Efficacy and safety of once-weekly tirzepatide for weight management compared to placebo: An updated systematic review and meta-analysis including the latest SURMOUNT-2 trial

The global obesity pandemic presents a serious and growing public health concern. Projections estimate that by 2035, nearly 2 billion individuals, accounting for 24% of the world’s population, will be classified as obese [1]. China is not immune to this challenge. The rate of obesity in China has risen at a pace more than double the global average since 2010 [2]. By 2018, an estimated 85 million Chinese adults (8.1%) were classified as obese, representing a threefold increase from 2004 [3]. Excess adiposity is associated with a significantly increased risk of numerous complications, including type 2 diabetes(T2D), hypertension, cardiovascular diseases, non-alcoholic steatohepatitis, dyslipidemia, orthopedic issues, and reduced life expectancy [4, 5]. Weight loss of at least 10% has been established as an effective strategy for improving health outcomes and preventing the progression of these obesity-related complications [6].

Due to the limited and poor long-term adherence to weight loss effects of lifestyle interventions and the low public acceptance of bariatric surgery, there has been a longstanding and unmet need for effective anti-obesity medications (AOMs) that can promote body weight management and combat obesity [7, 8]. In recent years, the US Food and Drug Administration (FDA) has approved liraglutide and semaglutide, glucagon-like peptide-1(GLP-1) receptor agonists (GLP-1RAs), for chronic weight management [9]. Notably, glucose-dependent insulinotropic polypeptide (GIP), another enteropancreatic hormone, also contributes to energy balance regulation through cell-surface receptor signaling in the brain and adipose tissue [10]. Clinical studies suggest that co-agonists targeting both GIP and GLP-1 receptors demonstrate a more pronounced effect on glycemia and body weight (BW) compared to selective GLP-1RAs [11].

Tirzepatide (LY3298176), a novel once-weekly subcutaneous dual GIP and GLP-1 receptor agonist, was originally authorized for treating type 2 diabetes. However, it represents a groundbreaking advancement in obesity pharmacotherapy, as it combines gut hormones to achieve substantial weight loss comparable to bariatric surgery [12, 13]. It has now been approved for treatment of T2D in the United States, Europe, Japan, and several other nations and is being investigated for the long-term management of weight in overweight or obese adults. However, it has not been approved for marketing in China. Therefore, we conducted this updated comprehensive review and meta-analysis to systematically explore the efficacy and safety of tirzepatide for weight loss compared to placebo in adults with or without T2D and to provide up-to-date evidence for the clinical promotion of new anti-obesity drugs.

To our knowledge, this is the first comprehensive review and meta-analysis to include data from the latest SURMOUNT-2 trial, evaluating the efficacy and safety of once-weekly subcutaneous tirzepatide for weight management. Our analysis of seven RCTs involving 4,795 patients revealed that all three tirzepatide doses (5, 10, and 15 mg) were significantly more effective than placebo in reducing BW. Compared to the placebo group, patients receiving tirzepatide achieved substantial weight loss: 8.07% (7.5 kg) with the 5 mg dose, 10.79% (11.0 kg) with the 10 mg dose, and 11.83% (11.5 kg) with the 15 mg dose. Additionally, a significantly greater proportion of participants in all tirzepatide groups achieved the weight loss goal of ≥5% (76% for 5 mg, 82% for 10 mg, and 84% for 15 mg). These findings suggest a dose-dependent effect, with the 15 mg dose demonstrating the most pronounced benefit. In this group, up to 69, 54, 48, and 29% of patients achieved weight reductions of ≥10, ≥15, ≥20, and ≥25%, respectively. The weight loss benefits observed with tirzepatide are noteworthy. Treatment with all doses also led to significant reductions in both BMI and WC. Moreover, tirzepatide demonstrated positive effects on cardiovascular and metabolic risk factors, including improvements in blood pressure, FPG, and fasting lipid profiles. Regarding safety endpoints, GI AEs such as nausea, diarrhea, vomiting, constipation, dyspepsia, and decreased appetite were the most common negative effects that occurred in all tirzepatide groups, which were usually mild-to-moderate and transient. Notably, the administration of tirzepatide did not show any correlation with an increased risk of SAEs or all-cause mortality.

Historically, most older anti-obesity medications approved by the FDA have resulted in modest placebo-adjusted weight loss, ranging from approximately 3 to 8.6%. Furthermore, some of these medications were limited by the severity of their side effects [26]. Semaglutide 2.4 mg, a recently approved selective GLP-1RA for long-term weight management in obese adults, has shown greater effectiveness compared to these earlier AOMs [27]. Tirzepatide is the first novel once-weekly drug that combines the actions of GIP and GLP-1 receptors. It targets tissues not affected by single-agonist agents and integrates activation signals from both GIP and GLP-1 receptor pathways in the brain circuits controlling food intake. This unique mechanism is believed to contribute to weight loss exceeding that achieved with selective GLP-1RAs [28, 29]. Preclinical studies in DIO mice observed greater weight loss, particularly during the initial treatment phase, with tirzepatide at a dose of 10 nmol/kg compared to semaglutide at a dose of 30 nmol/kg. This was associated with a more significant decrease in food consumption, increased fat burning, and indications of slightly higher energy expenditure [28]. Similar findings were observed in two head-to-head clinical trials involving individuals with T2D. These trials demonstrated significantly greater weight loss with tirzepatide compared to selective GLP-1RAs. The estimated treatment differences in weight loss between the 5‐mg, 10‐mg, and 15‐mg tirzepatide groups and the semaglutide 1 mg group were −1.9, −3.6, and −5.5 kg, respectively [30]. Likewise, the mean differences for 5, 10, and 15 mg tirzepatide versus dulaglutide 1.5 mg were –2 ∙ 1, −4∙4, and ‐6 ∙ 2 kg, respectively [11]. These preclinical findings are consistent with the results of multiple RCTs [11, 12, 16–20] that evaluated the impact of tirzepatide on weight loss, and further supported by the results of our meta-analysis.

The ongoing SURMOUNT clinical trial program is particularly noteworthy as it investigates the efficacy of tirzepatide as an anti-obesity medication. Achieving a ≥ 5% reduction in body weight has long been established as a clinically significant benchmark for improving metabolic health [31]. In SURMOUNT-1 [12], a remarkable finding was that the majority of participants (85, 89, and 91%) in the 5, 10, and 15 mg tirzepatide groups, respectively, achieved the ≥5% weight loss benchmark, compared to only 35% in the placebo group. Notably, the 15 mg tirzepatide group in this trial exhibited an average weight decrease of 20.9%, and an impressive 36.2% of participants successfully achieved the≥25% weight-loss goal, approaching the effects observed with bariatric surgery [32, 33]. It is generally understood that people with obesity and T2D have greater difficulty losing significant weight compared to those without T2D [23]. Consistent with this, the degree of weight loss achieved with tirzepatide 10 and 15 mg in individuals with obesity and T2D in SURMOUNT-2(12.8 and 14.7%) was lower than that observed in SURMOUNT-1 without T2D (19·5 and 20·9%, respectively) [12, 20]. Nevertheless, some argue that medications that result in an average reduction of approximately 15% in body weight among obese individuals represent a new generation of AOMs, as this degree of weight loss is considered sufficient to treat or prevent a broader range of obesity-related comorbidities [34]. Long-term weight loss maintenance is the ultimate goal of weight management. Following diet and exercise interventions, patients typically regain nearly 33% of the weight they initially lost within the first year [35]. The SURMOUNT-3 trial demonstrated that for participants who achieved ≥5.0% weight loss after a 12-week intensive lifestyle intervention lead-in period, tirzepatide could contribute an additional significant 18.4% reduction in body weight [36]. Meanwhile, the SURMOUNT-4 trial showed that withdrawing tirzepatide and switching to placebo led to substantial 14.0% regain of lost weight, whereas continued tirzepatide therapy maintained and even slightly augmented the initial 5.5% weight reduction [37]. Based on the findings of the SURMOUNT program, we believe that tirzepatide represents a unique, successful, and effective pharmacological strategy with promising results for individuals suffering from obesity.

In addition to promoting weight loss, our meta-analysis of exploratory secondary outcomes discovered that tirzepatide treatment was accompanied by significantly greater improvements in various cardiometabolic risk factors. These include WC, FPG, blood pressure, and fasting lipid profile. These improvements could translate over time to a decreased risk of metabolic syndrome, cardiovascular disease, hypertension, T2D, non-alcoholic fatty liver disease (NAFLD), and chronic renal disease, ultimately leading to a marked improvement in the health-related quality of life for overweight or obese people [31, 38]. Several trials have been completed or are in progress to assess the impact of tirzepatide on additional obesity-related issues, and the results of these trials are expected to further expand the indications for tirzepatide. As the first research assessing the effects of tirzepatide versus insulin degludec on liver fat content (LFC), visceral adipose tissue (VAT), and abdominal subcutaneous adipose tissue (ASAT) through MRI techniques, the SURPASS-3 MRI trial revealed promising results. All three doses of tirzepatide (5, 10, and 15 mg) resulted in a substantial reduction in LFC (29.78 to 47.11%) compared with insulin degludec (11.17%) after 52 weeks, as well as a statistically greater change in VAT and ASAT volumes [39]. These data provide additional evidence on the metabolic benefits of tirzepatide for NAFLD. Notably, tirzepatide is also being investigated for its cardiovascular safety in patients with T2D at various levels of cardiovascular risk. The ongoing SURPASS-CVOT trial (NCT04255433↗) is anticipated to yield conclusive answers regarding tirzepatide’s effect on major cardiovascular events when compared to dulaglutide, a long-acting GLP-1 RA that has demonstrated cardioprotective properties in people with T2D who are at high cardiovascular risk [40]. The SUMMIT trial, estimated to be completed in 2024, is designed to evaluate tirzepatide for improvements in all-cause mortality, heart failure events, and a 6- minute walk test in individuals with heart failure [41]. Overall, these ongoing trials suggest that tirzepatide might be the optimal option for obese people suffering from various metabolic diseases.

This meta-analysis also evaluated the safety of weekly tirzepatide based on various AE data. The safety profile observed was consistent with findings from other incretin-based therapies, particularly similar to the safety profile of GLP-1RA like liraglutide and semaglutide used for obesity treatment [27, 42]. GI AEs such as nausea, diarrhea, vomiting, constipation, dyspepsia, and decreased appetite were the most frequently reported events in all three tirzepatide dose groups compared to placebo. This is likely due to the drug’s effect on long-term gastric emptying. However, these GI AEs were mostly mild to moderate in severity, temporary, and tolerable. They typically occurred at treatment initiation or during dose-escalation phases, and gradually diminished over time, rarely leading to treatment discontinuation [12, 18–20]. Therefore, gradual dose escalation in small increments during clinical use of tirzepatide can minimize these side effects and improve tolerability [11, 16, 43]. Notably, previous analyses of the SURPASS trials suggest that tirzepatide-induced sustained and significant weight loss is independent of GI AEs [44], similar to findings with once-weekly semaglutide 2.4 mg [45]. Intriguingly, despite a notable reduction in HbA1c, the incidence of hypoglycemia did not significantly differ between the tirzepatide and placebo groups. This might be explained by the mechanisms through which tirzepatide lowers blood glucose: it stimulates glucose-dependent insulin release from pancreatic β-cells, resulting in a minimal risk of hypoglycemia when used alone [28].Our meta-analysis further found that treatment with tirzepatide did not increase the incidence of SAEs or lead to an increase in all-cause mortality. In summary, tirzepatide demonstrates a promising safety profile, making it a potentially valuable option for pharmacological treatment of obesity.

Tirzepatide’s recent success and clinical application have reignited interest in the search for even more effective and safer AOMs. GLP-1RAs remain a foundational element of all current AOM candidates. Recently, several trials have included multi-targeting agonists of GLP-1R, GIPR, or glucagon receptor (GCGR) for the treatment of both T2D and obesity. There is particular excitement surrounding the potential of combining GLP-1R/GIPR/GCGR agonism as “triple agonists”. A recent phase 2 trial investigating the triple-hormone-receptor agonist Retatrutide (LY3437943), targeting GLP-1R/GIPR/GCGR, yielded impressive results. At the maximum dosage (12 mg) over 48 weeks, this drug produced a remarkable 24.2% reduction in BW in individuals with obesity. Additionally, a staggering 26% of participants in this group achieved a weight loss exceeding 30% of their initial BW [46]. This represents the most significant weight loss effect observed to date. Significant progress is also being made in the development of GLP-1R/GCGR dual agonists like SAR425899. In a nearly month-long therapy, this drug led to a maximum weight reduction of 5.46 kg in individuals with T2D and 5.32 kg in healthy participants [47]. Another promising approach involves combining a long-acting amylin analog with a GLP-1RA. A trial administering multiple doses of cagrilintide alongside semaglutide 2.4 mg for weight management yielded encouraging results. In this trial, overweight participants experienced a significant 17% reduction in BW when given the highest dose (2.4 mg of cagrilintide with semaglutide 2.4 mg) in 20 weeks [48]. The discovery of dual and triple agonists of human gut hormones has opened exciting new avenues for pharmacological weight loss. We eagerly anticipate the future approval of even more effective medications for obesity management.

This study has several limitations that warrant consideration. First, our meta-analysis relied on published, study-level data rather than real-world patient data. Additionally, all RCTs included received support from the pharmaceutical industry. These factors may have led to an overestimation of tirzepatide’s therapeutic benefits due to potential reporting bias. Second, we were unable to quantify or assess the potential influence of the varying exercise and dietary regimens prescribed across the different studies on participant outcomes. Third, with the exception of the SURMOUNT-1 trial, which focused solely on obese patients, six out of the seven included studies involved selected populations with diabetes. This may have resulted in deviations in primary and secondary endpoint data compared to the non-diabetic population. Fourth, due to the novelty of tirzepatide as an AOM, both the sample sizes and the number of included studies were limited. Finally, the majority of the research originated from North and South America, Europe, and Japan, primarily involving participants of Caucasian ethnicity. Thus, to validate the generalizability of these findings, further clinical trials from diverse geographic regions and involving participants of various racial backgrounds are necessary.

In summary, this updated meta-analysis of seven RCTs involving 4795 participants confirms the significant and sustained, dose-dependent superiority of all three once-weekly tirzepatide doses in promoting weight loss compared to placebo. Furthermore, tirzepatide demonstrates the ability to improve multiple aspects of metabolic syndrome simultaneously, including glycemia, blood pressure, and lipid profiles, while maintaining a well-tolerated safety profile.

We thank all trial participants, investigators, and site personnel who made contributions to these studies. Eli Lilly and Company provided support for all of these trials.

W. Q., J. Y., P. Z., and K. D. contributed to the study design, literature search, data extraction and analysis, bias assessment, and manuscript writing. Y. N., C. D., Q. R. and J. R. were responsible for the figures and tables. W. Q., P. Z., and K. D. performed data checking and manuscript revision. The manuscript’s final version was read and approved by all authors for submission. P. Z. and K. D. are the guarantors of this research and bear complete accountability for the entire work.

The research article contains the data that supports the study’s findings. For any more queries, please contact the corresponding author via email or consult the article’s supporting materials.

Peng Zhou, Email: chowpeng@hust.edu.cn.

Kai Duan, Email: kaiduancn@163.com.

The online version contains supplementary material available at 10.1007/s12020-024-03896-z.