Once-weekly IcoSema lowers weight and systolic blood pressure in type 2 diabetes

A once-weekly injection that combines a long-acting basal insulin with semaglutide was linked to meaningful reductions in body weight, lower systolic blood pressure and better atherogenic lipid profiles in adults with type 2 diabetes, according to a systematic review and meta-analysis in Cardiovascular Diabetology – Endocrinology Reports. The analysis combined results from two large phase 3 trials in the COMBINE program and included 1,970 adults whose diabetes was not adequately controlled on basal insulin. The treatment, called IcoSema, is the first fixed-ratio pairing of basal insulin icodec with a GLP-1 receptor agonist that can be administered once a week, reducing injections from at least 365 per year to 52.

The review was led by Adir Alper and Robert Faillace, followed PRISMA guidelines and was prospectively registered in PROSPERO. The authors searched MEDLINE/PubMed, Embase, the Cochrane Central Register of Controlled Trials and Web of Science, with the final search completed in 2026, and had two blinded reviewers screen records independently. Of the three COMBINE trials, two met the eligibility criteria: COMBINE 1, led by Mathieu and colleagues, which compared IcoSema with once-weekly insulin icodec, and COMBINE 3, led by Billings and colleagues, which compared IcoSema with basal-bolus therapy using once-daily insulin glargine U100 plus two to four daily doses of insulin aspart. COMBINE 2 was excluded because it compared IcoSema with semaglutide alone in people escalating from GLP-1 receptor agonist treatment, a different clinical question that would have added substantial heterogeneity to the pooled analysis.

The clearest result was seen in body weight. Compared with control regimens, IcoSema produced a pooled mean weight loss of 6.10 kilograms, with a 95 percent confidence interval of 7.21 to 5.00 kilograms and a P value below 0.00001. Heterogeneity was moderate to high, with an I-squared of 79 percent, because the benefit was larger against basal-bolus therapy in COMBINE 3, where the difference was 6.72 kilograms, than against icodec monotherapy in COMBINE 1, where it was 5.59 kilograms. The authors say this likely reflects the weight-promoting effect of conventional basal-bolus insulin regimens, which makes the contrast more pronounced.

Blood pressure improved as well. Systolic blood pressure fell by a pooled mean of 2.45 millimeters of mercury with IcoSema, with a confidence interval of 3.52 to 1.38 and consistent effects across both trials, showing no detectable heterogeneity. Diastolic blood pressure moved in the same direction, but the average decline of 0.51 millimeters of mercury was smaller and not significant. On lipid outcomes, reported as exponentiated treatment ratios equivalent to ratios of geometric means, total cholesterol dropped by about 3 percent, while LDL cholesterol, VLDL cholesterol and triglycerides each fell by roughly 6 percent, all with statistical significance. HDL cholesterol showed a slight, borderline increase of about 1 percent that did not meet conventional significance.

Glycemic control was more complex. The pooled HbA1c difference of 0.37 percentage points favored IcoSema but was not statistically significant, and heterogeneity was extreme at an I-squared of 98 percent. The authors caution that this pooled value should not be treated as a single summary effect. It masks two very different comparisons: IcoSema was clearly better than once-weekly icodec alone, lowering HbA1c by an additional 0.66 percentage points, but was essentially equivalent to intensive basal-bolus therapy, with a difference of only 0.07 percentage points. The authors therefore interpret glycemic performance using the trial-level data rather than the pooled estimate, concluding that IcoSema outperforms icodec alone but is similar to more intensive daily insulin regimens.

Safety findings were also important to the clinical interpretation. In COMBINE 1, clinically significant or severe hypoglycemia occurred at 0.21 episodes per person-year with IcoSema versus 0.39 with icodec alone. In COMBINE 3, the difference was much larger: 0.21 versus 2.23 episodes per person-year when compared with basal-bolus therapy, corresponding to an estimated rate ratio of 0.09. These low rates were achieved alongside superior or non-inferior glycemic control. As expected with a GLP-1 receptor agonist-containing regimen, gastrointestinal adverse events such as nausea, diarrhea, vomiting and reduced appetite were the most common treatment-emergent effects, usually mild to moderate, appearing mainly during dose escalation and generally temporary. The authors did not pool hypoglycemia or gastrointestinal events quantitatively because only two trials with different comparators and reporting methods were available.

The biologic explanation for the cardiometabolic improvements largely points to the semaglutide component. GLP-1 receptor agonists can lower systolic blood pressure through natriuresis, better endothelial function and arterial compliance, reduced vascular inflammation and the hemodynamic effects of weight loss. Their lipid effects are thought to stem from reduced hepatic VLDL production, delayed gastric emptying that blunts post-meal lipemia, and weight-loss-related improvements in insulin sensitivity. The basal insulin portion contributes little independent benefit for blood pressure or lipids, so the authors attribute the observed signal mainly to semaglutide and the weight loss it promotes. GLP-1 receptor agonists already have a well-established cardiovascular record: meta-analyses of cardiovascular outcome trials have shown reductions in major adverse cardiovascular events of 13 to 14 percent, cardiovascular mortality of 12 to 13 percent and heart failure hospitalizations of 11 to 14 percent, with injectable semaglutide reducing events by 26 percent in SUSTAIN-6 and oral semaglutide by 14 percent in the SOUL trial.

The authors emphasize that these findings should be viewed as hypothesis-generating rather than definitive. With only two studies contributing to each outcome, the pooled estimates remain fragile, between-study variance is imprecise, subgroup and meta-regression analyses are not possible, and funnel plots or asymmetry testing are not informative with fewer than ten trials. Sensitivity analyses specified in advance were also of limited value. Both source trials were open-label, which introduces possible performance and detection bias, especially for subjective outcomes, although centrally measured endpoints such as weight, blood pressure and laboratory lipids are less vulnerable. Both trials were sponsored by Novo Nordisk, which helped with design, conduct and analysis, creating a potential sponsorship bias, even though the meta-analysis itself was investigator-initiated and unfunded. The 52-week follow-up may also be too short to detect long-term cardiometabolic effects or late safety concerns.

The findings also do not apply to every patient group. Because COMBINE 2 was excluded, the results do not extend to people switching from GLP-1 receptor agonist monotherapy or to those who are naive to both insulin and GLP-1 therapy. In that excluded trial, IcoSema lowered HbA1c more than semaglutide alone, 1.35 versus 0.90 percentage points, but also caused modest weight gain of 0.84 kilograms rather than the weight loss seen with semaglutide alone, a pattern that differs from the insulin-comparator setting analyzed here. The authors suggest that a future three-way meta-analysis using comparator-adjusted methods may help address this gap. GRADE certainty ranged from low for HbA1c, downgraded because of very serious inconsistency, to moderate for the other outcomes.

No dedicated cardiovascular outcome trial for IcoSema has been completed, and the authors are not aware of one that is registered or expected to report soon. An exploratory modeling exercise in the supplementary appendix applied the pooled surrogate-marker changes to the 2013 ACC/AHA Pooled Cohort Equations, but this was presented only as an illustration and not as a clinical prediction. The authors caution that it should not guide treatment decisions. For now, any expectation of cardiovascular benefit rests on indirect evidence from semaglutide rather than the combination product itself. They conclude that once-weekly IcoSema offers meaningful improvements in weight, blood pressure and atherogenic lipids, while reducing injection burden and maintaining a low risk of hypoglycemia, but that dedicated cardiovascular outcome trials are needed to confirm whether these surrogate gains translate into fewer cardiovascular events.

Subject of Research: Cardiometabolic effects of once-weekly IcoSema in adults with type 2 diabetes

Article Title: Cardiometabolic outcomes of once-weekly IcoSema in adults with type 2 diabetes: systematic review and meta-analysis of the COMBINE trials

Article References: Alper, A., Fagin, A., Karthikeyan, A., Lerner, M., Gershon, A., Morgan, A. A., Rubinstein, G., Agarwal, R., & Faillace, R. (2026). Cardiometabolic outcomes of once-weekly IcoSema in adults with type 2 diabetes: systematic review and meta-analysis of the COMBINE trials. Cardiovascular Diabetology – Endocrinology Reports, 12(1), Article 59. https://doi.org/10.1186/s40842-026-00333-0

Image Credits: AI Generated

Keywords: IcoSema, type 2 diabetes, insulin icodec, semaglutide, meta-analysis, COMBINE trials, body weight, blood pressure, lipids, hypoglycemia, cardiovascular risk, GLP-1 receptor agonist

Cite Scienmag News

Ophelia Keating. (October 28, 2026). Once-weekly IcoSema lowers weight and systolic blood pressure in type 2 diabetes. Scienmag. https://scienmag.com/weekly-icosema-injection-cuts-weight-and-blood-pressure-in-type-2-diabetes/

Ophelia Keating. "Once-weekly IcoSema lowers weight and systolic blood pressure in type 2 diabetes." Scienmag, 28 October 2026, https://scienmag.com/weekly-icosema-injection-cuts-weight-and-blood-pressure-in-type-2-diabetes/. Accessed 28 October 2026.