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Effect of Semaglutide on Regression and Progression of Glycemia in Individuals With Overweight/Obesity but Without Diabetes
abstract
This abstract is available on the publisher's site.
Access this abstract nowOBJECTIVE
To determine whether semaglutide slows progression of glycemia in people with cardiovascular disease and overweight or obesity but without diabetes.
RESEARCH DESIGN AND METHODS
In a multicenter, double-blind trial, participants aged ≥45 years, with BMI ≥27 kg/m2, and with preexisting cardiovascular disease but without diabetes (HbA1c <6.5%) were randomized to receive subcutaneous semaglutide (2.4 mg weekly) or placebo. Major glycemic outcomes were HbA1c and proportions achieving biochemical normoglycemia (HbA1c <5.7%) and progressing to biochemical diabetes (HbA1c ≥6.5%).
RESULTS
Of 17,604 participants, 8,803 were assigned to semaglutide and 8,801 to placebo. Mean ± SD intervention exposure was 152 ± 56 weeks and follow-up 176 ± 40 weeks. In both treatment arms mean nadir HbA1c for participants was at 20 weeks. Thereafter, HbA1c increased similarly in both arms, with a mean difference of −0.32 percentage points (95% CI −0.33 to −0.30; −3.49 mmol/mol [−3.66 to −3.32]) and with the difference favoring semaglutide throughout the study (P < 0.0001). Body weight plateaued at 65 weeks and was 8.9% lower with semaglutide. At week 156, a greater proportion treated with semaglutide were normoglycemic (69.5% vs. 35.8%; P < 0.0001) and a smaller proportion had biochemical diabetes by week 156 (1.5% vs. 6.9%; P < 0.0001). The number needed to treat was 18.5 to prevent a case of diabetes. Both regression and progression were dependent on glycemia at baseline, with the magnitude of weight reduction important in mediating 24.5% of progression and 27.1% of regression.
CONCLUSIONS
In people with preexisting cardiovascular disease and overweight or obesity but without diabetes, long-term semaglutide increases regression to biochemical normoglycemia and reduces progression to biochemical diabetes but does not slow glycemic progression over time.
Additional Info
Disclosure statements are available on the authors' profiles:
Effect of Semaglutide on Regression and Progression of Glycemia in People With Overweight or Obesity but Without Diabetes in the SELECT Trial
Diabetes Care 2024 Jun 22;[EPub Ahead of Print], SE Kahn, JE Deanfield, OK Jeppesen, SS Emerson, TW Boesgaard, HM Colhoun, RF Kushner, I Lingvay, B Burguera, G Gajos, DB Horn, IM Hramiak, AM Jastreboff, A Kokkinos, M Maeng, ALSA Matos, FJ Tinahones, AM Lincoff, DH RyanFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
These papers1,2 are secondary publications from the SELECT trial, a cardiovascular trial considered a landmark as the first demonstration of a reduction in major adverse cardiovascular events (MACE) among individuals with established cardiovascular disease and overweight or obesity but without diabetes. However, “secondary publication” should not be used to trivialize the additional observations derived from the SELECT population as these two papers expand our knowledge of the broad effects of semaglutide in cardiometabolic disease.
SELECT enrolled 17,604 individuals from 41 countries, with 72.3% being male and the average age being 61.6 years, and randomized them to weekly semaglutide 2.4 mg subcutaneously or placebo on a background of cardiovascular risk-reduction counseling. There was no weight-loss counseling; still, weight loss continued for 65 weeks and was 8.9% greater with semaglutide, remaining stable through 4 years. Both analyses looked at three categories of HbA1c (<5.7%, 5.7% to <6.0%, and 6.0% to <6.5%), from normoglycemia to two categories of prediabetes.
Kahn et al showed that, overall, at 3 years, semaglutide increased regression to normoglycemia approximately fourfold while reducing the risk of progression to diabetes by 73% compared with placebo, with 18.5 individuals needing to be treated to prevent one case of diabetes.1 As expected, individuals in the highest HbA1c category had the greatest absolute reduction in the risk for progression to diabetes with semaglutide. Weight-loss categories and their effect on glycemia progression or regression were also studied. This paper adds to the evidence that improvements in glycemia progression or regression with semaglutide are related to both weight loss effects and the independent effects of semaglutide on glycemia, as even those who lost less than 2% of weight in the semaglutide group experienced glycemic benefits.
The paper by Lingvay et al provides several interesting observations.2 Semaglutide reduced the risk of MACE and other cardiovascular outcomes independent of baseline HbA1c category — meaning that even individuals with normoglycemia experienced the benefits of MACE risk reduction. This study also looked at the effects of different degrees of HbA1c change on MACE (< −0.3 percentage points, −0.3 to 0.3 percentage points, >0.3 percentage points). Again, semaglutide reduced the risk of MACE independent of changes in HbA1c. Even those without HbA1c improvements showed MACE risk reduction with semaglutide.
These two studies add to our expanding appreciation of the multiple effects of semaglutide. Two prior secondary papers from SELECT document the weight loss3 and nephropathy4 benefits. Taken with these two papers, the SELECT analyses support that semaglutide is a powerful medication with multiple benefits in the cardio–renal–metabolic disease spectrum. We are encouraged by these demonstrations of broad benefits and are eager for more mechanistic analyses.
References
Previous results from the SELECT study showed a significant benefit with weekly subcutaneous semaglutide 2.4 mg by reducing major adverse cardiovascular events by 20% in people aged ≥45 years with pre-existing cardiovascular disease and overweight or obesity but without diabetes.1 In this prespecified secondary analysis, Kahn et al expanded on the previously reported secondary end points of glycemic status through 156 weeks. They compared patterns of glycemia in people treated with semaglutide (n = 8803) versus placebo (n = 8801) to determine whether semaglutide normalizes glycemia in people with prediabetes and reduces the progression to diabetes defined according to HbA1c.
After 65 weeks, the mean difference in bodyweight averaged at −8.89% (95% CI: 9.12–8.66; P < .0001) in the semaglutide group compared with the placebo group and remained stable throughout the study, whereas the nadir in mean HbA1c occurred at 20 weeks in both treatment groups (mean HbA1c reduced to 5.45 ± 0.00% with semaglutide vs 5.77 ± 0.00% with placebo [95% CI, 0.32 to –0.30; P < .0001]).
At each time point, the proportion of participants with normoglycemia (HbA1c <5.7%) was greater with semaglutide compared with placebo, respectively (20 weeks, 76.1% vs 38.0%; 52 weeks, 74.3% vs 37.2%; 104 weeks, 73.9% vs 38.4%; and 156 weeks, 69.5% vs 35.8% [P < .0001]). Participants with the lowest baseline HbA1c levels (5.7% to <6.0%) were the most likely to be normoglycemic at week 156.
Conversely, at each time point, the proportion of participants with diabetes (HbA1c ≥6.5%) was lower with semaglutide compared with placebo, respectively (20 weeks, 0.5% vs 3.2%; 52 weeks, 0.8% vs 4.5%; 104 weeks, 1.3% vs 5.5%; and 156 weeks, 1.5% vs 6.9% [P < .0001]). Participants with the highest baseline HbA1c levels (6.0% to <6.5%) were the most likely to have a HbA1c >6.5% at week 156; however, only 3.5% of those on semaglutide versus 17% on placebo developed a HbA1c >6.5%, indicating the greatest benefit for these high-risk participants. Overall, semaglutide lowered the risk diabetes by 73% compared with placebo, with a number needed to treat of 18.5 to prevent one case of diabetes after 156 weeks.
The authors reported that 27.1% of the effect to induce regression to normglycemia and 34.5% of the effect to prevent progression to diabetes was mediated through weight change. As expected, participants who lost the most weight were more likely to develop normoglycemia and less likely to develop diabetes. These are novel observations from a long-term study using a GLP-1 receptor agonist, and the effects seen on improving glycemia are likely due to weight loss which improves insulin sensitivity and improvement in islet secretory responses. Moreover, while HbA1c began rising after 20 weeks, participants continued to lose weight until week 65, indicating that improvement in glycemia was not solely the result of weight loss.
Finally, to add context to this study, in the landmark Diabetes Prevention Program, intensive lifestyle intervention and metformin lowered the overall risk of developing diabetes (HbA1c ≥6.5%) by 49% and 44%, respectively.2 Future research is needed to evaluate the mechanisms for diabetes prevention and to determine whether there are any long-term effects of semaglutide that change the natural history of prediabetes or whether there are any legacy effects after discontinuation of semaglutide. Nevertheless, this is a potential exciting addition to the armamentarium of diabetes prevention tools.
References