled adult patients (n=2002) with type 2 diabetes that was not adequately controlled with stable therapy with one to three oral antidiabetic drugs (metformin, sulfonylurea derivatives, SGLT2 inhibitors). The subjects had to be characterized by an increased risk of cardiovascular complications (more than 85% of recruited patients had a history of cardiovascular events).

The main criteria for inclusion in the trial were: adherence to a stable course of one to three oral antidiabetic drugs (metformin, sulfonylurea derivatives, SGLT2 inhibitors) for at least 3 months before screening; glycated hemoglobin (HbA1c) levels in the 7.5–10.5% range; body mass index (BMI) ≥25 kg/m2.

For 52 weeks, participants received subcutaneous injections of either once weekly tirzepatide at a dose of 5, 10, or 15 mg or daily Lantus (insulin glargine) by Sanofi (biosimilars already available).

Tirzepatide was administered in a stepwise manner. All patients started with a dose of 2.5 mg, which was increased by an additional 2.5 mg every 4 weeks until the required maintenance dose was reached. The starting dose in the insulin glargine group was 10 units/day, then it could be increased until reaching the target fasting glucose level below 100 mg/dL (the average dose at week 52 was 43 units/day).

Regardless of the methods used to evaluate the effectiveness of tirzepatide, it provided statistically significant reductions in glycated hemoglobin and body weight compared with insulin glargine.

Tirzepatide: results of treating type 2 diabetes in SURPASS-4 (NCT03730662) phase 3 clinical trial [first evaluation method]

 Tirzepatide 5 mgTirzepatide 10 mgTirzepatide 15 mgInsulin glargine
Absolute HbA1c reduction from baseline of 8.52%−2.24%−2.43%−2.58%−1.44%
Absolute weight reduction from baseline of 90.3 kg−7.1 kg (−8.1%)−9.5 kg (−10.7%)−11.7 kg (−13.0%)+1.9 kg (+2.2%)
Percent of participants achieving HbA1c < 7.0%81.0%88.2%90.7%50.7%
Percent of participants achieving HbA1c <5.7%23.0%32.7%43.1%3.4%

Tirzepatide: results of treating type 2 diabetes in SURPASS-4 (NCT03730662) phase 3 clinical trial [second evaluation method]

 Tirzepatide 5 mgTirzepatide 10 mgTirzepatide 15 mgInsulin glargine
Absolute HbA1c reduction from baseline of 8.52%−2.11%−2.30%−2.41%−1.39%
Absolute weight reduction from baseline of 90.3 kg−6.4 kg−8.9 kg−10.6 kg+1.7 kg
Percent of participants achieving HbA1c <7.0%75.1%82.9%84.9%48.8%

A meta-analysis of cardiovascular events recorded throughout the SURPASS clinical program showed that tirzepatide reduced by 19% (hazard ratio [HR] 0.81 [95% CI: 0.52–1.26]) the risk of major adverse cardiovascular events (MACE), a composite endpoint including such outcomes as death from cardiovascular or undetermined causes, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina.

In the SURPASS-4 clinical trial, which contributed most to MACE statistics, the risk reduction was 26% (HR 0.74 [95% CI: 0.51–1.08]).

The overall safety profile of tirzepatide is similar to that of drugs in the GLP-1R agonist class. The most common adverse reactions to the therapy with tirzepatide occurred in the gastrointestinal tract. In most cases they were mildly-moderate, detected during dose escalation and decreased during treatment: nausea (in 11.9%, 15.9%, and 22.2% of patients in 5, 10, and 15 mg tirzepatide groups) — versus 1.6% of patients in the insulin glargine group; diarrhea (12.2%, 19.5%, and 20.4%) — vs. 3.2%; vomiting (4.9%, 8.2%, and 8.3%) — vs. 1.1%.

Hypoglycemic events with glucose levels below 54 mg/dL were reported in 6.7% of patients in the 5-mg dose tirzepatide group, 5.5% (10-mg), and 6.5% (15-mg). This was encountered in 15.0% of patients receiving insulin glargine. Episodes of hypoglycemia occurred more frequently in subjects on background therapy with sulfonylurea derivatives.

Treatment discontinuation due to adverse events was noted among 8.2%, 7.3%, and 8.9% of participants in the respective tirzepatide dose groups — versus 2.9% in the control group.

 

SURPASS-5 Results

The SURPASS-5 (NCT04039503) phase 3 clinical trial (randomized, double-blind, placebo-controlled, multicenter, international) enrolled adult patients (n=2002) with type 2 diabetes that was not adequately controlled with stable insulin glargine therapy with (or without) metformin.

The main criteria for inclusion in the trial were: adherence to a stable course of insulin glargine with (or without) metformin for at least 3 months before screening; glycated hemoglobin (HbA1c) levels in the 7.0–10.5% range; body mass index (BMI) ≥23 kg/m2.

For 40 weeks, participants received subcutaneous injections once a week of either tirzepatide at a dose of 5, 10, or 15 mg or placebo. Patients continued on Lantus (insulin glargine) from Sanofi (biosimilars already available) with (or without) metformin.

Tirzepatide was administered in a stepwise manner. All patients started with a dose of 2.5 mg, which was increased by an additional 2.5 mg every 4 weeks until the required maintenance dose was reached. The starting dose in the insulin glargine group was 10 units/day, then it could be increased until reaching the target fasting glucose level below 100 mg/dL.

Regardless of the methods used to evaluate the effectiveness of tirzepatide, it provided statistically significant reductions in glycated hemoglobin and body weight compared with placebo.

After 40 weeks of treatment, the average dose of insulin glargine received was lower in all tirzepatide groups (37.6, 35.7, and 29.4 units/day) than in the control group (58.8 units/day).

Tirzepatide: results of treating type 2 diabetes in SURPASS-5 (NCT04039503) phase 3 clinical trial [first evaluation method]

 Tirzepatide 5 mgTirzepatide 10 mgTirzepatide 15 mgPlacebo
Absolute HbA1c reduction from baseline of 8.31%−2.23%−2.59%−2.59%−0.93%
Absolute weight reduction from baseline of 95.2 kg−6.2 kg (−6.6%)−8.2 kg (−8.9%)−10.9 kg (−11.6%)+1.7 kg (+1.7%)
Percent of participants achieving HbA1c < 7.0%93.0%97.4%94.0%33.9%
Percent of participants achieving HbA1c <5.7%26.1%47.8%62.4%2.5%

Tirzepatide: results of treating type 2 diabetes in SURPASS-5 (NCT04039503) phase 3 clinical trial [second evaluation method]

 Tirzepatide 5 mgTirzepatide 10 mgTirzepatide 15 mgPlacebo
Absolute HbA1c reduction from baseline of 8.31%−2.11%−2.40%−2.34%−0.86%
Absolute weight reduction from baseline of 95.2 kg−5.4 kg−7.5 kg−8.8 kg+1.6 kg
Percent of participants achieving HbA1c <7.0%87.3%89.6%84.7%34.5%

The overall safety profile of tirzepatide is similar to that of drugs in the GLP-1R agonist class. The most common adverse reactions to the therapy with tirzepatide occurred in the gastrointestinal tract. In most cases they were mildly-moderate, detected during dose escalation and decreased during treatment: nausea (in 12.9%, 17.6%, and 18.3% of patients in the 5, 10, and 15 mg tirzepatide groups) versus 2.5% of patients in the placebo group; diarrhea (12.1%, 12.6%, and 20.8%) — vs. 10.0%; vomiting (6.9%, 7.6%, and 12.5%) — vs. 2.5%; constipation (6.0%, 6.7%, and 6.7%) —vs. 1.7%.

Hypoglycemic events with glucose levels below 54 mg/dL were reported in 15.5% of patients in the 5-mg dose tirzepatide group, 19.3% (10-mg), and 14.2% (15-mg). This was seen in 12.5% of patients receiving placebo.

Treatment discontinuation due to adverse events was noted among 6.0%, 8.4%, and 10.8% of participants in the respective tirzepatide dose groups — versus 2.5% in the control group.

 

Safety of Mounjaro

In preclinical trials in rats, tirzepatide caused a dose-dependent and duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas). Molecular processes in the human body are fundamentally different, and therefore it is not yet known whether tirzepatide has the same side effect in humans, leading to the development of thyroid C-cell tumors, including medullary thyroid carcinoma (MTC).

To definitively clarify this question, the NCT01511393 clinical program of active surveillance of patients undergoing multi-year treatment with any commercially available GLP-1 receptor agonists continues.

Nevertheless, analysis of patient histories confirms that long-term prescription of GLP-1 analogues is indeed associated with an increased risk of developing thyroid tumors. However, there are many questions about this kind of research for lack of bias and systematic errors.

Anyway, the prescribing information for Mounjaro, as well as other drugs from the GLP-1 analogues class, has a black box warning regarding the above mentioned risk of thyroid tumors.

Mounjaro is contraindicated in persons with a personal or family history of MTC or multiple endocrine neoplasia type 2 (MEN2).

Among the most common adverse reactions in response to administration of Mounjaro (in a maximum 15-mg dose) were nausea (in 18% of patients), diarrhea (17%), decreased appetite (11%), vomiting (9%), constipation (7%), dyspepsia (5%), and abdominal pain (5%). Gastrointestinal tract adverse events are usually mild-to-moderate in severity and become increasingly rare as treatment progresses.

 

Mounjaro in Type 2 Diabetes Mellitus: Mechanism of Action of Tirzepatide

Tirzepatide (LY3298176) is a biological drug compound that is an agonist for the glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP-1R).

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) belong to the incretins, a group of metabolic hormones that stimulate blood glucose lowering. The incretins are released after meals, by a glucose-dependent mechanism, enhancing the production of insulin secreted by the beta cells of the islets of Langerhans in the pancreas. Together, GIP and GLP-1 are responsible for secreting approximately 70% of insulin in response to food intake.

Since type 2 diabetes therapy is aimed at lowering blood sugar levels and body weight, GLP-1R agonists are quite adequate. However, their effectiveness is still insufficient, so it makes sense to increase it.

Historically, the therapeutic applicability of GIPR agonists has not been found in practice. This is due to the fact that in type 2 diabetes the incretin response to GIPR is severely impaired due to the impaired regulation of GIPR mediated by high circulating glucose levels. One solution to bypass GIP resistance involves lowering glucose levels — by GLP-1R agonists.

What Is Glucagon-Like Peptide-1 (GLP-1)?
Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by enteroendocrine L-cells in the mucosa of the distal ileum and in the colon and by certain neurons of the solitary tract in the brainstem. Agonist activation of GLP-1 receptor (GLP-1R) signaling has an insulinotropic effect that promotes insulin secretion in response to food intake. GLP-1R is expressed in pancreatic beta cells, various types of gastrointestinal cells, and neurons of the central and peripheral nervous systems.

Additional effects of GLP-1R agonism, beneficial in the therapy of type 2 diabetes mellitus, are manifested by delayed gastric evacuation, decreased gastric juice secretion, and weakened gastric motility. All this leads to a suppression of appetite and a decrease in the postprandial rise in blood glucose levels. Among other things: decrease in plasma glucagon levels (glucagon raises blood glucose concentration and promotes gluconeogenesis and glycogenolysis) and activation of anorexigenic pathways in the brain (mediates weight loss).

The metabolic effects of GLP-1R agonism are not accompanied by a risk of hypoglycemic events in diabetics.

What Is Glucose-Dependent Insulinotropic Polypeptide (GIP)?
Glucose-dependent insulinotropic polypeptide (GIP), formerly known as gastric inhibitory polypeptide (mistakenly thought to inhibit gastric juice secretion), is a peptide hormone secreted by enteroendocrine K-cells of the duodenal and jejunum mucosa.

The function of GIP is to induce insulin secretion, which is stimulated primarily by hyperosmolarity of glucose in the duodenum. GIP suppresses apoptosis of pancreatic beta cells by promoting their proliferation. GIP stimulates glucagon secretion and triglyceride accumulation. GIP receptors (GIPRs) are expressed in many organs and tissues, including the central nervous system, allowing GIP to influence appetite and satiety regulation.

GIP, unlike GLP-1, simultaneously exhibits glucagonotropic and insulinotropic effects, depending on glycemia: it dose-dependently stimulates glucagon secretion in hypoglycemic conditions and insulin secretion in hyperglycemic conditions.

Although both GIPR and GLP-1R are present in pancreatic beta cells, the expression of GIPR in tissues outside the pancreas differs from that of GLP-1R. Thus, GIPRs are abundantly present in adipose tissue and many non-overlapping regions of the central nervous system.

 

Pharmacological Features of Tirzepatide

The pharmacology of tirzepatide differs from that of other multi-incretin agonists in clinical trials. The pertinent characterization of tirzepatide is as follows: “unbalanced” agonist equally in terms of both enhanced affinity and potency to GIPR versus GLP-1R and in terms of offset GLP-1R agonism versus pleiotropic GIPR activity.

Tirzepatide shows an affinity for GIPR equivalent to native GIP, but binds GLP-1R with an affinity attenuated by a factor of approximately 5 relative to that of native GLP-1.

The unbalanced nature of tirzepatide is critical to maximizing its effectiveness as a dual agonist because dose escalation to activate GLP-1R is usually limited by gastrointestinal adverse reactions, such as nausea and vomiting, whereas GIPR activation is not associated with such phenomena. As a consequence, the pharmacological profile of tirzepatide, which favors GIPR potentiation, provides an opportunity for full incorporation into this pathway while minimizing GLP-1R agonist tolerability problems.

 

Mounjaro and Treatment of Type 2 Diabetes Mellitus: Tirzepatide’s Comparative Efficacy and Safety With Competitors

To better understand the efficacy of tirzepatide in the treatment of patients with type 2 diabetes, it is appropriate to summarize the efficacy and safety of competing and already commercialized GLP-1R agonists (GLP-1RAs) that have been clinically compared to placebo groups. It should be understood that it is methodologically incorrect to make such comparisons because of the differences in baseline characteristics of clinical trial participants, trial designs, and their durations. But it is already clear that tirzepatide easily outperforms all other GLP-1RAs.

Treatment of type 2 diabetes: comparison of efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs)

DrugOriginatorPivotal trial phase 3Dosage and regimenDurations, weeksHbA1c, %Success, %Weight, kgNausea, %
Mounjaro (tirzepatide)Eli LillySURPASS-1 (NCT03954834)5/10/15 mg once a week401.69–1.7578–857.0–9.512–18
Trulicity (dulaglutide)Eli LillyAWARD-3 (NCT01126580)0.75/1.50 mg once a week260.71–0.7862–631.4–2.311–19
Ozempic (semaglutide)Novo NordiskSUSTAIN 1 (NCT02054897)0.5/1.0 mg once a week301.45–1.5572–743.7–4.520–24
Rybelsus (semaglutide) [oral]Novo NordiskPIONEER 1 (NCT02906930)7/14 mg once a day261.2–1.469–772.3–3.75–16
Victoza (liraglutide)Novo NordiskLEAD-3 (NCT00294723)1.2/1.8 mg once a day520.84–1.1443–512.1–2.527–29
Byetta (exenatide)AstraZenecaNCT003813425/10 mcg twice a day240.7–0.948–532.8–3.18
Bydureon/Byetta Long (exenatide)AstraZenecaDURATION-4 (NCT00676338)2.0 mg once a week261.6562.011
Adlyxin/Lyxumia (lixisenatide)SanofiGETGOAL-MONO (NCT00688701)20 mcg once a day120.85471.920
Tanzeum/Eperzan (albiglutide)GlaxoSmithKlineHARMONY 2 (NCT00849017)30/50 mg once a week520.70–0.8940–490.4–0.99–10
Table notes:

  • HbA1c, % — reduction in glycated hemoglobin (HbA1c) from baseline

  • success, % — the proportion of patients who reached the target value of HbA1c <7.0%

  • weight, kg — decrease in body weight in kilograms from baseline

  • nausea, % — the proportion of patients who experienced an adverse event in the form of nausea.

 

Tirzepatide Clinical Program: Diabetes Mellitus, Obesity, and Non-alcoholic Steatohepatitis

Eli Lilly has taken the issue of evidence for the therapeutic validity of tirzepatide seriously. In the context of type 2 diabetes, the experimental drug is being tested not only in terms of reducing blood glucose levels and body weight but also in terms of its ability to have a beneficial effect on cardiovascular outcomes. This is done because existing antidiabetic drugs on the market are seeking to demonstrate cardiac benefit to patients, not just diabetics. Competitive tensions are too high — patient and physician interests have to be nurtured.

In parallel, tirzepatide is being rolled out in the therapy of overweight and obesity, as well as non-alcoholic steatohepatitis (NASH) as a sought-after pharmacological topic in every sense.

The phase 3 clinical program of tirzepatide, launched in late 2018, has already enrolled more than 27,000 people.

 

Tirzepatide: Treatment of Type 2 Diabetes Mellitus

Phase 3 clinical trials of tirzepatide in the treatment of patients (n≈21934) with type 2 diabetes mellitus are as follows:

  • SURPASS-1 (NCT03954834): tirzepatide versus placebo
  • SURPASS-2 (NCT03987919): tirzepatide vs. Ozempic (semaglutide), Novo Nordisk’s GLP-1R agonist, — on background metformin
  • SURPASS-3 (NCT03882970): tirzepatide vs. Novo Nordisk’s Tresiba (insulin degludec)
  • SURPASS-4 (NCT03730662): tirzepatide vs. Lantus (insulin glargine) [original developed by Sanofi, biosimilars already available] — among diabetics with increased cardiovascular risk
  • SURPASS-5 (NCT04039503): tirzepatide vs. placebo — among diabetics following a course of insulin glargine (with or without metformin)
  • SURPASS-6 (NCT04537923): tirzepatide vs. Humalog (insulin lispro) [original developed by Eli Lilly, biosimilars already available] — among diabetics following a course of insulin glargine along with (or without) oral antidiabetic drugs such as metformin, sulfonylurea derivative, or dipeptidyl peptidase-4 (DPP-4; gliptins) inhibitors
  • SURPASS J-Mono (NCT03861052) [Japan only]: tirzepatide vs. Trulicity (dulaglutide), Eli Lilly’s GLP-1R agonist
  • SURPASS J-Combo (NCT03861039) [Japan only]: tirzepatide in combination with oral antidiabetic drugs such as sulfonylurea derivatives, biguanides (metformin), thiazolidinediones (glitazones), alpha-glucosidase inhibitors, glinides, gliflozins (sodium-glucose cotransporter type 2 [SGLT2] inhibitors)
  • SURPASS-AP-Combo (NCT04093752): tirzepatide vs. insulin glargine — on background metformin (with or without sulfonylurea derivative)
  • SURPASS-CVOT (NCT04255433): tirzepatide vs. Trulicity — among diabetics at increased risk of cardiovascular complications (confirmed atherosclerotic cardiovascular disease)
  • SURPASS-PEDS (NCT05260021): tirzepatide vs. placebo —among adolescent or childhood diabetics (10–18 years old) following a course of metformin (with or without basal insulin)

 

Tirzepatide: Treatment of Overweight and Obesity

Phase 3 clinical trials of tirzepatide in the treatment of patients (n≈6021) with overweight or obesity are as follows:

  • SURMOUNT-1 (NCT04184622): tirzepatide versus placebo — among patients without type 2 diabetes who are either obese or overweight with comorbidities (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease)
  • SURMOUNT-2 (NCT04657003): tirzepatide vs. placebo — among patients with type 2 diabetes and obesity or overweight adhering to either diet and/or exercise or any oral antidiabetic drug except DPP-4 inhibitors and GLP-1R agonists
  • SURMOUNT-3 (NCT04657016): tirzepatide vs. placebo — among patients without type 2 diabetes who were obese with the aforementioned comorbidity and who had previously completed an intensive lifestyle change program
  • SURMOUNT-4 (NCT04660643): an extension of the SURMOUNT-1 clinical trial
  • SURMOUNT-J (NCT04844918) [Japan only]: tirzepatide vs. placebo — among patients without type 2 diabetes who are obese and have some associated condition (impaired glucose tolerance, hyperlipidemia, nonalcoholic fatty liver disease) on a low-fat diet and increased physical activity
  • SURMOUNT-CN (NCT05024032) [China only]: tirzepatide versus placebo — among patients without type 2 diabetes who are either obese or overweight with comorbidities (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease)
  • SUMMIT (NCT04847557): tirzepatide vs. placebo — among patients with obesity and heart failure (NYHA class II–IV) with preserved ejection fraction (≥50%).

 

Tirzepatide: Treatment of Non-alcoholic Steatohepatitis

Phase 2 clinical trials of tirzepatide in the treatment of patients (n≈196) with non-alcoholic steatohepatitis (NASH) are as follows:

  • SYNERGY-NASH (NCT04166773): tirzepatide versus placebo — among patients with (or without) type 2 diabetes and NASH with stage 2 or 3 liver fibrosis.

 

Mounjaro: Market Outlook of Tirzepatide

There are quite a few GLP-1R agonists on the market showing decent consumer demand. This is understandable considering their metabolic benefits for patients with type 2 diabetes mellitus. Unfortunately, many diabetics still do not reach their glycemic targets, and the weight loss induced by such drugs is relatively modest when compared to bariatric surgery — the most powerful approach to addressing obesity. As a result, the pharma industry has decided to improve the therapeutic efficacy of GLP-1R agonists.

Eli Lilly is trying to do this by combining GLP-1R agonism with GIPR agonism, in an unbalanced and in this case therapeutically useful way.

Marketed glucagon-like peptide-1 receptor agonists (GLP-1RAs)

DrugINNOriginatorRegimenUS approval (FDA)Europe approval (EMA)Japan approval (PMDA)Russia approval
MounjaroTirzepatideEli LillyOnce a weekMay 13, 2022
Wegovy (for weight loss)SemaglutideNovo NordiskOnce a weekJune 8, 2021January 6, 2022
RybelsusSemaglutide (oral)Novo NordiskOnce a daySeptember 20, 2019April 3, 2020June 29, 2020April 9, 2021
OzempicSemaglutideNovo NordiskOnce a weekDecember 5, 2017February 8, 2018March 23, 2018August 15, 2018
Adlyxin/LyxumiaLixisenatideSanofiOnce a dayJuly 27, 2016February 1, 2013June 28, 2013December 2, 2014
Saxenda (for weight loss)LiraglutideNovo NordiskOnce a dayDecember 23, 2014May 23, 20159 March 2016
TrulicityDulaglutideEli LillyOnce a weekSeptember 18, 2014November 21, 2014July 3, 2015June 16, 2016
Tanzeum/Eperzan (withdrawn)AlbiglutideGlaxoSmithKlineOnce a weekApril 15, 2014March 21, 2014June 28, 2013
Bydureon/Byetta LongExenatideAstraZenecaOnce a weekJanuary 27, 2012June 17, 2011March 10, 2015March 21, 2017
VictozaLiraglutideNovo NordiskOnce a dayJanuary 25, 2010June 30, 2009January 20, 2010May 18, 2010
ByettaExenatideAstraZenecaOnce a dayApril 28, 2005November 20, 2006October 27, 2010June 9, 20101

Global sales of glucagon-like peptide-1 receptor agonists (GLP-1RAs), million dollars

DrugINNOriginator201620172018201920202021
TrulicityDulaglutideEli Lilly92620303199412850686472
OzempicSemaglutideNovo Nordisk285168532435359
VictozaLiraglutideNovo Nordisk297935113856328828672393
Saxenda (for weight loss)LiraglutideNovo Nordisk234388613851857Combine

1335

Wegovy (for weight loss)SemaglutideNovo Nordisk
Bydureon/Byetta LongExenatideAstraZeneca578574584549448385
RybelsusSemaglutide (oral)Novo Nordisk7286769
ByettaExenatideAstraZeneca2541761261106855
Adlyxin/LyxumiaLixisenatideSanofi363011
Tanzeum/Eperzan (withdrawn)AlbiglutideGlaxoSmithKline16511341
MounjaroTirzepatideEli Lilly
Table notes:

  • In August 2017, GlaxoSmithKline announced that sales of Tanzeum/Eperzan (albiglutide) had been stopped for economic reasons; it could not survive the competition.

  • As of 2019, sales of Adlyxin/Lyxumia (lixisenatide) are too insignificant for Sanofi to include their volumes in the financial annual report.

Tirzepatide is central to Eli Lilly’s pipeline of experiments with diabetes treatment. This drug is important in part because Trulicity will lose patent protection in 2027.

The therapeutic efficacy of tirzepatide, as shown by its large-scale clinical testing, was superior to that of all commercialized GLP-1R agonists, both in terms of normalizing blood sugar levels and reducing excessive weight. Tirzepatide has also proven its ability to reduce risks of cardiovascular events.

Thus, a direct comparison with Ozempic established the advantage of tirzepatide on all counts. Remarkably, half of the patients in the tirzepatide group (true for the maximum 15-mg dose) and only one-fifth in Ozempic group reached normal blood sugar levels (euglycemia), fair for people without diabetes. Many antidiabetic medications fail to take the patient to euglycemia.

Eli Lilly has tried to address the gastrointestinal (GI) tolerance of tirzepatide; by gradually increasing its dose every 4 weeks. Alas, the problem was not completely eliminated; mild-to-moderate nausea, vomiting, and diarrhea are still present. However, in the course of treatment, these side effects gradually subside, the body actually adapts.

It should be understood that similar adverse GI events have in no way prevented Trulicity and Ozempic from steadily increasing sales, earning billions of dollars for Eli Lilly and Novo Nordisk. Again, all the same Novo Nordisk’s Victoza has been making a lot of money for years for years even though a third of patients are experiencing nausea. Overall, the safety profile of tirzepatide looks manageable. In other words, adverse GI events are unlikely to reduce consumer demand for tirzepatide, which is destined to be a first-line antidiabetic drug.

The price of Mounjaro has not yet been announced, but industry experts suggest that it will be about a quarter higher than the current cost of Trulicity or Ozempic. And this is justified, given the enhanced efficacy of the treatment, you have to pay for innovation.

Predictions about the commercial future of tirzepatide are very optimistic. Mounjaro will quickly become a blockbuster, crossing the $1 billion annual sales bar as early as 2024. The skyrocketing demand for the drug will get a significant boost when tirzepatide adds new indications: to combat overweight ( efficacy has already been proven, and it is impressive), to reduce cardiovascular risks (for heart failure with preserved ejection fraction), and to treat non-alcoholic steatohepatitis (NASH). Obviously, the latter two pathological conditions are associated with excess body weight and/or increased body fat, and the mechanism of action of tirzepatide is precisely directed against them. But we should not forget that there are always risks of clinical trial failure.

It is thought that Mounjaro could make at least $4 billion a year on obesity alone, while diabetes would allow Eli Lilly to eventually add $10 billion to its account annually. Optimistic forecasters project that Mounjaro’s maximum sales could well reach $20 billion a year.

 

Extras

Mounjaro (tirzepatide). Prescribing information. U.S. [PDF]

Tirzepatide SURPASS phase 3 program overview. Eli Lilly. November 20, 2020. [PDF]

LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab. 2018 Dec;18: 3–14. [source]

Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020 Sep 3;5(17): e140532. [source]

Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens. Diabetes Obes Metab. 2020 Jun;22(6):938-946. [source]

Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet. 2018 Nov 17;392(10160):2180-2193. [source]

Effects of novel dual GIP and GLP-1 receptor agonist tirzepatide on biomarkers of nonalcoholic steatohepatitis in patients with type 2 diabetes. Diabetes Care. 2020 Jun;43(6):1352-1355. [source]

Pharmacological characterization of mono-, dual- and tri-peptidic agonists at GIP and GLP-1 receptors. Biochem Pharmacol. 2020 Jul;177:114001. [source]

How may GIP enhance the therapeutic efficacy of GLP-1? Trends Endocrinol Metab. 2020 Jun;31(6):410-421. [source]

The novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide transiently delays gastric emptying similarly to selective long-acting GLP-1 receptor agonists. Diabetes Obes Metab. 2020 Oct;22(10):1886-1891. [source]

Tirzepatide: a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) dual agonist in development for the treatment of type 2 diabetes. Expert Rev Endocrinol Metab. 2020 Nov;15(6):379-394. [source]

Dual GIP and GLP-1 receptor agonist tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes. J Clin Endocrinol Metab. 2021 Jan 23;106(2):388-396. [source]

The role of tirzepatide, dual GIP and GLP-1 receptor agonist, in the management of type 2 diabetes: the SURPASS clinical trials. Diabetes Ther. 2021 Jan;12(1):143-157. [source]

The dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist, tirzepatide, improves lipoprotein biomarkers associated with insulin resistance and cardiovascular risk in patients with type 2 diabetes. Diabetes Obes Metab. 2020 Dec;22(12):2451-2459. [source]

Effects of renal impairment on the pharmacokinetics of the dual GIP and GLP-1 receptor agonist tirzepatide. Clin Pharmacokinet. 2021 Mar 29. [source]

GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice. J Clin Invest. 2021 May 18;146353. [source]

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