madman
Super Moderator
Tirzepatide Once Weekly for the Treatment of Obesity (2022)
Ania M. Jastreboff, M.D., Ph.D., Louis J. Aronne, M.D., Nadia N. Ahmad, M.D., M.P.H., Sean Wharton, M.D., Pharm.D., Lisa Connery, M.D., Breno Alves, M.D., Arihiro Kiyosue, M.D., Ph.D., Shuyu Zhang, M.S., Bing Liu, Ph.D., Mathijs C. Bunck, M.D., Ph.D., and Adam Stefanski, M.D., Ph.D., for the SURMOUNT-1 Investigators*
BACKGROUND
Obesity is a chronic disease that results in substantial global morbidity and mortality. The efficacy and safety of tirzepatide, a novel glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1 receptor agonist, in people with obesity are not known.
METHODS
In this phase 3 double-blind, randomized, controlled trial, we assigned 2539 adults with a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or more, or 27 or more and at least one weight-related complication, excluding diabetes, in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period. Coprimary endpoints were the percentage change in weight from baseline and a weight reduction of 5% or more. The treatment-regimen estimand assessed effects regardless of treatment discontinuation in the intention-to-treat population.
RESULTS
At baseline, the mean body weight was 104.8 kg, the mean BMI was 38.0, and 94.5% of participants had a BMI of 30 or higher. The mean percentage change in weight at week 72 was −15.0% (95% confidence interval [CI], −15.9 to −14.2) with 5-mg weekly doses of tirzepatide, −19.5% (95% CI, −20.4 to −18.5) with 10-mg doses, and −20.9% (95% CI, −21.8 to −19.9) with 15-mg doses and −3.1% (95% CI, −4.3 to −1.9) with placebo (P<0.001 for all comparisons with placebo). The percentage of participants who had a weight reduction of 5% or more was 85% (95% CI, 82 to 89), 89% (95% CI, 86 to 92), and 91% (95% CI, 88 to 94) with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and 35% (95% CI, 30 to 39) with placebo; 50% (95% CI, 46 to 54) and 57% (95% CI, 53 to 61) of participants in the 10-mg and 15-mg groups had a reduction in body weight of 20% or more, as compared with 3% (95% CI, 1 to 5) in the placebo group (P<0.001 for all comparisons with placebo). Improvements in all prespecified cardiometabolic measures were observed with tirzepatide. The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively.
CONCLUSIONS
In this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight. (Supported by Eli Lilly; SURMOUNT-1 ClinicalTrials.gov number, NCT04184622.)
Obesity is the most prevalent chronic disease worldwide, affecting approximately 650 million adults.1 Excess adiposity and its numerous complications, including cardiovascular disease and type 2 diabetes, impose a considerable economic burden and constitute major contributors to global morbidity and mortality.2-4 Treatments that result in substantial weight reductions may improve outcomes for people living with obesity.
Historically, the treatment of obesity focused almost exclusively on lifestyle-based approaches. However, evidence that diet and exercise prompt physiological counterregulatory mechanisms that limit weight reduction and impede weight maintenance has led to the realization that obesity is a complex, multicomponent metabolic disease of energy homeostasis involving central and peripheral mechanisms.5 Once obesity is present, those mechanisms render a return to lower weight difficult.6 Accordingly, several clinical guidelines now recommend treatment with antiobesity medications for people with obesity or for those with overweight and weight-related complications.7,8 Recent studies with long-acting glucagonlike peptide-1 (GLP-1) receptor agonists demonstrated that greater efficacy with acceptable safety could be achieved by targeting the pathways of endogenous nutrient-stimulated hormones.9,10 Glucose-dependent insulinotropic polypeptide (GIP), another nutrient-stimulated hormone, regulates energy balance through cell-surface receptor signaling in the brain and adipose tissue.11 A molecule that combines both GIP and GLP receptor agonism theoretically may lead to greater efficacy in weight reduction.
Tirzepatide is a once-weekly subcutaneous injectable peptide (approved by the Food and Drug Administration [FDA] for type 2 diabetes) engineered from the native GIP sequence, with agonist activity at both the GIP and GLP-1 receptors.12 Preclinical data demonstrated that the affinity of tirzepatide for GIP receptors was equal to the affinity of native GIP for GIP receptors, whereas tirzepatide bound GLP-1 receptors with an affinity approximately five times weaker than native GLP-1 bound GLP-1 receptors.12 GIP activation appeared to act synergistically with GLP-1 receptor activation to allow greater weight reduction in mice than that achieved with GLP-1 receptor monoagonism.12 In phase 2 studies in people with type 2 diabetes, tirzepatide induced clinically relevant weight reduction, warranting further investigation for the treatment of obesity. The present trial, SURMOUNT-1, evaluated the efficacy and safety of tirzepatide in adults with obesity or overweight who did not have diabetes.
Discussion
In the present trial, adults with obesity had average weight reductions of 19.5% and 20.9% with 10-mg and 15-mg doses of tirzepatide, respectively, as compared with a 3.1% weight reduction with placebo (treatment-regimen estimand). This is an unusually substantial degree of weight reduction in response to an antiobesity medication as compared with findings reported in other phase 3 clinical trials. Given that tirzepatide is both a GIP receptor and GLP-1 receptor agonist, we speculate that there may be an additive benefit in targeting multiple endogenous nutrient-stimulated hormone pathways that have been implicated in energy homeostasis.
A body-weight reduction of 5% or more has long been considered the threshold for clinically meaningful effect on the basis of improvement in metabolic health.15 It is remarkable that in this trial, the majority (89% to 91%) of participants receiving 10-mg or 15-mg doses of tirzepatide achieved this benchmark. Weight reductions of 10% or more, 15% or more, and 20% or more yield additional clinical benefits,15,16 may be required for improvement in certain weight-related complications,17 and are often more desired therapeutic goals in clinical practice. The majority of participants reached these three higher weight-loss targets (78–84%, 67–71%, and 50–57%, respectively), across the 10-mg and 15-mg dose groups.
For perspective: the average placebo-adjusted weight reductions with older antiobesity medications that are currently approved by the FDA for the treatment of obesity are approximately 3.0 to 8.6%,18 whereas a recently introduced antiobesity medication, semaglutide (2.4 mg), resulted in a placebo-adjusted weight reduction of 12.4%, with nearly one-third of persons having a weight reduction of 20% or more.10 In the current trial, participants receiving the lowest maintenance dose of tirzepatide (5 mg) had a mean placebo-adjusted weight reduction of 11.9% from baseline, with 30% of participants reaching the weight-loss target of 20% or more. It is important to note that no direct comparison of these trials can be made since trial populations and designs differed. Finally, bariatric surgery results in a weight reduction of approximately 25 to 30% in 1 to 2 years.19,20 In the current trial, 36.2% of participants in the 15-mg tripeptide group met the prespecified exploratory endpoint of weight reduction of 25% or more. With substantial observed weight reductions at all three doses, tirzepatide may serve as an important tool in the medical management of obesity.
The 10-mg and 15-mg tirzepatide groups were similar in mean percentage weight reduction, yet a higher proportion of participants in the 15-mg group met the 10% or more, 15% or more, and 20% or more weight-loss targets. The incidence of adverse events was similar in the 10-mg and 15-mg groups. This finding suggests that the 15-mg dose may confer additional benefits in some patients, without added safety concerns. It will be important to identify which patients may garner the greatest degree of benefit from various doses of tirzepatide.
In the present trial, weight reduction with tirzepatide was accompanied by greater improvements with respect to all measured cardiovascular and metabolic risk factors, including waist circumference, systolic and diastolic blood pressure, fasting insulin, lipid, and aspartate aminotransferase levels, than placebo. Participants treated with tirzepatide had a percent reduction in fat mass approximately three times greater than the reduction in lean mass, resulting in an overall improvement in body composition. The ratio of fat-mass loss to lean-mass loss was similar to that reported with lifestyle-based and surgical treatments for obesity.21 In addition, nearly all participants (>95%) treated with tirzepatide who had prediabetes at baseline had converted to normoglycemia by the end of the primary trial period, as compared with 62% of participants who received placebo. These improvements may translate to reduced risk of cardiovascular disease, chronic kidney disease, nonalcoholic fatty liver disease, and type 2 diabetes, among other outcomes.15,16,22 Future trials are needed to test this hypothesis.
*Our trial had several strengths. Its global nature, large sample size, and overall high completion rate make the findings relatively generalizable. Overall, 86% (approximately 90% across the tirzepatide groups) of the participants completed the trial, despite the Covid-19 pandemic. The weight reduction in the placebo group was similar to results observed with placebo in other recent obesity pharmacotherapy trials and is likely to reflect a similar level of adherence to the lifestyle intervention.9,10 Finally, the duration of the trial (72 weeks) enabled participants to reach a weight plateau in the 5-mg group and near-plateaus in the 10-mg and 15-mg groups; the additional 2-year treatment period for participants with prediabetes should provide further insight into the maximum and long-term weight-lowering effect of tirzepatide in people with prediabetes.
*This trial had certain limitations. The enrolled participants with obesity and overweight may represent a subpopulation with a greater commitment to weight-management efforts than the general population with obesity. Furthermore, the measured baseline cardiometabolic risk factors in the trial population, such as blood pressure and lipids, were relatively normal, possibly attenuating the potential to show improvement, though meaningful changes in these variables were observed. Overall, only 5.5% of trial participants with overweight (BMI of 27 to <30) were included; further studies would be needed in such patients.
*In the present trial, all three doses of once-weekly tirzepatide demonstrated substantial and sustained weight reduction in adults with obesity.
Ania M. Jastreboff, M.D., Ph.D., Louis J. Aronne, M.D., Nadia N. Ahmad, M.D., M.P.H., Sean Wharton, M.D., Pharm.D., Lisa Connery, M.D., Breno Alves, M.D., Arihiro Kiyosue, M.D., Ph.D., Shuyu Zhang, M.S., Bing Liu, Ph.D., Mathijs C. Bunck, M.D., Ph.D., and Adam Stefanski, M.D., Ph.D., for the SURMOUNT-1 Investigators*
BACKGROUND
Obesity is a chronic disease that results in substantial global morbidity and mortality. The efficacy and safety of tirzepatide, a novel glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1 receptor agonist, in people with obesity are not known.
METHODS
In this phase 3 double-blind, randomized, controlled trial, we assigned 2539 adults with a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or more, or 27 or more and at least one weight-related complication, excluding diabetes, in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period. Coprimary endpoints were the percentage change in weight from baseline and a weight reduction of 5% or more. The treatment-regimen estimand assessed effects regardless of treatment discontinuation in the intention-to-treat population.
RESULTS
At baseline, the mean body weight was 104.8 kg, the mean BMI was 38.0, and 94.5% of participants had a BMI of 30 or higher. The mean percentage change in weight at week 72 was −15.0% (95% confidence interval [CI], −15.9 to −14.2) with 5-mg weekly doses of tirzepatide, −19.5% (95% CI, −20.4 to −18.5) with 10-mg doses, and −20.9% (95% CI, −21.8 to −19.9) with 15-mg doses and −3.1% (95% CI, −4.3 to −1.9) with placebo (P<0.001 for all comparisons with placebo). The percentage of participants who had a weight reduction of 5% or more was 85% (95% CI, 82 to 89), 89% (95% CI, 86 to 92), and 91% (95% CI, 88 to 94) with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and 35% (95% CI, 30 to 39) with placebo; 50% (95% CI, 46 to 54) and 57% (95% CI, 53 to 61) of participants in the 10-mg and 15-mg groups had a reduction in body weight of 20% or more, as compared with 3% (95% CI, 1 to 5) in the placebo group (P<0.001 for all comparisons with placebo). Improvements in all prespecified cardiometabolic measures were observed with tirzepatide. The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively.
CONCLUSIONS
In this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight. (Supported by Eli Lilly; SURMOUNT-1 ClinicalTrials.gov number, NCT04184622.)
Obesity is the most prevalent chronic disease worldwide, affecting approximately 650 million adults.1 Excess adiposity and its numerous complications, including cardiovascular disease and type 2 diabetes, impose a considerable economic burden and constitute major contributors to global morbidity and mortality.2-4 Treatments that result in substantial weight reductions may improve outcomes for people living with obesity.
Historically, the treatment of obesity focused almost exclusively on lifestyle-based approaches. However, evidence that diet and exercise prompt physiological counterregulatory mechanisms that limit weight reduction and impede weight maintenance has led to the realization that obesity is a complex, multicomponent metabolic disease of energy homeostasis involving central and peripheral mechanisms.5 Once obesity is present, those mechanisms render a return to lower weight difficult.6 Accordingly, several clinical guidelines now recommend treatment with antiobesity medications for people with obesity or for those with overweight and weight-related complications.7,8 Recent studies with long-acting glucagonlike peptide-1 (GLP-1) receptor agonists demonstrated that greater efficacy with acceptable safety could be achieved by targeting the pathways of endogenous nutrient-stimulated hormones.9,10 Glucose-dependent insulinotropic polypeptide (GIP), another nutrient-stimulated hormone, regulates energy balance through cell-surface receptor signaling in the brain and adipose tissue.11 A molecule that combines both GIP and GLP receptor agonism theoretically may lead to greater efficacy in weight reduction.
Tirzepatide is a once-weekly subcutaneous injectable peptide (approved by the Food and Drug Administration [FDA] for type 2 diabetes) engineered from the native GIP sequence, with agonist activity at both the GIP and GLP-1 receptors.12 Preclinical data demonstrated that the affinity of tirzepatide for GIP receptors was equal to the affinity of native GIP for GIP receptors, whereas tirzepatide bound GLP-1 receptors with an affinity approximately five times weaker than native GLP-1 bound GLP-1 receptors.12 GIP activation appeared to act synergistically with GLP-1 receptor activation to allow greater weight reduction in mice than that achieved with GLP-1 receptor monoagonism.12 In phase 2 studies in people with type 2 diabetes, tirzepatide induced clinically relevant weight reduction, warranting further investigation for the treatment of obesity. The present trial, SURMOUNT-1, evaluated the efficacy and safety of tirzepatide in adults with obesity or overweight who did not have diabetes.
Discussion
In the present trial, adults with obesity had average weight reductions of 19.5% and 20.9% with 10-mg and 15-mg doses of tirzepatide, respectively, as compared with a 3.1% weight reduction with placebo (treatment-regimen estimand). This is an unusually substantial degree of weight reduction in response to an antiobesity medication as compared with findings reported in other phase 3 clinical trials. Given that tirzepatide is both a GIP receptor and GLP-1 receptor agonist, we speculate that there may be an additive benefit in targeting multiple endogenous nutrient-stimulated hormone pathways that have been implicated in energy homeostasis.
A body-weight reduction of 5% or more has long been considered the threshold for clinically meaningful effect on the basis of improvement in metabolic health.15 It is remarkable that in this trial, the majority (89% to 91%) of participants receiving 10-mg or 15-mg doses of tirzepatide achieved this benchmark. Weight reductions of 10% or more, 15% or more, and 20% or more yield additional clinical benefits,15,16 may be required for improvement in certain weight-related complications,17 and are often more desired therapeutic goals in clinical practice. The majority of participants reached these three higher weight-loss targets (78–84%, 67–71%, and 50–57%, respectively), across the 10-mg and 15-mg dose groups.
For perspective: the average placebo-adjusted weight reductions with older antiobesity medications that are currently approved by the FDA for the treatment of obesity are approximately 3.0 to 8.6%,18 whereas a recently introduced antiobesity medication, semaglutide (2.4 mg), resulted in a placebo-adjusted weight reduction of 12.4%, with nearly one-third of persons having a weight reduction of 20% or more.10 In the current trial, participants receiving the lowest maintenance dose of tirzepatide (5 mg) had a mean placebo-adjusted weight reduction of 11.9% from baseline, with 30% of participants reaching the weight-loss target of 20% or more. It is important to note that no direct comparison of these trials can be made since trial populations and designs differed. Finally, bariatric surgery results in a weight reduction of approximately 25 to 30% in 1 to 2 years.19,20 In the current trial, 36.2% of participants in the 15-mg tripeptide group met the prespecified exploratory endpoint of weight reduction of 25% or more. With substantial observed weight reductions at all three doses, tirzepatide may serve as an important tool in the medical management of obesity.
The 10-mg and 15-mg tirzepatide groups were similar in mean percentage weight reduction, yet a higher proportion of participants in the 15-mg group met the 10% or more, 15% or more, and 20% or more weight-loss targets. The incidence of adverse events was similar in the 10-mg and 15-mg groups. This finding suggests that the 15-mg dose may confer additional benefits in some patients, without added safety concerns. It will be important to identify which patients may garner the greatest degree of benefit from various doses of tirzepatide.
In the present trial, weight reduction with tirzepatide was accompanied by greater improvements with respect to all measured cardiovascular and metabolic risk factors, including waist circumference, systolic and diastolic blood pressure, fasting insulin, lipid, and aspartate aminotransferase levels, than placebo. Participants treated with tirzepatide had a percent reduction in fat mass approximately three times greater than the reduction in lean mass, resulting in an overall improvement in body composition. The ratio of fat-mass loss to lean-mass loss was similar to that reported with lifestyle-based and surgical treatments for obesity.21 In addition, nearly all participants (>95%) treated with tirzepatide who had prediabetes at baseline had converted to normoglycemia by the end of the primary trial period, as compared with 62% of participants who received placebo. These improvements may translate to reduced risk of cardiovascular disease, chronic kidney disease, nonalcoholic fatty liver disease, and type 2 diabetes, among other outcomes.15,16,22 Future trials are needed to test this hypothesis.
*Our trial had several strengths. Its global nature, large sample size, and overall high completion rate make the findings relatively generalizable. Overall, 86% (approximately 90% across the tirzepatide groups) of the participants completed the trial, despite the Covid-19 pandemic. The weight reduction in the placebo group was similar to results observed with placebo in other recent obesity pharmacotherapy trials and is likely to reflect a similar level of adherence to the lifestyle intervention.9,10 Finally, the duration of the trial (72 weeks) enabled participants to reach a weight plateau in the 5-mg group and near-plateaus in the 10-mg and 15-mg groups; the additional 2-year treatment period for participants with prediabetes should provide further insight into the maximum and long-term weight-lowering effect of tirzepatide in people with prediabetes.
*This trial had certain limitations. The enrolled participants with obesity and overweight may represent a subpopulation with a greater commitment to weight-management efforts than the general population with obesity. Furthermore, the measured baseline cardiometabolic risk factors in the trial population, such as blood pressure and lipids, were relatively normal, possibly attenuating the potential to show improvement, though meaningful changes in these variables were observed. Overall, only 5.5% of trial participants with overweight (BMI of 27 to <30) were included; further studies would be needed in such patients.
*In the present trial, all three doses of once-weekly tirzepatide demonstrated substantial and sustained weight reduction in adults with obesity.
