Abstract
OBJECTIVE
To identify predictors of body weight (BW) reduction of ≥15% with tirzepatide treatment and to describe associated clinical parameters of participants with type 2 diabetes (T2D) who achieved different categorical measures of BW reduction (<5%, ≥5 to <10%, ≥10 to <15%, and ≥15%) across four studies from the phase 3 SURPASS clinical trial program for T2D.
RESEARCH DESIGN AND METHODS
The multivariate model for predictor of a BW reduction of ≥15% included age, sex, race, BW, HbA1c, tirzepatide dose and baseline metformin use, fasting serum glucose, and non-HDL cholesterol. Baseline characteristics and change from baseline to week 40/42 for efficacy parameters were described and analyzed in treatment-adherent participants (≥75% doses administered and on treatment at week 40/42) receiving once weekly tirzepatide (5 mg, 10 mg, or 15 mg) (N = 3,188).
RESULTS
Factors significantly associated with achieving a BW reduction of ≥15% with tirzepatide were higher tirzepatide doses, female sex, White or Asian race, younger age, metformin background therapy, and lower HbA1c, fasting serum glucose, and non-HDL cholesterol at baseline. With higher categorical BW reduction, there were greater reductions in HbA1c, triglycerides, ALT, waist circumference, and blood pressure.
CONCLUSIONS
Baseline factors associated with a higher likelihood of achieving a BW reduction of ≥15% with tirzepatide were higher tirzepatide doses, female sex, White or Asian race, younger age, metformin background therapy, better glycemic status, and lower non-HDL cholesterol. With greater BW reduction, participants with T2D achieved larger improvements in glycemia and cardiometabolic risk parameters. These findings help inform which people with T2D are most likely to achieve greater BW reduction with improved cardiometabolic risk factors with tirzepatide.
Graphical Abstract
Introduction
Obesity is a complex, chronic, progressive disease associated with numerous life-limiting complications, including type 2 diabetes (T2D) and cardiovascular diseases (1). A more robust body weight (BW) reduction beyond the widely accepted goal of ≥5% has been suggested to be necessary to prevent or delay complications related to T2D and obesity. For example, a BW reduction of ≥10% has been shown to be disease modifying, potentially leading to T2D remission (2). The current international guidelines suggest that weight loss of 5–15% should be a primary target of diabetes management for many people living with T2D (3). Lifestyle intervention alone, however, may not be sufficient to achieve and sustain (at least beyond the first year) a 10–15% BW reduction needed to achieve and sustain these health goals.
Tirzepatide is a first-in-class once weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of people with T2D and under investigation for long-term weight management (4). In the phase 3 SURPASS clinical trial program for T2D, in addition to substantial improvements in glycemic control, treatment with tirzepatide at doses of 5 mg, 10 mg, and 15 mg resulted in greater weight reductions compared with placebo or active comparators in people with T2D on various background medications across the diabetes continuum (5–9). Notably, weight reduction did not plateau in any of the three tirzepatide treatment groups by the end of the treatment periods of 40 and 52 weeks.
The purpose of this post hoc analysis was to identify predictors of a BW reduction of ≥15% with tirzepatide treatment (5 mg, 10 mg, or 15 mg) and to describe baseline characteristics and changes in cardiometabolic risk factors, such as lipids, blood pressure, and glycemia, of tirzepatide-treated participants who achieved different categorical measures of BW reduction (<5%, ≥5 to <10%, ≥10 to <15%, and ≥15%) across four studies from the phase 3 SURPASS clinical trial program for T2D.
Research Design and Methods
Design of the SURPASS Clinical Trial Program
The study design, full inclusion and exclusion criteria, and primary results of the SURPASS-1 through SURPASS-4 clinical trials are published (5–8). Data from the SURPASS-5 (A Study of Tirzepatide [LY3298176] Versus Placebo in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin) study were excluded given the confounder of background of basal insulin use on all its participants (9). Briefly, the SURPASS clinical trials were randomized controlled clinical studies designed to evaluate the safety and efficacy of tirzepatide (5 mg, 10 mg, or 15 mg) in 5,788 adults with T2D (mean baseline HbA1c ranging from 7.94 to 8.52% and BMI ranging from 31.9 to 34.2 kg/m2). The primary efficacy measure of HbA1c reduction from baseline was superiority of tirzepatide compared with placebo or noninferiority of tirzepatide compared with active comparators (semaglutide 1 mg, insulin degludec, or insulin glargine) at the primary end points of 40 or 52 weeks. Specific BW reduction recommendations regarding diet and exercise beyond the usual practice of each study center were not included in the SURPASS clinical trials. Concomitant therapy that promoted BW reduction was not allowed.
The SURPASS clinical trials assessed in this analysis were conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki. All participants provided signed informed consent, and protocols were approved by local ethical review boards.
Baseline Clinical Assessments
Participant demographics, including age, sex, race, ethnicity, and duration of diabetes, and clinical characteristics, including BW, BMI, waist circumference, previous oral antihyperglycemia medication (OAM) use, tobacco use, and vitals (pulse rate and blood pressure) were obtained at baseline.
Laboratory Parameters
Changes from baseline in cardiometabolic risk factors were evaluated at week 40/42, including HbA1c, fasting serum glucose, estimated glomerular filtration rate, lipid profile, and hepatic enzymes. The proportion of patients reaching HbA1c targets of <7.0%, ≤6.5%, and <5.7% was also assessed.
Statistical Analyses
Participants from SURPASS-1 through SURPASS-4 adherent to treatment (≥75% doses received and on treatment at week 40/42) and treated with tirzepatide (5 mg, 10 mg, or 15 mg), without rescue glycemic medication and inadvertent enrollment, were included in the analyses. To identify predictors of achieving a BW reduction of ≥15% with tirzepatide, univariate analysis was performed on all demographic and baseline clinical characteristics collected for the assessments of outcomes using logistic regression with tirzepatide dose group as a covariate. Variables associated with achieving a BW reduction of ≥15% with a P value <0.2 from univariate analysis were further selected into a multivariate model using stepwise regression with Akaike information criterion. Total cholesterol, LDL cholesterol, and non-HDL cholesterol were closely correlated (Pearson correlation >0.8) with each other, and only non-HDL cholesterol was evaluated with stepwise regression to prevent collinearity in models based on their clinical relevance and role in risk stratification of coronary artery disease (10). The same rules were applied for choosing triglyceride over VLDL cholesterol and BW over BMI for multivariate modeling. The multivariate model adjusted for tirzepatide dose, metformin use, sex, race, age, baseline HbA1c, and baseline BW regardless of their P values (base model). To identify clinical characteristics of participants achieving different categorical measures of BW reduction, baseline characteristics and change from baseline to week 40/42 for several efficacy parameters were analyzed. Baseline OAM was classified as “metformin” versus “no metformin.” Other classifications, such as use of sulfonylurea, use of sodium–glucose cotransporter 2 inhibitor, and use of any antihyperglycemia medication were also explored.
Data Resource and Availability
Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the U.S. and European Union and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.
Results
The analyses included 3,188 (83% of all randomized to tirzepatide) participants with T2D from the SURPASS-1 through SURPASS-4 clinical trials who were adherent to tirzepatide treatment (tirzepatide 5 mg, n = 1,094; tirzepatide 10 mg, n = 1,054; tirzepatide 15 mg, n = 1,040). The baseline demographics and clinical characteristics within each trial were similar across treatment arms (5–8). Of the 3,188 participants, 756 participants (24%) achieved <5% BW reduction, 878 participants (28%) achieved ≥5 to <10% BW reduction, 762 participants (24%) achieved ≥10 to <15% BW reduction, and 792 participants (25%) achieved ≥15% BW reduction (Table 1).
Table 1.
Baseline demographics and clinical characteristics by BW reduction categories
BW reduction % (week 40/42) | ||||
---|---|---|---|---|
<5% (n = 756) | ≥5 to <10% (n = 878) | ≥10 to <15% (n = 762) | ≥15% (n = 792) | |
Baseline characteristics | ||||
Age, years | 56.9 ± 10.2 | 58.1 ± 10.4 | 59.2 ± 10.2 | 57.3 ± 10.4 |
Sex | ||||
Male | 477 (63.1) | 514 (58.5) | 411 (53.9) | 297 (37.5) |
Female | 279 (36.9) | 364 (41.5) | 351 (46.1) | 495 (62.5) |
Diabetes duration, years | 8.9 ± 6.7 | 8.9 ± 6.5 | 9.6 ± 7.2 | 8.6 ± 7.3 |
Current smoker | 107 (14.2) | 139 (15.8) | 121 (15.9) | 126 (15.9) |
Race | ||||
American Indian or Alaska Native | 86 (11.4) | 105 (12.0) | 72 (9.4) | 58 (7.3) |
Asian | 49 (6.5) | 53 (6.0) | 52 (6.8) | 49 (6.2) |
Black or African American | 37 (4.9) | 33 (3.8) | 31 (4.1) | 18 (2.3) |
Other or missing | 7 (0.9) | 9 (1.0) | 7 (0.9) | 8 (1.0) |
White | 577 (76.3) | 678 (77.2) | 600 (78.7) | 659 (83.2) |
Ethnicity | ||||
Hispanic or Latino | 386 (51.1) | 459 (52.3) | 403 (52.9) | 389 (49.1) |
Not Hispanic or Latino | 345 (45.6) | 398 (45.3) | 345 (45.3) | 392 (49.5) |
Not reported | 25 (3.3) | 21 (2.4) | 14 (1.8) | 11 (1.4) |
Baseline antihyperglycemia therapy | ||||
Metformin only | 443 (58.6) | 533 (60.7) | 503 (66.0) | 528 (66.7) |
None | 86 (11.4) | 106 (12.1) | 55 (7.2) | 57 (7.2) |
SGLT2i ± metformin | 95 (12.6) | 109 (12.4) | 88 (11.5) | 111 (14.0) |
Sulfonylurea (any)a | 132 (17.5) | 130 (14.8) | 116 (15.2) | 96 (12.1) |
Clinical baseline characteristics | ||||
HbA1c, % | 8.5 ± 1.0 | 8.4 ± 1.0 | 8.3 ± 1.0 | 8.1 ± 0.9 |
Fasting serum glucose, mg/dL | 177.3 ± 52.1 | 173.1 ± 50.4 | 173.5 ± 50.7 | 163.9 ± 45.9 |
Weight, kg | 95.6 ± 21.8 | 93.4 ± 20.0 | 91.6 ± 18.7 | 91.6 ± 20.8 |
BMI, kg/m2 | 33.9 ± 6.4 | 33.5 ± 6.6 | 33.2 ± 5.7 | 34.0 ± 6.7 |
Waist circumference, cm | 110.5 ± 15.1 | 109.2 ± 14.4 | 108.5 ± 14.1 | 109.2 ± 15.1 |
Systolic blood pressure, mmHg | 132.0 ± 13.7 | 131.2 ± 13.4 | 131.7 ± 14.4 | 130.8 ± 14.9 |
Diastolic blood pressure, mmHg | 79.7 ± 8.9 | 79.1 ± 8.7 | 78.4 ± 8.9 | 79.2 ± 9.3 |
eGFR, mL/min/1.73 m2 | 95.1 ± 19.1 | 91.9 ± 19.2 | 89.9 ± 19.6 | 91.9 ± 19.1 |
Total cholesterol, mg/dL | 173.2 ± 41.2 | 175.4 ± 43.6 | 169.9 ± 42.6 | 168.5 ± 40.6 |
Non-HDL cholesterol, mg/dL | 130.2 ± 39.3 | 132.1 ± 42.7 | 126.6 ± 40.8 | 124.1 ± 38.5 |
HDL cholesterol, mg/dL | 43.1 ± 11.3 | 43.3 ± 10.6 | 43.3 ± 10.9 | 44.1 ± 11.9 |
LDL cholesterol, mg/dL | 94.2 ± 35.1 | 93.9 ± 35.2 | 91.0 ± 36.0 | 90.1 ± 33.6 |
Triglycerides, mg/dL | 189.6 ± 118.4 | 202.2 ± 160.9 | 184.6 ± 104.0 | 178.5 ± 123.0 |
ALT, IU/L | 30.1 ± 17.8 | 28.6 ± 19.3 | 28.5 ± 17.1 | 27.9 ± 16.4 |
AST, IU/L | 23.5 ± 13.2 | 22.7 ± 13.0 | 22.3 ± 12.2 | 22.4 ± 11.9 |
Descriptive statistics are presented as mean ± SD for continuous variables and n (%) for categorical variables and were calculated for baseline values. Note: The race categories of “Multiple,” “Native Hawaiian or Other Pacific Islander,” and “Missing” were merged in the “Other or missing” category for analysis. eGFR, estimated glomerular filtration rate; SGLT2i, sodium–glucose cotransporter 2 inhibitor.
The term “any” refers sulfonylurea only, ± SGLT2i use, and ± metformin use.
Potential Predictors of Achieving a BW Reduction of ≥15% With Tirzepatide
Univariate analyses found the following baseline factors were independently associated (P < 0.2) with higher odds of achieving a BW reduction of ≥15% after adjusting for tirzepatide doses: female sex, White or Asian race, non-Hispanic ethnicity, antihyperglycemia medications, being treated with metformin, not being treated with sulfonylurea, age, T2D duration, baseline HDL cholesterol, ALT, HbA1c, BW, systolic blood pressure, fasting serum glucose, fasting serum triglycerides, and non-HDL cholesterol. A stepwise regression with base model covariates was then performed on those associated variables from the univariate regression to build a multivariate model. The final multivariate model included fasting serum glucose and non-HDL cholesterol as predictors in addition to the base model covariates, which included age, sex, race, BW, HbA1c, tirzepatide dose, and baseline metformin use (Fig. 1). The multivariate analysis of these covariates showed that higher tirzepatide dose, female sex, White or Asian race, younger age, receiving metformin, lower HbA1c, fasting serum glucose, non-HDL cholesterol at baseline were significantly associated with higher odds of achieving a ≥15% BW reduction with tirzepatide treatment.
Figure 1.
Multivariate analysis of demographic variables, baseline OAM, and laboratory parameters. Note: The odds ratios (ORs) for base model parameters were calculated from a logistic regression model with tirzepatide dose, baseline OAM, sex, race, age, baseline HbA1c, and baseline weight. The odds ratios for additional laboratory parameters were calculated from the logistic regression with each baseline laboratory parameter added to the base model parameters, respectively.
Characterization of Achieving Different Categorical Measures of BW Reduction With Tirzepatide
Participants achieving higher categorical BW reduction categories were more likely to be women, White race (compared with American Indian or Alaska Native, Asian, Black or African American, or other), and on metformin at baseline (Table 1). There were no apparent differences across the groups in mean age, T2D duration, or current smoker status. Higher BW reduction categories were associated with greater reductions in HbA1c, fasting serum glucose, waist circumference, blood pressure, serum triglycerides, and serum ALT.
Changes in Cardiometabolic Parameters With Differing Categorical BW Reduction
Higher BW reduction was associated with greater chance of achieving HbA1c <5.7% (Table 2). Clinical characteristics by BW reduction subgroups over time are presented in Fig. 2. Overall, improvements in cardiometabolic parameters were categorically associated with weight reduction. Mean BW reductions reached −18.5 kg (−20.1%) at week 40/42. Participants who achieved a BW reduction of ≥15% reached a mean BW of 73 kg, with a mean waist circumference of 94 cm at week 40/42 (Figs. 2A and B). Participants who achieved a BW reduction of ≥15% experienced a mean reduction in HbA1c from 8.1% at baseline to 5.5% at week 40/42 (Fig. 2C). Furthermore, mean systolic blood pressure decreased from 131 mmHg at baseline to 120 mmHg (Fig. 2D), with mean decreases in triglycerides from 179 mg/dL to 121 mg/dL (Fig. 2E) and in ALT from 28 IU/L to 18 IU/L (Fig. 2F).
Table 2.
Assessment of efficacy parameters and safety profile by BW reduction categories
BW reduction % (week 40/42) | ||||
---|---|---|---|---|
<5% (n = 756) | ≥5 to <10% (n = 878) | ≥10 to <15% (n = 762) | ≥15% (n = 792) | |
HbA1c, % | −1.9 ± 1.2 | −2.3 ± 1.1 | −2.5 ± 1.0 | −2.6 ± 0.9 |
Participants reaching HbA1c | ||||
<7% | 548 (72.9) | 788 (89.9) | 724 (95.3) | 778 (98.5) |
≤6.5% | 415 (55.2) | 705 (80.4) | 698 (91.8) | 761 (96.3) |
<5.7% | 93 (12.4) | 243 (27.7) | 347 (45.7) | 510 (64.6) |
Fasting serum glucose, mg/dL | −46.0 ± 55.4 | −58.1 ± 49.4 | −65.7 ± 49.7 | −66.6 ± 45.3 |
Weight, kg (%) | −1.7 ± 2.6 (−2) | −7.1 ± 2.1 (−8) | −11.3 ± 2.6 (−12) | −18.5 ± 6.0 (−20) |
BMI, kg/m2 | −0.6 ± 0.9 | −2.5 ± 0.7 | −4.1 ± 0.9 | −6.9 ± 2.1 |
Waist circumference, cm | −2.4 ± 7.3 | −6.4 ± 6.8 | −9.5 ± 7.5 | −15.1 ± 9.0 |
Systolic blood pressure, mmHg | −2.4 ± 13.0 | −4.6 ± 14.1 | −6.8 ± 14.4 | −10.3 ± 15.8 |
Diastolic blood pressure, mmHg | −0.8 ± 8.4 | −1.7 ± 8.8 | −2.7 ± 9.1 | −4.3 ± 9.9 |
eGFR, mL/min/1.73 m2 | −4.7 ± 10.0 | −3.8 ± 9.9 | −3.2 ± 11.0 | −3.2 ± 12.2 |
Total cholesterol, % | −0.1 ± 21.0 | −5.1 ± 21.1 | −4.6 ± 21.2 | −6.8 ± 20.2 |
Non-HDL cholesterol, % | −0.7 ± 28.7 | −8.1 ± 28.0 | −8.4 ± 29.0 | −12.2 ± 27.2 |
HDL cholesterol, % | 4.7 ± 20.0 | 7.2 ± 18.1 | 9.5 ± 18.7 | 11.5 ± 19.3 |
LDL cholesterol, % | 1.8 ± 39.2 | −1.9 ± 46.8 | −0.3 ± 41.6 | −3.6 ± 41.8 |
Triglycerides, % | 1.9 ± 45.4 | −11.7 ± 40.9 | −17.9 ± 37.3 | −24.2 ± 33.3 |
ALT, % | −4.5 ± 43.2 | −14.6 ± 41.7 | −23.4 ± 38.9 | −22.1 ± 70.8 |
AST, % | 2.2 ± 37.4 | −4.5 ± 34.5 | −8.9 ± 33.9 | −8.6 ± 53.8 |
Participants with ≥1 serious adverse event | 32 (4.2) | 37 (4.2) | 30 (3.9) | 31 (3.9) |
Participants with ≥1 TEAE | 420 (55.6) | 515 (58.7) | 470 (61.7) | 540 (68.2) |
TEAEs occurring in ≥5% of participants in any BW reduction category by preferred term | ||||
Nausea | 77 (10.2) | 128 (14.6) | 123 (16.1) | 183 (23.1) |
Diarrhea | 103 (13.6) | 112 (12.8) | 103 (13.5) | 128 (16.2) |
Decreased appetite | 27 (3.6) | 60 (6.8) | 65 (8.5) | 85 (10.7) |
Dyspepsia | 47 (6.2) | 49 (5.6) | 58 (7.6) | 55 (6.9) |
Vomiting | 30 (4.0) | 37 (4.2) | 44 (5.8) | 65 (8.2) |
Data are mean ± SD change, n (%), or percentage change from baseline at week 40/42, unless otherwise noted, with n indicating pooled number of participants across SURPASS-1 through SURPASS-4 tirzepatide doses Percentage change in BW is presented in parenthesis. Lipid data are percentage change from baseline. Note: Waist circumference data for SURPASS-4 were not available at weeks 40/42 so week 36 measures were used.
Figure 2.
Clinical characteristics over time by BW reduction categories. BW (A), waist circumference (B), HbA1c (C), systolic blood pressure (D), triglycerides (E), and ALT (F). Data are least squares mean (SE) actual values over time from baseline to week 40. Least squares mean values were calculated from mixed-model repeated-measures model: value = treatment + time + treatment ∗ time.
Safety
Across the population analyzed, at least one treatment-emergent adverse event (TEAE) was reported by 56%, 59%, 62%, and 68% of participants who achieved a BW reduction of <5%, ≥5 to <10%, ≥10 to <15%, and ≥15%, respectively (Table 2). The most common TEAEs were gastrointestinal-related (32% vs. 36% vs. 39% vs. 46%, respectively). A similar number of participants experienced serious adverse events across groups (4.2% vs. 4.2% vs. 3.9% vs 3.9%, respectively) (Table 2).
Conclusions
Achieving a substantial and sustainable BW reduction (i.e., 10–15%) in individuals living with T2D and obesity is an important clinical goal supported by guidelines as it may prevent or delay many chronic diabetes-related complications (11–14). In some cases, higher BW reduction may lead to sustained glycemic control and diabetes remission (15). In the SURPASS 1–4 studies, most participants with T2D treated with tirzepatide achieved clinically meaningful weight reduction of varying magnitudes, particularly at higher doses. In these analyses, approximately one in four participants achieved a ≥15% BW reduction after 40 weeks of treatment with tirzepatide. The substantial weight reduction observed with tirzepatide is considered to be the result of glucose-dependent insulinotropic polypeptide receptor activation acting synergistically with GLP-1 receptor activation (4–8).
Factors associated with greater odds of achieving a ≥15% BW reduction were higher doses of tirzepatide, concurrent use of metformin, female sex, White or Asian race, younger age, and lower HbA1c, fasting serum glucose, and non-HDL cholesterol at baseline. The observation that treatment with higher tirzepatide doses was more likely to lead to a ≥15% BW reduction is consistent with dose-dependent BW reduction seen across the SURPASS program (5–9). Additionally, concurrent use of metformin was associated with achieving a ≥15% BW reduction. This finding aligns with the known modest weight-lowering effect of metformin in adults with T2D likely related to its appetite-reducing effect (16,17). Accordingly, the weight-lowering effect of tirzepatide appears greater when used in combination with metformin versus as monotherapy, although these trials were not designed for direct comparisons (5, 6). We also observed that better glycemic control at baseline was associated with greater BW reduction, similar to what has been observed in bariatric surgery as a predictor of the weight reduction response (18). In addition, individual predisposition may also play a role in the weight and glycemic responses to tirzepatide, and further research should provide more information on this topic.
The observation that women are more likely than men to achieve a ≥15% BW reduction with tirzepatide treatment has also been made in other pharmacotherapy or bariatric surgery studies (18,19). The underlying mechanism is unknown for why women tend to lose more weight compared with men in various BW reduction intervention studies, but there are potential physiological factors, such as differential body fat distributions by sex and proportionally greater fat mass in women, influencing the variability of responses to BW reduction interventions depending on sex (20).
This study showed that African American and American Indian/Alaska Native individuals had lower odds of achieving a ≥15% BW reduction compared with White individuals. Previous analyses of the selective GLP-1 receptor agonist semaglutide did not show similar findings, but the data were limited in the number achieving a ≥15% BW reduction (21). On the other hand, similar observations were made in bariatric surgery literature with a decreased BW reduction response in African American compared with White individuals (22, 23). Given the limited sample size of African American and American Indian/Alaska Native individuals in this analysis and the lack of socioeconomic data needed to fully understand the context, results regarding race as predictor of weight reduction with tirzepatide treatment should be interpreted with caution. Further research is needed to understand the impact of race on BW reduction.
Also, younger age was associated with higher odds of achieving a ≥15% BW reduction. This observation adds to the mixed results in the literature, including higher BW reduction in younger adults after bariatric surgery, but higher odds of BW reduction in older adults with behavioral or lifestyle interventions (18, 24–26). Notably, baseline BW was not predictive of achieving a ≥15% BW reduction with tirzepatide treatment. In other words, most of the individuals with T2D receiving tirzepatide achieved a clinically meaningful BW reduction regardless of their baseline BW.
With higher weight reduction, participants achieved greater improvements in HbA1c and other cardiometabolic parameters, including waist circumference, blood pressure, lipids, and liver enzymes, in particular serum ALT, which has been associated with liver fat in people with T2D (27). Specifically, among those achieving a ≥15% BW reduction, there was a mean decrease in systolic blood pressure by up to 10 mmHg, in triglycerides by >20 mg/dL, and in ALT by >20%. Additionally, we observed that the number of participants who achieved normoglycemia (HbA1c <5.7%) with tirzepatide treatment increased with higher weight reduction categories, such that >60% of those achieving a ≥15% BW reduction also achieved normoglycemia. Combined, these observations demonstrate that the cardiometabolic benefits are likely greater with a higher BW reduction with tirzepatide treatment. A dedicated study, SURPASS-CVOT (A Study of Tirzepatide [LY3298176] Compared With Dulaglutide on Major Cardiovascular Events in Participants With Type 2 Diabetes, NCT04255433]), is ongoing to assess whether such risk factor changes will contribute to meaningful cardioprotective benefits of higher-dose tirzepatide in patients with T2D relative to dulaglutide, which leads to far less weight loss.
Regarding the safety data associated with greater BW reduction, we observed similarly low rates of adverse events across the different weight loss groups, with numerically higher rates of gastrointestinal adverse events seen with greater weight loss. This observation is likely due to the greater proportion of participants treated with tirzepatide 15 mg in these subgroups and not a direct result of gastrointestinal adverse events influencing BW reduction. In the SURPASS program, a slightly higher rate of gastrointestinal adverse events was observed in participants treated with tirzepatide 15 mg; however, post hoc analyses suggest that gastrointestinal adverse events have little to no impact on tirzepatide-induced BW reduction (28).
The strengths of this analysis include a large number of well-characterized participants across the disease continuum in a large phase 3 clinical trial program and a well-balanced number of participants who have achieved various categorical weight loss evaluated in this study, including ≥15% BW. Limitations include the post hoc analysis design focused on those adherent to treatment and the limited follow-up period that may not be adequate for some to reach the BW plateau with tirzepatide treatment. This work focused on baseline factors as potential predictors of weight reduction. In the future, the predictor model may be enhanced by incorporating postbaseline and genetic data. Also, the studies were far too short to see any impacts on long-term cardiovascular outcomes.
In conclusion, the majority adherent to tirzepatide in SURPASS 1–4 studies achieved a clinically meaningful BW reduction, and one in four (25%, n = 792) achieved a ≥15% weight reduction with tirzepatide treatment. Factors associated with a higher likelihood of achieving a ≥15% BW reduction in these studies were higher tirzepatide doses, female sex, White or Asian race, younger age, receiving metformin, better glycemic status, and lower non-HDL cholesterol at baseline. With greater BW reduction, participants achieved larger improvements in glycemia and cardiometabolic parameters, including waist circumference, blood pressure, lipids, and liver enzymes. These findings may provide valuable information to clinicians and people with T2D regarding the likelihood of achieving substantial BW reduction with tirzepatide. They also help to signal likely improvements to be seen in a range of cardiometabolic risk parameters with tirzepatide-induced weight loss. Ongoing trials will determine impact of such changes on cardiovascular outcomes.
Article Information
Acknowledgments. The authors thank Chrisanthi A. Karanikas, MS (Eli Lilly and Company) for her writing and editorial assistance.
Duality of Interest. This study was supported by Eli Lilly and Company. M.T.M. has received honoraria from Abbott, Alfa-Sigma, AstraZeneca, Ascentia, Adamed, Bayer, Berlin-Chemie, Boehringer Ingelheim, Dexcom, Eli Lilly and Company, Krka, Medtronic, Merck, Novo Nordisk, Sanofi, Sandoz, and Servier. R.L.B. has participated in speakers bureaus for Novo Nordisk, Eli Lilly and Company, and ViiV Healthcare, reports research grant support from Novo Nordisk and consultancy with Boehringer Ingelheim, Eli Lilly and Company, Gila Therapeutics Inc, GSK, Novo Nordisk, and Pfizer, and became an employee and shareholder of Eli Lilly and Company at the time of this study. N.S. has consulted for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Hanmi Pharmaceuticals, Novo Nordisk, Novartis, Sanofi, and Pfizer, and received grant support from Boehringer Ingelheim. C.J.L., A.R., B.K.B., G.G., and J.L. are employees and shareholders of Eli Lilly and Company. H.W. is contracted by Eli Lilly and Company. No other potential conflicts of interest relevant to this article were reported.
Author Contributions. Á.R., B.K.B., and C.J.L. conducted and provided medical oversight during the trial. H.W. was responsible for the statistical analyses. H.W. and C.J.L. contributed to the post hoc design. All authors participated in interpretation of the data and critical review of the manuscript, had full access to all the data in the study, and approved of this manuscript to be submitted for publication. C.J.L. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Prior Presentation. Parts of this study were presented in abstract form at the International Diabetes Federation (IDF) World Diabetes Congress, Lisbon, Portugal, 5–8 December 2022.
Footnotes
Clinical trial reg. no. NCT03954834, NCT03987919, NCT03882970, NCT03730662, clinicaltrials.gov
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