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Cited by 15Diabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and LipoproteinsHeart Failure Treatment and Management

Real-world sex differences in type 2 diabetes patients treated with GLP-1 receptor agonists

Open access
Piccini, Sara, Favacchio, Giuseppe, Morenghi, Emanuela, Mazziotti, Gherardo, A. Lania, Andrea G., Mirani, Marco·2024·Diabetes Research and Clinical Practice
DOI 10.1016/j.diabres.2024.111689
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Abstract

AIMS: To evaluate the determinants of cardiovascular (CV) protection in men and women treated with glucagon-like peptide-1 receptor agonists (GLP1-RA). METHODS: Retrospective cohort study of 550 patients (43% women), with and without established CV disease, followed at a single center after the first prescription of a GLP1-RA. We analyzed the determinants of major adverse cardiovascular events (MACE) in men and women. RESULTS: The rate of MACE was similar between sexes. In primary prevention, among men, older age (HR 1.13, 95 % C.I. 1.05-1.22; P = 0.001) and GLP-1 RA withdrawal by time (HR 2.77, 95 % C.I. 1.15-6.68; P = 0.023) increased the HR for MACE. Among women, significant predictors of MACE were diabetes duration (HR 1.05, C.I. 1.01-1.10; P = 0.020), GLP-1 withdrawal by time (HR 2.84, 95 % C.I. 1.13-7.10; P = 0.026) and BMI at GLP-1 RA withdrawal (HR 1.08, 95 % C.I. 1.01-1.15; P = 0.026). For individuals with prior CV disease, the HR for MACE was solely impacted by GLP-1 withdrawal over time in males (HR 2.18, 95 % C.I. 1.10-4.30; P = 0.025) and by older age at GLP-1 RA initiation (HR 1.17, 95 % C.I. 1.03-1.33; P = 0.015) in females. CONCLUSIONS: Although MACE rates were similar, the factors contributing to MACE differed by sex.

AI snapshot

Written from the paper’s full text.

TL;DR

In a single-center retrospective cohort of 550 adults with type 2 diabetes initiating a GLP-1 receptor agonist, MACE rates were similar between men and women. However, the factors associated with MACE differed by sex and prevention setting, with GLP-1 RA withdrawal over time predicting MACE in men in both primary and secondary prevention and in women only in primary prevention.

Key findings

  • Overall MACE rate did not differ significantly between men and women; the cohort included 550 patients (43% women; 312 males, 238 females), with 395 in primary prevention (202 females, 193 males) and 155 in secondary prevention (36 females, 119 males).
  • In primary prevention, multivariable time-dependent Cox analysis showed MACE in men was increased by older age at GLP-1 start (HR 1.13, 95% CI 1.05–1.22; P=0.001) and GLP-1 RA withdrawal by time (HR 2.77, 95% CI 1.15–6.68; P=0.023); in women, predictors were diabetes duration (HR 1.05, 95% CI 1.01–1.10; P=0.020), GLP-1 withdrawal by time (HR 2.84, 95% CI 1.13–7.10; P=0.026), and BMI at GLP-1 RA withdrawal (HR 1.08, 95% CI 1.01–1.15; P=0.026).
  • In secondary prevention, MACE in men was affected only by GLP-1 withdrawal by time (HR 2.18, 95% CI 1.10–4.30; P=0.025), while in women it was affected only by older age at GLP-1 RA initiation (HR 1.17, 95% CI 1.03–1.33; P=0.015).
  • Among patients continuing GLP-1 RA, women had greater weight loss at year 1 in primary prevention (−3.68 vs −2.25 kg, P=0.005) and in secondary prevention at year 1 (−5.47 vs −1.61 kg, P=0.007), year 2 (−6.29 vs −1.27 kg, P=0.007), and year 8 (−18.3 vs −3.92 kg, P=0.019).

Methods

  • Retrospective cohort study at Humanitas Research Hospital, Milan, including patients with type 2 diabetes receiving a first injectable GLP-1 RA (liraglutide, exenatide, lixisenatide, dulaglutide, or semaglutide) between December 1, 2009, and December 31, 2019, with follow-up through December 31, 2021; inclusion required age >18, consent, type 2 diabetes, no prior GLP-1 RA, and at least 2 years of follow-up. Of 837 first prescriptions, 550 patients met inclusion criteria (65.7%).
  • Main outcome was a composite of MACE: non-fatal myocardial infarction or unstable angina, non-fatal stroke, and all-cause death; deaths were identified via the Lombardy Region administrative data repository. Baseline clinical/demographic data, CV risk factors, diabetes complications, and medications were assessed, with follow-up for treatment persistence, side effects, and CV/metabolic outcomes.
  • Sex differences were tested with chi-squared or Fisher’s exact tests and Student t or Mann-Whitney U tests; survival from MACE was analyzed with univariable Cox regression, then multivariable time-dependent Cox regression for factors with P<0.2, adjusted by year of therapy commencement and interactions where present. Results reported as hazard ratios with 95% CI; P<0.05 significant; analyses used Stata version 15.

Limitations

  • The paper states the analysis is retrospective, conducted at a single tertiary university center, which may limit generalizability, and that the relatively small number of secondary prevention participants may have influenced the results for women with CVD.
  • Evident from the text: the observational design cannot establish causality and may leave residual confounding; sex was based on sex assigned at birth, and no patient reported gender transitioning.
  • Evident from the text: missing baseline LDLc values in 95/550 patients excluded LDLc from the multivariable analysis, and other missing values were noted (e.g., 68 subjects in primary prevention and 27 in secondary prevention for some comparisons).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.diabres.2024.111689

Cites

25 of 25 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 18 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In primary prevention, women had longer follow-up duration than men (5.5 vs 4.3 years).

    “In both primary and secondary prevention, women had longer follow-up duration (5.5 vs. 4.3 years in primary prevention, 4.8 vs. 3.2 years in secondary prevention), while there were no significant differences in the duration of GLP-1 treatment or in the proportion of individuals who discontinued the GLP-1, nor in discontinuation due to gastrointestinal (GI) adverse events.”
    Quote in the paperNot a substantial claim
  • Findingown data

    In secondary prevention, among women, older age at GLP-1 RA initiation increased the hazard ratio for MACE (HR 1.17, 95% CI 1.03-1.33; P=0.015).

    “For individuals with prior CV disease, the HR for MACE was solely impacted by GLP-1 withdrawal over time in males (HR 2.18, 95 % C.I. 1.10-4.30;P = 0.025) and by older age at GLP-1 RA initiation (HR 1.17, 95 % C.I. 1.03-1.33;P = 0.015) in females.”
    • Also stated in: § 3.4. CV outcomes · plain
      “In secondary prevention, in the multivariate time-dependent Cox regression analysis, in males MACE HR turned out to be only affected by GLP-1 withdrawal by time, while in females older age at GLP-1 RA beginning increased the HR.”
    Quote in the paperSubstantial claim
  • Findingown data

    In the group with cardiovascular disease, women who continued GLP-1 RA lost more weight than men at year 1, year 2, and year 8.

    “In the group with CVD, women who continued GLP-1 RA treatment lost more weight at year 1, year 2 and year 8 (year 1: -5.47 vs. -1.61kg in women and in men respectively; P = 0.007; year 2: -6.29 vs. -1.27kg respectively, P = 0.007; year 8: -18.3 vs. -3.92respectively.P = 0.019).”
    Quote in the paperSubstantial claim
  • Findingown data

    In primary prevention, among men, GLP-1 RA withdrawal by time increased the hazard ratio for MACE (HR 2.77, 95% CI 1.15-6.68; P=0.023).

    “In primary prevention, among men, older age (HR 1.13, 95 % C.I. 1.05-1.22;P = 0.001) and GLP-1 RA withdrawal by time (HR 2.77, 95 % C.I. 1.15-6.68;P = 0.023) increased the HR for MACE.”
    • Also stated in: § 3.4. CV outcomes · plain
      “In primary prevention, in the multivariate time-dependent Cox regression analysis (Table 3) in males, older age and GLP-1 RA withdrawal by time were the only variables that significantly increased the HR for MACE.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: GLP-1 RA withdrawal is not simply a marker of underlying disease severity or confounding by indication, so its association with increased MACE risk reflects a causal effect of withdrawal.
  • Findingown data

    In the group with cardiovascular disease, women who stopped GLP-1 RA treatment showed greater weight loss than men at year 4 (-4.87 kg vs +1.39 kg, P=0.003).

    “Females who stopped GLP1-RA treatment also showed a trend of greater weight loss compared to males, but it was significant only at year 4 (-4.87 kg in women vs. + 1.39 kg in men, P = 0.003).”
    Quote in the paperSubstantial claim
  • May combine two claims. 12
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingown data

    In this study, the greater weight loss advantage in women treated with GLP-1 RA was observed only during the first year of treatment and was subsequently lost.

    “Additionally, in previous studies [19], women were found to achieve greater weight loss when treated with GLP-1 RA.This study observed the mentioned trend only during the first year of treatment, and subsequently, this advantage in women was lost.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among patients without prior cardiovascular disease, women were slightly older, had higher BMI, better glycemic control, worse LDLc, and fewer were smokers compared to men.

    “At baseline, in the primary prevention group, female patients were slightly older (62.2 vs. 60.5 years), had higher BMI (34.8 vs. 33.6 kg/ m 2 ), lower fasting blood glucose concentrations (168 vs. 181 mg/dl), lower HbA1c (8.12 vs. 8.31 %) and a greater proportion had HbA1c at target (18.09% vs. 7.37 %).Women had higher total cholesterol, high density lipoprotein (HDL) and calculated low density”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the secondary prevention group, women had higher BMI, higher HDL, lower triglycerides, and a greater proportion had diabetic retinopathy, but a lower proportion had dyslipidemia compared to men.

    “In the secondary prevention group, women had higher BMI (34.9 vs. 31.3kg/m 2 ), higher HDL (49.7 vs. 39.1 mg/dl), lower triglycerides (136 vs. 167 mg/dl).A greater proportion of women had diabetic retinopathy (39.39 vs. 21.82%), but a lower proportion had dyslipidemia (88.89 % vs. 98.32 %).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There were no between-gender differences in cardioactive therapies or in the GLP-1 RA molecules prescribed at baseline.

    “There were no between-gender differences in cardioactive therapies or in the GLP-1 RA molecules prescribed at baseline.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In primary prevention, women who continued GLP-1 RA had lower HbA1c at baseline than men (7.88 vs 8.29, P=0.001), but this difference was lost during follow-up.

    “There was a significant difference in HbA1c at baseline (7.88 in women vs. 8.29 in men, P = 0.001), which was lost during follow-up.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In primary prevention, women who continued GLP-1 RA had lower fasting blood glucose than men at baseline and at years 1, 2, and 4.

    “In primary prevention, females who continued the GLP-1 RA showed a significantly greater weight loss at year 1 (-3.68 kg vs. -2.25 kg, P = 0.005) and lower fasting blood glucose (FBG) at baseline, and up to year 4 of follow-up (at baseline: 159.9 vs. 178.9mg/dl, p = 0.001; at year 1: 132.2 vs. 142.1 mg/dl, P = 0.003; at year 2: 132.2 vs. 142.1 mg/dl, P = 0.008; at year 4: 131.4 vs. 143.0mg/dl, P =”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In secondary prevention, fasting blood glucose and HbA1c were comparable between men and women, apart from lower HbA1c in women continuing GLP-1 RA at year 4.

    “FBG and HbA1c were comparable between men and women in the secondary prevention group, apart from lower HbA1c in women continuing the GLP1-RA at year 4.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Women with type 2 diabetes have a three- to six-fold increase in cardiovascular risk compared to women without diabetes, while men have a two- to four-fold increased risk.

    “Women with T2DM have a three-to six-fold increase in CV risk compared to women without diabetes.By contrast, men have a twoto fourfold increased risk [4][5][6][7][8][9][10][11].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4][5][6][7][8][9][10][11]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In that large cohort, the enrolled subjects had a low cardiovascular risk, with the majority having no history of cardiovascular disease.

    “In addition, the enrolled subjects had a low cardiovascular risk, with the majority having no history of CVD (6.5 % of men and 6.4 % of women had cerebrovascular disease, 2.9 % and 1.5 %, respectively, had a history of myocardial infarction, and 4.7 % and 3.6 %, respectively, had peripheral vascular disease).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    The study enrolled all patients who received any GLP-1 receptor agonist over a period of ten years, with an estimated subject count of around 500, due to the exploratory nature of the study.

    “Due to the exploratory nature of the study, we enrolled all patients who received any GLP-1 receptor agonist over a period of ten years, with an estimated subject count of around 500.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In contrast to the RIACE study, women in this cohort exhibited an equal or better risk factor profile than men, except for a higher BMI, indicating a potential improvement in the care of women with type 2 diabetes over the last decade.

    “However, in contrast to the RIACE study, women exhibited an equal or better risk factor profile than men, except for a higher BMI, indicating a potential improvement in the care of women with type 2 diabetes over the last decade.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Sex-specific biological factors can influence the pathophysiology of type 2 diabetes complications and the pharmacodynamics and pharmacokinetics of medications used in type 2 diabetes.

    “Sex-specific biological factors can influence the pathophysiology of type 2 diabetes (T2DM) complications as well as the pharmacodynamics and pharmacokinetics of the medications used in the treatment of persons with T2DM [1,2].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1]

      Not checked in the free run.

    • cites [2] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Previous studies found that women achieve greater weight loss when treated with GLP-1 RA.

    “Additionally, in previous studies [19], women were found to achieve greater weight loss when treated with GLP-1 RA.This study observed the mentioned trend only during the first year of treatment, and subsequently, this advantage in women was lost.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    It is not known whether GLP-1 RAs are equally beneficial in women.

    “It is not known whether these newer diabetes medications are equally beneficial in women [12,13].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] source

      Not checked in the free run.

    • cites [13]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the REWIND trial, women remained at lower cardiovascular risk for the composite cardiovascular outcome, both in the primary prevention group and in the secondary prevention group.

    “On the other hand, a post-hoc analysis of the REWIND trial (dulaglutide vs. placebo) reported that women were less likely than men to meet treatment targets (unlike women in our cohort) but remained at lower CV risk for the composite CV outcome, both in the primary prevention group and in secondary prevention group [22].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The proportion of women in the study (43%) is similar to the proportion of women in the REWIND study (46.3%).

    “and similar to the proportion of women in the REWIND study, which was to date the cardiovascular outcome trial (CVOT) that included the largest cohort of women (46.3 %) [25]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The inclusion of a single tertiary university center may limit the possibility to generalize the results.

    “the inclusion of a single tertiary university center which may limit the possibility to generalize the results”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The present analysis is retrospective.

    “Limitations of the present analysis are the retrospective nature of the study”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The relatively small number of secondary prevention participants in our cohort may have influenced the results for women with cardiovascular disease.

    “It cannot be excluded that the relatively small number of secondary prevention participants in our cohort may have influenced the results for women with CVD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study had a relatively long duration of follow-up.

    “Strengths of this study include the relatively long duration of followup”
    Quote in the paperNot a substantial claim
20 of 20

  • The paper relies on this without support.

    GLP-1 RA withdrawal is not simply a marker of underlying disease severity or confounding by indication, so its association with increased MACE risk reflects a causal effect of withdrawal.

    “In primary prevention, in the multivariate time-dependent Cox regression analysis (Table 3) in males, older age and GLP-1 RA withdrawal by time were the only variables that significantly increased the HR for MACE.”

  • The paper relies on this without support.

    The administrative data repository accurately identifies all-cause deaths.

    “The Lombardy Region's (Italy) administrative data repository was used to identify all-cause deaths.”

  • The paper relies on this without support.

    The study is adequately powered to detect a difference in MACE rates between sexes.

    “Overall, the rate of MACE did not differ significantly between men and women included in the cohort (Fig. 1).”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Obesity and type 2 diabetes are characterized by sexual dimorphism, which appears to be an important determinant of presentation, diagnosis, disease progression and complications.

    “Obesity and T2D are characterized by sexual dimorphism, which appears to be an important determinant of presentation, diagnosis, disease progression and complications, and, therefore, may be important for individual treatment approaches ([76,77,78]; and references therein).”

    From Adipose Tissue: A Novel Target of the Incretin Axis? A Paradigm Shift in Obesity-Linked Insulin Resistance (2024) · cites this paper as [78]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Reported follow-up durations fall below the eligibility minimum

    Major

    Eligibility required at least two years of follow-up, but Table 2 reports follow-up ranges beginning below two years, including 0.25 years for men in primary prevention.

  • Primary-prevention women's baseline age differs from Table 1

    Minor

    The results text reports a mean age of 62.2 years for women in primary prevention, whereas Table 1 reports 62.6 years.

  • Primary-prevention female proportion is not 52%

    Minor

    The reported counts give 202 women among 395 primary-prevention patients, or 51.14%, which rounds to 51% rather than 52%.

    Reported 52 · recomputed 51.139241

3 of 3

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Related

Authors
Piccini, S., Favacchio, G., Morenghi, E., Mazziotti, G., A. Lania, A. G., & Mirani, M.
Affiliations
  • IRCCS Humanitas Research Hospital (IT)
  • Humanitas University (IT)
Corresponding author
Mirani, Marco
ORCID
Venue
Diabetes Research and Clinical Practice
Publisher
Elsevier BV
Published
2024-06
Volume
212
Pages
111689
ISSN
0168-8227 (ISSN-L)
DOI
10.1016/j.diabres.2024.111689
OpenAlex
W4396569244
Cited by
15
References
25
Citations by year
2026: 5 · 2025: 6 · 2024: 4
FWCI
4.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes Research and Clinical Practice (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
Ministero della Salute
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
Keywords
type 2 diabetes, GLP-1 receptor agonists, sex differences, major adverse cardiovascular events, cardioprotection, diabetes duration, body mass index, age, prior cardiovascular disease, primary prevention
MeSH terms
Glucagon-Like Peptide-1 Receptor, Glucagon-Like Peptide-1 Receptor Agonists, Aged, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Female, Humans, Hypoglycemic Agents, Male, Middle Aged, Retrospective Studies, Sex Factors

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