Leiter et al. Cardiovasc Diabetol (2019) 18:73
`https://doi.org/10.1186/s12933-019-0871-8
`
`Cardiovascular Diabetology
`
`Open Access
`
`ORIGINAL INVESTIGATION
`Cardiovascular risk reduction
`with once-weekly semaglutide in subjects
`with type 2 diabetes: a post hoc analysis
`of gender, age, and baseline CV risk profile
`in the SUSTAIN 6 trial
`
`Lawrence A. Leiter1*, Stephen C. Bain2, Irene Hramiak3, Esteban Jódar4, Sten Madsbad5, Theis Gondolf6,
`Thomas Hansen6, Ingrid Holst6 and Ildiko Lingvay7
`
`Abstract
`Background: The SUSTAIN 6 trial demonstrated that once-weekly semaglutide (0.5 and 1.0 mg) significantly reduced
`major adverse cardiovascular (CV) events (MACE) vs placebo in subjects with type 2 diabetes (T2D) and high CV risk.
`The effects of gender, age and baseline CV risk on outcomes are important considerations for further study.
`Methods: Subjects were grouped according to gender, age (50–65 years and > 65 years), and CV risk profile at
`baseline (prior myocardial infarction [MI] or stroke vs no prior MI or stroke, and established CV disease [CVD] vs CV risk
`factors alone, including subjects with chronic kidney disease). Time to MACE and its individual components (CV death,
`nonfatal MI, nonfatal stroke), hospitalization for unstable angina or heart failure, and revascularization (coronary and
`peripheral) were analyzed for all subgroups. Additional analyses were performed for gender and age to investigate
`change from baseline in HbA1c and body weight, as well as tolerability.
`Results: A total of 3297 subjects were included. The majority of subjects (60.7%) were male; 43% were > 65 years
`of age; 41.5% had a history of MI or stroke; and 76.8% had established CVD. Compared with placebo, semaglutide
`reduced the risk of the first occurrence of MACE and each MACE component consistently across all subgroups
`(gender, age, and baseline CV risk profile). Revascularizations, HbA1c and body weight were also reduced consistently
`across all subgroups compared with placebo. Gastrointestinal adverse events in all treatment groups were more com-
`mon among women than men, but rates of premature treatment discontinuation were similar for both genders.
`Conclusions: In this post hoc analysis of SUSTAIN 6, once-weekly semaglutide vs placebo reduced the risk of MACE
`in all subjects included in the trial, regardless of gender, age, or baseline CV risk profile.
`Trial registry Clinicaltrials.gov, Identifying number: NCT01720446, Date of registration: October 29, 2012
`Keywords: Semaglutide, Cardiovascular events, Gender, Age, Baseline cardiovascular risk, Type 2 diabetes, SUSTAIN 6,
`Cardiovascular outcome trial
`
`*Correspondence: leiterl@smh.ca
`1 Division of Endocrinology and Metabolism, Li Ka Shing Knowledge
`Institute, St. Michael’s Hospital, University of Toronto, 61 Queen St. East
`#6121, Toronto, ON M5C 2T2, Canada
`Full list of author information is available at the end of the article
`
`© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
`(http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
`provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
`and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/
`publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
`
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`Leiter et al. Cardiovasc Diabetol (2019) 18:73
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`
`Background
`Cardiovascular disease (CVD) is the leading cause of
`morbidity and mortality in people with type 2 diabe-
`tes (T2D) [1, 2], and diabetes itself confers a substantial
`independent risk of coronary heart disease, stroke, and
`death from other vascular causes [3]. Current diabetes
`guidelines recommend multifactorial CV risk manage-
`ment and the preferential use of a glucagon-like pep-
`tide-1 receptor agonist  (GLP-1RA) or sodium–glucose
`cotransporter-2 inhibitor with proven CV benefits as a
`first choice add-on to metformin in patients with T2D
`and established atherosclerotic CVD [2, 4]. Semaglutide
`is a GLP-1 analogue approved as a once-weekly, subcu-
`taneous treatment for T2D [5, 6]. The phase 3 SUSTAIN
`(Semaglutide Unabated Sustainability in Treatment of
`Type 2 Diabetes) clinical trial program evaluated the effi-
`cacy and safety of semaglutide in subjects with T2D in a
`range of patient populations across the continuum of dia-
`betes care [7–14]. In the SUSTAIN 6 CV outcomes trial
`(CVOT), once-weekly semaglutide (0.5 or 1.0 mg) added
`to standard of care significantly reduced the occurrence
`of a first major adverse CV event (MACE: CV death,
`nonfatal myocardial infarction [MI], or nonfatal stroke)
`vs placebo over 2  years in 3297 subjects with T2D and
`high CV risk [12]. Given the increasing emphasis on indi-
`vidualized patient care in the management of T2D [4],
`this post hoc analysis assessed the effects of gender, age,
`and baseline CV risk on the reduction of CV risk in the
`SUSTAIN 6 trial.
`
`Methods
`SUSTAIN 6 study design
`(clinicaltrials.gov
`6
`The
`design
`of
`SUSTAIN
`NCT01720446) has been described previously [12]. In
`brief, SUSTAIN 6 was a randomized, double-blind, pla-
`cebo-controlled, parallel-group trial to evaluate once-
`weekly semaglutide 0.5 or 1.0  mg vs volume-matched
`placebo over a 104-week treatment period plus a 5-week
`follow-up period. The trial was conducted in compliance
`with the International Conference on Harmonisation
`Good Clinical Practice guidelines and the Declaration of
`Helsinki [15, 16]. The protocol was approved by local eth-
`ics committees and institutional review boards. Written
`informed consent was obtained from all subjects before
`trial commencement.
`A total of 3297 subjects with T2D (HbA1c ≥ 7%)
`were randomized to receive once-weekly semaglutide
`0.5 or 1.0  mg or placebo for 104  weeks. Subjects were
`≥ 50 years of age with established CVD (defined as previ-
`ous CV, cerebrovascular, or peripheral vascular disease),
`chronic heart failure (New York Heart Association class
`II or III), or chronic kidney disease (CKD) of stage 3 or
`higher, or were ≥ 60 years of age with at least one CV risk
`
`factor (microalbuminuria or proteinuria, hypertension
`and left ventricular hypertrophy, left ventricular systolic
`or diastolic dysfunction or ankle–brachial index < 0.9).
`All subjects treated with semaglutide followed a fixed
`dose-escalation regimen, with a starting dose of 0.25 mg
`for 4 weeks that escalated to 0.5 mg for 4 weeks until the
`maintenance dose (0.5 or 1.0 mg) was reached.
`The primary composite outcome (MACE) was the first
`occurrence of death from CV causes, nonfatal MI, or
`nonfatal stroke. Other outcomes included time to first
`hospitalization for unstable angina and heart failure, time
`to first revascularization (coronary or peripheral), and
`changes in HbA1c and weight. All outcomes were col-
`lected after 104 weeks of treatment.
`
`Statistical analysis
`This post hoc analysis examined the effect of gender, age
`(subjects aged 50–65 and > 65 years), and CV risk profile
`at baseline on time to first occurrence of MACE, the indi-
`vidual components of MACE (CV death, nonfatal MI, or
`nonfatal stroke), hospitalization for unstable angina or
`heart failure, and revascularization. Additional analyses
`were performed by gender and age to investigate changes
`from baseline in HbA1c and body weight, adverse events
`(AEs), and hypoglycemia, as defined by the American
`Diabetes Association (ADA) [17].
`For comparison of outcomes between men and women,
`estimated hazard ratios (HRs) and associated confidence
`intervals (CIs) were determined by a Cox proportional
`hazards model with an interaction between treatment
`(semaglutide, placebo) and gender as a fixed factor. Effi-
`cacy and safety were assessed by age group using post
`hoc subgroup analyses of subjects ≤ 65 and > 65  years.
`Post-baseline responses for time to first occurrence of
`MACE, CV death, nonfatal MI, nonfatal stroke, hospi-
`talization for unstable angina or heart failure, revascu-
`larization, and change from baseline in HbA1c and body
`weight were analyzed using a mixed model for repeated
`measurements with interaction between subgroup, ran-
`domized treatment, and baseline value as covariate. No
`adjustment for multiplicity was performed. A significance
`level for interaction of 5% was considered significant. To
`investigate more general linear and non-linear effects of
`age at baseline, individual outcomes and AEs were mod-
`elled as a function of age, controlling for randomized
`treatment and CVD at baseline via negative-binomial
`log regression (see “Post hoc analysis by age”). Analyses
`were based on pooled data using semaglutide 0.5 mg and
`1.0 mg doses for MACE and its components, hospitaliza-
`tion due to angina or heart failure, revascularization, and
`AEs. HbA1c and body weight were reported separately for
`both semaglutide doses following the statistical methods
`used in the primary SUSTAIN 6 trial [12].
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`Leiter et al. Cardiovasc Diabetol (2019) 18:73
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`
`CV risk profile subgroups
`To assess the effect of baseline CV risk profiles on
`outcomes, two separate subgroup analyses were per-
`formed: (1) for subjects who had experienced a prior
`MI or stroke compared with those who had not, and (2)
`for those with established CVD, defined as prior stroke,
`ischemic heart disease (including MI), peripheral
`arterial disease, ≥ 50% arterial stenosis in any artery,
`coronary revascularization (percutaneous coronary
`intervention or coronary artery bypass graft), or heart
`failure vs those with CV risk factors alone and no mani-
`festations of CVD as defined above. The risk classifica-
`tion in the latter subgroup comparison differs from the
`prespecified group of evidence of CVD in SUSTAIN
`6, in which subjects with CKD stage 3 or higher were
`included [12]. In this post hoc analysis, however, sub-
`jects with CKD were included in the CV risk factor
`alone group to reflect the usual definition of established
`CVD used in clinical practice. Statistical analyses were
`carried out using Cox proportional hazards models for
`time to first MACE with treatment, and treatment by
`subgroup interaction, if applicable, as fixed factor(s).
`No adjustment for multiplicity was performed. A sig-
`nificance level for interaction of 5% was considered
`significant.
`
`Results
`Post hoc analysis by gender
`Among 3297 subjects in the SUSTAIN 6 study
`population, 2002 were male and 1295 were female
`(Table 1A). There were no clear differences in subject
`demographics or key baseline characteristics between
`men and women, with the exception of weight (men
`tended to be heavier) and smoking status (51.7 vs
`26.1% and 56.1 vs 23.0% of men vs women had a
`history of smoking in the semaglutide and placebo
`groups, respectively). Similar proportions of male
`and female subjects completed the trial and treat-
`ment. MACE occurred in lower proportions of sub-
`jects treated with semaglutide vs placebo in both men
`and women, and this overall benefit was independ-
`ent of gender (p = 0.45 for interaction) (Fig.  1). The
`same pattern was noted across the individual MACE
`components of CV death, nonfatal MI and nonfatal
`stroke; lower or similar proportions of both men and
`women experienced events with semaglutide vs pla-
`cebo, and p-values for interaction were nonsignificant
`(p = 0.46, p = 0.34 and p = 0.74, respectively, for each
`endpoint) (Fig. 1). Gender had no apparent effect on
`first hospitalization for unstable angina (p = 0.35 for
`interaction) or heart failure (p = 0.55 for interaction),
`or time to first revascularization procedure (p = 0.50
`for interaction; Fig. 2).
`
`Post hoc analysis by age
`In
`the SUSTAIN 6 study, 1879 subjects were
`50–65 years of age and 1418 were > 65 years (Table 1B).
`There were no clear differences in subject demograph-
`ics or key baseline characteristics between groups.
`Duration of diabetes was greater in subjects > 65 years
`compared with those ≤ 65  years (16.4 vs 12.6  years
`for the semaglutide group and 15.2 vs 12.4  years for
`the placebo group). Similar proportions of subjects
`in each age group completed the trial and treatment.
`HRs for time to first confirmed MACE were all below
`1.0 for subjects treated with semaglutide vs placebo,
`irrespective of age (p = 0.92 for interaction, Fig.  1).
`Results were consistent for the individual components
`of MACE across age groups (Fig. 1; p = 0.35, p = 0.42,
`and p = 0.45 for interaction, respectively, for CV death,
`nonfatal MI, and nonfatal stroke). Age had no appar-
`ent effect on first hospitalization due to unstable angina
`(p = 0.16 for interaction), heart failure (p = 0.26 for
`interaction) or revascularization procedures (p = 0.97
`for interaction; Fig.  2). A series of regression analyses
`were conducted to assess more general linear and non-
`linear trends for the incidence of MACE by age; since
`no significant effects were found, these have not been
`reported further (see Additional file 1).
`
`Post hoc analysis by CV risk
`Pooled key baseline characteristics, CV risk factors, and
`manifestation of CVD at baseline for the two CV sub-
`groups [subjects with prior MI or stroke vs no prior MI
`or stroke and subjects with established CVD vs risk fac-
`tors only (including CKD)] are shown in Table  1C. In
`total, 1367 subjects had a history of MI or stroke (vs 1930
`without prior history) and 2533 had established CVD (vs
`764 with CV risk factors only).
`Hazard ratios for time to first confirmed MACE were
`all below 1.0 in subjects treated with semaglutide vs
`placebo, irrespective of baseline CV risk profile (Fig. 3).
`Similar results were observed across the individual com-
`ponents of MACE, with the exception of CV death in
`subjects with a prior MI or stroke or with established
`CVD (p = 0.22 for interaction between subjects with
`prior MI or stroke vs no prior MI or stroke; p = 0.52 for
`interaction between subjects with established CVD vs
`risk factors only) (Fig. 2).
`In the SUSTAIN 6 trial, there was no difference in
`hospitalization for angina or heart failure between
`semaglutide and placebo [12], and this result was
`independent of baseline CV risk profile (Fig.  2). The
`between-group interaction for unstable angina in sub-
`jects with prior MI or stroke compared with no prior MI
`or stroke was significant (p = 0.02 for interaction), with
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`
`Table 1 Baseline characteristics and demographics of subjects in the SUSTAIN 6 trial
`
`A. Post hoc analysis by gender
`
` Subject demographics
` Full analysis set, N
` Trial completers, n (%)
` Treatment completers, n (%)
` Baseline characteristicsa
` Age, years
` Body weight, kg
` BMI, kg/m2
` Diabetes duration, years
` HbA1c, %
` Smoking status (never/previous/current),
`%
`B. Post hoc analysis by age
`
`Semaglutide
`
`Male
`
`1013
`959 (94.7)
`773 (76.3)
`
`64.6 (7.3)
`96.7 (20.5)
`32.3 (5.9)
`13.9 (8.1)
`8.6 (1.4)
`33.5/51.7/14.8
`
`Semaglutide
`≤ 65 years
`
` Subject demographics
` Full analysis set, N
` Trial completers, n (%)
` Treatment completers, n (%)
` Baseline characteristicsb
` Age, years
` Females, %
` Body weight, kg
` BMI, kg/m2
` Diabetes duration, years
` HbA1c, %
` Smoking status (never/previous/cur-
`rent), %
`C. Post hoc analyses by CV risk profile at baseline
`
`950
`899 (94.6)
`745 (78.4)
`
`59.7 (4.1)
`38.4
`94.0 (21.1)
`33.3 (6.4)
`12.6 (7.2)
`8.9 (1.6)
`47.0/37.1/16.0
`
`Female
`
`635
`602 (94.8)
`481 (75.7)
`
`64.8 (7.1)
`85.4 (19.0)
`33.7 (6.6)
`14.5 (8.4)
`8.8 (1.6)
`65.4/26.1/8.5
`
`> 65 years
`
`698
`662 (94.8)
`509 (72.9)
`
`71.4 (4.7)
`38.7
`90.0 (19.8)
`32.2 (5.9)
`16.4 (8.9)
`8.4 (1.2)
`44.1/48.4/7.5
`
`Placebo
`
`Male
`
`989
`926 (93.6)
`788 (79.7)
`
`64.6 (7.6)
`95.8 (21.0)
`32.1 (6.0)
`13.5 (8.0)
`8.6 (1.4)
`30.1/56.1/13.7
`
`Placebo
`≤ 65 years
`
`929
`875 (94.2)
`745 (80.2)
`
`59.2 (4.3)
`40.9
`93.0 (21.4)
`33.1 (6.4)
`12.4 (7.4)
`8.9 (1.6)
`45.3/39.0/15.7
`
`Female
`
`660
`623 (94.4)
`514 (77.9)
`
`64.6 (7.5)
`86.0 (18.4)
`33.9 (6.3)
`13.8 (8.1)
`8.8 (1.6)
`66.8/23.0/10.2
`
`> 65 years
`
`720
`674 (93.6)
`557 (77.4)
`
`71.6 (4.5)
`38.9
`90.5 (19.3)
`32.4 (5.8)
`15.2 (8.5)
`8.4 (1.3)
`44.2/47.9/7.8
`
`Semaglutide
`
`Prior MI/
`stroke
`
`No prior MI/
`stroke
`
`Placebo
`
`Prior MI/
`stroke
`
`Semaglutide
`
`No prior MI/
`stroke
`
`Established
`CVD
`
`CV risk
`factors
`
`Placebo
`
`Established
`CVD
`
`CV risk factors
`
`673
`
` Full analysis
`set, N
` Baseline characteristics
` Age, years
`63.8 (7.5)
` Female, n (%)
`208 (30.9)
` Diabetes
`13.7 (8.5)
`duration, years
` BMI, kg/m2
` HbA1c, %
` CV risk factors
` Systolic blood
`pressure,
`mmHg
`
`32.6 (6.0)
`8.8 (1.6)
`
`134.6 (17.7)
`
`975
`
`694
`
`955
`
`1262
`
`386
`
`1271
`
`378
`
`65.2 (6.9)
`427 (43.8)
`14.5 (8.0)
`
`33.0 (6.4)
`8.7 (1.4)
`
`63.6 (7.9)
`225 (32.4)
`13.3 (8.1)
`
`32.7 (6.2)
`8.7 (1.5)
`
`65.3 (7.2)
`435 (45.5)
`13.8 (8.0)
`
`32.8 (6.2)
`8.7 (1.4)
`
`64.2 (7.3)
`445 (35.3)
`14.0 (8.4)
`
`32.8 (6.1)
`8.7 (1.5)
`
`66.1 (6.5)
`190 (49.2)
`14.8 (7.6)
`
`32.8 (6.5)
`8.7 (1.4)
`
`64.2 (7.7)
`463 (36.4)
`13.3 (7.9)
`
`33.0 (6.2)
`8.7 (1.5)
`
`66.0 (6.7)
`197 (52.1)
`14.6 (8.2)
`
`32.3 (6.1)
`8.7 (1.5)
`
`136.9 (17.3)
`
`134.9 (17.1)
`
`135.5 (16.6)
`
`135.5 (17.5)
`
`137.5 (17.5)
`
`134.9 (16.6)
`
`136.5 (17.4)
`
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`
`Table 1 (continued)
`
`C. Post hoc analyses by CV risk profile at baseline
`
`Semaglutide
`
`Prior MI/
`stroke
`
`No prior MI/
`stroke
`
`Placebo
`
`Prior MI/
`stroke
`
`Semaglutide
`
`No prior MI/
`stroke
`
`Established
`CVD
`
`CV risk
`factors
`
`Placebo
`
`Established
`CVD
`
`CV risk factors
`
`76.8 (9.9)
`
`77.1 (10.1)
`
`76.7 (10.4)
`
`77.4 (9.8)
`
`76.7 (10.0)
`
`77.9 (9.8)
`
`77.0 (10.2)
`
`77.5 (9.6)
`
`4.2 (26.8)
`
`4.4 (25.5)
`
`4.2 (27.9)
`
`4.3 (26.5)
`
`4.3 (26.9)
`
`4.4 (23.6)
`
`4.2 (27.6)
`
`4.4 (25.4)
`
`72.1 (39.2)
`
`70.1 (41.4)
`
`73.8 (39.8)
`
`69.0 (44.6)
`
`72.9 (38.7)
`
`64.9 (44.8)
`
`73.9 (39.7)
`
`61.7 (49.2)
`
`106 (15.8)
`
`98 (10.1)
`
`109 (15.7)
`
`93 (9.74)
`
`170 (13.5)
`
`34 (8.8)
`
`167 (13.1)
`
`35 (9.3)
`
`542 (78.1)
`589 (84.9)
`
`–
`417 (43.7)
`
`530 (42.0)
`988 (78.3)
`
`–
`–
`
`542 (42.6)
`1006 (79.2)
`
`–
`–
`
` Diastolic blood
`pressure,
`mmHg
` Total
`cholesterol,
`mmol/L
`[mean (CoV)]
` eGFR, mL/
`min/1.73 m2
`[mean (CoV)]
` Current
`smoker,
`n (%)
` Manifestation of CVD
`530 (78.8)
` Prior MI, n (%)
` Ischemic heart
`571 (84.8)
`disease,
`n (%)
` Prior stroke,
`n (%)
` Peripheral
`arterial
`disease, n (%)
` ≥ 50% arterial
`stenosis,
`n (%)
` Percutaneous
`coronary
`intervention,
`n (%)
` Coronary
`artery
`bypass graft,
`n (%)
` Heart failure,
`n (%)
`
`182 (27.0)
`
`187 (27.8)
`
`191 (28.4)
`
`87 (12.9)
`
`327 (48.6)
`
`327 (48.6)
`
`–
`417 (42.8)
`
`–
`
`210 (30.3)
`
`–
`
`191 (15.1)
`
`139 (14.3)
`
`89 (12.8)
`
`138 (14.5)
`
`226 (17.9)
`
`240 (24.6)
`
`361 (52.0)
`
`239 (25.0)
`
`567 (44.9)
`
`163 (16.7)
`
`342 (49.3)
`
`180 (18.8)
`
`490 (38.8)
`
`106 (10.9)
`
`182 (26.2)
`
`107 (11.2)
`
`288 (22.8)
`
`194 (19.9)
`
`185 (26.7)
`
`211 (22.1)
`
`381 (30.2)
`
`–
`
`–
`
`–
`
`–
`
`–
`
`–
`
`210 (16.5)
`
`227 (17.9)
`
`600 (47.2)
`
`522 (41.1)
`
`289 (227)
`
`396 (31.2)
`
`–
`
`–
`
`–
`
`–
`
`–
`
`–
`
`Data presented as mean (SD) unless otherwise indicated. Data were pooled for semaglutide groups and placebo groups in each SUSTAIN 6 subgroup
`BMI body mass index, CoV coefficient of variation, CV cardiovascular, CVD cardiovascular disease, eGFR estimated glomerular filtration rate, MI myocardial infarction,
`SD standard deviation
`a Numbers are based on an in-trial analysis comprising events with onset on or after the day of randomization and until end of trial
`b Data were pooled for semaglutide groups and placebo groups in each SUSTAIN 6 subgroup
`
`a significant reduction in hospitalization for unstable
`angina for semaglutide vs placebo in subjects with no
`prior MI or stroke (p = 0.03). No significant interactions
`were noted for hospitalization for heart failure between
`the various risk groups (Fig. 2; p = 0.59 for interaction
`between subjects with prior MI or stroke vs no prior MI
`or stroke and p = 0.93 for interaction between subjects
`with established CVD vs CV risk factors only).
`
`Semaglutide reduced time to first revasculariza-
`tion vs placebo in the overall study; this result was
`observed regardless of baseline CV risk profile, with
`no significant differences between subgroups (p = 0.25
`for interaction between subjects with prior MI or
`stroke vs no prior MI or stroke and p = 0.27 for inter-
`action between subjects with established CVD vs CV
`risk factors only).
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`Leiter et al. Cardiovasc Diabetol (2019) 18:73
`
`Page 6 of 12
`
`Event/subgroup
`
`MACE
`All subjects
`Gender
`Male
`Female
`Age, years
`≤65
`>65
`CV risk
`Prior MI/stroke
`No prior MI/stroke
`Established CVD
`CV risk factors
`
`CV death
`All subjects
`Gender
`Male
`Female
`Age, years
`≤65
`>65
`CV risk
`Prior MI/stroke
`No prior MI/stroke
`Established CVD
`CV risk factors
`
`Nonfatal MI
`All subjects
`Gender
`Male
`Female
`Age, years
`≤65
`>65
`CV risk
`Prior MI/stroke
`No prior MI/stroke
`Established CVD
`CV risk factors
`
`Nonfatal stroke
`All subjects
`Gender
`Male
`Female
`Age, years
`≤65
`>65
`CV risk
`Prior MI/stroke
`No prior MI/stroke
`Established CVD
`CV risk factors
`
`Events (subjects)
`semaglutide / placebo
`
`HR
`
`[95% CI]
`
`Interaction
`p-value
`
`108 (1648) / 146 (1649)
`
`0.74
`
`[0.58;0.95]
`
`73 (1013) / 103 (989)
`35 (635) / 43 (660)
`
`57 (950) / 76 (929)
`51 (698) / 70 (720)
`
`66 (673) / 88 (694)
`42 (975) / 58 (955)
`97 (1262) / 124 (1271)
`11 (386) / 22 (378)
`
`0.68
`0.84
`
`0.72
`0.74
`
`0.76
`0.70
`0.78
`0.48
`
`[0.50;0.92]
`[0.54;1.31]
`
`[0.51;1.02]
`[0.52;1.06]
`
`[0.55;1.05]
`[0.47;1.04]
`[0.60;1.01]
`[0.23;0.99]
`
`44 (1648) / 46 (1649)
`
`0.98
`
`[0.65;1.48]
`
`30 (1013) / 34 (989)
`14 (635) / 12 (660)
`
`26 (950) / 22 (929)
`18 (698) / 24 (720)
`
`27 (673) / 23 (694)
`17 (975) / 23 (955)
`40 (1262) / 40 (1271)
`4 (386) / 6 (378)
`
`0.86
`1.21
`
`1.15
`0.77
`
`1.22
`0.72
`1.01
`0.65
`
`[0.53;1.40]
`[0.56;2.61]
`
`[0.65;2.03]
`[0.42;1.43]
`
`[0.70;2.11]
`[0.38;1.35]
`[0.65;1.56]
`[0.18;2.30]
`
`47 (1648) / 64 (1649)
`
`0.74
`
`[0.51;1.08]
`
`32 (1013) / 48 (989)
`15 (635) / 16 (660)
`
`22 (950) / 34 (929)
`25 (698) / 30 (720)
`
`30 (673) / 44 (694)
`17 (975) / 20 (955)
`44 (1262) / 54 (1271)
`3 (386) / 10 (378)
`
`0.64
`0.97
`
`0.63
`0.85
`
`0.70
`0.83
`0.82
`0.29
`
`[0.41;1.01]
`[0.48;1.96]
`
`[0.37;1.07]
`[0.50;1.45]
`
`[0.44;1.11]
`[0.43;1.58]
`[0.55;1.22]
`[0.08;1.05]
`
`27 (1648) / 44 (1649)
`
`0.61
`
`[0.38;0.99]
`
`18 (1013) / 27 (989)
`9 (635) / 17 (660)
`
`12 (950) / 23 (929)
`15 (698) / 21 (720)
`
`16 (673) / 25 (694)
`11 (975) / 19 (955)
`23 (1262) / 37 (1271)
`4 (386) / 7 (378)
`
`0.65
`0.55
`
`0.51
`0.73
`
`0.66
`0.56
`0.62
`0.55
`
`[0.36;1.17]
`[0.24;1.22]
`
`[0.25;1.02]
`[0.38;1.42]
`
`[0.35;1.23]
`[0.27;1.18]
`[0.37;1.04]
`[0.16;1.89]
`
`0.45
`
`0.92
`
`0.75
`
`0.22
`
`0.46
`
`0.35
`
`0.22
`
`0.52
`
`0.34
`
`0.42
`
`0.67
`
`0.13
`
`0.74
`
`0.45
`
`0.75
`
`0.87
`
`1
`
`2
`
`2.5
`
`3
`
`1.5
`0
`0.5
`Favors semaglutide
`Favors placebo
`HR (semaglutide:placebo)
`Fig. 1 Treatment differences in MACE and MACE components in SUSTAIN 6. Analysis of time from randomization to first event adjudication
`committee-confirmed event. Subjects were censored at their planned end-of-trial visit, last direct subject-site contact or all-cause death of the
`subject, whichever occurred first. Estimated HRs and associated CIs are from a Cox proportional hazards model with an interaction between
`treatment (semaglutide, placebo) and subgroups as fixed factors. The p-values are 2-sided for test for heterogeneity of treatment between
`subgroups. CI confidence interval, CV cardiovascular, CVD cardiovascular disease, HR hazard ratio, MI myocardial infarction
`
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`Leiter et al. Cardiovasc Diabetol (2019) 18:73
`
`Page 7 of 12
`
`Event/subgroup
`Hospitalization for
`unstable angina
`All subjects
`Gender
`Male
`Female
`Age, years
`≤65
`>65
`CV risk
`Prior MI/stroke
`No prior MI/stroke
`Established CVD
`CV risk factors
`
`Hospitalization for
`heart failure
`All subjects
`Gender
`Male
`Female
`Age, years
`≤65
`>65
`CV risk
`Prior MI/stroke
`No prior MI/stroke
`Established CVD
`CV risk factors
`
`Revascularization
`All subjects
`Gender
`Male
`Female
`Age, years
`≤65
`>65
`CV risk
`Prior MI/stroke
`No prior MI/stroke
`Established CVD
`CV risk factors
`
`Events (subjects)
`semaglutide / placebo
`
`HR
`
`[95% CI]
`
`Interaction
`p-value
`
`22 (1648) / 27 (1649)
`
`0.82
`
`[0.47;1.44]
`
`13 (1013) / 19 (989)
`9 (635) / 8 (660)
`
`0.66
`1.17
`
`[0.33;1.35]
`[0.45;3.03]
`
`16 (950) / 14 (929)
`6 (698) / 13 (720)
`
`1.40
`0.47
`
`[0.80;2.44]
`[0.18;1.24]
`
`17 (673) / 12 (694)
`5 (975) / 15 (955)
`22 (1262) / 25 (1271)
`0 (386) / 2 (378)
`
`1.47
`0.32
`0.89
`0
`
`[0.70;3.08]
`[0.12;0.89]
`[0.50;1.57]
`[0;NE]
`
`59 (1648) / 54 (1649)
`
`1.11
`
`[0.77;1.61]
`
`41 (1013) / 34 (989)
`18 (635) / 20 (660)
`
`1.18
`0.93
`
`[0.75;1.86]
`[0.49;1.76]
`
`30 (950) / 21 (929)
`29 (698) / 33 (720)
`
`1.40
`0.91
`
`[0.80;2.44]
`[0.55;1.49]
`
`27 (673) / 28 (694)
`32 (975) / 26 (955)
`52 (1262) / 48 (1271)
`7 (386) / 6 (378)
`
`0.99
`1.21
`1.09
`1.15
`
`[0.58;1.68]
`[0.72;2.04]
`[0.74;1.62]
`[0.39;3.41]
`
`83 (1648) / 126 (1649)
`
`0.65
`
`[0.50;0.86]
`
`55 (1013) / 87 (989)
`28 (635) / 39 (660)
`
`0.61
`0.74
`
`[0.43;0.85]
`[0.46;1.20]
`
`48 (950) / 71 (929)
`35 (698) / 55 (720)
`
`0.65
`0.65
`
`[0.45;0.94]
`[0.42;0.99]
`
`49 (673) / 66 (694)
`34 (975) / 60 (955)
`80 (1262) / 117 (1271)
`3 (386) / 9 (378)
`
`0.76
`0.55
`0.68
`0.32
`
`[0.52;1.10]
`[0.36;0.83]
`[0.51;0.90]
`[0.09;1.19]
`
`0.35
`
`0.16
`
`0.02
`
`0.99
`
`0.55
`
`0.26
`
`0.59
`
`0.93
`
`0.50
`
`0.97
`
`0.25
`
`0.27
`
`1
`
`2.5
`
`3
`
`3.5
`
`2
`1.5
`0
`0.5
`Favors semaglutide
`Favors placebo
`HR (semaglutide:placebo)
`Fig. 2 Treatment differences in hospitalization for unstable angina or heart failure, and revascularization in SUSTAIN 6. Analysis of time from
`randomization to first event adjudication committee-confirmed event. Subjects were censored at their planned end-of-trial visit, last direct
`subject-site contact or all-cause death of the subject, whichever occurred first. Estimated HRs and associated CIs are from a Cox proportional
`hazards model with an interaction between treatment (semaglutide, placebo) and subgroups as fixed factors. The p-values are 2-sided for test for
`heterogeneity of treatment between subgroups. CI confidence interval, CV cardiovascular, HR hazard ratio, NE non-estimable
`
`Reductions in  HbA1c and body weight by gender and age
`Significantly greater reductions in HbA1c were achieved
`by subjects treated with semaglutide than by those
`receiving placebo, and this decrease was consistent for
`both genders (ETD for semaglutide 0.5 and 1.0  mg vs
`placebo: − 0.65% [95% CI − 0.80; − 0.49] and − 0.96%
`
`[95% CI − 1.11; − 0.81], respectively in males and
`− 0.75% [95% CI − 0.94; − 0.56] and − 1.09% [95%
`CI − 1.28; − 0.89], respectively in females; Fig.  4a)
`and across age groups (ETDs for semaglutide 0.5 and
`1.0 mg vs placebo were − 0.72% [95% CI − 0.88; − 0.56]
`and − 1.13% [95% CI − 1.29; − 0.97], respectively,
`
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`Leiter et al. Cardiovasc Diabetol (2019) 18:73
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`Page 8 of 12
`
`Fig. 3 Time from baseline to first confirmed MACE in SUSTAIN 6. In subjects with a prior MI/stroke (a) vs no prior MI/stroke (b) (p = 0.75 for
`interaction) and in subjects with established CVD (c) vs CV risk factors only (including CKD) (p = 0.22 for interaction) (d). Kaplan–Meier estimates:
`Cox proportional hazards models of time from randomization to first EAC-confirmed MACE in the full analysis set, and treatment by subgroup
`interaction, if applicable, as fixed factor(s). Data were pooled for semaglutide groups and placebo groups, respectively. CI confidence interval, CKD
`chronic kidney disease, CV cardiovascular, CVD cardiovascular disease, EAC event adjudication committee, HR hazard ratio, MACE major adverse
`cardiovascular event, MI myocardial infarction
`
`Fig. 4 Change from baseline in HbA1c and body weight by gender (a, c) and age (b, d) in SUSTAIN 6. ETD estimated treatment difference
`
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`Page 9 of 12
`
`1.4
`
`2.0
`
`1.7
`
`1.4
`
`Severe hypoglycemia
`
`†
`
`55.6
`
`48.5
`
`32.0
`
`37.7
`
`32.8
`
`33.3
`
`38.9
`
`33.0
`
`36.2
`
`32.5
`
`33.0
`
`27.9
`
`12.5
`
`7.1
`
`13.9
`
`6.1
`
`88.2
`
`89.1
`
`89.1
`
`87.4
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Proportion of patients (%)
`
`Any AE*
`
`Serious AE*
`
`AE leading to premature
`treatment
`discontinuation*
`
`Gastrointestinal AE*
`
`Symptomatic
`†
`hypoglycemia
`
`Placebo females
`Semaglutide females
`Placebo males
`Semaglutide males
`Fig. 5 Adverse events by gender in SUSTAIN 6. *On-treatment analysis comprising events with onset from the date of first dose to either the
`end-of-treatment follow-up visit, the date of last dose plus 42 days, the end-of-trial follow-up visit, or the date of withdrawal from trial, whichever
`came first (semaglutide males: n = 1007; semaglutide females: n = 635; placebo males: n = 987; placebo females: n = 657). †Full analysis set
`documented symptomatic hypoglycemia and severe hypoglycemia as defined by the American Diabetes Association [17] (semaglutide males:
`n = 1013; semaglutide females: n = 635; placebo males: n = 989; placebo females: n = 660). AE adverse event
`
`in ≤ 65  years, and − 0.66% [95% CI − 0.84; − 0.47]
`and − 0.85% [95% CI − 1.03; − 0.67], respectively, in
`> 65  years; Fig.  4b). The  p-values for all comparisons
`between gender and age groups were nonsignificant.
`Greater weight loss was observed with semaglutide
`0.5 and 1.0 mg compared with placebo in both genders
`(ETD − 2.86 kg [95% CI − 3.52; − 2.19] and − 3.68 kg
`[95% CI − 4.33; − 3.03] in males and − 3.04 kg [95% CI
`− 3.85; − 2.23] and − 5.27 kg [95% CI − 6.11; − 4.43] in
`females; Fig. 4c) and in subjects ≤ 65 and > 65 years of
`age (ETDs for semaglutide 0.5 and 1.0 mg vs placebo:
`− 2.90 kg [95% CI − 3.58; − 2.23] and − 3.87 kg [− 4.56;
`− 3.18], respectively, and − 3.02  kg [− 3.82; − 2.22]
`and − 4.72  kg [− 5.50; − 3.95], respectively; Fig.  4d).
`The  p-values for all between-group comparisons were
`nonsignificant.
`
`Adverse effects by gender and age
`Similar proportions of men and women reported AEs
`across treatment groups (Fig. 5). Proportions of serious
`AEs were comparable between semaglutide and placebo
`for males (32.5 vs 36.2%) and females (27.9 vs 33.0%). The
`most frequently reported AEs were gastrointestinal (GI)
`in nature, and they occurred more often with semaglu-
`tide than placebo in both males and females. Female sub-
`jects reported more GI AEs in all groups compared with
`men (55.6 vs 48.5% for semaglutide and 37.7 vs 32.0% for
`placebo). Comparable proportions of men and women
`prematurely discontinued treatment due to AEs (12.5 and
`13.9%, respectively). A similar proportion of males and
`females reported hypoglycemia (symptomatic as well as
`severe) with semaglutide as well as placebo treatment.
`
`To investigate the potential effects of age on AEs, a
`series of regression analyses were conducted. One in-
`trial AE type was chosen (GI events) and tested both for
`treatment-dependent and treatment-independent linear
`and non-linear effects of age on AE incidence; no clear or
`consistent patterns or significant effects were found (see
`Additional file 1).
`
`Discussion
`Treatment guidelines recommend the use of antidiabetes
`agents with proven CV benefits as second-line therapy
`in T2D populations with CVD [2, 4, 18]. All currently
`approved injectable GLP-1RAs have demonstrated CV
`safety (non-inferiority) in CVOTs [12, 19–23], but only
`four have demonstrated both CV safety and superiority
`relative to standard of care [12, 20, 22, 23]. While there
`appears to be a class effect among human-based GLP-1
`analogs with respect to CV benefit, additional studies
`are needed to further elucidate whether CV protective
`effects are provided by all GLP-1RAs [24, 25].
`Semaglutide has demonstrated a consistent effect with
`respect to glycemic efficacy and safety in T2D popu-
`lations across the spectrum of care [7–14, 26–28]. In
`SUSTAIN 6, subjects with T2D at high CV risk treated
`with semaglutide had a 26% lower risk of the primary
`composite outcome of first MACE (death from CV
`causes, nonfatal MI, or nonfatal stroke) vs those receiv-
`ing placebo over 2  years (p = 0.02 for superiority [post
`hoc]) [12]. Results of this post hoc analysis of the SUS-
`TAIN 6 trial suggest the beneficial effects of semaglu-
`tide vs