Dataset Information

Semaglutide reduces cardiovascular events regardless of metformin use: a post hoc subgroup analysis of SUSTAIN 6 and PIONEER 6.

ABSTRACT:

Background

Cardiovascular outcome trials (CVOTs) are conducted on a background of standard of care including metformin. These analyses sought to determine whether the cardiovascular (CV) effects of semaglutide and other glucagon-like peptide-1 receptor agonists (GLP-1RAs) vary according to baseline metformin use.

Methods

A post hoc analysis was conducted using pooled SUSTAIN 6 and PIONEER 6 CVOT data in subjects with and without metformin use at baseline. Additionally, a trial-level meta-analysis was conducted using data from seven CVOTs with GLP-1RAs-SUSTAIN 6, PIONEER 6, HARMONY OUTCOMES, LEADER, REWIND, EXSCEL and AMPLITUDE-O-including adults with type 2 diabetes at high CV risk, and a primary endpoint of time to first major adverse CV event (MACE).

Results

In the post hoc analysis, the no-metformin subgroup was older, with a higher body mass index, lower estimated glomerular filtration rate and higher CV risk at baseline vs the metformin subgroup. Hazard ratios (95% confidence intervals) for the reduction in risk of MACE with semaglutide vs placebo in the metformin and no-metformin subgroups were 0.70 (0.55;0.89) and 0.86 (0.60;1.22), respectively. No significant interaction between the treatment effect on MACE and metformin subgroup was observed. Findings for other CV endpoints were similar. In the meta-analysis, treatment effect (GLP-1RA vs placebo) on CV outcomes was no different with vs without baseline metformin (overall ratio between the hazard ratios for metformin vs no-metformin 1.09 [0.96;1.22]).

Conclusion

These findings indicate that the CV outcomes for semaglutide were similar regardless of baseline metformin use, which may also apply to all GLP-1RAs. Trial registration SUSTAIN 6 (NCT01720446), PIONEER 6 (NCT02692716).

SUBMITTER: Husain M

PROVIDER: S-EPMC9052629 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Semaglutide reduces cardiovascular events regardless of metformin use: a post hoc subgroup analysis of SUSTAIN 6 and PIONEER 6.

Husain Mansoor M Consoli Agostino A De Remigis Alessandra A Pettersson Meyer Anna Sina AS Rasmussen Søren S Bain Stephen S

Cardiovascular diabetology 20220428 1

<h4>Background</h4>Cardiovascular outcome trials (CVOTs) are conducted on a background of standard of care including metformin. These analyses sought to determine whether the cardiovascular (CV) effects of semaglutide and other glucagon-like peptide-1 receptor agonists (GLP-1RAs) vary according to baseline metformin use.<h4>Methods</h4>A post hoc analysis was conducted using pooled SUSTAIN 6 and PIONEER 6 CVOT data in subjects with and without metformin use at baseline. Additionally, a trial-lev ...[more]

PMID: 35484580

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Project description:BackgroundSemaglutide is a glucagon-like peptide-1 (GLP-1) analog treatment for type 2 diabetes (T2D) available in subcutaneous (s.c.) and oral formulations. Two cardiovascular (CV) outcomes trials showed that in subjects with T2D at high risk of CV events there were fewer major adverse CV events (MACE; defined as CV death, non-fatal stroke, non-fatal myocardial infarction) with semaglutide than with placebo (hazard ratio [95% CI]: 0.74 [0.58;0.95] for once-weekly s.c. semaglutide and 0.79 [0.57;1.11] for once-daily oral semaglutide). However, there is little evidence for an effect of semaglutide on MACE in subjects not at high risk of CV events. This post hoc analysis examined CV effects of semaglutide in subjects across a continuum of baseline CV risk.MethodsData from the s.c. (SUSTAIN) and oral (PIONEER) semaglutide phase 3a clinical trial programs were combined according to randomized treatment (semaglutide or comparators) and analyzed to assess time to first MACE and its individual components. A CV risk model was developed with independent data from the LEADER trial (liraglutide vs placebo), considering baseline variables common to all datasets. Semaglutide data were analyzed to assess effects of treatment as a function of CV risk predicted using the CV risk prediction model.ResultsThe CV risk prediction model performed satisfactorily when applied to the semaglutide data set (area under the curve: 0.77). There was a reduced relative and absolute risk of MACE for semaglutide vs comparators across the entire continuum of CV risk. While the relative risk reduction tended to be largest with low CV risk score, the largest absolute risk reduction was for intermediate to high CV risk score. Similar results were seen for relative risk reduction of the individual MACE components and also when only placebo comparator data were included.ConclusionSemaglutide reduced the risk of MACE vs comparators across the continuum of baseline CV risk in a broad T2D population. Trial registrations ClinicalTrials.gov identifiers: NCT02054897, NCT01930188, NCT01885208, NCT02128932, NCT02305381, NCT01720446, NCT02207374, NCT02254291, NCT02906930, NCT02863328, NCT02607865, NCT02863419, NCT02827708, NCT02692716, NCT02849080, NCT03021187, NCT03018028, NCT03015220.

Project description:IntroductionThe efficacy and safety of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, were investigated in patients with type 2 diabetes (T2D) in the Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) programme. The current post-hoc exploratory subgroup analyses evaluated outcomes by background medication and insulin regimen subgroups.MethodsData from patients in the PIONEER 3-5, 7 and 8 trials receiving once-daily oral semaglutide (14 mg/flexibly dosed) or a comparator (placebo, sitagliptin 100 mg or liraglutide 1.8 mg) were analysed for efficacy (glycated haemoglobin [HbA1c] and body weight changes from baseline to planned end of treatment) and safety outcomes. Patients were grouped according to background medication (metformin, sulphonylurea, thiazolidinedione, sodium-glucose cotransporter-2 inhibitor, insulin, or combinations thereof). Efficacy outcomes were analysed using the trial product estimand (which assumes that patients remained on the trial product without rescue medication use). A separate analysis by background insulin regimen (basal, premixed or basal-bolus) was done for PIONEER 8 using the treatment policy estimand (regardless of trial product discontinuation or rescue medication use). Safety outcomes were analysed descriptively for all patients.ResultsIn total, 2836 patients receiving oral semaglutide 14 mg/flexibly dosed or comparators were included. Baseline characteristics were generally similar across background medication subgroups within each trial. Diabetes duration tended to be longer in patients receiving more background medications. Greater HbA1c and body weight reductions were seen across background medication subgroups with oral semaglutide (changes from baseline: - 1.0 to - 1.5% and - 2.2 to - 5.0 kg, respectively) than with comparators (except for similar HbA1c reductions vs liraglutide). There were no statistically significant interactions by treatment and background medication subgroup for change in HbA1c or body weight except for change in HbA1c (background insulin vs insulin plus metformin) in PIONEER 8 (p = 0.0408). Changes in HbA1c and body weight were generally similar across insulin regimen subgroups, without significant treatment interactions by subgroup, and the total daily insulin dose was decreased for patients receiving oral semaglutide. The incidence of adverse events was generally similar in background medication subgroups.ConclusionOral semaglutide was effective at lowering HbA1c and body weight, regardless of background medications, and appears suitable for a broad range of patients with T2D in combination with other glucose-lowering agents.Trial registrationClinicaltrials.gov: NCT02607865 (PIONEER 3), NCT02863419 (PIONEER 4), NCT02827708 (PIONEER 5), NCT02849080 (PIONEER 7) and NCT03021187 (PIONEER 8).

Project description:BackgroundSemaglutide is a glucose-lowering treatment for type 2 diabetes (T2D) with demonstrated cardiovascular benefits; semaglutide may also have kidney-protective effects. This post hoc analysis investigated the association between major adverse cardiovascular events (MACE) and baseline kidney parameters and whether the effect of semaglutide on MACE risk was impacted by baseline kidney parameters in people with T2D at high cardiovascular risk.MethodsParticipants from the SUSTAIN 6 and PIONEER 6 trials, receiving semaglutide or placebo, were categorised according to baseline kidney function (estimated glomerular filtration rate [eGFR] < 45 and ≥ 45-<60 versus ≥ 60 mL/min/1.73 m2) or damage (urine albumin:creatinine ratio [UACR] ≥ 30-≤300 and > 300 versus < 30 mg/g). Relative risk of first MACE by baseline kidney parameters was evaluated using a Cox proportional hazards model. The same model, adjusted with inverse probability weighting, and a quadratic spline regression were applied to evaluate the effect of semaglutide on risk and event rate of first MACE across subgroups. The semaglutide effects on glycated haemoglobin (HbA1c), body weight (BW) and serious adverse events (SAEs) across subgroups were also evaluated.ResultsIndependently of treatment, participants with reduced kidney function (eGFR ≥ 45-<60 and < 45 mL/min/1.73 m2: hazard ratio [95% confidence interval]; 1.36 [1.04;1.76] and 1.52 [1.15;1.99]) and increased albuminuria (UACR ≥ 30-≤300 and > 300 mg/g: 1.53 [1.14;2.04] and 2.52 [1.84;3.42]) had an increased MACE risk versus those without. Semaglutide consistently reduced MACE risk versus placebo across all eGFR and UACR subgroups (interaction p value [pINT] > 0.05). Semaglutide reduced HbA1c regardless of baseline eGFR and UACR (pINT>0.05); reductions in BW were affected by baseline eGFR (pINT<0.001) but not UACR (pINT>0.05). More participants in the lower eGFR or higher UACR subgroups experienced SAEs versus participants in reference groups; the number of SAEs was similar between semaglutide and placebo arms in each subgroup.ConclusionsMACE risk was greater for participants with kidney impairment or damage than for those without. Semaglutide consistently reduced MACE risk across eGFR and UACR subgroups, indicating that semaglutide provides cardiovascular benefits in people with T2D and at high cardiovascular risk across a broad spectrum of kidney function and damage.Trial registrationsNCT01720446; NCT02692716.

Project description:INTRODUCTION:Despite treatment with oral antidiabetic drugs (OADs), achieving effective glycaemic control in type 2 diabetes (T2D) remains a challenge. The objective of this post hoc analysis of data from the SUSTAIN 2, 3, 4 and 10 active-controlled trials was to assess the efficacy and safety of the once-weekly glucagon-like peptide 1 receptor agonist (GLP-1RA) semaglutide in patients on background treatment with metformin (MET), with or without a sulphonylurea (SU). METHODS:Data from the randomised phase 3 trials SUSTAIN 2, 3, 4 and 10 for subjects who received background MET alone or MET + SU were analysed. Change from baseline in HbA1c and body weight at the end of treatment visit (week 30 in SUSTAIN 4 and 10, week 56 in SUSTAIN 2 and 3), and rates of hypoglycaemia and adverse events leading to premature treatment discontinuation were assessed. RESULTS:In total, 3411 subjects were included in the full analysis set (3410 in the safety analysis set). Across the four trials, semaglutide significantly reduced HbA1c (estimated treatment difference [ETD] - 0.32 to - 0.79%-points for semaglutide 0.5 mg, and - 0.38 to - 1.07%-points for semaglutide 1.0 mg vs comparators; p < 0.01) in subjects receiving both MET and MET + SU. Regardless of background OAD, semaglutide significantly reduced body weight (ETD - 2.35 to - 4.72 kg for semaglutide 0.5 mg, and - 2.96 to - 6.76 kg for semaglutide 1.0 mg vs comparators; p < 0.0001). Across the trials, hypoglycaemic events were more common with background MET + SU than MET alone, in subjects receiving either semaglutide or a comparator. The rate of adverse events (AEs) leading to premature treatment discontinuations in subjects treated with semaglutide were generally consistent regardless of background therapy. CONCLUSION:Semaglutide 0.5 mg and 1.0 mg significantly improve glycaemic control (HbA1c) and body weight in subjects with T2D, with a similar tolerability profile, regardless of whether they receive background MET or MET + SU. TRIAL REGISTRATION:Clinicaltrials.gov: NCT01930188 (SUSTAIN 2), NCT01885208 (SUSTAIN 3), NCT02128932 (SUSTAIN 4) and NCT03191396 (SUSTAIN 10).

Project description:BackgroundGLP-1 RA (glucagon-like peptide-1 receptor agonists), including semaglutide, may reduce stroke risk in people with type 2 diabetes. This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk.MethodsSUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and PIONEER 6 (Peptide Innovation for Early Diabetes Treatment) were randomized cardiovascular outcome trials of subcutaneous and oral semaglutide in people with type 2 diabetes at high cardiovascular risk, respectively. Time to first stroke and stroke subtypes were analyzed using a Cox proportional hazards model stratified by trial with pooled treatment as a factor. The impact of prior stroke, prior myocardial infarction or stroke, age, sex, systolic blood pressure, estimated glomerular filtration rate, and prior atrial fibrillation on treatment effects was assessed using interaction P values. Risk of major adverse cardiovascular event was analyzed according to prior stroke.ResultsA total of 106/6480 participants had a stroke (1.0 event/100 patient-years of observation [PYO]). Semaglutide reduced incidence of any stroke versus placebo (0.8 versus 1.1 events/100 PYO; hazard ratio, 0.68 [95% CI, 0.46-1.00]; P=0.048), driven by significant reductions in risk of small-vessel occlusion (0.3 versus 0.7 events/100 PYO; hazard ratio, 0.51 [95% CI, 0.29-0.89]; P=0.017). Hazard ratios for risk of any stroke with semaglutide versus placebo were 0.60 (95% CI, 0.37-0.99; 0.5 versus 0.9 events/100 PYO) and 0.89 (95% CI, 0.47-1.69; 2.7 versus 3.0 events/100 PYO) in those without and with prior stroke, respectively. Except for prior atrial fibrillation (Pinteraction=0.025), no significant interactions were observed between treatment effects on risk of any stroke and subgroups investigated, or between treatment effects on risk of major adverse cardiovascular event and prior stroke (Pinteraction >0.05 for all).ConclusionsSemaglutide reduced incidence of any first stroke during the trials versus placebo in people with type 2 diabetes at high cardiovascular risk, primarily driven by small-vessel occlusion prevention. Semaglutide treatment, versus placebo, lowered the risk of stroke irrespective of prior stroke at baseline.RegistrationURL: https://www.Clinicaltrialsgov; Unique identifier: NCT01720446 and NCT02692716.

Project description:To exclude an excess risk of cardiovascular (CV) events, CV outcomes trials (CVOTs) have assessed the effects of new glucose-lowering therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), in patients with type 2 diabetes and established CV disease or CV risk factors. The CV safety of semaglutide vs. placebo, when added to standard care, was evaluated in the SUSTAIN 6 trial for the formulation administered once-weekly subcutaneously and in PIONEER 6 for the new once-daily oral formulation. In SUSTAIN 6 and PIONEER 6, both powered to demonstrate noninferiority (upper 95% confidence interval [CI] of the hazard ratio [HR] <1.8), there were fewer first major adverse CV events with semaglutide vs. placebo, with HRs of 0.74 (95% CI 0.58-0.95) and 0.79 (0.57-1.11), respectively. In SUSTAIN 6, the results were significant for noninferiority and superiority, although the latter was not prespecified. Surprisingly, CV and all-cause mortality were significantly reduced by oral semaglutide in PIONEER 6. The ongoing SOUL CVOT will further inform about CV outcomes with oral semaglutide vs. placebo (NCT03914326). Findings from SUSTAIN 6 and PIONEER 6 fall within the spectrum reported with other GLP-1RA CVOTs: noninferiority vs. placebo for major CV events was seen with lixisenatide and exenatide extended-release, while superiority was demonstrated with liraglutide, albiglutide, and dulaglutide. Beneficial outcomes have been recognized in international guidelines, which recommend subcutaneous liraglutide, semaglutide, and dulaglutide to reduce the risk of CV events in high-risk patients. Both indirect mechanisms via risk factor modification and direct effects via GLP-1 receptors in the CV system have been proposed to be responsible for CV event reductions. The exact mechanism(s) remains to be characterized, but appears to be mainly linked to anti-atherosclerotic effects. Further research is needed to elucidate the relevant mechanisms for CV benefits of GLP-1RAs.

Dataset Information

Semaglutide reduces cardiovascular events regardless of metformin use: a post hoc subgroup analysis of SUSTAIN 6 and PIONEER 6.

Background

Methods

Results

Conclusion

Publications

Semaglutide reduces cardiovascular events regardless of metformin use: a post hoc subgroup analysis of SUSTAIN 6 and PIONEER 6.

Similar Datasets

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