semaglutide decreases cardiovasc events in nondiabetics

 A new study found that patients with pre-existing cardiovascular disease who were overweight or obese but did not have diabetes still had significantly better cardiovascular outcomes with semaglutide, in the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT trial):  cardiovasc better with semaglutide without diabetes NEJM2023 in dropbox, or DOI: 10.1056/NEJMoa2307563  

  

Details: 

-- 17,604 patients who had a BMI of at least 27 with a history of cardiovascular disease but no history of diabetes were enrolled in this multicenter, double-blind, drug company-sponsored randomized controlled, event-driven superiority trial 

-- patients were recruited in 41 countries, were at least 45 years old, but did not have NYHA class IV heart failure, or end-stage renal disease/dialysis 

-- mean age 62, 72% male, 84% white/8% Asian/4% Black/10% Latinx 

-- BMI 33 (72% had BMI>30), waist circumference 111 cm 

-- mean A1c 5.78%, with 33% having A1c<5.7% and 67% at least 5.7% 

-- high-sensitivity CRP 1.9, eGFR 82,  total cholesterol 153/HDL 44/LDL 78/triglycerides 134, blood pressure 131/79, pulse 69 

-- cardiovascular history: MI in 68%, stroke in 18%, PAD 4%, two or more criteria 8% 

-- lipid lowering medications 90%, platelet inhibitors 86%, beta blockers 70%, ACE inhibitors 45%, ARBs 30% 

-- health status: EQ-5D-5L 0.88 (range 0-1, higher score indicating better patient reported health status); EQ-5D-VAS score 77 (range 0 to 100, higher scores indicating better patient reported health status) 

-- patients were randomized to weekly subcutaneous semaglutide 2.4 mg versus placebo 

    -- the starting dose was semaglutide 0.25 mg, escalating to 0.5, 1.0, 1.7, and 2.4 mg doses every four weeks 

  

-- primary cardiovascular endpoint: composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke, in a time-to-first-event analysis 

    -- safety outcomes were also assessed 

-- confirmatory secondary endpoints included a hierarchical analysis of death from cardiovascular causes, a composite of heart failure endpoints, and death from any cause 

  

-- semaglutide was given a mean of 34.2 months, with a mean duration of follow-up of 39.8 months

  

Results: 

-- patients were on semaglutide for 82.5% of the study and on placebo for 87.7%; 77% of patients on semaglutide were on the full 2.4 mg weekly dose 

  

-- primary cardiovascular endpoint: 

    -- semaglutide 569 of 8803 patients (6.5%) 

    -- placebo: 701 of 8801 patients (8.0%) 

         -- 20% decreased risk with semaglutide, HR 0.80 (0.72-0.90), p<0.001 

  

Death from cardiovascular causes: 

    -- semaglutide: 223 patients (2.5%) 

    -- placebo: 262 patients (3.0%) 

        -- 15% reduction, HR 0.85 (0.71-1.01), p=0.07 (higher than what was considered the nominal significance level for superiority: 0.023) 

  

-- Heart failure composite endpoint: 

    -- semaglutide associated with 18% decrease, HR 0.82 (0.71-0.96) 

  

-- Death from any cause: 

    -- semaglutide associated with 19% decrease in death, HR 0.81 (0.71-0.93) 

  

-- mean change in body weight over the 104 weeks: -9.39% with semaglutide and -0.88% with placebo 

-- mean change in waist circumference: decrease of approximately 6.5 cm 

-- high-sensitivity CRP: decreased 39.12% with semaglutide, 2.08% with placebo 

-- blood pressure decreased 3.82/1.02 mmHg with semaglutide vs 0.51/0.47 with placebo 

  

--Subgroup analysis: 

    -- no significant difference in results by assessing expanded cardiovascular endpoint (including coronary revascularization or unstable angina leading to hospitalization), nonfatal MI, coronary revascularization, nephropathy endpoint of persistent GFR <15, or 50% reduction in GFR relative to baseline, or onset of persistent microalbuminuria of >300 mg/g

    -- there was a 67% decrease (HR 0.33 (0.30- 0.36)) in cardiovascular events in those with hemoglobin A1c at least 5.7% who had a baseline A1c <5.7% 

    -- for those patients with initial A1c<5.7%, there was an 18% decrease in cardiovascular events, HR 0.82 (0.68-1.00), 

    -- for those with A1c at least 5.7%: 30% decreased risk, HR 0.70( 0.60 -0.90) 

        -- ie better results in those with "prediabetes", which we know to be an important cardiovascular risk factor: http://gmodestmedblogs.blogspot.com/2022/11/prediabetes-increases-risk-heart.html

    -- very strong trend to benefit but not reaching statistical significance: death from cardiovascular causes, nonfatal stroke, severe heart failure, or unstable angina leading to hospitalization 

    -- BMI: a pretty strong trend to benefit, but only statistically significant for those <35 (small numbers of people and events in those with higher BMIs) 

-- time to first event: 

  

 

   

-- no patient was on an SGLT-2 inhibitor at the time of randomization but that treatment was initiated in 213 patients on semaglutide and 332 on placebo 

  

-- adverse events: 

    -- those leading to permanent discontinuation of the trial semaglutide: 1461 patients (16.6%), placebo 718 patients (8.2%), p<0.001 

    -- serious adverse events: 33.4% on semaglutide and 36.4% on placebo, p<0.001 

        -- GI disorders in 10% versus 2% 

    -- gallbladder related disorders in 2.8% versus 2.3% 

    -- no difference in acute pancreatitis, acute kidney failure (these last two actually had more cases on placebo), or malignant neoplasms 

  

Commentary: 

-- as we all know, overweight/obesity is increasing around the world. It is projected that more than half of the world’s population will be overweight/obese by year 2035 

-- in 2015, it was estimated that there were 4 million deaths globally related to a high BMI, two thirds of which were caused by cardiovascular diseases 

    -- it is difficult to tease out the exact causes of this increased cardiovascular mortality, since obesity is so intertwined with all of the major cardiovascular risk factors, as well as with many of those risk factors not in the standard ASCVD risk calculator:

https://gmodestmedblogs.blogspot.com/2023/10/update-ascvd-risk-factor-critique.html 

-- as has become abundantly clear, GLP-1 receptor agonists are remarkably effective in treating obesity, as well as diabetes, and in the latter case are associated with decreased cardiovascular events. 

    -- 2 year followup of the STEP trial showed persistent weight loss: https://gmodestmedblogs.blogspot.com/2022/11/obesity-semaglutide-continues-to-work.html 

    -- and very large numbers of studies over the past 15-20 years have confirmed the profound benefits of various GLP-1 agonists on diabetes 

-- semaglutide also has benefit for patients with heart failure and preserved ejection fraction (this type of heart failure is more of a metabolic disease, as opposed to patients who have reduced ejection fraction with diminished left ventricular function):  https://gmodestmedblogs.blogspot.com/2023/10/heart-failure-preserved-in-obese.html 

  

-- this current study found a significant decrease in cardiovascular risks in this cohort at high cardiovascular risk without diabetes, but with overweight/obesity. There was a significant 20% decrease in their primary cardiovascular outcome over a 33-month period with the effects becoming apparent early after the initiation of treatment (see graphs above, effects evident within the first six months). 

    -- this translated to an absolute difference in cardiovascular events of only 1.5% (6.5% with semaglutide, 8.0% with placebo) after 33 months 

    -- but the actual change in body weight was a difference of 8.51% (-9.39% on semaglutide vs -0.88% on placebo) 

        -- this is really different from what was found in the 2-year outcomes of the STEP trial, mentioned above, where they achieved a 12.6% weight loss (-15.2% on semaglutide vs -2.6% on placebo) in their intention-to-treat analysis 

        -- not sure why there was such a difference in achieved weight loss, but this could explain why there was only a 1.5% absolute difference in the benefit of semaglutide 

            -- a likely candidate is that only 63.5% of the current group actually took the 2.4mg dose of semaglutide (77% of the 82.5% of patients who actually took the semaglutide)

            -- and another potential confounder: although none of the patients were on SGLT-2 inhibitors at the start of the study, 332 in the placebo group (vs 213 on semaglutide) were on this medication known to decrease cardiovascular endpoints

        -- and, it should be noted that the curves above of cardiovascular benefits do continue to splay apart over time, suggesting that longer therapy is more efficacious 

        -- to unravel this difference between semaglutide's effects in the current study vs the 2-yr followup of the STEP study, it would have been useful to present subgroup data: was there more cardiovascular benefit in those achieving the full 2.4mg semaglutide dose and staying on it for the full study? or assessing those achieving 10% loss of body weight vs 15% vs 20%? 

        -- it also might well turn out that the newer and more potent meds (eg tirzepatide) will have better results if studied in a non-diabetic cohort 

  

-- overall adverse effects were lower in the semaglutide group, though there was a higher percentage of patients who discontinued semaglutide because of severe adverse effects 

  

-- mechanistically, it is hard to know exactly how semaglutide provides broad cardiovascular benefits, since it affects many of the cardiac risk factors as noted above (weight, blood pressure, prediabetes/diabetes, likely decreased smoking as well).  studies have also found that GLP-1 receptor agonists reduce inflammation, improve endothelial left ventricular function, promote plaque stability, and decrease platelet aggregation (though several of these affects also could be related to weight reduction, and weight loss itself can lead to full remission of diabetes: https://gmodestmedblogs.blogspot.com/2019/03/weight-loss-can-cure-diabetes-for-at.html). 

     -- in fact, the reduction in cardiovascular events found in this study is similar to that found in studies in patients with diabetes on subcutaneous semaglutide (HR 0.74) and oral semaglutide (HR 0.79), further supporting that the main function of semaglutide in cardiovascular disease prevention may well be weight loss 

    -- and, if this is the case, the cardiovascular benefits should pertain to the other GLP-1 receptor agonists, as well as (likely) tirzepatide: https://pubmed.ncbi.nlm.nih.gov/36507900/ 

  

-- one other issue (as emphasized in the last few blogs) is the role of "prediabetes" (A1c 5.7-6.4%) as a cardiovascular risk factor in itself. This study assessed this group and found that there was an even greater cardiovascular protection (decrease of 30%) in cardiovascular events, vs 20% for the overall group  

  

Limitations: 

-- this study included only patients who had pre-existing cardiovascular disease. It is therefore not clear that the results pertain to someone without that history. However, a trial based on such primary prevention individuals would need to be much larger and of much longer duration to prove cardiovascular benefit 

-- the study was limited to patients who were at least 45 years old, limiting generalizability to younger patients (who would also need to be enrolled for a longer study with larger numbers of patients) 

-- patients were overall not on optimal cardiovascular therapy, since 10% were not on lipid lowering medications and 14% were not on platelet inhibitors, and 25% were not on ACE inhibitors/ARBs. these should probably have been part of the secondary prevention treatments, though we do not have granular information of what meds were given in different countries (multinational studies have huge benefits in understanding the likely generalizability of the results, but have the problem that the baseline treatments for diseases may vary considerably from one country to another) 

  

so, 

-- another impressive study on the benefits of GLP-1 receptor agonists, extending documentation of cardiovascular benefits to overweight patients who do not have diabetes 

-- maybe, maybe, maybe this will help push insurance companies to allow these pretty amazing meds to be available to those without diabetes???? 

    -- current data in the US are that 39.6% of adults are obese and another 31.6% are overweight. 

    -- and we do know that obesity is strongly associated with a myriad of medical conditions, including premature deaths, as well as often profound effects on people's psychosocial situations/family lives, etc etc 

  

  

geoff 

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