Weekly Issue — 2025-07-06

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.

The most consequential trial of the year for this thesis is also the one that, on its face, delivered the most ambiguous result. Investigators ran a phase 3, multicentre, double-blind, randomised, placebo-controlled trial across six UK research hospitals, assigning people with early Parkinson's disease to either extended-release exenatide 2 mg once weekly or a visually identical placebo for 96 weeks. The primary outcome was the MDS-UPDRS Part III motor score, measured off dopaminergic medication at the two-year mark — a deliberately demanding endpoint, because it tries to read the underlying disease through the noise of symptomatic therapy.

The rationale was not speculative. GLP-1 receptor agonists have neurotrophic effects in cellular and animal models of Parkinson's, and earlier small randomised trials and epidemiology had hinted at slower progression in treated patients. A properly powered phase 3 in a neurodegenerative disease is, in itself, a milestone for this class. Whether exenatide bends the trajectory of Parkinson's is a question the field has been waiting a decade to ask seriously; the trial provides the first rigorous, well-controlled answer at scale.

If the Parkinson's story is high-risk, high-reward, the kidney story is closer to consolidation. A 2025 systematic review and meta-analysis in the American Journal of Kidney Diseases pooled 12 randomised trials enrolling 17,996 participants whose baseline estimated glomerular filtration rate was below 60 mL/min/1.73m² — the threshold defining chronic kidney disease. Across those trials, GLP-1 receptor agonists were associated with improvements in a composite kidney outcome and in cardiovascular endpoints, in a population that historically has been under-represented in cardiometabolic research and harder to treat safely.

That matters for two reasons. First, CKD and cardiovascular disease are so tightly coupled that a drug class which moves both needles in the same direction is genuinely useful. Second, much of the GLP-1 conversation has implicitly assumed an otherwise healthy patient losing weight; this evidence speaks to people with established organ disease, where the risk-benefit math is different and the stakes are higher.

The ocular signal is the most surprising of the new findings, and the one to read with the most caution. A retrospective cohort study published in Ophthalmology drew on a U.S. electronic health records platform, restricting to patients over 60 with at least five years of ophthalmology follow-up. Propensity-matched against users of metformin, insulin, and statins, GLP-1 receptor agonist users showed a reduced hazard of non-exudative age-related macular degeneration: hazard ratios of 0.68 versus metformin, 0.72 versus insulin, and 0.70 versus statins, each statistically significant.

This is a retrospective design, not a randomised trial, and 84% of the GLP-1 cohort had diabetes — a population whose ocular risk profile differs from the general public. Residual confounding is unavoidable. But the direction and consistency of the effect across multiple comparator groups is the kind of signal that, in any other organ system, would launch a prospective study. It probably will here, too.

The mechanistic case is where the futurist in me has to slow down. A recent review in The American Journal of Medicine maps the central and peripheral pathways through which GLP-1 receptor agonists drive weight loss: they modulate appetite circuits in the brain, enhance insulin secretion and suppress glucagon, delay gastric emptying, reduce triglycerides and LDL cholesterol, dampen adipose tissue inflammation, and limit ectopic fat. The same review notes the rise of dual and triple co-agonists targeting GLP-1 alongside glucose-dependent insulinotropic polypeptide and glucagon — a pharmacological direction that is already in late-stage development.

Several of those mechanisms — anti-inflammatory effects on the vasculature, modulation of neuronal energy metabolism, improvements in lipid handling — are plausible upstream causes of benefit in kidneys, retina, and brain. That does not prove the connection. It does mean the cross-organ pattern is biologically coherent rather than coincidental, which is the minimum bar for taking a hypothesis seriously.

Earlier-stage work is also feeding the pipeline. A preclinical study in a zebrafish model of high-fat-diet-induced type 2 diabetes reported that tirzepatide, a dual GIP/GLP-1 agonist, mitigated cognitive decline on behavioural tests and improved antioxidant and anti-inflammatory markers. Zebrafish are zebrafish — this is hypothesis-generating, nothing more — but it is the kind of preclinical signal that, combined with human data in adjacent indications, makes a research program rather than an anecdote.

The honest synthesis is that GLP-1 receptor agonists are graduating from a metabolic drug class into something more interesting — a candidate platform for multi-system intervention in aging-related disease. The evidence is moderate, not definitive: one phase 3 in neurodegeneration, one strong meta-analysis in kidney disease, one observational cohort in ophthalmology, and a coherent mechanistic story tying them together. That is exactly the stage at which a careful reader pays attention and a cautious patient waits for the next round of data.

The next eighteen months should clarify a great deal: longer follow-up in CKD, prospective ocular studies, replication of the Parkinson's signal in other neurodegenerative endpoints, and head-to-head data on the dual and triple agonists already in trials. For now, the right posture is the one this magazine tries to take consistently — intellectually excited, disciplined about the caveats, and unwilling to confuse a promising signal with a settled result.

In a questionnaire study of 165 internal and family medicine attendings, with 122 responding, physicians estimated that patients on semaglutide or tirzepatide lose, on average, about 9.22% of their body weight. The pivotal trials tell a more striking story: 14.9% mean weight loss in STEP for semaglutide and 18.5% in SURMOUNT for tirzepatide. That is not a rounding error. For a 220-pound adult, the gap between a doctor's mental model and the trial average is roughly twenty pounds of expected loss.

The cardiovascular picture is more unsettling. Only 48.4% of surveyed physicians perceived a cardiovascular benefit for patients with diabetes — statistically indistinguishable from a coin flip — and just 39.3% perceived one in nondiabetic patients, a result the authors note is significantly below what random guessing would produce. In other words, when it came to the heart, doctors were not merely uncertain; a meaningful share were leaning the wrong way.

Tolerability perceptions were skewed too, though in a different direction. Physicians estimated side effect rates around 32.6%, far below the 89.7% and 80.5% reported in the STEP and SURMOUNT trials, while expected discontinuation (8.59%) ran higher than the trial data. The composite portrait is a profession that, at least in this sample, underestimates how much weight the drugs move, underestimates how often patients feel something, and overestimates how often they quit.

Survey studies have well-known limits. A questionnaire of 122 internal and family medicine attendings is not a verdict on American medicine, and self-reported perceptions are not the same as prescribing behavior. The evidence here is best described as moderate: suggestive, internally consistent, and worth taking seriously, but not the last word. Even with those caveats, the direction of the gap matters. A clinician who quietly expects 9% weight loss may be less likely to raise GLP-1s with a patient who would, in trial conditions, lose closer to 15% or 18%. A clinician unsure whether the drugs help the heart may frame them as cosmetic rather than cardiometabolic.

That framing has consequences downstream. Patients who are told the drugs are modest and risky tend to behave accordingly: they wait, they hesitate, they stop at the first wave of nausea. Patients who are told the drugs are powerful but demanding — meaningful weight loss, real gastrointestinal side effects, slow titration, long-term commitment — tend to enter treatment with a more accurate map.

The other half of the gap is on the patient side. A retrospective cohort study in JAMA Network Open used the Merative MarketScan commercial claims database to follow adults with a first obesity diagnosis between June 2021 and July 2022 who had no prior antiobesity medication, no prior GLP-1, no bariatric surgery and no diabetes-related claim in the year before diagnosis. The question was simple: who, in this eligible-on-paper population, actually initiated semaglutide within six months?

The answer, in broad strokes, is: not many, and not evenly. Using a cross-validated random forest model, the authors identified sociodemographic factors, prior medication classes and co-occurring diagnoses among the top predictors of initiation. Translation: who gets started on semaglutide for obesity is shaped less by a single clean clinical signal and more by a thicket of context — insurance, prior prescribing relationships, comorbidity load, and the patient's broader medical footprint. That is not unusual for a new, expensive therapy, but it is a reminder that "eligible" and "treated" are different categories.

None of this is a recommendation to start, stop, or switch a medication. It is context for a better conversation. If you are weighing a GLP-1 with a clinician, a few questions follow naturally from the evidence. What weight loss does the trial data actually show for the specific drug being discussed, and how does that compare with what your clinician expects in practice? What is known — and not yet known — about cardiovascular benefit in people without diabetes who share your risk profile? How will side effects be managed in the first months, when the trials suggest most patients feel something? What is the plan if the drug works, and the plan if it does not?

If you are already on a GLP-1 and tolerating it, the perception data is a quieter kind of reassurance: the trial weight loss numbers your clinician may be implicitly anchoring to could be lower than what the studies report. If you are struggling with side effects, the same data argues for patience and titration rather than assuming you are an outlier.

The GLP-1 story is genuinely new, and new drugs always arrive faster than the collective clinical intuition that surrounds them. The survey data suggest that intuition is still catching up — undercounting the weight loss, undercounting the cardiovascular signal, miscounting the tolerability picture in both directions. The claims data suggest that, in the meantime, the people most likely to benefit are reaching the drugs through an uneven set of pathways. Neither finding calls for hype. Both call for more careful conversations, in more exam rooms, with more accurate numbers on the table.