obesity: semaglutide continues to work at 2 years

 There was an update of the STEP trials, which initially found that semaglutide led to impressive weight loss through week 68. The new update assessed the effects at 2 years, finding stabilization of the 68-week weight loss (see obesity semaglut at 2 years NatureMed2022 in dropbox or doi.org/10.1038/s41591-022-02026-4.)  

For the details and analysis of the original semaglutide study at week 68, see http://gmodestmedblogs.blogspot.com/2021/03/semaglutide-for-weight-loss.html 

 

Details: 

--304 participants with a BMI >30 (or >27, if at least one weight-related coexisting condition, such as hypertension, dyslipidemia, OSA, or cardiovascular disease) were randomized to once-weekly semaglutide vs placebo; patients were recruited from October 2018 to February 2019, 152 randomized to semaglutide 2.4mg injection weekly vs 152 to placebo. From 129 sites in 16 countries in Asia, Europe, North and South America 

-- diabetic patients were excluded from the study

-- mean age 47, 81% female, 93% white/12% Latinx/5% Black 

-- body weight 106 kg, BMI 39 (6% <30/ 33% 30-35/ 31% 35-40/ 30% >40), waist circumference 116 cm 

-- A1c=5.7%, fasting glucose 95, fasting insulin 88 pmol/L, BP 126/80, pulse 73, LDL 112/HDL 46/TG 115; eGFR 96 

-- dylipidemia 38%, hypertension 37%, OSA 18%, NAFLD 11% 

-- therapy was initiated at 0.25 mg weekly for the 1st 4 weeks (the typical approach in diabetics) then increased every 4 weeks to a maintenance dose of 2.4 mg weekly by week 16 (though lower doses were permitted if there were unacceptable adverse effects) 

-- there was also individual counseling every 4 weeks to help with adherence to a 500 kcal deficit diet relative to their energy expenditure estimates; and increased exercise was encouraged up to 150 minutes per week of physical activity such as walking 

-- SF-36 (mean score in general US population is 50, higher score means better quality of life): physical functioning score 51, physical component summary score 51, mental component summary score 55 

-- Impact of Weight on Quality of Life (IWQOL, score 0-100): physical function score 65, total score 63 

-- primary endpoints: percentage change in body weight, and weight reduction of at least 5% 

-- secondary endpoints: weight loss of at least 10%, 15% and 20%, and an array of cardiometabolic factors (fasting glucose and insulin, lipids, CRP, BMI, waist circumference, glycemic control, blood pressure) 

 

-- 282 people (93%) completed the trial, 272 (90%) had body weight measurement at end-of-treatment visit at week 104 

-- 243 (80%) adhered to the treatment (per-protocol analysis) 

 

Results: 

-- intention-to-treat analysis (all participants randomized into each group): 

    -- Body weight change from baseline to week 104:  

        -- semaglutide: -15.2% 

        -- placebo: -2.6% 

            -- treatment difference: -12.6% (-15.3 to -9.8), p<0.00001 

    -- >5% weight loss at week 104:  

        -- semaglutide: 111/144 (77.1%)

        -- placebo: 17/128 (13.3%) 

            -- OR 5.0 (3.0-8.4), p<0.00001 

    -- >10% weight loss at week 104:  

        -- semaglutide: 89/144 (61.8%) 

        -- placebo:17/144 (12.8%) 

            -- OR 7.2 (4.0-13.2), p<0.00001 

    -- >15% weight loss at week 104:  

        -- semaglutide: 75/144 (52.1%) 

        -- placebo: 9/128 (7.0%) 

             -- OR 9.4(4.4-20), p<0.00001 

    -- >20% weight loss at week 104:  

        -- semaglutide: 52/144 (36.1%) 

        -- placebo: 3/128 (2.3%) 

             -- OR 12.8 (3.9-41.9) 

   -- also, comparing semaglutide to placebo:  

       -- prediabetes at baseline:  normoglycemia at week 104 in 79.7% vs 37.0% 

       -- normoglycemia at baseline: prediabetes at week 104 in 1.4% vs 13.0% (and 0 vs 3 people developed diabetes) 

 

-- analysis by per-protocol (ie, people actually taking the med or placebo they were assigned to): 

    -- Body weight change from baseline to week 104:  

        -- semaglutide: -16.7% 

        -- placebo: -0.6% 

            -- treatment difference: -16.0% (-18.6 to -13.5) 

    -- >5% weight loss at week 104:  

        -- semaglutide: 110/132 (83.3%) 

        -- placebo: 38/109 (34.9%) 

            -- OR 18.1 (10.0-32.5) 

    -- >10% weight loss at week 104:  

        -- semaglutide: 89/132 (67.4%) 

        -- placebo:148/109 (12.8%) 

            -- OR 17.6 (9.4-32.9) 

    -- >15% weight loss at week 104:  

        -- semaglutide: 75/132 (56.8%) 

        -- placebo: 7/109 (6.4%) 

             -- OR 23.6 (10.4-53.8) 

    -- >20% weight loss at week 104:  

        -- semaglutide: 52/132 (39.4%) 

        -- placebo: 3/109 (2.8%) 

             -- OR 26.7 (8.1-87.7) 

    -- waist circumference at week 104: 

        -- semaglutide: -15.8 cm 

        -- placebo: -3.7 cm 

            -- treatment difference: -12.1 cm (-14.7 to -9.4) 

    -- systolic blood pressure at week 24: 

        -- semaglutide: -6.1 mmHg 

        -- placebo: -0.1 mmHg 

            -- treatment difference: -6.1 mmHg (-9.4 to -2.7) 

    -- body weight change at week 104: 

        -- semaglutide: -7.6 kg 

        -- placebo: -0.8kg 

            -- treatment difference: -12.1 kg (-16.8 to -13.9) 

    -- BMI change at week 104 

        -- semaglutide: -6.5 

        -- placebo: -0.3 

            -- treatment difference: -6.2 (-7.3 to -5.1) 

    -- HbA1c change at week 104: 

        -- semaglutide: -0.5% 

        -- placebo: -0.1% 

            -- treatment difference: -0.4 (-0.5 to -0.3) 

                 -- though, note that the average A1c at baseline was 5.7% (no patients were initially diabetic)

    -- CRP change at week 104: 

        -- semaglutide: -59.5% 

        -- placebo: -8.0% 

            -- treatment difference: -56.0% (-66.0% to 43.1%) 

    -- LDL change at week 104: 

        -- semaglutide: -8.0% 

        -- placebo:  0.5% 

            -- treatment difference:  -8.4% (-13.1% to -3.4%) 

 

the first graph (a) represents the weight change over time in those who actually took their alloted medication (semaglutide vs placebo); the second (b) the observed proportions of participants and odds ratio for achieving weight loss of at least 5% from baseline at week 104

--safety/tolerability, comparing semaglutide to placebo: 

    -- adverse events leading to discontinuation: 5.9% vs 4.6% 

        --most frequently GI disorders (nausea, diarrhea, vomiting, constipation): 82.2% vs 53.9% 

            -- mostly mild to moderate symptoms, and transient 

            -- 6 people (3.9%) vs 1 (0.7%) permanently discontinued treatment 

 

Commentary: 

-- this study extends the results of prior reports, noting that the very large reported  benefit after about 66 weeks was maintained over the next year. The information on the threshold of weight loss >5% is highlighted since this is considered a clinically meaningful response to therapy 

    -- the fact that weight loss stabilized during the second year of treatment is significant: regaining weight is quite common in nonsurgical interventions (both lifestyle and other meds), and not so uncommon after surgery (depends on the type of surgery)

    -- tracking with the weight loss is an improvement in many of the cardiometabolic factors: waist circumference, blood pressure, HbA1c, LDL, CRP (CRP, a marker of inflammation, tends to be elevated with obesity), fasting insulin levels (likely reflecting improved insulin sensitivity, and insulin resistance itself is associated with cardiovascular disease: see https://cardiab.biomedcentral.com/articles/10.1186/s12933-018-0762-4 ) 

-- I did h8ghlight the data above on the per-protocol numbers (significantly better than the intention-to-treat ones), since those numbers reflect what we should be able to tell patients about what their likely results would be if they are able to persist in taking the semaglutide 

-- one interesting point is that GI toxicity is quite common with semaglutide (as with all GLP-1 agonists) but it was also reported in >50% in those on placebo!! This all reinforces that many reported adverse effects in trials are just because many symptoms are common, especially over a 1-2 year period (headaches, GI effects, etc) and may be falsely attributed to the meds. Which means that we should look at the relative differences between med and placebo and not the absolute reported med-related number (in this case about 23%, as opposed to the reported number of 82%)…  There also is a nocebo-like effect: just being on a medicine (or placebo) in an RCT leads to more reporting of problems (especially if people are asked directly). and, notably, the quality of these reported adverse effects was mild-to-moderate and transient

 

-- for prior blogs on GLP-1 agonists and weight loss: 

    -- for the original semaglutide study, at week 68: http://gmodestmedblogs.blogspot.com/2021/03/semaglutide-for-weight-loss.html 

     -- for the comparison of semaglutide with liraglutide (the first FDA-approved GLP-1 agonist for weight loss), semaglutide was way better (see http://gmodestmedblogs.blogspot.com/2022/01/weight-loss-semaglutide-better-than.html ) 

        -- semaglutide is also FDA-approved (though insurance companies seem to approve bariatric surgery much more easily than semaglutide, and semaglutide actually has similar weight loss as sleeve gastrectomy) 

--of note, there is a new drug, tirzepatide (combo of GLP-1 agonist and glucose-dependent insulinotropic polypeptide), which was better than semaglutide. See http://gmodestmedblogs.blogspot.com/2021/07/diabetes-and-weight-loss-tirzepatide.html 

    --  semaglutide was dosed at 1mg only, not the 2.4 mg as in the above study. so hard to really compare the results.  semaglutide at a dose of 1mg is associated with less weight loss than the 2.4g dose (eg see https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2796491, noting a dose-response curve)

 Limitations: 

-- limited patient population studied (largely white women), thereby limiting potential generalizability to others 

-- there is always an issue with generalizability from a study vs the general population, with those in the study being willing participants, likely more motivated to lose weight (and the placebo group in the study actually did lose weight) 

    --and, in this study there was regular pretty aggressive counseling about diet and exercise, which may be quite different from what we can do in the community setting 

 

So, a very impressive study finding stabilization of quite significant weight loss in those continuing semaglutide 2.4 mg/week injections (though regaining weight if they stop the semaglutide). a very important finding since:

-- obesity is remarkably common in our society (see http://gmodestmedblogs.blogspot.com/2018/03/increasing-childhood-and-adult-obesity.html)

-- obesity is associated with chronic inflammation as well as a slew of medical complications, disabilities, social stigma/alienation, discrimination (including from employment), attendant effects on family and community, mental health issues (several studies confirm a relationship with depression: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449839/ ), and shortened life expectancy

-- non-pharmacologic therapy is effective as a sustainable treatment for obesity in only a small % of patients (ie, it is really very hard for most obese patients to lose lots of weight and maintain that weight loss; though nonpharmacologic therapies should always be part of any weight-loss solution... )

    -- and, many obese patients do have genetic causes (eg leptin deficiency, and a slew of others: there are about 100 genes identified that are associated with obesity, and about 21% of BMI variation can be attributed to the most common variants: see obesity genetic analysis Nature2015 in dropbox, or DOI: 10.1038/nature14177)

    -- also, in those very obese, losing weight is associated with decreased resting metabolic rates (ie their metabolism slows down when they eat less, so that even eating much less than before, they might gain weight by burning fewer calories!!!  see http://gmodestmedblogs.blogspot.com/2016/07/weight-loss-and-resting-metabolic-rate.html )

-- other medications besides semaglutide are not very effective and typically are associated with weight regain

-- many patients are reluctant to have surgery, and the results for semaglutide are similar to sleeve gastrectomies

-- though, the big caveat, many major insurers do not cover semaglutide or weight loss drugs in general, including Medicare and Medicaid (at least in Boston: weight loss drugs are not a mandated Medicaid benefit), but ironically they do cover bariatric surgery....

geoff

 

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