Introduction

Obesity and diabetes are acknowledged as significant health concerns of the 21st century, leading to higher rates of illness, death, and escalating healthcare expenses. Tirzepatide is a novel drug approved by the US Food and Drug Administration (FDA) and the European Medicines Agency to treat obesity and type 2 diabetes. Initially created for the management of type 2 diabetes, Tirzepatide’s additional advantage of aiding users in weight loss has transformed it into a worldwide sensation. It is globally available as Zepbound®as for weight management and Mounjaro for diabetes and has shown encouraging results in clinical trials. However, it is crucial to consider both the potential benefits and the risks, adopting a balanced approach to its evaluation.

This blog aims to provide a concise overview of Tirzepatide in the context of treating diabetes and obesity, while also emphasizing its advantages and potential risks.

Tirzepatide – Approvals & Launches

• On 13^th May 2022, the US FDA approved Tirzepatide (Trade Name – MOUNJARO) injection as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.¹
• On 8^th November 2023, the US FDA approved Tirzepatide (Trade Name -ZEPBOUND) injection for chronic weight management in adults with obesity (BMI of ≥ 30 kg/ m2) or overweight (BMI of ≥ 27 kg/m2) with at least one weight-related condition (such as high blood pressure, type 2 diabetes or high cholesterol) for use, in addition to a reduced calorie diet and increased physical activity.²
• On December 20th, 2024, the U.S. FDA approved Zepbound^®as the first and only prescription medicine for the treatment of moderate to severe obstructive sleep apnea (in adults with obesity, to be used in combination with a reduced-calorie diet and increased physical activity.³
• Eli Lilly introduced Tirzepatide under the brand name MOUNJARO to the Indian market in March 2025.

Understanding Tirzepatide “A Twincretin”⁴

• Tirzepatide is a synthetic polypeptide comprising 39 amino acids.
• Tirzepatide is the first dual agonist of the incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors (Figure 1).

Figure 1: Mechanism of Action of Tirzepatide

• Incretin like GLP-1 and GIP are the hormones produced by small intestine that regulate blood sugar levels and appetite.
• Tirzepatide enhances the activity of GLP-1 and GIP by mimicking or copying their actions. 
• GLP-1 and GIP plasma concentrations rise 15 to 20 minutes after meal consumption, activating their receptors on pancreatic cells to trigger a glucose-dependent, proportionate insulinotropic response that aids in the removal of the absorbed carbohydrate and fat load.
• Since the incretin effect is diminished in diabetes, Tirzepatide is an effective alternative to achieving glycemic control.
• Due to this unique dual activity, it is also called ‘Twincretin’.

Tirzepatide – Strength Available ^5-6

• Injection: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg per 0.5 mL in a single-dose pen.

Tirzepatide – Dosage and Administration ^5-6

• Starting dose- 2.5 mg subcutaneous (SC) injection once weekly.
• Dose Titration- After 4 weeks, increase to 5 mg injected SC once weekly. Increase the dosage in 2.5 mg increments on the current dose after at least 4 weeks.
• Maximum dosage – 15 mg SC once weekly.
• Administration time – Any time of day, irrespective of meals.
• Missed dose- If a dose is not taken, it should be administered promptly within four days of the missed dose. If the four-day window has passed, the missed dose should be skipped, and the next dose should be taken as per the usual schedule.
• Injection sites- Abdomen, thigh, or upper arm.
• Site rotation – Rotate injection sites with each dose.

Tirzepatide Landmark Clinical Trials in Type 2 Diabetes

SURPASS -1 Trial ⁷

• A 40-week, double-blind, randomised, placebo-controlled, phase 3 trial was conducted to assess the efficacy, safety, and tolerability of once weekly Tirzepatide monotherapy in type 2 diabetes patients inadequately controlled by diet and exercise alone.
• 478 participants with mean baseline HbA1c 7.9%, age 54, diabetes duration 4.7 years and BMI of 31.9 kg/m2 were enrolled in the study.
• Results
  • HbA1c reductions were 1.9%, 1.9% and 2% with 5mg, 10mg and 15mg Tirzepatide, respectively.
  • A dose-dependent weight loss of 7–9.5 kg was seen.
  • The most frequent adverse events (AEs) with Tirzepatide were mild to moderate and transient gastrointestinal (GI) events, including nausea (12-18% vs 6%), diarrhoea (12-14% vs 8%), and vomiting (2-6% vs 2%).
  • No clinically significant or severe hypoglycaemia (<54mg/dl) was reported with Tirzepatide.

SURPASS -2 Trial ⁸

• An open-label, 40-week, phase 3 trial was conducted to assess the efficacy and safety of once-weekly Tirzepatide vs Semaglutide.
• 1879 people with a mean diabetes duration of 8.6 years, mean HbA1c of 8.28%, a mean age of 56.6 years, and a mean weight of 93.7 kg were enrolled in the study.
• Results
  • The mean change from baseline in the HBA1c was −2.01 %, −2.24 %, and −2.30 % with 5 mg, 10 mg, and 15 mg of Tirzepatide, respectively, and −1.86 % with Semaglutide.
  • The mean reductions in body weight with Tirzepatide at a dose of 5 mg, 10 mg, and 15 mg were −7.6 kg, −9.3 kg, and −11.2 kg, respectively, as compared with −5.7 kg with Semaglutide.
  • The most common AEs were GI in the Tirzepatide and Semaglutide groups (nausea, 17 to 22% and 18%; diarrhoea, 13 to 16% and 12%; and vomiting, 6 to 10% and 8%, respectively).
  • Hypoglycemia (<54 mg/dl) was reported in 0.6% (5-mg group), 0.2% (10-mg group), and 1.7% (15-mg group) with 5 mg, 10 mg and 15 mg Tirzepatide respectively and was reported in 0.4% of those who received Semaglutide.

SURPASS -3 Trial ⁹

• This was an open-label, 52-week phase 3 study that compared the efficacy and safety of Tirzepatide (5, 10, or 15 mg) Vs titrated Insulin degludec in 1444 type 2 diabetes patients taking metformin with or without SGLT2 inhibitors.
• The proportion of participants achieving a HbA_1c < 7·0% at week 52 was greater (p<0·0001) in all three Tirzepatide groups (82%-93%) versus Insulin degludec (61%).
• Results
  • At all three Tirzepatide doses, body weight decreased between -7·5 kg to -12·9 kg, whereas in the Insulin degludec group, body weight increased by 2·3 kg.
  • A higher incidence of nausea (12-24%), diarrhoea (15-17%), decreased appetite (6-12%), and vomiting (6-10%) was reported in participants treated with Tirzepatide than in those treated with Insulin degludec (2%, 4%, 1%, and 1%, respectively).
  • Hypoglycaemia (<54 mg/dL) was reported in 1- 2% of participants on Tirzepatide Vs 7% on Insulin degludec. 

SURPASS-4 Trial ¹⁰

• This was an open-label, parallel-group, 52-week phase 3 study that assessed the efficacy and safety of Tirzepatide vs. insulin glargine in adults with type 2 diabetes and high cardiovascular risk inadequately controlled on oral glucose-lowering medications.
• The study enrolled a high cardiovascular-risk cohort (87% had a previous event) who had lived with diabetes for a median of 10.5 years and a mean HbA1c of 8.5% despite multiple oral antidiabetic agents.
• Results
  • In a head-to-head 52-week trial vs insulin glargine U100, 5mg, 10mg and 15mg of Tirzepatide led to HbA_1c reductions of 2.2%, 2.4% and 2.6%, respectively, vs 1.4% with insulin.
  • Nausea (12-23%), diarrhoea (13-22%), decreased appetite (9-11%), and vomiting (5-9%) were more frequent with Tirzepatide than glargine (nausea 2%, diarrhoea 4%, decreased appetite <1%, and vomiting 2%, respectively); most cases were mild to moderate and occurred during the dose-escalation phase.
  • The percentage of participants with hypoglycaemia (glucose <54 mg/dL or severe) was lower with Tirzepatide (6-9%) versus glargine.
  • At 78 weeks (1166 participants) and 104 weeks (199), the Tirzepatide glycemic and weight benefits were sustained.

SURPASS – 5 Trial ¹¹

• The study investigated the efficacy and safety of Tirzepatide added to insulin glargine in patients with type 2 diabetes with inadequate glycemic control with or without metformin over 40 weeks.
• A total of 475 participants with mean baseline HbA_1c 8.3%, age 60, diabetes duration 13.4 years, BMI 33.4 kg/m² received either Tirzepatide or placebo.
• Results
  • Mean HbA_1c reductions were 2.1%, 2.4%, and 2.3% with 5, 10 and 15 mg Tirzepatide vs 0.9% in the placebo arm.
  • Mean body weight reductions were 5.4kg, 7.5kg and 8.8kg with 5, 10 and 15 mg Tirzepatide compared with an increase of 1.6kg on placebo.
  • Premature treatment discontinuation was high at 10–18% in the intervention arms vs 3% with placebo. 
  • Tirzepatide also showed statistically significant improvements in cholesterol in addition to improvements in blood pressure readings.
  • The most common treatment-emergent AEs in the Tirzepatide groups vs placebo group were diarrhoea (12%-21% vs 10%) and nausea (13%-18% vs 3%).

Tirzepatide – Clinical Trials in Type 2 Diabetes Patients with Fatty Liver Disease

 SURPASS -3 MRI Trial ¹²

• This randomised, open-label, parallel-group investigated the changes in liver fat content, volume of visceral adipose tissue, and abdominal subcutaneous adipose tissue in response to Tirzepatide or insulin degludec in a subpopulation of the SURPASS-3 study.
• 502 diabetic participants with a fatty liver index of at least 60 were included in the study.
• Results
  • The absolute reduction in liver fat content at week 52 was significantly more significant for the pooled Tirzepatide 10 mg and 15 mg groups (-8·09%) Vs insulin degludec group (-3·38%).
  • Tirzepatide showed significant improvements in visceral adipose tissue volume and abdominal subcutaneous adipose tissue.

Tirzepatide Landmark Clinical Trials in Obesity

SURMOUNT -1 Trial ¹³

• A 72-week phase 3 double-blind, randomised, controlled trial evaluated the efficacy and safety of Tirzepatide in non-diabetic obese patients.
• Over 2500 adults with a BMI of ≥30 kg/m² or ≥27 kg/m² with at least one weight-related complication were randomised to receive either once-weekly, Tirzepatide (5 mg, 10 mg, or 15 mg) or placebo.
• The mean baseline BMI was 38kg/m², and the body weight was 104.8kg.
• Results
  • The mean percentage change in weight at week 72 was between 15–20.9% in the Tirzepatide group vs 3.1% in the placebo group.
  • Tirzepatide improved all predetermined cardiometabolic parameters .
  • Remarkably, at 72 weeks, 95% of individuals with pre-diabetes returned to normoglycemia.
  • The most common AEs with Tirzepatide were GI, and most were mild to moderate in severity.

SURMOUNT-2 Trial ¹⁴

• This Phase 3, double-blind, randomised, placebo-controlled trial investigated the efficacy and safety of Tirzepatide (10, 15 mg) for weight management in people with obesity and type 2 diabetes.
• The study included over 1500 adults with a mean bodyweight of 100·7 kg, BMI 36·1 kg/m2, and HbA1c 8·02%.
• Results
  • Weight reductions of 12.8–14.7 % were observed with Tirzepatide vs 3.2% with placebo at 72 weeks.
  • The most frequent AEs with Tirzepatide were GI, including nausea, diarrhoea, and vomiting and were primarily mild to moderate in severity.

SURMOUNT-3 Trial ¹⁵

• This double-blind, placebo-controlled trial evaluated the effect of Tirzepatide on weight reduction after a successful intensive lifestyle intervention in obese patients without diabetes.
• 579 adults with a mean BMI of 38.6 kg/m², mean body weight of 109.5 kg and at least one obesity-related complication, who achieved ≥5.0% weight reduction after a 12-week intensive lifestyle intervention, were randomised to Tirzepatide (10 or 15 mg) or placebo once weekly for 72 weeks.
• Results
  • The mean change at week 72 was −18.4% with Tirzepatide maximum tolerated dose and gain of 2.5% with the placebo.
  • 87.5% of Tirzepatide-treated participants lost an additional ≥5% of their randomisation weight compared vs. 16.5% of placebo-treated participant.
  • The most common AEs with Tirzepatide were GI, with most being mild to moderate in severity.

SURMOUNT- 4 Trial ¹⁶

• This phase 3, randomised withdrawal clinical trial investigated the effect of Tirzepatide, with diet and physical activity, on the maintenance of weight reduction.
• There were 2 periods in the trial:
  • 36 weeks -open-label lead-in period where783 participants received the maximum tolerated dose (10 or 15 mg) of Tirzepatide
  • 52-week- double-blind treatment period in which 670 participants were randomised to either continue on Tirzepatide or switch to placebo
• Results
  • A 36-week lead-in period mean weight reduction of 20.9% was observed.
  • 36- 88 weeks, the mean per cent weight change was -5.5% with Tirzepatide vs 14.0% with placebo.
  • At 88 weeks, 89.5% receiving Tirzepatide maintained at least 80% of the weight loss during the lead-in period c vs 16.6% with a placebo.
  • Overall mean weight reduction from 88 weeks was 25.3% for Tirzepatide and 9.9% for placebo.
  • The most common AEs were primarily mild to moderate GI events.

Tirzepatide- Upcoming Major Trials¹⁷

• SURPASS‐CVOT- will provide information on the cardiovascular events effects of Tirzepatide as compared to Dulaglutide in people with type 2 diabetes and established atherosclerotic cardiovascular disease.

Tirzepatide – Side Effect Profile⁶

• Common Side – Effects
  • Nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain
• Serious Side – Effects
  • Severe allergic reactions
  • Thyroid tumors
  • Pancreatitis (Inflammation of the pancreas)
  • Hypoglycemia (Low blood sugar)
  • Kidney damage
  • Gall bladder diseases
  • Vision changes due to diabetic retinopathy
  • Severe gastrointestinal diseases

Tirzepatide – Pros n Cons ¹⁸

Further Reading

1. https://investor.lilly.com/news-releases/news-release-details/fda-approves-lillys-mounjarotm-tirzepatide-injection-first-and
2. https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-chronic-weight-management
3. https://www.fda.gov/news-events/press-announcements/fda-approves-first-medication-obstructive-sleep-apnea
4. https://www.mdpi.com/1420-3049/27/13/4315
5. https://www.ncbi.nlm.nih.gov/books/NBK585056/
6. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf
7. https://pubmed.ncbi.nlm.nih.gov/34186022/
8. https://www.nejm.org/doi/full/10.1056/NEJMoa2107519
9. https://pubmed.ncbi.nlm.nih.gov/34370970/
10. https://www.sciencedirect.com/science/article/abs/pii/S0140673621021887
11. https://pubmed.ncbi.nlm.nih.gov/35133415/
12. https://pubmed.ncbi.nlm.nih.gov/35468325/
13. https://www.nejm.org/doi/full/10.1056/NEJMoa2206038
14. https://pubmed.ncbi.nlm.nih.gov/37385275/
15. https://pubmed.ncbi.nlm.nih.gov/37840095/\
16. https://pubmed.ncbi.nlm.nih.gov/38078870/
17. https://pubmed.ncbi.nlm.nih.gov/37758044/
18. https://www.tandfonline.com/doi/full/10.1080/14656566.2023.2237414#d1e184