25-06-2025
‘Twincretin' Weight Loss Scales Up Cardiometabolic Gains
Patients who lose weight taking the drug tirzepatide experience robust improvements in cardiometabolic health, gains that appear to increase with the extent of pounds lost, researchers have found.
The findings from a post hoc analysis of the SURMOUNT-1 trial confirm the close association between weight loss and improvements in cardiovascular risk factors and point to potential trajectories patients may experience when taking the medication, experts said.
Tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist — commonly known as a 'twincretin' agent — had already shown efficacy in reducing body weight in individuals without diabetes. The current analysis stratifies these effects by the amount of weight loss and how that translates to improvements in blood pressure, glycemic control, lipid profiles, and insulin resistance. The study appeared on June 24 in Annals of Internal Medicine .
The analysis included 1605 participants from the SURMOUNT-1 trial who were randomly assigned to one of the three doses of tirzepatide — 5, 10, or 15 mg weekly — for 72 weeks. All participants had a baseline BMI of 30 or higher, or 27 or greater with weight-related comorbidities, and all were engaged in a concurrent lifestyle intervention. Individuals with type 2 diabetes were excluded to isolate weight-related effects on cardiometabolic outcomes.
Weight loss was categorized into eight brackets, from less than 5% to 35% or more of their baseline body weight.
'One of the more notable and somewhat unexpected findings was the clear linearity in outcomes — specifically, the incremental benefits observed in each cardiometabolic risk factor with every additional 5% of weight reduction,' said Bruno Linetzky, MD, PhD, a co-author of the paper and an executive director of research and development at Eli Lilly and Company, Indianapolis. 'It highlighted how even continued improvements in weight loss can contribute meaningfully across multiple endpoints. While this trend aligns with prior hypotheses, seeing it so consistently reflected in the data was both affirming and informative.'
Scaling Down and Scaling Up
The analysis revealed a largely linear relationship between percentage weight loss and improvements in key risk markers.
Blood pressure: Participants who lost at least 35% of their baseline body weight experienced reductions of 14.2 mm Hg in systolic and 9.2 mm Hg in diastolic blood pressure. These declines were dose-dependent and more pronounced in systolic values, the researchers reported.
Participants who lost at least 35% of their baseline body weight experienced reductions of 14.2 mm Hg in systolic and 9.2 mm Hg in diastolic blood pressure. These declines were dose-dependent and more pronounced in systolic values, the researchers reported. Waist circumference: Waist circumference dropped an average of 32.4 cm in the group who lost the most weight, suggesting significant reductions in visceral fat.
Waist circumference dropped an average of 32.4 cm in the group who lost the most weight, suggesting significant reductions in visceral fat. Insulin resistance: Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) decreased by nearly 60% in those with the most weight loss, with noticeable improvements starting at modest reductions.
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) decreased by nearly 60% in those with the most weight loss, with noticeable improvements starting at modest reductions. Glycemic markers: Hemoglobin A1c decreased across all categories of weight loss and among people who did not lose weight. The average reduction in the group that lost the most weight was 0.65 percentage points.
Hemoglobin A1c decreased across all categories of weight loss and among people who did not lose weight. The average reduction in the group that lost the most weight was 0.65 percentage points. Lipid profile: Significant improvements in triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were generally observed with weight losses exceeding 10%. HDL increased by nearly 18%, while LDL dropped by more than 15% in the highest weight loss group.
Even modest weight loss, between 5% and 10% of body weight, was associated with meaningful improvements in key health markers among participants treated with tirzepatide. For glycemic control, individuals in this weight loss range experienced an average reduction in hemoglobin A1c of 0.33 percentage points, a clinically relevant improvement that helps lower the risk of progressing to type 2 diabetes. Insulin resistance, as measured by HOMA-IR, improved by 23.2%, indicating better insulin sensitivity even with relatively small reductions in weight.
Blood pressure also responded favorably within this modest weight loss category. Systolic blood pressure dropped by 3.4 mm Hg, and diastolic pressure decreased by 2.7 mm Hg. These reductions, while moderate, are statistically significant and align with guideline-recommended targets for reducing cardiovascular risk in individuals with overweight or obesity.
'The analysis suggests physicians could consider targeting 5% weight loss to improve blood pressure and waist circumference. For meaningful changes in lipids, particularly LDL and HDL cholesterol, reductions of more than 10% may be needed,' Linetzky said.
Implications and Limitations
The researchers said their analysis was limited by its post hoc nature and exclusion of placebo participants due to small sample sizes across weight categories. And while surrogate endpoints showed improvement, cardiovascular outcomes were not evaluated, although these are the focus of ongoing trials, they noted.
The new findings strengthen the case for setting individualized weight loss targets in obesity treatment. 'Understanding whether there are specific thresholds of weight reduction associated with minimum or maximum cardiometabolic benefits may assist clinicians in tailoring weight reduction goals to individual patients seeking to reduce their cardiometabolic risk,' the researchers wrote. Clinicians may consider aiming for at least 10% weight loss to initiate meaningful changes in lipid parameters, while more substantial reductions may be necessary for optimal cardiometabolic benefit.
'There certainly has been a paucity of data on the effect that greater than 20% of the body weight from baseline has on the cardiometabolic parameters,' said Tina K. Thethi, MD, MPH, an endocrinologist at AdventHealth in Orlando, Florida. 'The threshold weight loss percentages were a gauge to understand what to expect in a patient that may follow a similar trajectory of weight loss as the participants in SURMOUNT-1, whose data were analyzed.'
'This data does equip a physician with an understanding of what can be expected when a patient is on the trajectory to losing more than 20% of their body weight with the use of tirzepatide,' she said. 'And this knowledge can also help guide the conversation with patients, which is an important piece, as these improvements can result in a decrease in background medications as well.'
'For the improvement in hemoglobin A1c with less than 5% weight reduction, the mechanism may be attributed to the direct glucose-lowering effect of tirzepatide and improvement in insulin resistance with weight reduction,' Linetzky and his colleague wrote.
The study was funded by Eli Lilly and Company. Linetzky is employed by Eli Lilly.
