Beyond Semaglutide: The Next Wave of GLP-1 Combos and Dual Agonists

Here's the lifter's version of the state of play. On one side, Novo Nordisk is pairing semaglutide with a once-weekly basal insulin (icodec) in a single shot called IcoSema. On the other, Eli Lilly's tirzepatide — a dual GIP/GLP-1 agonist — keeps stacking post-hoc analyses that explain why the weight loss is as durable as it looks. Two different bets on where incretin therapy goes next, both backed by real Phase III evidence rather than vibes.

If you care about body composition, metabolic health, or you've simply got a family history that makes you pay attention to HbA1c, this is the moment to understand what's actually being tested — and what the trials do and don't say.

IcoSema is exactly what it sounds like: insulin icodec (a once-weekly basal insulin) co-formulated with semaglutide in a single weekly injection. The clinical question is obvious — if you're already on a GLP-1 and it isn't quite getting you there, is bolting on a weekly basal insulin in the same pen better than just pushing semaglutide to 1.0 mg?

The COMBINE 2 trial set out to answer that. It's a 52-week, randomised, multicentre, open-label Phase IIIa study across 121 sites in 13 countries, enrolling adults with type 2 diabetes inadequately managed on existing GLP-1 RA therapy (HbA1c 7.0–10.0%, mean baseline 8.0%, mean diabetes duration 12.6 years, mean BMI just over 31). Six hundred and eighty-three participants were randomised 1:1 to IcoSema or semaglutide 1.0 mg, with the primary endpoint being change in HbA1c from baseline to week 52 — and superiority of IcoSema explicitly being tested.

That last detail matters. This isn't a non-inferiority trial dressed up in a press release. The protocol was designed to ask whether the combination beats a real, modern comparator at a real, modern dose.

The other big story in incretin land is tirzepatide. Anyone who lifts has heard the same gym-floor theory: sure, people lose weight, but isn't that just because the drug makes them too nauseated to eat? It's a fair question, and a post-hoc analysis pooling SURMOUNT-1 through SURMOUNT-4 took a serious swing at it.

The analysis compared weight change at the primary endpoint among participants who reported no nausea/vomiting/diarrhoea, nausea alone, or any N/V/D, and ran formal mediation analyses to quantify how much of the weight loss could be attributed to GI side effects. Two findings are worth tattooing on your gym bag.

First: weight reduction with tirzepatide was similar across participants reporting no nausea, nausea alone, or any N/V/D. The people who didn't feel sick lost roughly as much as the people who did. Second: mediation analyses suggested that N/V/D and dyspepsia together accounted for up to 3.1% of total weight reduction. The rest — the overwhelming majority — is the pharmacology doing pharmacology things, not a nausea-induced hunger strike.

The safety picture is consistent with what the original SURMOUNT readouts showed: GI adverse events were more common on tirzepatide (27.8%–72.8% across trials) than placebo (12.2%–32.5%), most were non-serious, most occurred during dose escalation, and discontinuation due to GI events ran between 1.0% and 10.5% depending on the trial.

Trials tell you what a drug can do. Claims data tell you what people are doing. A U.S. utilization study of 15,665 adults with type 2 diabetes initiating tirzepatide between May 2022 and January 2023 paints a useful picture: mean age 53.2, 58.5% women, mean HbA1c 7.6%, mean BMI 38.7 kg/m², and 87.8% with Class 1, 2, or 3 obesity. Just over half (51.2%) had already been on a GLP-1 before switching.

The dosing pattern is the part worth flagging. 84.1% of patients initiated at ≤5 mg, and at the sixth refill, 56.5% were still on doses under 10 mg. Translation: in practice, clinicians and patients are titrating slowly and often parking below the top doses used in the headline trials. If you're benchmarking expectations against the biggest SURMOUNT numbers, calibrate — real-world weight outcomes track real-world doses.

Stack these readouts and a pattern emerges. The incretin class is splitting into two strategies. One is combination — pair an established GLP-1 with another mechanism (basal insulin, in IcoSema's case) and consolidate weekly therapy into one shot. The other is multi-agonism — engineer a single molecule that hits multiple incretin receptors, like tirzepatide's GIP/GLP-1 dual action, and let the pharmacology do more of the work.

Both approaches are landing real Phase III evidence in the same window, which is why the 'best-in-class' label is genuinely contested for the first time since semaglutide arrived. The competitive pressure is good news for patients: more options, better-characterised tolerability, and trials designed to answer the questions that actually matter (does combination beat monotherapy at a fair dose? is the weight loss real pharmacology or just side-effect-driven undereating?).

The skeptic's caveat still applies. These are prescription drugs studied in defined populations over defined windows. Long-term cardiovascular, oncologic and body-composition data will keep maturing for years. Lean mass preservation, in particular, remains an open question the lifting world should keep pressing on — the trials cited here measured weight, not DEXA-quantified fat-vs-muscle partitioning.

The headline for the smart lifter is this: the GLP-1 era isn't winding down, it's leveling up. IcoSema is testing whether combination therapy can outperform a maxed-out semaglutide dose head-to-head. Tirzepatide's SURMOUNT post-hoc work is dismantling the lazy critique that incretin weight loss is just side-effect theater. And the utilization data are a reminder that the gap between trial protocol and pharmacy counter is real.

If you or someone you train with is weighing these options, the move is the same as it always is when the evidence is genuinely strong but the decision is genuinely personal: bring the trials to a clinician who actually reads them, and make the call together.