Tirzepatide is a lab-made peptide that activates two hormone receptors at once, GIP and GLP-1, both of which your gut normally releases after you eat to help control blood sugar and appetite. Made by Eli Lilly, it was approved by the FDA in 2022 for type 2 diabetes and in 2023 for chronic weight management, after one of the largest clinical trial programs ever run for a metabolic drug (the SURPASS trials for diabetes and SURMOUNT trials for obesity), covering tens of thousands of patients. In head-to-head trials it beat semaglutide (Ozempic/Wegovy), the previous leading drug in this class, for both blood sugar control and weight loss. This is a serious, prescription-only medicine that needs a doctor's involvement, not a casual supplement.
How strong is the evidence?
This is about as strong as evidence gets in this field. Tirzepatide is an FDA-approved drug backed by more than a dozen large, randomized, placebo- or active-controlled phase 3 trials (the SURPASS program for diabetes, the SURMOUNT program for obesity, plus dedicated trials in liver disease, heart failure, sleep apnea, and even adolescents), several of them published in the New England Journal of Medicine, JAMA, and The Lancet with thousands of participants each. These are backed up by multiple independent systematic reviews and meta-analyses. A handful of papers in the file are early lab and animal studies that explain the mechanism, but the case for effectiveness and safety rests overwhelmingly on large human trials, not preclinical data.
Uses
What people use it for
Type 2 diabetes blood sugar control
Human trialsThe original approved use. In every SURPASS trial, tirzepatide lowered HbA1c (a 2-3 month average blood sugar score) more than placebo, other injectable diabetes drugs, or daily insulin.
Chronic weight management in people with obesity or overweight
Human trialsApproved as Zepbound for adults with obesity, or overweight plus a weight-related health problem, alongside diet and exercise. This is now the best-studied use in terms of raw effect size, with average weight losses over 20% in top-dose trials.
Fatty liver disease with scarring (MASH/NASH with fibrosis)
Some human dataA phase 2 trial in people with biopsy-confirmed liver damage found tirzepatide reversed the disease and improved liver scarring far more often than placebo. This is not yet an FDA-approved use, but the evidence is a real, well-designed human trial.
Obesity-related heart failure (HFpEF)
Some human dataIn people with heart failure with preserved ejection fraction plus obesity, tirzepatide reduced heart muscle mass and the fat pad around the heart, and large real-world data show lower rates of hospitalization or death compared with a placebo-like comparator.
Sleep apnea tied to obesity
Some human dataReviews summarizing the SURMOUNT-OSA trial report meaningful improvements in obstructive sleep apnea severity with weight loss on tirzepatide, though the primary trial paper itself isn't in this file.
Potential benefits
What it may help with
Large, consistent drops in blood sugar
Human trialsAcross the SURPASS trials, tirzepatide cut HbA1c by roughly 1.9 to 2.6 percentage points depending on dose, more than semaglutide, dulaglutide, or insulin comparators, and got 80-90%+ of patients under the standard blood sugar target.
Major weight loss, more than other GLP-1 drugs
Human trialsIn head-to-head trials against semaglutide, tirzepatide produced about 20% average body weight loss versus about 14% for semaglutide over 72 weeks. In people without diabetes, weight loss of 15-22% was common depending on dose.
Weight loss holds up if you keep taking it, but comes back if you stop
Human trialsA trial that had people lose about 21% of their weight, then either kept them on the drug or switched them to placebo, found continued treatment kept the weight off (and added more), while the placebo group regained most of it within a year.
Reverses early liver scarring in fatty liver disease
Some human dataIn a dedicated liver trial, tirzepatide resolved fatty liver inflammation without worsening scarring in 44-62% of patients (dose-dependent), versus 10% on placebo, over one year.
Studies:38856224Improves cholesterol, blood pressure, and inflammation markers
Some human dataMultiple trials and a dedicated meta-analysis found tirzepatide lowers LDL cholesterol, triglycerides, and blood pressure, and reduces inflammation markers (hsCRP and IL-6) in the blood, on top of its effects on weight and blood sugar.
Reduces appetite and calorie intake, with more fat burned
Some human dataStudies measuring actual eating behavior found tirzepatide lowers appetite and how much food people eat, and a mechanistic trial found it increases fat burning without slowing metabolism down the way strict dieting usually does.
What to watch for
Side effects & risks
- Mild
- Mild
- Moderate
- Moderate
Some loss of muscle along with fat
An MRI substudy found thigh muscle volume dropped alongside the large amount of weight lost, roughly in line with what would be expected just from losing that much weight, but it's a real tradeoff worth knowing about, especially for older adults.
- Serious
Gallbladder problems and acute pancreatitis (rare)
A meta-analysis and a documented case report found rare instances of gallstones, gallbladder inflammation, and acute pancreatitis (a painful, serious inflammation of the pancreas). These occurred in 1% or fewer of patients but can be serious when they happen.
- Moderate
Dosing
Dosing — what studies used
Tirzepatide has a well-established, FDA-approved dosing schedule that matches what was used in the pivotal trials. It's always started low and increased gradually to reduce stomach side effects, never started at the target dose. The same drug and dose range is used for both diabetes and weight management; the difference is mainly which top dose is typically reached and how it's marketed (Mounjaro for diabetes, Zepbound for weight loss).
Starting dose and titration (used across both diabetes and obesity trials)
Human trialStart at 2.5 mg, then increase by 2.5 mg roughly every 4 weeks
Once weekly · Titration over the first 4-20 weeks depending on target dose · Subcutaneous injection
The 2.5 mg starting dose is meant to help the body adjust and is not intended as an effective treatment dose on its own.
Type 2 diabetes maintenance dose (SURPASS program)
Human trial5 mg, 10 mg, or 15 mg
Once weekly · Studied for 40 to 104 weeks · Subcutaneous injection
Higher doses gave more blood sugar and weight benefit but also more stomach side effects and higher dropout.
Chronic weight management dose (SURMOUNT program)
Human trial10 mg or 15 mg (maximum tolerated dose)
Once weekly · Studied for 36 to 112 weeks, with maintenance data out to 88-112 weeks · Subcutaneous injection
Trials found weight loss regain when treatment was stopped or reduced, meaning long-term treatment is what maintains the benefit.
Dosing is well established because this is an approved medicine, not an experimental peptide; there's no legitimate reason to deviate from labeled/trial dosing schedules without medical supervision, and doing so raises the risk of side effects without added benefit.
These figures describe what researchers used in studies. They are not a recommendation or a prescription.
Mechanism
How it works
After you eat, your gut releases two natural hormones, GIP and GLP-1, that tell your pancreas to release insulin, tell your brain you're full, and slow down how fast your stomach empties. Tirzepatide is a manufactured peptide that latches onto both of those hormone's docking stations (receptors) at once, acting like a stronger, longer-lasting version of both signals combined. It has a fat molecule attached that lets it stick around in the blood for about a week, which is why it only needs to be injected once weekly. The result is less hunger, more fullness after smaller meals, and better-controlled blood sugar because insulin is released only when it's actually needed, which is also why it doesn't tend to cause blood sugar to crash on its own.
Who should avoid it
- Anyone with a personal or family history of medullary thyroid cancer or Multiple Endocrine Neoplasia syndrome type 2, a standard warning across this drug class based on animal thyroid tumor findings
- Anyone pregnant, trying to become pregnant, or breastfeeding, since it hasn't been established as safe in these groups
- People with a history of pancreatitis should discuss the risk carefully with a doctor before starting
- People with severe stomach-emptying problems (gastroparesis), since the drug further slows digestion
- Type 1 diabetes was not the population studied here; trials focused on type 2 diabetes and obesity without type 1 diabetes
Interactions to know
- Insulin and sulfonylurea diabetes medications may need lower doses since combined use raises the risk of low blood sugar
- Because it slows stomach emptying, it can change how fast oral medications are absorbed, which matters most for drugs with a narrow safe-dose window
- Birth control pills taken by mouth may be affected by delayed stomach emptying, particularly during dose increases
The papers that matter most
Key studies
First major phase 3 trial; tirzepatide alone cut HbA1c by up to 2.07 percentage points and body weight by up to 9.5 kg versus placebo, with no significant low blood sugar risk.
Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1)
Head-to-head against semaglutide; all tirzepatide doses beat semaglutide on both blood sugar control and weight loss.
Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (SURPASS-2)
In people with obesity but no diabetes, tirzepatide produced 20.2% weight loss versus 13.7% with semaglutide over 72 weeks.
Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5)
Reversed liver inflammation without worsening scarring in up to 62% of patients versus 10% on placebo, suggesting a promising use beyond diabetes and weight.
Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis (SYNERGY-NASH)
Showed weight loss is only maintained with continued treatment; stopping the drug led to substantial regain within a year.
Continued Treatment With Tirzepatide for Maintenance of Weight Reduction (SURMOUNT-4)
Confirmed gastrointestinal side effects are common and dose-dependent, while serious events like pancreatitis, gallbladder problems, and severe low blood sugar are rare (1% or less).
Adverse Events Related to Tirzepatide
Bottom line
Tirzepatide has some of the strongest clinical evidence of any metabolic drug available today, with large approved-drug trials showing major, reliable improvements in blood sugar and weight, often beating the previous best-in-class drug, semaglutide. The tradeoffs are common stomach side effects (especially early on), a rare but real risk of pancreatitis or gallbladder problems, some muscle loss alongside the fat loss, and the reality that benefits fade once you stop taking it, meaning it works best as a long-term, medically supervised treatment rather than a short course.
Research papers
Studies we have on file for Tirzepatide. Tap a title to open it on PubMed. Labels like “animal” or “human trial” are rough guides.
38 papers
Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial.
The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction. This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period. Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was -5.5% with tirzepatide vs 14.0% with placebo (difference, -19.4% [95% CI, -21.2% to -17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo. In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction. ClinicalTrials.gov Identifier: NCT04660643.
Tirzepatide as Compared with Semaglutide for the Treatment of Obesity.
Tirzepatide and semaglutide are highly effective medications for obesity management. The efficacy and safety of tirzepatide as compared with semaglutide in adults with obesity but without type 2 diabetes is unknown. In this phase 3b, open-label, controlled trial, adult participants with obesity but without type 2 diabetes were randomly assigned in a 1:1 ratio to receive the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg) subcutaneously once weekly for 72 weeks. The primary end point was the percent change in weight from baseline to week 72. Key secondary end points included weight reductions of at least 10%, 15%, 20%, and 25% and a change in waist circumference from baseline to week 72. A total of 751 participants underwent randomization. The least-squares mean percent change in weight at week 72 was -20.2% (95% confidence interval [CI], -21.4 to -19.1) with tirzepatide and -13.7% (95% CI, -14.9 to -12.6) with semaglutide (P<0.001). The least-squares mean change in waist circumference was -18.4 cm (95% CI, -19.6 to -17.2) with tirzepatide and -13.0 cm (95% CI, -14.3 to -11.7) with semaglutide (P<0.001). Participants in the tirzepatide group were more likely than those in the semaglutide group to have weight reductions of at least 10%, 15%, 20%, and 25%. The most common adverse events in both treatment groups were gastrointestinal, and most were mild to moderate in severity and occurred primarily during dose escalation. Among participants with obesity but without diabetes, treatment with tirzepatide was superior to treatment with semaglutide with respect to reduction in body weight and waist circumference at week 72. (Funded by Eli Lilly; SURMOUNT-5 ClinicalTrials.gov number, NCT05822830.).
Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes.
Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is under development for the treatment of type 2 diabetes. The efficacy and safety of once-weekly tirzepatide as compared with semaglutide, a selective GLP-1 receptor agonist, are unknown. In an open-label, 40-week, phase 3 trial, we randomly assigned 1879 patients, in a 1:1:1:1 ratio, to receive tirzepatide at a dose of 5 mg, 10 mg, or 15 mg or semaglutide at a dose of 1 mg. At baseline, the mean glycated hemoglobin level was 8.28%, the mean age 56.6 years, and the mean weight 93.7 kg. The primary end point was the change in the glycated hemoglobin level from baseline to 40 weeks. The estimated mean change from baseline in the glycated hemoglobin level was -2.01 percentage points, -2.24 percentage points, and -2.30 percentage points with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and -1.86 percentage points with semaglutide; the estimated differences between the 5-mg, 10-mg, and 15-mg tirzepatide groups and the semaglutide group were -0.15 percentage points (95% confidence interval [CI], -0.28 to -0.03; P = 0.02), -0.39 percentage points (95% CI, -0.51 to -0.26; P<0.001), and -0.45 percentage points (95% CI, -0.57 to -0.32; P<0.001), respectively. Tirzepatide at all doses was noninferior and superior to semaglutide. Reductions in body weight were greater with tirzepatide than with semaglutide (least-squares mean estimated treatment difference, -1.9 kg, -3.6 kg, and -5.5 kg, respectively; P<0.001 for all comparisons). The most common adverse events were gastrointestinal and were primarily mild to moderate in severity in the tirzepatide and semaglutide groups (nausea, 17 to 22% and 18%; diarrhea, 13 to 16% and 12%; and vomiting, 6 to 10% and 8%, respectively). Of the patients who received tirzepatide, hypoglycemia (blood glucose level, <54 mg per deciliter) was reported in 0.6% (5-mg group), 0.2% (10-mg group), and 1.7% (15-mg group); hypoglycemia was reported in 0.4% of those who received semaglutide. Serious adverse events were reported in 5 to 7% of the patients who received tirzepatide and in 3% of those who received semaglutide. In patients with type 2 diabetes, tirzepatide was noninferior and superior to semaglutide with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks. (Funded by Eli Lilly; SURPASS-2 ClinicalTrials.gov number, NCT03987919.).
Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.
Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear. We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH. Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity. In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).
Tirzepatide: A Systematic Update.
Tirzepatide is a new molecule capable of controlling glucose blood levels by combining the dual agonism of Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide-1 (GLP-1) receptors. GIP and GLP1 are incretin hormones: they are released in the intestine in response to nutrient intake and stimulate pancreatic beta cell activity secreting insulin. GIP and GLP1 also have other metabolic functions. GLP1, in particular, reduces food intake and delays gastric emptying. Moreover, Tirzepatide has been shown to improve blood pressure and to reduce Low-Density Lipoprotein (LDL) cholesterol and triglycerides. Tirzepatide efficacy and safety were assessed in a phase III SURPASS 1-5 clinical trial program. Recently, the Food and Drug Administration approved Tirzepatide subcutaneous injections as monotherapy or combination therapy, with diet and physical exercise, to achieve better glycemic blood levels in patients with diabetes. Other clinical trials are currently underway to evaluate its use in other diseases. The scientific interest toward this novel, first-in-class medication is rapidly increasing. In this comprehensive and systematic review, we summarize the main results of the clinical trials investigating Tirzepatide and the currently available meta-analyses, emphasizing novel insights into its adoption in clinical practice for diabetes and its future potential applications in cardiovascular medicine.
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.
Despite advancements in care, many people with type 2 diabetes do not meet treatment goals; thus, development of new therapies is needed. We aimed to assess efficacy, safety, and tolerability of novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide monotherapy versus placebo in people with type 2 diabetes inadequately controlled by diet and exercise alone. We did a 40-week, double-blind, randomised, placebo-controlled, phase 3 trial (SURPASS-1), at 52 medical research centres and hospitals in India, Japan, Mexico, and the USA. Adult participants (≥18 years) were included if they had type 2 diabetes inadequately controlled by diet and exercise alone and if they were naive to injectable diabetes therapy. Participants were randomly assigned (1:1:1:1) via computer-generated random sequence to once a week tirzepatide (5, 10, or 15 mg), or placebo. All participants, investigators, and the sponsor were masked to treatment assignment. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) from baseline at 40 weeks. This study is registered with ClinicalTrials.gov, NCT03954834. From June 3, 2019, to Oct 28, 2020, of 705 individuals assessed for eligibility, 478 (mean baseline HbA1c 7·9% [63 mmol/mol], age 54·1 years [SD 11·9], 231 [48%] women, diabetes duration 4·7 years, and body-mass index 31·9 kg/m2) were randomly assigned to tirzepatide 5 mg (n=121 [25%]), tirzepatide 10 mg (n=121 [25%]), tirzepatide 15 mg (n=121 [25%]), or placebo (n=115 [24%]). 66 (14%) participants discontinued the study drug and 50 (10%) discontinued the study prematurely. At 40 weeks, all tirzepatide doses were superior to placebo for changes from baseline in HbA1c, fasting serum glucose, bodyweight, and HbA1c targets of less than 7·0% (<53 mmol/mol) and less than 5·7% (<39 mmol/mol). Mean HbA1c decreased from baseline by 1·87% (20 mmol/mol) with tirzepatide 5 mg, 1·89% (21 mmol/mol) with tirzepatide 10 mg, and 2·07% (23 mmol/mol) with tirzepatide 15 mg versus +0·04% with placebo (+0·4 mmol/mol), resulting in estimated treatment differences versus placebo of -1·91% (-21 mmol/mol) with tirzepatide 5 mg, -1·93% (-21 mmol/mol) with tirzepatide 10 mg, and -2·11% (-23 mmol/mol) with tirzepatide 15 mg (all p<0·0001). More participants on tirzepatide than on placebo met HbA1c targets of less than 7·0% (<53 mmol/mol; 87-92% vs 20%) and 6·5% or less (≤48 mmol/mol; 81-86% vs 10%) and 31-52% of patients on tirzepatide versus 1% on placebo reached an HbA1c of less than 5·7% (<39 mmol/mol). Tirzepatide induced a dose-dependent bodyweight loss ranging from 7·0 to 9·5 kg. The most frequent adverse events with tirzepatide were mild to moderate and transient gastrointestinal events, including nausea (12-18% vs 6%), diarrhoea (12-14% vs 8%), and vomiting (2-6% vs 2%). No clinically significant (<54 mg/dL [<3 mmol/L]) or severe hypoglycaemia were reported with tirzepatide. One death occurred in the placebo group. Tirzepatide showed robust improvements in glycaemic control and bodyweight, without increased risk of hypoglycaemia. The safety profile was consistent with GLP-1 receptor agonists, indicating a potential monotherapy use of tirzepatide for type 2 diabetes treatment. Eli Lilly and Company.
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.
The effects of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, as an addition to insulin glargine for treatment of type 2 diabetes have not been described. To assess the efficacy and safety of tirzepatide added to insulin glargine in patients with type 2 diabetes with inadequate glycemic control. Randomized phase 3 clinical trial conducted at 45 medical research centers and hospitals in 8 countries (enrollment from August 30, 2019, to March 20, 2020; follow-up completed January 13, 2021) in 475 adults with type 2 diabetes and inadequate glycemic control while treated with once-daily insulin glargine with or without metformin. Patients were randomized in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of 5-mg (n = 116), 10-mg (n = 119), or 15-mg (n = 120) tirzepatide or volume-matched placebo (n = 120) over 40 weeks. Tirzepatide was initiated at 2.5 mg/week and escalated by 2.5 mg every 4 weeks until the assigned dose was achieved. The primary end point was mean change from baseline in glycated hemoglobin A1c (HbA1c) at week 40. The 5 key secondary end points included mean change in body weight and percentage of patients achieving prespecified HbA1c levels. Among 475 randomized participants (211 [44%] women; mean [SD] age, 60.6 [9.9] years; mean [SD] HbA1c, 8.31% [0.85%]), 451 (94.9%) completed the trial. Treatment was prematurely discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the 10-mg tirzepatide group, 18% in the 15-mg tirzepatide group, and 3% in the placebo group. At week 40, mean HbA1c change from baseline was -2.40% with 10-mg tirzepatide and -2.34% with 15-mg tirzepatide vs -0.86% with placebo (10 mg: difference vs placebo, -1.53% [97.5% CI, -1.80% to -1.27%]; 15 mg: difference vs placebo, -1.47% [97.5% CI, -1.75% to -1.20%]; P < .001 for both). Mean HbA1c change from baseline was -2.11% with 5-mg tirzepatide (difference vs placebo, -1.24% [95% CI, -1.48% to -1.01%]; P < .001]). Mean body weight change from baseline was -5.4 kg with 5-mg tirzepatide, -7.5 kg with 10-mg tirzepatide, -8.8 kg with 15-mg tirzepatide and 1.6 kg with placebo (5 mg: difference, -7.1 kg [95% CI, -8.7 to -5.4]; 10 mg: difference, -9.1 kg [95% CI, -10.7 to -7.5]; 15 mg: difference, -10.5 kg [95% CI, -12.1 to -8.8]; P < .001 for all). Higher percentages of patients treated with tirzepatide vs those treated with placebo had HbA1c less than 7% (85%-90% vs 34%; P < .001 for all). The most common treatment-emergent adverse events in the tirzepatide groups vs placebo group were diarrhea (12%-21% vs 10%) and nausea (13%-18% vs 3%). Among patients with type 2 diabetes and inadequate glycemic control despite treatment with insulin glargine, the addition of subcutaneous tirzepatide, compared with placebo, to titrated insulin glargine resulted in statistically significant improvements in glycemic control after 40 weeks. ClinicalTrials.gov Identifier: NCT04039503.
Tirzepatide: A Review in Type 2 Diabetes.
Tirzepatide (Mounjaro®), a first-in-class dual incretin agonist of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, is approved for use as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus (T2DM) in the USA, EU, Japan and other countries. It comes as single-dose prefilled pens and single-dose vials. In phase III SURPASS trials, once-weekly subcutaneous tirzepatide, as monotherapy or add-on-therapy to oral glucose-lowering medications and insulin, was superior to the GLP-1 receptor agonists (RAs) dulaglutide 0.75 mg and semaglutide 1 mg as well as basal and prandial insulin for glycaemic control and weight loss in adults with inadequately controlled T2DM. Tirzepatide was generally well tolerated, with a safety profile consistent with that of GLP-1 RAs. Tirzepatide was associated with a low risk of clinically significant or severe hypoglycaemia and no increased risk of major adverse cardiovascular events. Adverse events were mostly mild to moderate in severity, with the most common being gastrointestinal events including nausea, diarrhoea, decreased appetite and vomiting. In conclusion, tirzepatide is a valuable addition to the treatment options for T2DM.
New Drug: Tirzepatide (Mounjaro™).
Type 2 diabetes mellitus (T2DM) is the most common form of diabetes and is a chronic and progressive illness. Millions of Americans have T2DM and many patients do not achieve the recommended blood glucose levels. Glucagon-like peptide 1 (GLP-1) based therapy is an established treatment for the management of T2DM and is recommended early in the treatment algorithm. GLP-1 therapy is associated with better glycemic control, weight reduction, and favorable cardiovascular outcomes. Tirzepatide (Mounjaro™) is a novel dual glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 receptor agonist. Evidence from five SURPASS clinical trials has demonstrated that tirzepatide has potent glucose lowering and weight loss with adverse effects comparable to GLP-1 receptor agonists. This paper gives an overview of tirzepatide and SURPASS clinical trials.
Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist.
Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal β-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.
Tirzepatide for overweight and obesity management.
Tirzepatide is a once-weekly dual agonist, acting on glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. It is approved at the same doses (5, 10 and 15 mg) for both type 2 diabetes (T2D) and chronic weight management. Following a search in PubMed, clinicaltrials.gov, conference abstracts and Lilly website, we review herein the global phase 3 SURMOUNT program on tirzepatide's safety and efficacy for chronic weight management. Additionally, we discuss findings from the regional SURMOUNT-CN and SURMOUNT-J trials (in East-Asian populations) and the phase 2 SYNERGY-NASH, phase 3 SURMOUNT-OSA and SUMMIT studies on tirzepatide's impact on obesity-related complications. We also explore the clinical implications of SURMOUNT program results, considerations for tirzepatide prescribing for overweight/obesity, ongoing research and evidence gaps. Tirzepatide marks a new era in overweight/obesity treatment, enabling many to achieve ≥ 20% weight loss. It is well-tolerated with a safety profile similar to GLP-1 receptor agonists. Tirzepatide also results in clinically important improvements in multiple obesity-related complications including sleep apnea, metabolic-dysfunction associated steatohepatitis, heart failure with preserved ejection fraction and diabetes prevention. Ongoing trials will provide further data on tirzepatide's long-term safety, efficacy (including cardiovascular outcomes) and potential cost-effectiveness for managing overweight/obesity and/or T2D.
Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial.
We aimed to assess efficacy and safety, with a special focus on cardiovascular safety, of the novel dual GIP and GLP-1 receptor agonist tirzepatide versus insulin glargine in adults with type 2 diabetes and high cardiovascular risk inadequately controlled on oral glucose-lowering medications. This open-label, parallel-group, phase 3 study was done in 187 sites in 14 countries on five continents. Eligible participants, aged 18 years or older, had type 2 diabetes treated with any combination of metformin, sulfonylurea, or sodium-glucose co-transporter-2 inhibitor, a baseline glycated haemoglobin (HbA1c) of 7·5-10·5% (58-91 mmol/mol), body-mass index of 25 kg/m2 or greater, and established cardiovascular disease or a high risk of cardiovascular events. Participants were randomly assigned (1:1:1:3) via an interactive web-response system to subcutaneous injection of either once-per-week tirzepatide (5 mg, 10 mg, or 15 mg) or glargine (100 U/mL), titrated to reach fasting blood glucose of less than 100 mg/dL. The primary endpoint was non-inferiority (0·3% non-inferiority boundary) of tirzepatide 10 mg or 15 mg, or both, versus glargine in HbA1c change from baseline to 52 weeks. All participants were treated for at least 52 weeks, with treatment continued for a maximum of 104 weeks or until study completion to collect and adjudicate major adverse cardiovascular events (MACE). Safety measures were assessed over the full study period. This study was registered with ClinicalTrials.gov, NCT03730662. Patients were recruited between Nov 20, 2018, and Dec 30, 2019. 3045 participants were screened, with 2002 participants randomly assigned to tirzepatide or glargine. 1995 received at least one dose of tirzepatide 5 mg (n=329, 17%), 10 mg (n=328, 16%), or 15 mg (n=338, 17%), or glargine (n=1000, 50%), and were included in the modified intention-to-treat population. At 52 weeks, mean HbA1c changes with tirzepatide were -2·43% (SD 0·05) with 10 mg and -2·58% (0·05) with 15 mg, versus -1·44% (0·03) with glargine. The estimated treatment difference versus glargine was -0·99% (multiplicity adjusted 97·5% CI -1·13 to -0·86) for tirzepatide 10 mg and -1·14% (-1·28 to -1·00) for 15 mg, and the non-inferiority margin of 0·3% was met for both doses. 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 (19%), particularly in participants not on sulfonylureas (tirzepatide 1-3% vs glargine 16%). Adjudicated MACE-4 events (cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina) occurred in 109 participants and were not increased on tirzepatide compared with glargine (hazard ratio 0·74, 95% CI 0·51-1·08). 60 deaths (n=25 [3%] tirzepatide; n=35 [4%] glargine) occurred during the study. In people with type 2 diabetes and elevated cardiovascular risk, tirzepatide, compared with glargine, demonstrated greater and clinically meaningful HbA1c reduction with a lower incidence of hypoglycaemia at week 52. Tirzepatide treatment was not associated with excess cardiovascular risk. Eli Lilly and Company.
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.
A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists in type 2 diabetes mellitus (T2DM). LY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice. A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25-8 mg) and 4-week multiple-ascending dose (MAD; doses 0.5-10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5-15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176. LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist. A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25-15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean [LSM] difference [95% CI]: -49.12 mg/dL [-78.14, -20.12] and -43.15 mg/dL [-73.06, -13.21], respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference [95% CI]: -1.75 kg [-3.38, -0.12], -5.09 kg [-6.72, -3.46] and -4.61 kg [-6.21, -3.01], respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference [95% CI]: -2.62 kg [-3.79, -1.45] and -2.07 kg [-3.25, -0.88], respectively. The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity. Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity.
Subcutaneously administered tirzepatide vs semaglutide for adults with type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials.
We conducted a systematic review and network meta-analysis to compare the efficacy and safety of s.c. administered tirzepatide vs s.c. administered semaglutide for adults of both sexes with type 2 diabetes mellitus. We searched PubMed and Cochrane up to 11 November 2023 for RCTs with an intervention duration of at least 12 weeks assessing s.c. tirzepatide at maintenance doses of 5 mg, 10 mg or 15 mg once weekly, or s.c. semaglutide at maintenance doses of 0.5 mg, 1.0 mg or 2.0 mg once weekly, in adults with type 2 diabetes, regardless of background glucose-lowering treatment. Eligible trials compared any of the specified doses of tirzepatide and semaglutide against each other, placebo or other glucose-lowering drugs. Primary outcomes were changes in HbA1c and body weight from baseline. Secondary outcomes were achievement of HbA1c target of ≤48 mmol/mol (≤6.5%) or <53 mmol/mol (<7.0%), body weight loss of at least 10%, and safety outcomes including gastrointestinal adverse events and severe hypoglycaemia. We used version 2 of the Cochrane risk-of-bias tool (ROB 2) to assess the risk of bias, conducted frequentist random-effects network meta-analyses and evaluated confidence in effect estimates utilising the Confidence In Network Meta-Analysis (CINeMA) framework. A total of 28 trials with 23,622 participants (44.2% female) were included. Compared with placebo, tirzepatide 15 mg was the most efficacious treatment in reducing HbA1c (mean difference -21.61 mmol/mol [-1.96%]) followed by tirzepatide 10 mg (-20.19 mmol/mol [-1.84%]), semaglutide 2.0 mg (-17.74 mmol/mol [-1.59%]), tirzepatide 5 mg (-17.60 mmol/mol [-1.60%]), semaglutide 1.0 mg (-15.25 mmol/mol [-1.39%]) and semaglutide 0.5 mg (-12.00 mmol/mol [-1.09%]). In between-drug comparisons, all tirzepatide doses were comparable with semaglutide 2.0 mg and superior to semaglutide 1.0 mg and 0.5 mg. Compared with placebo, tirzepatide was more efficacious than semaglutide for reducing body weight, with reductions ranging from 9.57 kg (tirzepatide 15 mg) to 5.27 kg (tirzepatide 5 mg). Semaglutide had a less pronounced effect, with reductions ranging from 4.97 kg (semaglutide 2.0 mg) to 2.52 kg (semaglutide 0.5 mg). In between-drug comparisons, tirzepatide 15 mg, 10 mg and 5 mg demonstrated greater efficacy than semaglutide 2.0 mg, 1.0 mg and 0.5 mg, respectively. Both drugs increased incidence of gastrointestinal adverse events compared with placebo, while neither tirzepatide nor semaglutide increased the risk of serious adverse events or severe hypoglycaemia. Our data show that s.c. tirzepatide had a more pronounced effect on HbA1c and weight reduction compared with s.c. semaglutide in people with type 2 diabetes. Both drugs, particularly higher doses of tirzepatide, increased gastrointestinal adverse events. PROSPERO registration no. CRD42022382594.
How May GIP Enhance the Therapeutic Efficacy of GLP-1?
Glucagon-like peptide-1 (GLP-1) receptor agonists improve glucose homeostasis, reduce bodyweight, and over time benefit cardiovascular health in type 2 diabetes mellitus (T2DM). However, dose-related gastrointestinal effects limit efficacy, and therefore agents possessing GLP-1 pharmacology that can also target alternative pathways may expand the therapeutic index. One approach is to engineer GLP-1 activity into the sequence of glucose-dependent insulinotropic polypeptide (GIP). Although the therapeutic implications of the lipogenic actions of GIP are debated, its ability to improve lipid and glucose metabolism is especially evident when paired with the anorexigenic mechanism of GLP-1. We review the complexity of GIP in regulating adipose tissue function and energy balance in the context of recent findings in T2DM showing that dual GIP/GLP-1 receptor agonist therapy produces profound weight loss, glycemic control, and lipid lowering.
Tirzepatide Reduces Appetite, Energy Intake, and Fat Mass in People With Type 2 Diabetes.
To evaluate the effects of tirzepatide on body composition, appetite, and energy intake to address the potential mechanisms involved in body weight loss with tirzepatide. In a secondary analysis of a randomized, double-blind, parallel-arm study, the effects of tirzepatide 15 mg (N = 45), semaglutide 1 mg (N = 44), and placebo (N = 28) on body weight and composition, appetite, and energy intake were assessed at baseline and week 28. Tirzepatide treatment demonstrated significant reductions in body weight compared with placebo and semaglutide, resulting in greater fat mass reduction. Tirzepatide and semaglutide significantly reduced appetite versus placebo. Appetite scores and energy intake reductions did not differ between tirzepatide and semaglutide. Differences in energy intake during ad libitum lunch were not sufficient to explain the different weight outcomes. Further evaluation is needed to assess mechanistic differences related to tirzepatide actions on 24-h energy intake, substrate utilization, and energy expenditure.
Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis.
Tirzepatide is a novel, once weekly, dual GIP/GLP-1 receptor agonist and is under development for the treatment of type 2 diabetes (T2D) and obesity. Its association with cardiovascular outcomes requires evaluation. This pre-specified cardiovascular meta-analysis included all seven randomized controlled trials with a duration of at least 26 weeks from the tirzepatide T2D clinical development program, SURPASS. The pre-specified primary objective of this meta-analysis was the comparison of the time to first occurrence of confirmed four-component major adverse cardiovascular events (MACE-4; cardiovascular death, myocardial infarction, stroke and hospitalized unstable angina) between pooled tirzepatide groups and control groups. A stratified Cox proportional hazards model, with treatment as a fixed effect and trial-level cardiovascular risk as the stratification factor, was used for the estimation of hazard ratios (HRs) and confidence intervals (CIs) comparing tirzepatide to control. Data from 4,887 participants treated with tirzepatide and 2,328 control participants were analyzed. Overall, 142 participants, 109 from the trial with high cardiovascular risk and 33 from the six trials with lower cardiovascular risk, had at least one MACE-4 event. The HRs comparing tirzepatide versus controls were 0.80 (95% CI, 0.57-1.11) for MACE-4; 0.90 (95% CI, 0.50-1.61) for cardiovascular death; and 0.80 (95% CI, 0.51-1.25) for all-cause death. No evidence of effect modifications was observed for any subgroups, although the evidence was stronger for participants with high cardiovascular risk. Tirzepatide did not increase the risk of major cardiovascular events in participants with T2D versus controls.
Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis.
Tirzepatide is a novel dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) currently under review for marketing approval. Individual trials have assessed the clinical profile of tirzepatide vs different comparators. We conducted a systematic review and meta-analysis to assess the efficacy and safety of tirzepatide for type 2 diabetes. We searched PubMed, Embase, Cochrane and ClinicalTrials.gov up until 27 October 2021 for randomised controlled trials with a duration of at least 12 weeks that compared once-weekly tirzepatide 5, 10 or 15 mg with placebo or other glucose-lowering drugs in adults with type 2 diabetes irrespective of their background glucose-lowering treatment. The primary outcome was change in HbA1c from baseline. Secondary efficacy outcomes included change in body weight, proportion of individuals reaching the HbA1c target of <53 mmol/mol (<7.0%), ≤48 mmol/mol (≤6.5%) or <39 mmol/mol (<5.7%), and proportion of individuals with body weight loss of at least 5%, 10% or 15%. Safety outcomes included hypoglycaemia, gastrointestinal adverse events, treatment discontinuation due to adverse events, serious adverse events, and mortality. We used version 2 of the Cochrane risk-of-bias tool for randomised trials to assess risk of bias for the primary outcome. Seven trials (6609 participants) were included. A dose-dependent superiority in lowering HbA1c was evident with all three tirzepatide doses vs all comparators, with mean differences ranging from -17.71 mmol/mol (-1.62%) to -22.35 mmol/mol (-2.06%) vs placebo, -3.22 mmol/mol (-0.29%) to -10.06 mmol/mol (-0.92%) vs GLP-1 RAs, and -7.66 mmol/mol (-0.70%) to -12.02 mmol/mol (-1.09%) vs basal insulin regimens. Tirzepatide was more efficacious in reducing body weight; reductions vs GLP-1 RAs ranged from 1.68 kg with tirzepatide 5 mg to 7.16 kg with tirzepatide 15 mg. Incidence of hypoglycaemia with tirzepatide was similar vs placebo and lower vs basal insulin. Nausea was more frequent with tirzepatide vs placebo, especially with tirzepatide 15 mg (OR 5.60 [95% CI 3.12, 10.06]), associated with higher incidence of vomiting (OR 5.50 [95% CI 2.40, 12.59]) and diarrhoea (OR 3.31 [95% CI 1.40, 7.85]). Odds of gastrointestinal events were similar between tirzepatide and GLP-1 RAs, except for diarrhoea with tirzepatide 10 mg (OR 1.51 [95% CI 1.07, 2.15]). Tirzepatide 15 mg led to higher discontinuation rate of study medication due to adverse events regardless of comparator, while all tirzepatide doses were safe in terms of serious adverse events and mortality. A dose-dependent superiority on glycaemic efficacy and body weight reduction was evident with tirzepatide vs placebo, GLP-1 RAs and basal insulin. Tirzepatide did not increase the odds of hypoglycaemia but was associated with increased incidence of gastrointestinal adverse events. Study limitations include presence of statistical heterogeneity in the meta-analyses for change in HbA1c and body weight, assessment of risk of bias solely for the primary outcome, and generalisation of findings mainly to individuals who are overweight or obese and already on metformin-based background therapy. PROSPERO registration no. CRD42021283449.
Adverse Events Related to Tirzepatide.
Tirzepatide is a dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) approved by the US Food and Drug Administration in May 2022 for patients with type 2 diabetes mellitus (T2DM). We aimed to determine the rates of individual adverse events (AEs) related to 3 studied doses of tirzepatide. We performed a systematic review with meta-analysis including 5 databases (PubMed, Embase, CINAHL, Scopus, and Web of Science) for all clinical trials reporting AEs related to tirzepatide. The safety data from individual studies were extracted and analyzed through meta-regression to assess rates of individual AEs. Study quality assessment was performed using the National Heart, Lung, and Blood Institute Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Ten trials (6836 participants) were included. Gastrointestinal (GI) AEs were the most commonly reported AEs and were dose dependent 39% (95% CI, 35%-43%), 46% (95% CI, 42%-49%), and 49% (95% CI, 38%-60%) for the 5, 10, and 15 mg dose, respectively. Among all GI AEs, nausea and diarrhea were most frequent at any dose of tirzepatide. Drug discontinuation due to AEs was highest with the 15 mg dose of tirzepatide (10%). Incidence of mild hypoglycemia (blood glucose < 70 mg/dL) was highest with tirzepatide 10 mg dose 22.6% (9.2%-39.8%). Rates of fatal AEs, severe hypoglycemia, acute pancreatitis, cholelithiasis, and cholecystitis were extremely low (≤ 1%) across all doses of tirzepatide. Tirzepatide is associated with a dose-dependent increase in incidence of GI AEs and AEs leading to drug discontinuation. Severe hypoglycemia, fatal AEs, acute pancreatitis, cholelithiasis, and cholecystitis are rare with this medication.
Efficacy and safety of once-weekly tirzepatide in Japanese patients with obesity disease (SURMOUNT-J): a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.
Data on tirzepatide in Asian patients with obesity are limited. This study aimed to gain a better understanding of tirzepatide for treatment of Japanese patients with obesity disease (BMI ≥25 kg/m2 with excessive fat accumulation) as defined by the Japanese Society for the Study of Obesity. This was a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial of the efficacy and safety of tirzepatide as an adjunct to lifestyle modifications. Japanese adults with obesity disease (BMI ≥27 kg/m2 accompanied by ≥2 obesity-related health disorders or ≥35 kg/m2 accompanied by ≥1 obesity-related health disorders), excluding diabetes, were assigned 1:1:1 via computer-generated random sequence to receive once weekly subcutaneous tirzepatide (10 mg or 15 mg) or placebo. Coprimary endpoints were the mean percent change in bodyweight and the proportion of participants achieving at least 5% bodyweight reduction at week 72, using the efficacy estimand. Efficacy and safety were assessed in the modified intention-to-treat (mITT) population. This study is registered with ClinicalTrials.gov, NCT04844918. Between May 10, 2021, and June 24, 2023, 413 participants were screened, and 267 were randomly assigned. Due to exclusion of one study site, the mITT population was 225 participants (133 [59%] men and 92 [41%] women, mean age 50·8 [SD 10·7] years), with 73 in the tirzepatide 10 mg group, 77 in the tirzepatide 15 mg group, and 75 in the placebo group, of whom 192 (85%) completed both study and treatment. Estimated treatment differences relative to placebo in change in bodyweight at week 72 were -16·1% (95% CI -18·7 to -13·5; p<0·0001) and -21·1% (95% CI -23·6 to -18·5; p<0·0001) following tirzepatide 10 mg and 15 mg, respectively. At week 72, a higher proportion of participants achieved at least 5% bodyweight reduction with tirzepatide 10 mg (67 [94%] of 71) and 15 mg (73 [96%] of 76) compared with placebo (15 [20%] of 75; both p<0·0001). Cardiometabolic and body composition indices were also improved with tirzepatide. Participants treated with tirzepatide experienced treatment-emergent adverse events more frequently (10 mg: n=61 [84%]; 15 mg: n=66 [86%]) than those who received placebo (52 [69%]), most commonly gastrointestinal symptoms. Study discontinuations due to adverse events were infrequent (placebo: n=3 [4%]; tirzepatide 10 mg: n=1 [1%]; tirzepatide 15 mg: n=0). In Japanese adults with obesity disease, tirzepatide provided clinically a meaningful reduction in bodyweight compared with placebo over 72 weeks, with a safety profile consistent with that observed in global populations. Eli Lilly and Company. For the Japanese translation of the abstract see Supplementary Materials section.
Semaglutide and Tirzepatide in Patients With Heart Failure With Preserved Ejection Fraction.
Heart failure with preserved ejection fraction (HFpEF) is a major cause of hospitalization, often occurring in patients with cardiometabolic comorbidities such as obesity and type 2 diabetes. Although early trials of semaglutide and tirzepatide have shown promising results in improving symptoms, those findings were based on few clinical events, leaving treatment recommendations uncertain. To evaluate the effectiveness and safety of semaglutide and tirzepatide in patients with cardiometabolic HFpEF in clinical practice. Five cohort studies using national US health care claims data from 2018 to 2024. Two cohort studies emulated the STEP-HFpEF DM (semaglutide) and SUMMIT (tirzepatide) trials to benchmark results. Eligibility criteria were then expanded to evaluate treatment effects in patients typically treated in clinical practice. Finally, a head-to-head comparison of tirzepatide and semaglutide was implemented. Follow-up was up to 52 weeks. New use of semaglutide, tirzepatide, or sitagliptin as a placebo proxy. The primary end point was a composite of hospitalization for heart failure or all-cause mortality. Negative control outcomes, secondary end points, subgroups, and sensitivity analyses were prespecified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by fitting proportional hazards models with propensity score weighting to adjust for a comprehensive set of pretreatment patient characteristics. Benchmarking of the 2 trial emulations demonstrated high agreement on all prespecified metrics. In analyses using expanded eligibility criteria, 58 333 patients were included in the semaglutide vs sitagliptin cohort, 11 257 for tirzepatide vs sitagliptin, and 28 100 for tirzepatide vs semaglutide. Initiators of semaglutide (HR, 0.58 [95% CI, 0.51-0.65]) and tirzepatide (HR, 0.42 [95% CI, 0.31-0.57]) had substantially lower risk of the primary end point compared with sitagliptin. Tirzepatide had no meaningfully lowered risk compared with semaglutide (HR, 0.86 [95% CI, 0.70-1.06]). Negative controls, secondary end points, subgroups, and sensitivity analyses showed consistent results. No substantially increased risk was observed for select safety end points. In patients with cardiometabolic HFpEF, semaglutide and tirzepatide showed more than 40% risk reduction for the composite of hospitalization for heart failure or all-cause mortality compared with a placebo proxy. Tirzepatide showed no meaningful benefit over semaglutide. ClinicalTrials.gov Identifiers: NCT06914102, NCT06914154, NCT06914141.
Acute Pancreatitis Caused by Tirzepatide.
Glucagon-like peptide-1 (GLP-1) receptor agonists, including tirzepatide (Mounjaro), are widely used to manage type 2 diabetes mellitus (T2DM) and obesity. While gastrointestinal side effects are common, acute pancreatitis remains a rare but significant complication. Limited evidence exists on the risks associated with switching between GLP-1 agonists, emphasizing the need for clinical awareness. We present a 59-year-old male with T2DM, hyperlipidemia, and hypertension, who was recently transitioned from semaglutide (Ozempic) to tirzepatide (Mounjaro). He presented with acute epigastric pain, nausea, and vomiting two days after initiating tirzepatide. Laboratory findings revealed elevated lipase levels (847 U/L), leukocytosis, and diagnostic imaging confirming acute pancreatitis with other causes ruled out. Supportive care improved symptoms initially, but the clinical course was complicated by fevers prompting repeat imaging, revealing worsening pancreatitis with colonic involvement and pleural effusion. The patient was treated with empiric antibiotics and supportive measures, resulting in resolution of symptoms. Tirzepatide was discontinued, with a follow-up arranged for glycemic management. Acute pancreatitis is a rare but documented adverse effect of GLP-1 agonists, with limited cases reported in the literature. Switching between GLP-1 agonists may increase the risk of adverse effects, especially if appropriate dose titration protocols are not followed. This case highlights the recognition of acute pancreatitis as a potential adverse effect of GLP-1 agonists when initiating or transitioning GLP-1 therapies and following titration protocols to help avoid this complication. GLP-1 agonists, including tirzepatide, offer significant therapeutic benefits for T2DM and obesity but carry risks of rare adverse effects like acute pancreatitis. Greater awareness, careful dose adjustments, and vigilant monitoring are essential to optimizing patient safety. Further research is needed to elucidate the safety profile of switching between GLP-1 agonists to guide clinical practice and improve patient outcomes.
Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation.
Tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, promoted significant body weight reduction in the phase 3 clinical trials. We conducted a preclinical study and a phase 1 clinical trial (NCT04081337) to understand potential mechanisms mediating tirzepatide-induced weight loss in mice and people with obesity. In calorie-restricted, obese mice, chronic treatment with tirzepatide reduced the drop in energy expenditure that occurred in vehicle-treated and pair-fed mice, indicating that tirzepatide attenuated metabolic adaptation. Respiratory exchange ratio also decreased in tirzepatide-treated mice, indicating increased fat oxidation. In the clinical trial, tirzepatide appeared to have no impact on metabolic adaptation but led to increased fat oxidation and reductions in appetite and calorie intake during an ad libitum test meal (vs. placebo). This is the first study to provide insights into the mechanisms of action of tirzepatide on weight loss with respect to calorie intake, energy expenditure, and macronutrient utilization.
Efficacy and safety of tirzepatide in children and adolescents with type 2 diabetes (SURPASS-PEDS): a randomised, double-blind, placebo-controlled, phase 3 trial.
Current treatment options for youth-onset type 2 diabetes are limited and have demonstrated lower glycaemic efficacy than those for adult-onset type 2 diabetes. We aimed to assess the safety and efficacy of tirzepatide, a glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, compared with placebo in youth-onset type 2 diabetes. We conducted a phase 3, double-blind, placebo-controlled, multicentre (39 sites), multinational (eight countries) trial over 30 weeks, followed by an open-label extension for 22 weeks in which all participants received tirzepatide. Participants aged 10 to <18 years with youth-onset type 2 diabetes inadequately controlled with metformin and/or basal insulin were randomly assigned (1:1:1) to receive tirzepatide 5 mg, 10 mg, or placebo administered by subcutaneous injection with a single-dose pen. Randomisation was stratified by age group (≤14 years or >14 years) and antihyperglycaemic medication use (metformin, basal insulin, or both). All participants, investigators, and the sponsor were masked to treatment assignment during the 30-week double-blind period. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to week 30. Data from all participants who received at least one dose of study drug were used to analyse efficacy and safety. This completed trial is registered with ClinicalTrials.gov (NCT05260021). Between April 12, 2022, and Dec 27, 2023, 146 participants were screened, of whom 99 (60 [61%] female, 39 [39%] male; mean age 14·7 years [SD 1·8]; mean baseline HbA1c 8·04% [1·23]) were randomly assigned to tirzepatide 5 mg (n=32), tirzepatide 10 mg (n=33), or placebo (n=34). At week 30, tirzepatide was superior to placebo in reducing HbA1c, with a mean reduction of 2·23% in the pooled tirzepatide group versus an increase of 0·05% in the placebo group (estimated treatment difference -2·28%; 95% CI -2·87 to -1·69; p<0·0001). Glycaemic efficacy was sustained up to 52 weeks with tirzepatide treatment. Tirzepatide also resulted in significant reductions in BMI of 7·4% and 11·2% for the 5 mg and 10 mg groups, respectively, compared with 0·4% in the placebo group at 30 weeks. The most common adverse events with tirzepatide treatment were gastrointestinal, all mild to moderate in severity, and decreased over time. Two (6%) patients in the tirzepatide 5 mg group discontinued study drug due to an adverse event. The safety profile of tirzepatide was consistent with that reported in adults. No deaths were reported during the study period. Tirzepatide demonstrated significant improvements in glycaemic control and BMI compared with placebo. These effects were sustained over 1 year. Eli Lilly and Company.
GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice.
Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor (GLP-1R) agonist, delivered superior glycemic control and weight loss compared with GLP-1R agonism in patients with type 2 diabetes. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes is not fully understood. Here, we show that tirzepatide is an effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine whether GIPR agonism contributes, we compared the effect of tirzepatide in obese WT and Glp-1r-null mice. In the absence of GLP-1R-induced weight loss, tirzepatide improved insulin sensitivity by enhancing glucose disposal in white adipose tissue (WAT). In support of this, a long-acting GIPR agonist (LAGIPRA) was found to enhance insulin sensitivity by augmenting glucose disposal in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched-chain amino acids (BCAAs) and ketoacids in the circulation. Insulin sensitization was associated with upregulation of genes associated with the catabolism of glucose, lipid, and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual-receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.
Efficacy and Safety of Tirzepatide in Type 2 Diabetes and Obesity Management.
The combination of glucagon-like peptide-1 (GLP-1) with other gut hormones including the glucose-dependent insulinotropic polypeptide (GIP) has been explored to complement and enhance further the GLP-1 effects on glycemia and weight loss. Tirzepatide is the first dual GLP-1/GIP receptor co-agonist which has been approved for treatment of type 2 diabetes mellitus (T2DM) based on the findings from the SURPASS program. The SURPASS trials assessed the safety and efficacy of tirzepatide in people with T2DM, from monotherapy through to insulin add-on in global populations, with another two trials dedicated to Japanese population. Over periods of treatment up to 104 weeks, once weekly tirzepatide 5 to 15 mg reduced glycosylated hemoglobin (1.87% to 3.02%), body weight (5.4 to 12.9 kg) and improved multiple cardiometabolic risk factors (including reduction in liver fat, new-onset macroalbuminuria, blood pressure, and lipids) across the T2DM spectrum. Tirzepatide provided better efficacy than placebo and other commonly used glucose-lowering medications such as semaglutide 1 mg, dulaglutide, insulin degludec, and glargine. All tirzepatide doses were well tolerated with similar side-effect profile to the GLP-1 receptor analogues. In people without diabetes, tirzepatide 5 to 15 mg once weekly for the treatment for obesity (SURMOUNT-1) resulted in substantial reductions in body weight (16.5% to 22.4%) over 72 weeks. Overall, the SURPASS program and SURMOUNT-1 study suggest that tirzepatide is marking a new era in T2DM and/or obesity management through dual agonism of gut hormones.
Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): a double-blind, multicentre, randomised, phase 3 trial.
As the disease progresses, many patients with type 2 diabetes have difficulty in reaching treatment goals. We aimed to assess the efficacy and safety of tirzepatide, a novel GIP and GLP-1 receptor agonist, compared with dulaglutide in Japanese patients with type 2 diabetes. This multicentre, randomised, double-blind, parallel, active-controlled, phase 3 trial was conducted in 46 medical research centres and hospitals in Japan. Adults aged 20 years or older with type 2 diabetes who had discontinued oral antihyperglycaemic monotherapy or were treatment-naïve were included. Participants were randomly assigned (1:1:1:1) to receive tirzepatide (5, 10, or 15 mg) or dulaglutide (0·75 mg) once per week using a computer-generated random sequence with an Interactive Web Response System. Participants were stratified based on baseline HbA1c (≤8·5% or >8·5%), baseline BMI (<25 or ≥25 kg/m2), and washout of antidiabetic medication. Participants, investigators, and the sponsor were masked to treatment assignment. The starting dose of tirzepatide was 2·5 mg once per week for 4 weeks, which was then increased to 5 mg in the tirzepatide 5 mg treatment group. For the tirzepatide 10 and 15 mg treatment groups, increases by 2·5 mg occurred once every 4 weeks until the assigned dose was reached. The primary endpoint was mean change in HbA1c from baseline at week 52 measured in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03861052. Between May 7, 2019, and March 31, 2021, 821 participants were assessed for study eligibility and 636 were randomly assigned to receive at least one dose of tirzepatide 5 mg (n=159), 10 mg (n=158), or 15 mg (n=160), or dulaglutide 0·75 mg (n=159). 615 (97%) participants completed the study and 21 (3%) discontinued. Participants had a mean age of 56·6 years (SD 10·3) and were mostly male (481 [76%]). At week 52, HbA1c decreased from baseline by a least squares mean of -2·4 (SE 0·1) for tirzepatide 5 mg, -2·6 (0·1) for tirzepatide 10 mg, -2·8 (0·1) for tirzepatide 15 mg, and -1·3 (0·1) for dulaglutide. Estimated mean treatment differences versus dulaglutide were -1·1 (95% CI -1·3 to -0·9) for tirzepatide 5 mg, -1·3 (-1·5 to -1·1) for tirzepatide 10 mg, and -1·5 (-1·71 to -1·4) for tirzepatide 15 mg (all p<0·0001). Tirzepatide was associated with dose-dependent reductions in bodyweight with a least square mean difference of -5·8 kg (SE 0·4; -7·8% reduction) for 5 mg, -8·5 kg (0·4; -11·0% reduction) for 10 mg, and -10·7 kg (0·4; -13·9% reduction) for 15 mg of tirzepatide compared with -0·5 kg (0·4; -0·7% reduction) for dulaglutide. The most common treatment-emergent adverse events were nausea (19 [12%] participants in the 5 mg group vs 31 [20%] in the 10 mg group vs 32 [20%] in the 15 mg group all receiving tirzepatide vs 12 (8%) in the group receiving dulaglutide), constipation (24 [15%] vs 28 [18%] vs 22 [14%] vs 17 [11%]), and nasopharyngitis (29 [18%] vs 25 [16%] vs 22 [14%] vs 26 [16%]). The most frequent adverse events were gastrointestinal (23 [4%] of 636). Tirzepatide was superior compared with dulaglutide for glycaemic control and reduction in bodyweight. The safety profile of tirzepatide was consistent with that of GLP-1 receptor agonists, indicating a potential therapeutic use in Japanese patients with type 2 diabetes. Eli Lilly and Company. For the Japanese translation of the abstract see Supplementary Materials section.
Cardiovascular effects of tirzepatide.
Tirzepatide is a first-in-class dual agonist at receptors for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) for the treatment of T2D and obesity, with unprecedented efficacy for glycaemic control, reductions in body weight and improvements in blood pressure and lipid profile compared with placebo and GLP-1 receptor agonists. To date, clinical trials of tirzepatide have fulfilled the requirement by regulatory authorities of demonstrated cardiovascular safety in high-risk patients. Whether cardiovascular benefits will be found with dual GLP-1/GIP receptor agonists remains uncertain, and the contribution of GIP receptor activation to cardiovascular risk has not been established. Several ongoing large-scale cardiovascular outcome trials for tirzepatide will provide a clearer understanding of where tirzepatide should be positioned in the treatment of established atherosclerotic cardiovascular disease or in people at high risk, in relation to current standard-of-care cardioprotective agents and approaches.
Tirzepatide Reduces LV Mass and Paracardiac Adipose Tissue in Obesity-Related Heart Failure: SUMMIT CMR Substudy.
Obesity is a known risk factor for heart failure with preserved ejection fraction (HFpEF) and is considered a distinct phenotype with more concentric remodeling. Epicardial adipose tissue (EAT) is also increased in obesity-related HFpEF and is associated with adverse events. The cardiac magnetic resonance (CMR) substudy of the SUMMIT trial aimed to examine the effects of tirzepatide on cardiac structure and function with the underlying hypothesis that it would reduce left ventricular (LV) mass and EAT in obesity-related HFpEF. A total of 175 patients with obesity-related HFpEF from the parent study of tirzepatide (2.5 mg subcutaneously weekly, increasing to a maximum of 15 mg weekly) or matching placebo underwent CMR at baseline, which consisted of multiplanar cine imaging. A total of 106 patients completed the CMR and had adequate image quality for analysis of LV and left atrial structure and function and paracardiac (epicardial plus pericardial) adipose tissue at both baseline and 52 weeks. The prespecified primary endpoint of this substudy was between-group changes in LV mass. LV mass decreased by 11 g (95% CI: -19 to -4 g) in the treated group (n = 50) when corrected for placebo (n = 56) (P = 0.004). Paracardiac adipose tissue decreased in the treated group by 45 mL (95% CI: -69 to -22 mL) when corrected for placebo (P < 0.001). The change in LV mass in the treated group correlated with changes in body weight (P < 0.02) and tended to correlate with changes in waist circumference and blood pressure (P = 0.06 for both). The LV mass change also correlated with changes in LV end-diastolic volume and left atrial end-diastolic and end-systolic volumes (P < 0.03 for all). The CMR substudy of the SUMMIT trial demonstrated that tirzepatide therapy in obesity-related HFpEF led to reduced LV mass and paracardiac adipose tissue as compared with placebo, and the change in LV mass paralleled weight loss. These physiologic changes may contribute to the reduction in heart failure events seen in the main SUMMIT trial. (A Study of Tirzepatide [LY3298176] in Participants With Heart Failure With Preserved Ejection Fraction [HFpEF] and Obesity: The SUMMIT Trial; NCT04847557).
Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes.
Novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide. Explore mechanisms of glucose control by tirzepatide. Post hoc analyses of fasting biomarkers and multiple linear regression analysis. Forty-seven sites in 4 countries. Three hundred and sixteen subjects with type 2 diabetes. Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo. Analyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks. Homeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively. Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.
Tirzepatide for maintenance of bodyweight reduction in people with obesity in the USA (SURMOUNT-MAINTAIN): a multicentre, double-blind, randomised, placebo-controlled trial.
Obesity treatment improves long-term health and quality of life outcomes. Weight reduction and its maintenance play an important role in achieving these goals. We evaluated the efficacy and safety of continuing tirzepatide at the maximum tolerated dose (MTD) or lowering the dose to 5 mg compared with switching to placebo on the maintenance of bodyweight reduction obtained with tirzepatide MTD in adults with obesity. This phase 3b, placebo-controlled, 112-week trial, including a 60-week open-label weight-loss period and a 52-week, double-blind weight maintenance period, was conducted across 20 sites in the USA. After completing the initial weight-loss period with once weekly subcutaneous tirzepatide at the MTD (10 mg or 15 mg), adults (aged ≥18 years) with a BMI of 30 kg/m2 and above or 27 kg/m2 and above with one or more weight-related comorbidity, and a history of at least one self-reported unsuccessful dietary effort to lose bodyweight were randomly assigned in a 3:3:2 ratio to continue tirzepatide MTD, reduce to tirzepatide 5 mg, or switch to placebo for an additional 52 weeks. Starting at week 84 (24 weeks after random allocation), participants could receive rescue tirzepatide if their weight regain exceeded 50%. The primary endpoint was the percentage change in bodyweight from baseline to week 112. The primary estimand was the modified treatment-regimen estimand, which assumed that participants who initiated rescue tirzepatide would not have gained further benefit from their assigned study treatment and included all randomly allocated participants, regardless of treatment discontinuation or initiation of prohibited medications. The efficacy estimand was supportive. Safety was assessed in all participants who received at least one dose of study drug. This completed trial was registered at ClinicalTrials.gov (NCT06047548). From Sept 20, 2023, to Jan 20, 2026, 441 patients were enrolled in and took at least one dose of study treatment during the weight-loss period, with 378 participants randomly allocated at week 60 (140 to tirzepatide MTD; 144 to dose-reduction to 5 mg tirzepatide; and 94 to placebo). 372 received at least one dose of study drug during the weight maintenance period (139 for tirzepatide MTD; 142 for 5 mg tirzepatide; and 91 for placebo). 345 (91%) of 378 participants completed the study. The majority of participants were White (67%); 288 (65%) participants were female and 153 (35%) were male; and the mean age was 46·6 years (SD 13·0). At baseline, participants had a mean bodyweight of 113·8 kg (SD 27·0), a BMI of 40·1 kg/m2 (SD 8·1), and HbA1c 5·64% (SD 0·4; 38·2 mmol/mol [SD 4·0]). The model-based estimate percent change in bodyweight from baseline to week 112 was -21·9% (95% CI -23·5 to -20·3) with MTD (estimated treatment difference [ETD] -12·0% [95% CI -13s·8 to -10·1]), -16·6% (95% CI -18·0 to -15·1) with 5 mg tirzepatide (ETD -6·6 [95% CI -8·3 to -5·0]), versus -9·9% (95% CI -11·1 to -8·8) with placebo (p<0·0001 for all comparisons). Among participants who regained at least 50% of lost bodyweight, observed means were 11 (8%) of 138, 35 (25%) of 142, and 60 (67%) of 90 participants received rescue therapy in the tirzepatide MTD, 5 mg tirzepatide, and placebo, respectively. The most common adverse events with tirzepatide were gastrointestinal events, which were mostly mild to moderate in severity and mostly occurred during dose escalation. In adults with obesity, long-term treatment is often necessary to maintain bodyweight reduction and its associated cardiometabolic benefits. In the SURMOUNT-MAINTAIN trial, continuing tirzepatide at MTD maintained bodyweight reduction and health-related benefits. Reducing to 5 mg tirzepatide might provide a valuable alternative to discontinuation, although individuals' treatment response might vary. Together, these findings support the importance of ongoing therapy for long-term obesity management and provide evidence to inform individualised, patient-centred obesity care. Eli Lilly.
Anti-inflammatory effects of tirzepatide: a systematic review and meta-analysis.
Tirzepatide, a dual GIP and GLP-1 receptor agonist, has shown significant metabolic benefits and weight reduction, but its anti-inflammatory effects have been less studied. This study was conducted in accordance with PRISMA guidelines, including observational (cohort) studies and randomized clinical trials that evaluated tirzepatide use and reported percentage changes in high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6). A random-effects model was used. Seven randomized clinical trials and one observational study were included (six studies were eligible for meta-analysis). Compared to placebo, tirzepatide reduced hsCRP (mean difference [MD]: -32.9; 95% confidence interval [CI]: -33.6 to - 32.2; I²=15.3%) and IL-6 (MD: -17.8; 95% CI: -24.3 to - 11.3; I² = 1.6%). Levels of hsCRP were significantly reduced with tirzepatide at 15 mg (MD: -32.9; 95% CI: -33.6 to - 32.2; I²=4.4%), 10 mg (MD: -33.9; 95% CI: -50.3 to - 17.6; I²=41.8%), and 5 mg (MD: -20.3; 95% CI: -35.2 to - 5.3; I²=0%). Similarly, IL-6 levels were significantly reduced with tirzepatide at 5 mg (MD: -18.8; 95% CI: -32.9 to - 4.6; I²=17.2%), 10 mg (MD: -17.9; 95% CI: -28.2 to - 7.7; I²=2.1%), and 15 mg (MD: -16.8; 95% CI: -31.1 to - 2.6; I²=47.4%). This study demonstrated that tirzepatide use is associated with a significant reduction in inflammatory markers, regardless of the population studied or treatment regimen.
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.
Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist under development for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of tirzepatide versus titrated insulin degludec in people with type 2 diabetes inadequately controlled by metformin with or without SGLT2 inhibitors. In this open-label, parallel-group, multicentre (122 sites), multinational (13 countries), phase 3 study, eligible participants (aged ≥18 years) had a baseline glycated haemoglobin (HbA1c) of 7·0-10·5%, body-mass index of at least 25 kg/m2, stable weight, and were insulin-naive and treated with metformin alone or in combination with an SGLT2 inhibitor for at least 3 months before screening. Participants were randomly assigned (1:1:1:1), using an interactive web-response system, to once-weekly subcutaneous injection of tirzepatide (5, 10, or 15 mg) or once-daily subcutaneous injection of titrated insulin degludec, and were stratified by country, HbA1c, and concomitant use of oral antihyperglycaemic medications. Tirzepatide was initially given at 2·5 mg and the dose was escalated by 2·5 mg every 4 weeks until the assigned dose was reached. Insulin degludec was initially given at 10 U per day and was titrated once weekly to a fasting self-monitored blood glucose of less than 5·0 mmol/L (<90 mg/dL), following a treat-to-target algorithm, for 52 weeks. The primary efficacy endpoint was non-inferiority of tirzepatide 10 mg or 15 mg, or both, versus insulin degludec in mean change from baseline in HbA1c at week 52. Key secondary efficacy endpoints were non-inferiority of tirzepatide 5 mg versus insulin degludec in mean change from baseline in HbA1c at week 52, superiority of all doses of tirzepatide versus insulin degludec in mean change from baseline in HbA1c and bodyweight, and the proportion of participants achieving HbA1c of less than 7·0% (<53 mmol/mol) at week 52. We used a boundary of 0·3% to establish non-inferiority in HbA1c difference between treatments. Efficacy and safety analyses were assessed in the modified intention-to-treat population (all participants who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, number NCT03882970, and is complete. Between April 1 and Nov 15, 2019, we assessed 1947 participants for eligibility, 1444 of whom were randomly assigned to treatment. The modified intention-to-treat population was 1437 participants from the tirzepatide 5 mg (n=358), tirzepatide 10 mg (n=360), tirzepatide 15 mg (n=359), and insulin degludec (n=360) groups. From a mean baseline HbA1c of 8·17% (SD 0·91), the reductions in HbA1c at week 52 were 1·93% (SE 0·05) for tirzepatide 5 mg, 2·20% (0·05) for tirzepatide 10 mg, and 2·37% (0·05) for tirzepatide 15 mg, and 1·34% (0·05) for insulin degludec. The non-inferiority margin of 0·3% was met. The estimated treatment difference (ETD) versus insulin degludec ranged from -0·59% to -1·04% for tirzepatide (p<0·0001 for all tirzepatide doses). The proportion of participants achieving a HbA1c of less than 7·0% (<53 mmol/mol) at week 52 was greater (p<0·0001) in all three tirzepatide groups (82%-93%) versus insulin degludec (61%). At week 52, from a baseline of 94·3 kg (SD 20·1), all three tirzepatide doses decreased bodyweight (-7·5 kg to -12·9 kg), whereas insulin degludec increased bodyweight by 2·3 kg. The ETD versus insulin degludec ranged from -9·8 kg to -15·2 kg for tirzepatide (p<0·0001 for all tirzepatide doses). The most common adverse events in tirzepatide-treated participants were mild to moderate gastrointestinal events that decreased over time. 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 or severe) was reported in five (1%), four (1%), and eight (2%) participants on tirzepatide 5, 10, and 15 mg, respectively, versus 26 (7%) on insulin degludec. Treatment discontinuation due to an adverse event was more common in the tirzepatide groups than in the insulin degludec group. Five participants died during the study; none of the deaths were considered by the investigators to be related to the study treatment. In patients with type 2 diabetes, tirzepatide (5, 10, and 15 mg) was superior to titrated insulin degludec, with greater reductions in HbA1c and bodyweight at week 52 and a lower risk of hypoglycaemia. Tirzepatide showed a similar safety profile to that of GLP-1 receptor agonists. Eli Lilly and Company.
Efficacy and safety of tirzepatide for treatment of overweight or obesity. A systematic review and meta-analysis.
Recent studies suggest that tirzepatide, a dual glucose-dependent insulinotropic-peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA), has significant weight loss effects. This systematic review and meta-analysis aims to assess the efficacy and safety of tirzepatide for weight loss in patients with overweight or obesity. Medline, Embase and Cochrane CENTRAL were searched for randomized controlled trials (RCTs) on tirzepatide's weight loss efficacy for these patients. A single arm meta-analysis of proportions estimated primary outcomes, ≥5%, ≥10%, and ≥15% weight loss, and adverse events (AEs); while meta-analysis of means estimated secondary outcomes. Comparative meta-analysis was conducted between tirzepatide and control arms where mean differences and odds ratios were estimated for continuous and dichotomous outcomes respectively. RCTs included in this study revealed that among 5800 patients, 78.22% (95% CI: 72.15% to 83.73%), 55.60% (95% CI: 46.54% to 64.47%), 32.28% (95% CI: 23.17% to 42.12%) achieved ≥5%, ≥10%, and ≥15% weight loss, respectively. Tirzepatide 5 mg demonstrated weight loss superiority relative to placebo (MD: -12.47 kg, 95% CI: -13.94 kg to -11.00 kg) and semaglutide (n = 1409, MD: -1.90 kg, 95% CI: -2.97 kg to -0.83 kg) with dose-dependent increase for 10 mg and 15 mg doses. The comparison between tirzepatide and semaglutide was examined in the SURPASS-2 trial that was included in this systematic review. For AEs, there was increase odds of experiencing gastrointestinal AEs with tirzepatide compared to placebo, but no significant difference with semaglutide. Tirzepatide has significant potential as a weight loss drug in patients with overweight and obesity, with little increase in AEs compared to other weight loss drugs. With its ability to concurrently target multiple aspects of metabolic syndrome, it should be considered as the next helm of weight loss therapies.
Population pharmacokinetics of the GIP/GLP receptor agonist tirzepatide.
Tirzepatide is a first-in-class glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved as for the treatment of type 2 diabetes mellitus. A population-based pharmacokinetic (PK) model was developed from 19 pooled studies. Tirzepatide pharmacokinetics were well-described by a two-compartment model with first order absorption and elimination. The tirzepatide population PK model utilized a semimechanistic allometry model to describe the relationship between body size and tirzepatide PK. The half-life of tirzepatide was ~5 days and enabled sustained exposure with once-weekly subcutaneous dosing. The covariate analysis suggested that adjustment of the dose regimen based on demographics or subpopulations was unnecessary. The tirzepatide PK model can be used to predict tirzepatide exposure for various scenarios or populations.
Tirzepatide and muscle composition changes in people with type 2 diabetes (SURPASS-3 MRI): a post-hoc analysis of a randomised, open-label, parallel-group, phase 3 trial.
Substantial weight reduction is often associated with loss of muscle mass. Tirzepatide has been associated with significant reductions in body weight in type 2 diabetes trials and a beneficial effect on body fat distribution in the SURPASS-3 MRI substudy. This post-hoc exploratory analysis studied the association of tirzepatide treatment with changes in thigh muscle volume, muscle volume Z score, and muscle fat infiltration, and aimed to contextualise the results using longitudinal MRI data from UK Biobank participants. SURPASS-3 was a randomised, open-label, parallel-group, phase 3 trial. The multicentre (45 sites) and multinational (eight countries) MRI substudy of SURPASS-3 enrolled insulin-naive adults (aged ≥18 years) with type 2 diabetes who were on treatment with metformin with or without a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, had an HbA1c of 7·0-10·5% (53-91 mmol/mol), a BMI of at least 25 kg/m2, and a fatty liver index of at least 60. Participants were randomly assigned (1:1:1:1) to receive subcutaneous injection once per week of tirzepatide (5, 10, or 15 mg), or subcutaneous injection once per day of titrated insulin degludec. Thigh muscle fat infiltration, muscle volume, and muscle volume Z score (invariant to sex, height, weight, and BMI) were quantified by MRI at baseline and week 52. In this post-hoc analysis, we assessed the differences between mean baseline and week 52 muscle composition values in the tirzepatide groups (pooled 5 mg, 10 mg, and 15 mg group, and per dose group) and insulin degludec group using paired t tests, and the differences in muscle composition changes with pooled tirzepatide versus insulin degludec via adjusted ANCOVA models. Observed changes in muscle fat infiltration, muscle volume, and muscle volume Z scores were compared using paired t tests to population-based estimates calculated from multiple linear regression models fitted to UK Biobank data (n=2942), capturing associations with change in body weight. Analyses were done by modified intention to treat, in the participants enrolled in the MRI substudy with a valid MRI scan at week 52. The SURPASS-3 clinical trial is registered with ClinicalTrials.gov, NCT03882970, and is complete. Participants were assessed for eligibility and recruited from April 1, 2019, to Nov 15, 2019. Among 502 participants assessed for eligibility to participate in the MRI substudy, 296 were enrolled, and 246 had a valid week 52 MRI scan and were included in the post-hoc analyses (tirzepatide 5 mg, n=63; tirzepatide 10 mg, n=60; tirzepatide 15 mg, n=67; insulin degludec, n=56; 147 [59·8%] male participants and 99 [40·2%] female participants). At baseline, overall mean age was 56·0 years (SD 9·9), median duration of type 2 diabetes was 6·7 years (IQR 3·7 to 10·7), mean HbA1c was 8·3% (SD 0·9), mean BMI was 33·4 kg/m2 (SD 4·8), and 76 (30·9%) were on an SGLT-2 inhibitor. Mean baseline muscle fat infiltration, muscle volume, and muscle volume Z scores were similar between the pooled tirzepatide group and insulin degludec group. For the pooled and individual tirzepatide dose groups, significant reductions were observed from baseline to week 52 in muscle fat infiltration (for pooled tirzepatide, mean change -0·36 percentage points [95% CI -0·48 to -0·25], p<0·0001), muscle volume (-0·64 L [95% CI -0·74 to -0·54], p<0·0001), and muscle volume Z score (-0·22 [95% CI -0·29 to -0·15], p<0·0001), which occurred in the context of significant weight reduction. Insulin degludec was associated with a modest and significant increase in bodyweight and muscle volume, but no significant change in the other variables. The changes in all three muscle composition variables with pooled tirzepatide were significantly different compared to those with insulin degludec. In tirzepatide-treated participants, observed muscle volume changes across all tirzepatide doses were similar to population-based estimated changes (for pooled tirzepatide, mean difference vs population-based estimate, -0·04 L [95% CI -0·11 to 0·03], p=0·22); whereas, observed reductions in muscle fat infiltration across all doses were significantly greater than population-based estimates (for pooled tirzepatide, mean difference -0·42 percentage points [95% CI -0·54 to -0·31], p<0·0001), and the observed reduction in muscle volume Z score with tirzepatide 15 mg was significantly greater than the population-based estimate (mean difference -0·18 [95% CI -0·29 to -0·07], p=0·0016). In the SURPASS-3 MRI substudy, in the context of significant improvements in bodyweight and fat distribution, tirzepatide treatment was associated with potentially favourable changes in muscle fat infiltration and reductions in muscle volume broadly in accordance with the general association between changes in muscle volume and bodyweight. The present findings provide additional information on the potential effect of tirzepatide on muscle health that might help health-care providers when deciding among treatment options for individual patients. Eli Lilly and Company.
Are Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists Central Nervous System (CNS) Penetrant: A Narrative Review.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that modulates glucose metabolism and insulin secretion. Recent translational and clinical research has evaluated the effects of GLP-1 receptor agonists (GLP-1 RAs), a class of drugs that mimic the action of native GLP-1 in the central nervous system (CNS). In addition to the efficacy of GLP-1 for the treatment of diabetes mellitus and obesity, preliminary evidence indicates GLP-1s have neuroprotective, therapeutic, and disease modification effects for select neurodegenerative disorders (e.g. Parkinson's disease, Alzheimer's disease). Among the available GLP-1 RAs, relatively few have been shown to be CNS penetrant. This article synthesizes extant literature reporting on CNS penetrants of GLP-1 RAs as proxied by brain imaging studies. Where available, studies that reported on the bioavailability of GLP-1 RAs in the CNS were identified. A comprehensive search of PubMed, Ovid, and Web of Science from database inception to July 2024 was conducted. Inclusion criteria were English language publications with no date restrictions, preclinical and clinical studies with participants aged 18-80 and studies which focused on GLP-1 RAs including: "Semaglutide" or "Ozempic" or "Rybelsus" or "Wegovy" or "Dulaglutide" or "Trulicity" or "Exenatide" or "Byetta" or "Bydureon" or "Liraglutide" or "Lixisenatide" or "Tirzepatide" or "Mounjaro" or "Zepbound" or "Bydureon BCise" or "Adlyxin" or "Victoza" or "Saxenda". We identified 14 studies that were included in this synthesis. Preclinical studies suggest that select GLP-1 RAs cross the blood-brain barrier (BBB) (i.e. liraglutide, semaglutide, and exenatide). Replicated evidence suggests that CNS penetration of GLP-1 RAs can be proxied by reported effects of GLP-1 RAs on brain connectivity in human participants.  Preclinical studies indicate that select GLP-1 RAs are CNS penetrant; whether GLP-1 RAs reproducibly engage neural targets hypothesized to subserve dimensions of psychopathology (e.g., general cognitive functions) remains incompletely characterized.
Tirzepatide and cardiometabolic parameters in obesity: Summary of current evidence.
Globally, cardiovascular diseases (CVDs) account for around one-third of all deaths. Clinical trial evidence suggests that treatment of people with obesity or type 2 diabetes (T2D) and CVD with glucagon-like peptide-1 (GLP-1) receptor agonists reduces the risk of major adverse cardiovascular events, heart failure outcomes and all-cause mortality. Tirzepatide is a once-weekly, dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist that has demonstrated dose-dependent efficacy in people with obesity, T2D or both, in terms of glycaemic control and bodyweight reduction in clinical trials. This narrative review summarizes the current evidence regarding the effects of tirzepatide treatment on cardiometabolic parameters, including lipid profile, blood pressure and markers of renal function. Additionally, it summarizes the reported impact of tirzepatide treatment on other relevant parameters, such as body composition, liver fat, progression to T2D among individuals with prediabetes, and incidence of heart failure events. Considering the changing landscape of clinical trial evidence of tirzepatide's effects, this review aims to compile the available evidence, which suggests a promising outlook for the cardiometabolic benefits of tirzepatide.
Quick links (PubMed)
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