Effect of semaglutide on major adverse cardiovascular events by baseline kidney parameters in participants with type 2 diabetes and at high risk of cardiovascular disease: SUSTAIN 6 and PIONEER 6 post hoc pooled analysis

Abstract

Background: Semaglutide 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.

Methods: Participants 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 (HbA_1c), body weight (BW) and serious adverse events (SAEs) across subgroups were also evaluated.

Results: Independently 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 [p_INT] > 0.05). Semaglutide reduced HbA_1c regardless of baseline eGFR and UACR (p_INT>0.05); reductions in BW were affected by baseline eGFR (p_INT<0.001) but not UACR (p_INT>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.

Conclusions: MACE 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 registrations: NCT01720446; NCT02692716.

Keywords: Cardiovascular disease; Estimated glomerular filtration rate; Glucagon-like peptide-1 receptor agonist; Kidney disease; Major cardiovascular events; NCT01720446; NCT02692716; Semaglutide; Type 2 diabetes; Urine albumin:creatinine ratio.

Fig. 1

Unadjusted analysis for risk of MACE by baseline eGFR and UACR regardless of treatment. *p values indicated for comparisons with reference groups (eGFR ≥ 60 mL/min/1.73 m² and UACR < 30 mg/g). ^†Participants with eGFR < 30 mL/min/1.73 m² from SUSTAIN 6 were included for the analysis in the eGFR < 45 mL/min/1.73 m² as well as UACR < 30, ≥30–≤300, and > 300 mg/g subgroups with the following numbers (%): 139 (19.0); 22 (1.1); 20 (2.3); 68 (16.2). ^‡SUSTAIN 6 data only; UACR was not measured in PIONEER 6. %, proportion of participants with ≥ 1 cardiovascular event; CI, confidence interval; eGFR, estimated glomerular filtration rate; HR, hazard ratio; MACE, major adverse cardiovascular event; N, total number of participants in pooled population or subgroup with eGFR or UACR values at baseline; n, number of participants with ≥ 1 cardiovascular event; UACR, urine albumin:creatinine ratio

Fig. 2

Adjusted analysis for the effect of semaglutide on MACE risk by baseline eGFR and UACR. *Cut-off point for ARR was 1 year for eGFR and 2 years for UACR. ^†Data previously published in Husain [18] (N numbers for total randomised participants, regardless of available baseline eGFR or UACR values, were 6,480 [total] and 3,297 [SUSTAIN 6]). ^‡Participants with eGFR < 30 mL/min/1.73 m² from SUSTAIN 6 were included for the analysis in the eGFR < 45 mL/min/1.73 m² as well as UACR < 30, ≥30–≤300, and > 300 mg/g subgroups with the following numbers (%): 139 (19.0); 22 (1.1); 20 (2.3); 68 (16.2). ^§SUSTAIN 6 data only; UACR was not measured in PIONEER 6. A Cox proportional hazards model was adjusted with inverse probability weighting, using baseline predictors of cardiorenal disease and continuous eGFR or UACR values at baseline. %, proportion of participants with ≥ 1 cardiovascular event; ARR, absolute risk reduction; CI, confidence interval; eGFR, estimated glomerular filtration rate; HR, hazard ratio; MACE, major adverse cardiovascular event; N, total number of participants in pooled population or subgroup with eGFR or UACR values at baseline; n, number of participants with ≥ 1 cardiovascular event; p_INT, interaction p value; UACR, urine albumin:creatinine ratio

Fig. 3

Event rate of first MACE by 2 years* by baseline eGFR and UACR values. *The event rate is defined as the probability (number of individuals per 100 individuals) to experience a first MACE within 2 years. A quadratic spline regression, using the Cox proportional hazard model, on predicted event rate of MACE by 2 years was calculated in per treatment arm across (A) eGFR and (B) UACR values, as well as in pooled treatment arms across the continuum of (C) eGFR and (D) UACR values. Data are presented as medians (solid lines); vertical black dashed lines represent percentile, quartile and median values. In panels A and B, blue and grey dashed lines represent 95% CIs for semaglutide and placebo, respectively. Baseline UACR values are transformed to the natural logarithmic (Ln) values. The number of events in defined intervals for each kidney parameter continuum are presented within the vertical black dashed lines defining the interval (two events occurred in participants without available UACR data at baseline). AIC, Akaike information criterion; CI, confidence interval; C-index, concordance index; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; E, number of events; M, median; MACE, major adverse cardiovascular event; P, percentile; Q, quartile; UACR, urine albumin:creatinine ratio