tirzepatide vs semaglutide for obesity without diabetes

 A recent article found tirzepatide to be superior to semaglutide in obese patients without diabetes, in this drug company sponsored and designed trial (see tirzepatide vs semaglutide obesity no diabetes NEJM2025 in dropbox, or DOI: 10.1056/NEJMoa2416394)

 

Details:

-- 750 individuals with obesity but without diabetes were randomized to maximum tolerated doses of tirzepatide (10 or 15 mg) or semaglutide (1.7 to 2.4mg) weekly in this 72 week  phase 3b, open-label, controlled trial of adults, in 32 sites in the US and Puerto Rico

    -- all were at least 18yo, had BMI of at least 30 or 27 with at least one obesity complication (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease) and at least one unsuccessful dietary effort for weight reduction

-- mean age 45 (8% at least 65yo), 65% females, 76% white/19% Black/26% Hispanic

-- BMI 39 (69% had BMI at least 35), 113 kg, duration of obesity 16 years

-- prediabetes 57%, 50% had multiple obesity-related complications

 

-- medication dosing:

   -- tirzepatide: started at 2.5mg weekly and increased to a maximum tolerated dose of 10 or 15mg, with 2.5mg increases every 4 weeks

   -- semaglutide: started at 0.25mg weekly and increased to a maximum tolerated dose of 2.4mg, with increases every 4 weeks to 0.5mg then to 1.0 mg, 1.7mg and 2.4mg 

        -- if intolerable adverse effects, then decrease to 1.7mg dose

 

-- primary endpoint: percent change in weight from baseline to week 72

-- key secondary endpoints: relative weight reduction of at least 10%, 15%, 20% and 25%; and change in waist circumference from baseline to week 72

 

Results:

-- trial completion:

    -- tirzepatide: 85.1%

        -- 89% received at least one prescription for the 15mg dose

        -- treatment discontinued from adverse effects: 6.1%

    -- semaglutide: 84.8%

        -- 93% received at least one prescription for the 2.4mg dose

        -- treatment discontinued from adverse effects: 8.0%

 

-- percent change in weight from baseline to week 72, least-squares mean percent

change (primary outcome), :

    -- tirzepatide: −20.2% (−21.4 to −19.1), mean change of -22.8kg, -8.0 BMI points

    -- semaglutide: −13.7% (−14.9 to −12.6), mean change of -15.0kg, -5.3 BMI points

         -- mean difference in body weight: -6.5 percentage points (-8.1 to -4.9), p<0.001

-- mean change in waist circumference:

    -- tirzepatide: −18.4 cm (−19.6 to −17.2)

    -- semaglutide: −13.0 cm (−14.3 to −11.7)

        -- difference in waist circumference: -5.4 cm (7.1 to -3.6), p<0.001

 

 

-- weight reduction by at least 10%:

    -- tirzepatide: 304 patients (82%)

    -- semaglutide: 227 patients (61%)

        -- treatment difference: relative risk 1.3 (1.2-1.5)

-- weight reduction by at least 15%:

    -- tirzepatide: 241 patients (65%)

    -- semaglutide: 151 patients (40%)

        -- treatment difference: relative risk 1.6 (1.4-1.9)

-- weight reduction by at least 20%:

    -- tirzepatide: 181 patients (48%)

    -- semaglutide: 103 patients (27%)

        -- treatment difference: relative risk 1.8 (1.5-2.2)

-- weight reduction by at least 25%:

    -- tirzepatide: 118 patients (32%)

    -- semaglutide: 60 patients (16%)

        -- treatment difference: relative risk 2.0 (1.5-2.6)

-- weight reduction by at least 30% (an additional secondary endpoint):

    -- tirzepatide: 74 patients (20%)

    -- semaglutide: 26 patients (7%)

        -- treatment difference: relative risk 2.8 (1.9-4.3)

 

-- Cardiometabolic endpoints change from baseline, tirzepatide vs semaglutide:

    -- systolic BP: -10.2 vs -7.7, difference -2.5 (-4.2 to -0.7)

    -- diastolic BP: -4.6 vs -3.2, difference -1.5 (-2.7 to -0.3)

    -- A1c: -0.50 vs -0.39 percentage points, difference -0.10 (-0.15 to -0.06)

    -- fasting serum glucose: -13.4 mg/dL vs -11.6, difference -1.8 mg/dL (-3.1 to -0.6)

    -- triglycerides: -34.9 mg/dL vs -27.5, difference -7.4 mg/dL (-12.0 to -2.8)

    -- VLDL: -6.8 mg/dL vs -5.3, difference -1.5 (-2.4 to -0.6)

    -- HDL: 5.7 mg/dL vs 2.9, difference 2.8 (1.5 to 4.1)

    -- changes in non-HDL and LDL both trended to being better with tirzepatide but were not statistically significant

 

 -- Safety:

    -- at least one adverse event: tirzepatide: 77%; semaglutide 79%

    -- serious adverse events: tirzepatide 18 individuals (4.8%); semaglutide 13 individuals (3.5%)

    -- adverse events leading to death: 0 for each

    -- medullary thyroid carcinoma or pancreatic cancer: 0 for each

    -- pancreatitis: one case on semaglutide only

    -- discontinuation from trial for GI adverse events: tirzepatide 10 individuals (2.7%); semaglutide 21 (5.6%)

    -- adverse events in at least 5% of participants, comparing tirzepatide vs semaglutide:

        -- nausea: 44% vs 44%

        -- constipation: 27% vs 29%

        -- diarrhea: 24% vs 23%

        -- vomiting: 15% vs 21%

        -- covid: 14% vs 13%

        -- fatigue: 10% vs 12%

        -- eructation: 10% vs 8%

        -- injection site reaction: 9% vs 0%

        -- URI: 9% vs 11%

        -- alopecia: 8% vs 6%

        -- dizziness: 6% vs 5%

        -- abdominal distention: 7% vs 6%

        -- GERD: 6% vs 11%

        -- dyspepsia: 6% vs 7%

        -- decreased appetite 5% vs 5%

Commentary:

-- semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist and tirzepatide is a combo of a GLP-1 receptor agonist and a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist

-- both semaglutide and tirzepatide have been clearly shown to be effective in improving glycemic control in patients with diabetes, and both are associated with major weight loss, including decreasing appetite and regulation food-related behaviors

-- adipocytes lack functional GLP-1 receptors but do have functional GIP receptors, perhaps an important factor in the superiority of tirzepatide (weight loss is greater with tirzepatide vs semaglutide in several studies in patients with diabetes https://gmodestmedblogs.blogspot.com/2021/07/diabetes-and-weight-loss-tirzepatide.html )

    --of note, other combinations of medications with somewhat different mechanisms of action have also been found to improve weight reduction, eg phentermine combined with extended-release topiramate, and bupropion combined with naltrexone. Similarly with many infectious or oncologic diseases. so, the concept of using multiple medications with different mechanisms of action is pretty common treatment in many clinical problems

-- this study found that in adults with obesity but without diabetes there was a significant difference in weight reduction at 72 weeks, with tirzepatide having a 20.2% reduction and semaglutide a 13.7% reduction, though the overall reduction was about 6% lower among men than among women

    -- prior trials included more women, and the amount of weight reduction was a bit higher than in the current study

    -- a recent trial of tirzepatide in patients with obstructive sleep apnea found significant benefit in terms of the sleep apnea as well as an 18-20% decrease in mean weight

-- this current study also found:

    -- assessing the percent weight reductions consistently show that tirzepatide was superior to semaglutide in the percentage of people who lost their body weight of at least 10%, 15%, 20%, 25% and 30%

    -- there was a significant reduction in waist circumference by 5.4 cm with tirzepatide

        -- a prior large pooled analysis found that a 5 cm increase in waist circumference predicted a 7% increase in mortality among men and a 9% increase in women, suggesting but not proving that a 5.4 cm reduction with tirzepatide may have profound beneficial effects

            -- the issue here is that waist circumference is a better reflection of visceral obesity than BMI, and it is visceral obesity which is associated with systemic inflammation. systemic inflamation is associated with an array of bad diseases including cardiovascular disease, type II diabetes, autoimmune diseases, respiratory diseases, neurodegenerative diseases, depression, stress, Alzheimer’s disease, ulcerative colitis, COPD, ….   It should be noted that there is not clear evidence that decreasing inflammation actually decreases these diseases, though there was clear clinical cardiovascular benefit by treating the associated inflammation with canakinumab, a specific monoclonal antibody which targets the inflammatory interleukin-1b: https://www.nejm.org/doi/full/10.1056/NEJMoa1707914 (and of note, statins, as well as regular exercise and a healthy diet with lots of fruits and vegetables and whole grains, are associated with decreased inflammation and decreased heart disease, and part of their benefits may well be from their anti-inflammatory effects)

-- this study also found significant improvements in cardiometabolic risk factors (e.g. blood pressure, glycemia, lipid levels) as found in prior studies, more so in individuals on tirzepatide than semaglutide

      -- for example, in assessing those who had weight reductions of at least 20% while receiving treatment, the mean reduction in systolic blood pressure ranged from 9.1 to 17.5 mmHg in the tirzepatide groups as compared to 3.4 to 6.7 mmHg (increasing with increased amount of weight reduction), and studies have found that systolic blood pressure decreases of 2 to 5 mmHg have been shown to reduce cardiovascular events

    -- greater weight reduction is also associated with improved quality of life in several studies

-- and there seem to be very important collateral benefits of these meds:

    -- these meds seem to be associated with decreased incident dementia: https://gmodestmedblogs.blogspot.com/2025/05/diabetes-meds-and-incident-dementia.html

    -- and perhaps not so surprisingly, these meds do decrease the dopamine "reward center" in the brain (a component of their effect on decreased eating), and also other "addictions":

        -- semaglutide (and others) are associated with tobacco cessation (https://gmodestmedblogs.blogspot.com/2024/09/semaglutide-assoc-with-tobacco-cessation.html), as well as alcohol consumption, and likely opiate and cocaine use

-- There is an important concern about sacrcopenia/muscle wasting with the use of GLP-1 receptor agonists. However a recent article suggested this was artifactual and that GLP-1 receptor agonists may actually even improve skeletal muscle and functioning: https://gmodestmedblogs.blogspot.com/2024/11/glp-1-agonists-improve-skeletal-muscle.html

 

-- this current study did have several strengths, including that there was a diverse group of patients participating, they did achieve high doses of these medications, and they found a dose-response curve: the more potent the medication, the better the clinical effect (ie, those who lost the most weight had the best effect, and tirzepatide consistently outperformed semaglutide) 

 

Limitations:

-- this was a non-blinded study, which tends to lead to biases if the researchers or patients have a bias for one drug or the other, creating a higher placebo response in the preferred drug. Or alternatively, given the large amount of bad press for semaglutide (Ozempic has been the target of many articles in the lay press), patients may have a bias toward higher tolerance and improvement with tirzepatide

 

So, what does this all mean?

-- It is clear from an abundance of studies that GLP-1 receptor agonists and the combination with a GIP receptor agonist as in tirzepatide have quite profound effects in a large number of patients with diabetes and without diabetes. And these effects include significant weight loss, much better diabetes control in patients with diabetes, decrease in MAFLD, decrease in OSA, improvements in blood pressure which are related to decreasing weight, as well as potentially decreasing incident dementia. And they are both cardioprotective and renoprotective

-- there also is a significant medical literature about decreasing use of cigarettes and alcohol, with some suggestive studies about opiates and cocaine (the GLP-1’s do affect several areas of the brain including the whole dopamine reward system).

-- those of us who have prescribed these medications regularly have largely been shocked by how well many patients with diabetes do on these medications (eg normalization of the A1c in patients with former A1c in the 12+% range)

-- of course, one of the big issues is the cost of these medications, a huge obstacle to prescribing them imposed by our healthcare systems/health insurance. there is the very real potential to bankrupt some of the systems, including Medicare (which does approve them for patients with diabetes, but seems to have a relatively steadfast policy at this point to not include weight loss medications, though it does include bariatric surgery….).

    -- most countries in Europe and elsewhere have much lower costs, typically under $100 per month

    -- studies on the actual cost of GLP-1 production have found that it is really cheap, as in $5/month for semaglutide: https://www.healthline.com/health-news/how-affordable-could-generic-ozempic-be-as-low-as-5-a-month-study-finds

    -- drug company profits are remarkably high and increasing

    -- so, why are these drugs costing about $1000/month in the US?

        -- apparent answer: because the drug companies can set their prices at whatever they want, independent of their production costs….  (ie, they can get away with usurious costs)

        -- which is so awful given the really important benefits of GLP-1’s and many other remarkably overpriced meds

        -- and this represents yet another of our health care system deficiencies related to our lack of a coherent, integrated, holistic, and more regulated system of care…..

geoff

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