Abstract
Abstract
Objectives
We hypothesise that women with type 2 diabetes and hypertension are less likely than comparable men to receive renin–angiotensin system (RAS)-inhibiting antihypertensive treatment, particularly as first-line therapy. This study’s main aim is to investigate the delivery of RAS inhibitor treatments by sex and number of antihypertensive treatments used.
Design
Cross-sectional study in a cohort.
Setting
Constances cohort, France, 2012–2019.
Participants
2541 participants with type 2 diabetes among the 196 477 individuals aged 18–69 included in the Constances cohort.
Outcome measures
Proportion of individuals treated with RAS inhibitors by sex and number of antihypertensive treatments dispensed. Factors associated with the use of RAS inhibitors.
Results
Among 2541 diabetics, 1742 (68.6%) had received at least one antihypertensive treatment during the year preceding inclusion—a percentage that did not differ significantly between men and women (p=0.07). In analyses stratified by the number of antihypertensive classes, RAS inhibitors were delivered significantly less often to women than men for single-drug therapy (OR 0.46, 95% CI 0.25 to 0.81; p=0.008) and two-drug therapy (0.35, 95% CI 0.16 to 0.75, p=0.007) but not in regimens of three or more drugs (0.29, 95% CI 0.05 to 1.56; p=0.15). In the multivariate analysis, women received RAS inhibitors significantly less often than men (0.41, 95% CI 0.27 to 0.62; p<0.001).
Conclusions
Women with type 2 diabetes are less likely than men to receive a prescription for RAS inhibitors, although this drug class is recommended as first-line therapy in this population.
Keywords: Hypertension; Diabetes Mellitus, Type 2; EPIDEMIOLOGIC STUDIES; CLINICAL PHARMACOLOGY
Strengths and limitations of this study.
This study included 2541 individuals with type 2 diabetes drawn from a large, nationally representative French cohort of 196 477 participants.
Comprehensive data were collected from self-administered questionnaires, standardised clinical examinations and healthcare reimbursement data.
Descriptive analyses were stratified by sex and number of antihypertensive drug classes.
Multivariate analyses were able to adjust for several potential confounders, including occupation, smoking status, blood pressure, low-density lipoprotein cholesterol levels and microalbuminuria, which are not included in reimbursement data.
Longitudinal analyses could not be conducted, as baseline data were only collected at the time of inclusion.
Background
Diabetes affects 1 in 10 individuals worldwide1 and significantly increases the risk of death from all causes.2 Cardiovascular diseases are the principal cause of death in patients with type 2 diabetes.3 A high level of evidence supports the importance of controlling the principal cardiovascular risk factors to reduce cardiovascular morbidity and mortality in this population. Each reduction of 10 mm Hg in patients with systolic blood pressure above 140 mm Hg diminishes the onset of cardiovascular events by 11% and of all-cause mortality by 13%.4 Better control of cardiovascular risk factors in recent years has accordingly reduced both morbidity and mortality among people with diabetes.5 6 Nonetheless, this reduction has been smaller among women than men.7 The relative risks of cardiovascular events, cardiovascular deaths and deaths from all causes remain higher among women than men with diabetes, especially among young women.8 Some of these differences may be due to better control among men than women with diabetes with risk factors, in particular, low-density lipoprotein cholesterol and chronic hypertension.9 10 Moreover, the pharmacological treatments used to control cardiovascular risk factors may differ by sex. Clinical practice guidelines for chronic hypertension in the USA and in Europe11 12 recommend the use of renin angiotensin system (RAS) inhibitors—such as ACE inhibitors or angiotensin receptor 2 blockers (ARB2). Studies have nonetheless shown that women are prescribed RAS inhibitors less often than men,13 14 and some authors suggest that this underprescription may cause excess mortality among women with diabetes.14
The reasons that might explain this difference between the sexes in RAS-inhibitor prescription are still not well understood. A study of a health-related administrative database between 1995 and 2005 showed that women with diabetes received RAS inhibitors less often than men with diabetes,15 but these results were not adjusted for confounding factors such as social position or clinical factors including microalbuminuria, which is another indication to initiate a RAS inhibitor. A study in Germany in 2010 of 1146 patients with diabetes found that women received RAS inhibitors less often than men, even when they had coronary disease (another specific indication for a RAS inhibitor), and after adjustment for the principal confounding factors of age, diabetic nephropathy and a cardiovascular history.16 Nonetheless, this work investigating the patients of 38 physicians failed to take into account the hierarchical structure of the data and thus the non-independence of patients of the same physician.
Although RAS-inhibitor treatment should be used preferentially as the first-line treatment for all hypertensive individuals with diabetes, to our knowledge, no study of antihypertensive treatments in type 2 diabetes has analysed treatment differences by sex according to the number of antihypertensive classes (one-drug, two-drug or three-drug therapy). We hypothesise that women with diabetes and chronic hypertension receive a RAS-inhibitor antihypertensive treatment as first-line treatment less often than men do and that this difference is attenuated when multiple antihypertensive drugs are used.
Our principal objective is to study in individuals with diabetes the delivery of RAS-inhibitor treatments by both sex and the number of antihypertensive treatments used.
Methods
Study design
The data we analysed come from the French CONSTANCES cohort.17 18 This cohort, constituted by a random drawing from the lists of individuals covered by the national health insurance fund of employed workers (CNAM-TS), included 196 477 individuals aged 18–69 years from 2012 to 2019. At inclusion, each individual completed several self-administered questionnaires, either in paper versions received and returned by post, or online via a secure platform, as the participant preferred. The study’s scientific team developed the CONSTANCES questionnaires by combining internationally validated instruments (eg, International Physical Activity Questionnaire (IPAQ), Center for Epidemiologic Studies Depression Scale (CES-D), Alcohol Use Disorders Identification Test (AUDIT)) with new questions specifically relevant to the cohort’s objectives. The participants also had a medical interview with a standardised clinical examination (blood pressure and body mass index, BMI) and laboratory tests (lipid profile, creatinine levels and microalbuminuria, determined by microalbumin/creatinine ratio) in one of the Caisse Nationale de l’Assurance Maladie des Travailleurs Salariés (National Health Insurance) (CNAM-TS)’s 21 health centres across France. These responses and findings were then linked with each cohort member’s reimbursement data for 2009–2019.19
Population
The study population comprises participants with type 2 diabetes treated pharmacologically for at least 2 years at inclusion. In accordance with the literature, subjects were considered to have type 2 diabetes treated pharmacologically if they had been reimbursed for oral antidiabetic agents and/or insulin purchased at a pharmacy at least three times during either one of the two preceding years.20 Moreover, subjects treated only by insulin were considered to have type 2 diabetes if they had started their insulin treatment after their 45th birthday or, for those younger than 45 years, if the interval between the diabetes diagnosis and the insulin treatment had exceeded 2 years.21 22
Among these individuals with diabetes, we subsequently analysed only those who had been reimbursed for at least one treatment for hypertension treatment in the year before their inclusion.
Variable of interest
The principal variable of interest was the delivery of at least one box of a RAS inhibitor (ACE inhibitor or ARB2) the year before inclusion, coded as ‘yes’ or ‘no’.
Explanatory variables
The self-administered questionnaires furnished the following data: social and demographic characteristics (sex, age, education level and occupational category, defined by the French socioprofessional classification-CSP), lifestyle habits (smoking status, classified as non-smoker, smoker and ex-smoker; alcohol consumption, via the AUDIT score,23 and physical activity on a continuous scale of 0–10), perceived health on a scale of 0–10 (and then reclassified as very good, good, intermediate or poor), and the following self-reported diabetes data: age at its diagnosis and at the start of insulin therapy. The duration of diabetes was calculated by subtracting the person’s age at inclusion from their age reported at the onset of diabetes.
Supplementary data came from the reimbursement data for the year before inclusion: presence of 1 of the 30 chronic diseases reimbursed at 100% by the national health insurance fund national disease for long-term serious conditions (affections longue durée, ALD) as well as the number (0, 1 and ≥2) of these conditions, laboratory test for a lipid profile, the number of HbA1c assays (<3 and ≥3), the delivery of antihypertensive, lipid-lowering, oral antidiabetic agents or insulin, the number of consultations with a general practitioner, and if they had consulted a cardiologist or endocrinologist. For consultations with endocrinologists, we considered the year before inclusion and for ophthalmologists and cardiologists, the 2 years before inclusion, consistent with guidelines. Cardiovascular history (ischaemic heart disease, peripheral arterial disease and strokes) was determined from a questionnaire completed by the physicians during the medical interview and from the reimbursement data (ALDs and the codes of diseases during any hospitalisations).
The sex of the general practitioner (family doctor) was obtained from national health insurance data.
Statistical analyses
We first described the study population and compared their social and demographic characteristics, medical history, healthcare pathway, and the antidiabetic and lipid-lowering treatments delivered between men and women. Descriptive statistics included frequencies and percentages for categorical variables and means (with SDs) for continuous variables. Comparisons between women and men were performed on the assumption of normality with χ² tests for categorical variables and Student’s t-tests for continuous variables. Next, we described the antihypertensives delivered, by sex. We first studied the number of antihypertensive drug classes delivered, and then the specific classes delivered (RAS inhibitors, diuretics, beta-blockers, calcium channel blockers and other antihypertensive treatments). These were each calculated first regardless of the number of these classes delivered and then according to the number of antihypertensive, single-drug, two-drug and three-drug (or more) treatments. Finally, we used χ² tests to compare the treatments delivered to women and to men.
During the third stage, we conducted bivariate and then multivariate analyses examining the associations between the principal variable of interest and the explanatory variables. Multivariate logistic regression models were used to estimate adjusted ORs (aORs) and their 95% CIs. The adjustment variables used for the multivariate model were the individual characteristics significantly associated with the delivery of a RAS inhibitor in the bivariate analysis (p<0.05) or related to it in the literature. These include age, socioprofessional category, the number of ALDs, duration of diabetes, insulin use, number of consultations with a general practitioner (GP), any consultations with an endocrinologist or cardiologist, cardiovascular history (ischaemic heart disease, stroke or arteriosclerosis obliterans) and creatinine clearance levels.
The fourth phase involved multivariate analyses with the same model as above, stratifying by the number of antihypertensive treatments delivered (one, two or three or more) rather than by adjusting for them.
To finish, we conducted supplementary bivariate analyses between RAS-inhibitor delivery and sex and after stratification for the presence of a coronary artery disease, given that it is a frequent specific indication for RAS-inhibitor treatment that women have less often than men. We also tested the interaction between RAS inhibitor delivery, the presence of coronary artery disease and sex.
For the multivariate analysis, we performed multiple imputations for missing data with the R MICE package.
A statistical test was considered statistically significant when the p value was less than 0.05.
The statistical analyses were performed with R software (V.3.14.0).
Patient and public involvement
Neither patients nor members of the public were involved in the design, conduct, reporting of this research or in its planned dissemination.
Results
Of the 2541 patients with diabetes in the total population, 1768 (69.5%) were men and 773 (30.4%) women. In all, 68.8% (n=1742) of all diabetic individuals had filled at least one prescription for an antihypertensive. Among them, 1232 (70.7%) were men and 510 (29.2%) women, with no difference in delivery of antihypertensive treatment between men (69.7% of men) and women (66% of women) (p=0.07). Hypertension was reported by 1489 (88.1%) individuals, with no difference by sex (p=0.13).
These individuals’ mean age was 61.9 (SD=6.5) years—61.2 (SD: 6.97) years for women and 62.3 (SD: 6.3) (p=0.003) for men (table 1).
Table 1. Characteristics at inclusion of the population with diabetes and hypertension (n=1742).
| Variables | Total | NA | Men | NA | Women | NA | P value (M/W) |
|---|---|---|---|---|---|---|---|
| Sex | 1742 | 1232 | 510 | ||||
| Age at inclusion | |||||||
| <55–34 years | 240 (13.8%) | 148 (12.0%) | 92 (18.0%) | 0.004 | |||
| 55–65 | 789 (45.3%) | – | 571 (46.3%) | – | 218 (42.7%) | – | |
| ≥65 | 713 (40.9%) | 513 (41.6%) | 200 (39.2%) | ||||
| Geographical origin | |||||||
| Europe | 1523 (89.9%) | 47 | 1089 (90.1%) | 23 | 434 (89.3%) | 24 | 0.074 |
| North Africa | 88 (5.2%) | 69 (5.7%) | 19 (3.9%) | ||||
| Sub-Saharan Africa | 44 (2.6%) | 26 (2.2%) | 18 (3.7%) | ||||
| Other | 40 (2.4%) | 25 (2.1%) | 15 (3.1%) | ||||
| Diploma | |||||||
| No diploma or middle school certificate | 384 (22.9%) | 67 | 225 (19.0%) | 45 | 159 (32.6%) | 22 | <0.001 |
| Vocational and apprenticeship qualifications | 557 (33.3%) | 437 (36.8%) | 120 (24.6%) | ||||
| Completed high school, passed school-leaving exam | 246 (14.7%) | 162 (13.6%) | 84 (17.2%) | ||||
| Completed high school, passed school-leaving exam +2 or 3 years of postsecondary education | 244 (14.6%) | 171 (14.4%) | 73 (15.0%) | ||||
| Completed high school, passed school-leaving exam +4 or more years of postsecondary education | 244 (14.6%) | 192 (16.2%) | 52 (10.7%) | ||||
| Socio-occupational categories | |||||||
| Tradespeople, shopkeepers, company heads | 50 (3.4%) | 273 | 38 (3.6%) | 178 | 12 (2.9%) | 95 | <0.001 |
| Managers, professionals | 348 (23.7%) | 296 (28.1%) | 52 (12.5%) | ||||
| Intermediate occupations | 378 (25.7%) | 285 (27.0%) | 93 (22.4%) | ||||
| Office, sales and department workers | 335 (22.8%) | 131 (12.4%) | 204 (49.2%) | ||||
| Workers/farmers | 358 (24.4%) | 304 (28.8%) | 54 (13.0%) | ||||
| Number of ALDs | |||||||
| 0 | 198 (11.4%) | – | 144 (11.7%) | – | 54 (10.6%) | – | 0.44 |
| 1 | 1119 (64.3%) | 797 (64.7%) | 322 (63.1%) | ||||
| ≥2 | 424 (24.4%) | 290 (23.6%) | 134 (26.3%) | ||||
| ALD diabetes | 1409 (80.9%) | – | 982 (79.7%) | – | 427 (83.7%) | – | 0.06 |
| ALD heart failure | 68 (3.9%) | – | 53 (4.3%) | – | 15 (2.9%) | – | 0.23 |
| ALD chronic kidney disease | 7 (0.4%) | – | 6 (0.5%) | 1 (0.2%) | – | 0.64 | |
| Duration of diabetes | |||||||
| <5 years | 282 (21.9%) | 454 | 188 (20.9%) | 332 | 94 (24.2%) | 122 | 0.35 |
| 5–10 years | 384 (29.8%) | 268 (29.8%) | 116 (29.9%) | ||||
| >10 years | 622 (45.3%) | 444 (49.3%) | 178 (45.9%) | ||||
| Perceived health compared with a person of the same age | |||||||
| Very good | 201 (12.4%) | 163 (14.2%) | 38 (8.0%) | <0.001 | |||
| Good | 406 (25.0%) | 97 | 310 (27.0%) | 84 | 96 (20.2%) | 34 | |
| Intermediate | 449 (27.6%) | 306 (26.7%) | 143 (30.0%) | ||||
| Poor | 568 (35.0%) | 369 (32.1%) | 199 (41.8%) | ||||
| Smoking status | |||||||
| Nonsmoker | 578 (35.5%) | 113 | 297 (25.6%) | 281 (59.9%) | <0.001 | ||
| Smoker | 191 (11.7%) | 154 (13.3%) | 72 | 37 (7.9%) | 41 | ||
| Ex-smoker | 860 (52.8%) | 709 (61.1%) | 151 (32.2%) | ||||
| Alcohol consumption (AUDIT) | |||||||
| Abstinence | 149 (9.7%) | 206 | 66 (6.0%) | 132 | 83 (19.0%) | 74 | <0.001 |
| Neither abuse nor dependence | 1068 (69.5%) | 759 (69.0%) | 309 (70.9%) | ||||
| Abuse | 224 (14.6%) | 197 (17.9%) | 27 (6.2%) | ||||
| Dependence | 95 (6.2%) | 78 (7.1%) | 17 (3.9%) | ||||
| Physical activity (1–7) | 4.27 (1.64) | 144 | 4.31 (1.64) | 83 | 4.18 (1.64) | 61 | 0.14 |
| HbA1c reported | 6.93% (1.22) | 933 | 7.01 (1.28) | 666 | 6.76 (1.04) | 267 | 0.01 |
| Ischaemic heart disease (n–1) | 324 (18.6%) | – | 280 (22.7%) | – | 44 (8.6%) | – | <0.001 |
| Stroke (n–1) | 105 (6.0%) | – | 82 (6.7%) | – | 23 (4.5%) | – | 0.66 |
| Peripheral artery disease (n–1) | 130 (7,5%) | – | 106 (8.6%) | – | 24 (4.7%) | – | <0001 |
| At least one macrovascular complication (n–1) | 444 (25.5%) | – | 370 (30%) | – | 74 (14.5%) | – | <0.001 |
| Body mass index | |||||||
| <25 | 163 (9.5%) | 24 | 119 (9.8%) | 16 | 44 (8.8%) | 8 | <0.001 |
| 25–30 | 585 (34.1%) | 467 (38.4%) | 118 (23.5%) | ||||
| ≥30 | 970 (56.5%) | 630 (51.8%) | 340 (67.7%) | ||||
| Mean systolic blood pressure | 143 (17.0) | 44 | 144.1 (16.5) | 33 | 140.3 (17.9) | 11 | <0.001 |
| Mean diastolic blood pressure | 81.4 (9.75) | 44 | 81.92 (9.69) | 33 | 80.14 (9.8) | 11 | <0.001 |
| Low density lipoprotein cholesterol g/L | 1.04 (0.34) | 236 | 1.00 (0.33) | 185 | 1.12 (0.35) | 51 | <0.001 |
| Estimated glomerular filtration rate (ml/min)—CKD | |||||||
| >60 | 1538 (93.7%) | 100 | 1098 (93.8%) | 61 | 440 (93.4%) | 39 | 0.68 |
| 45–60 | 73 (4.4%) | 53 (4.5%) | 20 (4.2%) | ||||
| <45 | 31 (1.9%) | 20 (1.7%) | 11 (2.3%) | ||||
| Microalbumin-creatinine ratio ≥3 | 113 (20.6%) | 1194 | 83 (21.5%) | 846 | 30 (18.5%) | 348 | 0.43 |
| Lipid-lowering agents | 1288 (73.9%) | 946 (76.8%) | 342 (67.1%) | <0.001 | |||
| Treatment diabetes 1 year before inclusion | |||||||
| Oral antidiabetic drug | 1402 (80.5%) | 994 (80.7%) | 408 (80.0%) | 0.76 | |||
| Oral antidiabetic drug+insulin | 148 (8.5%) | 106 (8.6%) | 42 (8.2%) | ||||
| Oral antidiabetic drug+GLP1 analogue | 96 (5.5%) | 66 (5.4%) | 3° (5.9%) | ||||
| Oral antidiabetic drug+insulin+GLP1 analogue | 65 (3.7%) | 42 (3.4%) | 23 (4.5%) | ||||
| Insulin+GLP1 analogue without oral antidiabetic drug | 1 (0.1%) | 1 (0.1%) | 0 | ||||
| Insulin only | 28 (1.6%) | 22 (1.8%) | 6 (1.2%) | ||||
| GLP-1 analogue only | 2 (0.1%) | 1 (0.1%) | 1 (0.2%) | ||||
| Number of consultations with general practitioner (n–1) | |||||||
| 0 | 108 (6.2%) | 74 (6.0%) | 34 (6.7%) | <0.001 | |||
| 1–4 | 602 (34.6%) | 467 (37.9%) | 135 (26.5%) | ||||
| 5 or more | 1032 (59.2%) | 691 (56.1%) | 341 (66.9) | ||||
| Sex of general practitioner (male) | 1249 (71.9%) | 69 | 905 (73.4%) | 42 | 344 (67.4%) | 27 | 0.04 |
| Endocrinologist (n–1) | 222 (12.7%) | – | 130 (10.6%) | – | 92 (18%) | – | <0.001 |
| Cardiologist (n–2) | 652 (37.4%) | – | 466 (37.8%) | – | 186 (36.5%) | – | 0.63 |
| Ophthalmologist (n–2) | 650 (37.3%) | – | 445 (36.1%) | – | 205 (40.2%) | – | 0.12 |
ALD: Serious long-term illness for which reimbursement from the national health insurance funds is 100%.
Bold values signifies p<0.05
ALD, affections de longue durée; AUDIT, Alcohol Use Disorders Identification Test; CKD, chronic kidney disease ; HbA1c, Glycated hemoglobin.
The women’s mean BMI was 32.9 (SD: 6.2) and men’s 30.8 (SD: 5.04) (p<0.001). The women had a lower rate of macrovascular complications (myocardial infarction, stroke, peripheral artery disease and arteriosclerosis obliterans) than the men (14.5% vs 30%, p<0.001). Women’s systolic blood pressure was lower than that of men (140.3 mm Hg vs 144.1 mm Hg; p<0.001), as was their diastolic blood pressure (80.1 vs 81.9 mm Hg; p<0.001).
Diabetes treatments and insulin treatment did not differ between the sexes. Their healthcare pathways differed somewhat: women consulted both GPs (p<0.001) and endocrinologists (18% vs 10.6%, p<0.001) more often than men. There was no significant difference for cardiologist visits. The GP was male for 1249 (71.9%) diabetic individuals: 344 (67.4%) for women and 905 (73.4%) for men (p=0.04).
The number of antihypertensive classes used among men and among women did not differ (p=0.46) (table 2).
Table 2. Distribution of antihypertensive treatments among patients with diabetes and hypertension (n=1742).
| Total | Men | Women | P value (M/W) | ||||
|---|---|---|---|---|---|---|---|
| Antihypertensive treatments | 1742 (68.6%) | – | 1232 (69.7%) | – | 510 (66%) | – | 0.07 |
| Number classes of hypertension treatment | |||||||
| 1 | 583 (22.9%) | – | 408 (23.1%) | – | 175 (22.6%) | – | 0.46 |
| 2 | 592 (23.3%) | 412 (23.3%) | 180 (23.3%) | ||||
| ≥3 | 567 (22.3%) | 412 (23.3%) | 155 (20.1%) | ||||
| ACE inhibitors or ARB2 if hypertension is treated | 1460 (83.8%) | – | 1075 (87.3%) | – | 385 (75.5%) | – | <0.001 |
| ACE inhibitors if hypertension is treated | 727 (41,7%) | – | 554 (44.9%) | – | 173 (33.9%) | – | <0.001 |
| ARB2 if hypertension is treated | 795 (45.6%) | – | 562 (45.6%) | – | 233 (45.6%) | – | 1 |
| Diuretics | 782 (44.9%) | 530 (43%) | – | 252 (49.4%) | – | 0.017 | |
| Beta-blocker | 666 (38.2%) | – | 468 (38%) | – | 198 (38.8%) | – | 0.78 |
| Calcium channel blockers | 611 (35.1%) | 442 (35.9%) | 169 (33.1%) | 0.30 | |||
| Other hypertensive treatment | 122 (7.0%) | – | 93 (7.5%) | – | 29 (5.7%) | – | 0.16 |
| Single-drug therapy | |||||||
| ACE inhibitors-ARB2 | 400 (68.6%) | – | 297 (72.8%) | – | 103 (58.9%) | – | <0.01 |
| Calcium channel blockers | 41 (7%) | – | 30 (7.4%) | – | 11 (6.3%) | – | 0.77 |
| Diuretics | 26 (4.5%) | 9 (2.2%) | – | 17 (9.7%) | – | <0.01 | |
| Beta-blocker | 108 (18.5%) | 68 (16.7%) | 40 (22.9%) | 0.09 | |||
| Other | 8 (1.4%) | 4 (1%) | 4 (2.3%) | 0.24 | |||
| Two-drug therapy | |||||||
| ACE inhibitors-ARB2 | 514 (86.8%) | – | 378 (91.7%) | – | 136 (75.6%) | – | <0.001 |
| Calcium channel blockers | 183 (30.9%) | – | 123 (29.9%) | – | 60 (33.3%) | – | 0.45 |
| Diuretics | 268 (45.3%) | 170 (41.3%) | – | 98 (54.4%) | – | <0.001 | |
| Beta-blocker | 194 (32.8%) | 135 (32.8%) | 59 (32.8%) | 1 | |||
| Other | 25 (4.2%) | 18 (4.3%) | 7 (3.8%) | 0.08 | |||
| Type of two-drug therapy (n=592) | |||||||
| ACE inhibitors/ARB2s and diuretics | 209 (35.3%) | 144 (35%) | 65 (36.1%) | 0.85 | |||
| ACE inhibitors/ARB2 and beta blockers | 136 (23%) | 109 (26.5%) | 27 (15%) | 0.003 | |||
| ACE inhibitors/ARB2 and calcium channel blockers | 155 (26.2%) | 113 (27.4%) | 42 (23.3%) | 0.34 | |||
| Beta-blockers and diuretics | 41 (6.9%) | 19 (4.6%) | 22 (12.2%) | 0.001 | |||
| Calcium channel blockers and diuretics | 10 (1.7%) | 3 (0.7%) | 7 (3.9%) | 0.01 | |||
| Calcium channel blockers and beta-blockers | 16 (2.7%) | 6 (1.5%) | 10 (5.6%) | 0.009 | |||
| Therapy by three or more drugs | |||||||
| ACE inhibitors-ARB2 | 546 (96.3%) | – | 400 (97.1%) | – | 146 (94.2%) | – | 0.16 |
| Calcium channel blockers | 387 (68.3%) | – | 289 (70.1%) | – | 98 (63.3%) | – | 0.13 |
| Diuretics | 488 (86.1%) | 351 (85.2%) | – | 137 (88.4%) | – | 0.39 | |
| Beta-blocker | 364 (64.2%) | 265 (64.3%) | 99 (63.9%) | 0.99 | |||
| Other | 89 (15.6%) | 71 (17.2%) | 18 (11.6%) | 0.10 |
ARB2, angiotensin 2 receptor blocker.
Independently of the number of classes delivered, women received RAS inhibitors less often than men (75.5% vs 87.3%; p<0.001). Women received ACE less often than men (33.9% vs 44.9%; p<0.001), while ARB2 was dispensed at the same rates to women and men (p>0.99). Women were more likely than men to be prescribed diuretics (49.4% vs 43%; p=0.017).
Among individuals receiving a single antihypertensive treatment, women received RAS inhibitors significantly less often than men (58.9% vs 72.8%, p<0.001); this was also the case for patients receiving two classes of antihypertensive treatment (75.6% vs 91.7%; p<0.001). Among those receiving three-drug (or more) treatments, women still received RAS inhibitors less often than men, but the difference was no longer significant (94.2% vs 97.1%; p<0.16).
In the multivariate analysis of all patients who filled an antihypertensive prescription, women received RAS-inhibitor treatment significantly less often than men (OR 0.41, 95% CI 0.27 to 0.62; p<0.001) (table 3). Similarly, in the multivariate analysis stratified by the number of antihypertensive classes, women received RAS inhibitors significantly less often than men as single-drug treatment (OR 0.46, 95% CI 0.25 to 0.81; p=0.008) and two-drug treatment (OR 0.35, 95% CI 0.16 to 0.75; p=0.007). This difference was not significant for treatment by three or more drugs (OR 0.29, 95% CI 0.05 to 1.56; p=0.15) (table 4).
Table 3. Factors related to the delivery of a RAS inhibitor (imputed multivariate analysis, n=1742).
| Variables | OR (95% CI) | P value |
|---|---|---|
| Sex (F/M) | 0.41 (0.27 to 0.62) | <0.001 |
| Age at inclusion | ||
| <55 years | Ref | 0.35 |
| 55–65 years | 1.15 (0.69 to 1.92) | |
| ≥65 | 0.92 (0.53 to 1.58) | |
| Socio-occupational categories | ||
| Tradespeople, shopkeepers, company heads | Ref | 0.66 |
| Manager, professionals | 0.68 (0.24 to 1.90) | |
| Intermediate occupations | 0.81 (0.29 to 2.26) | |
| Office, sales and service workers | 0.73 (0.26 to 2.04) | |
| Workers/farmers | 0.62 (0.22 to 1.72) | |
| Smoking status | ||
| Nonsmoker | Ref | 0.31 |
| Smoker | 1.56 (0.85 to 2.86) | |
| Ex-smoker | 1.21 (0.82 to 1.78) | |
| Number of ALD | ||
| 0 | Ref | 0.26 |
| 1 | 0.84 (0.50–1.42) | |
| 2 or more | 0.64 (0.34–1.18) | |
| Duration of diabetes | ||
| <5 years | Ref | <0.001 |
| (5–10) | 2.04 (1.25–3.34) | |
| >10 years | 2.21 (1.43–3.42) | |
| Ischaemic heart disease | 0.55 (0.34–0.89) | 0.01 |
| Stroke | 1.23 (0.57–2.67) | 0.59 |
| Peripheral arterial disease at inclusion | 1.03 (0.51–2.07) | 0.93 |
| Mean systolic blood pressure at inclusion | 1.00 (0.99–1.01) | 0.20 |
| LDL g/L at inclusion | 1.29 (0.75–2.23) | 0.34 |
| Microalbuminuria (ACR) at inclusion | 0.87 (0.41–1.83) | 0.71 |
| eGFR (mL/min) at inclusion | 1.00 (0.99–1.01) | 0.63 |
| Number of classes of antihypertensive treatments | ||
| 1 | Ref | |
| 2 | 3.72 (2.56–5.41) | <0.001 |
| 3 or more | 15.4 (8.68–27.41) | |
| Lipid-lowering treatment (n−1) | 1.01 (0.68–1.49) | 0.94 |
| Insulin (n−1) | 1.14 (0.65–2.01) | 0.64 |
| Number consultations general practitioner | ||
| 0 | Ref | 0.53 |
| 1–4 | 1.24 (0.62–2.46) | |
| 5 or more | 1.14 (0.58–2.23) | |
| Sex of general practitioner (M/F) | 1.22 (0.82–1.81) | 0.31 |
| Endocrinologist (n−1) | 1.23 (0.73–2.07) | 0.41 |
| Cardiologist (n−2) | 0.95 (0.67–1.35) | 0.79 |
ALD: Serious long-term illness for which reimbursement from the national health insurance funds is 100%.
ACR, albumin-creatinine ratio; ALD, affections de longue durée; eGFR, estimated glomerular filtration rate; F/M, female-to-male ratio ; LDL, low density lipoprotein; RAS, renin–angiotensin system.
Table 4. Factors related to delivery of a RAS inhibitor.
| Variables | Single-drug therapy for hypertension (n=583) | Two-drug therapy for hypertension (n=592) | Three-drug therapy for hypertension (n=567) | |||
|---|---|---|---|---|---|---|
| OR (95% CI) | P value | OR (95% CI) | OR (95% CI) | P value | ||
| Sex (female/male) | 0.46 (0.25 to 0.81) | 0.008 | 0.35 (0.16 to 0.75) | 0.007 | 0.29 (0.05 to 1.56) | 0.15 |
| Age | ||||||
| <55 years | Ref | 0.90 | Ref | 0.87 | Ref | 0.54 |
| 55–65 | 1.11 (0.55 to 2.21) | 1.17 (0.41 to 3.33) | 1.78 (0.29 to 10.83) | |||
| ≥65 | 1.01 (0.47 to 2.10) | 0.98 (0.33 to 2.94) | 7.66 (0.10 to 5.82) | |||
| Socio-occupational categories | ||||||
| Tradespeople, shopkeepers, company heads | Ref | 0.60 | Ref | 0.61 | Ref | 0.66 |
| Manager, professionals | 0.59 (0.15 to 2.33) | 1.59 (0.27 to 9.37) | (0-inf) | |||
| Intermediate occupations | 0.89 (0.22 to 3.59) | 0.93 (0.17 to 5.05) | (0-inf) | |||
| Office, sales and service workers | 0.53 (0.13 to 2.10) | 1.77 (0.31 to 9.98) | (0-inf) | |||
| Workers/farmers | 0.70 (0.17 to 2.93) | 1.02 (0.17 to 6.04) | (0-inf) | |||
| Smoking status at inclusion | ||||||
| Non-smoker | Ref | 0.53 | Ref | 0.78 | Ref | 0.99 |
| Smoker | 1.59 (0.70 to 3.59) | 1.35 (0.44 to 4.15) | 0.95 (0.07 to 12.74) | |||
| Ex-smoker | 1.18 (0.68 to 2.04) | 1.23 (0.61 to 2.49) | 1.02 (0.23 to 4.54) | |||
| Number of ALDs | ||||||
| 0 | Ref | 0.51 | Ref | 0.71 | Ref | 0.55 |
| 1 | 1.05 (0.52 to 2.09) | 0.84 (0.30 to 2.32) | 0.32 (0.02 to 3.94) | |||
| 2 or more | 0.74 (0.32 to 1.69) | 0.65 (0.20 to 2.03) | 0.61 (0.03 to 9.72) | |||
| Duration of diabetes | ||||||
| <5 years | Ref | 0.02 | Ref | 0.42 | Ref | 0.06 |
| 5–10 years | 2.04 (1.02 to 4.06) | 1.76 (0.65 to 4.75) | 4.66 (0.63 to 34.06) | |||
| >10 years | 2.38 (1.24 to 4.58) | 1.67 (0.69 to 4.02) | 7.81 (1.23 to 49.56) | |||
| Ischaemic heart disease | 0.30 (0.14 to 0.63) | 0.001 | 1.27 (0.47 to 3.36) | 0.62 | 0.29 (0.05 to 1.57) | 0.15 |
| Stroke | 0.76 (0.26 to 2.19) | 0.62 | 3.42 (0.42 to 27.3) | 0.24 | (0-inf) | 0.99 |
| Peripheral arterial disease | 0.76 (0.25 to 2.28) | 0.62 | 0.72 (0.22 to 2.39) | 0.59 | (0-inf) | 0.99 |
| Mean systolic blood pressure | 1.00 (0.99 to 1.02) | 0.45 | 1.02 (0.99 to 1.04) | 0.053 | 0.98 (0.95 to 1.01) | 0.40 |
| LDL cholesterol g/L | 1.70 (0.79 to 3.64) | 0.17 | 1.01 (0.24 to 1.88) | 0.45 | 2.87 (0.31 to 25.87) | 0.34 |
| Microalbuminuria (ACR) | 0.48 (0.16 to 1.41) | 0.17 | 1.72 (0.46 to 6.47) | 0.40 | 0.90 (0-inf) | 0.99 |
| eGFR (mL/min) | 0.99 (0.98 to 1.02) | 0.82 | 1.01 (0.99 to 1.03) | 0.13 | 0.97 (0.92 to 1.01) | 0.20 |
| Lipid-lowering treatment | 1.04 (0.61 to 1.76) | 0.87 | 0.84 (0.40 to 1.77) | 0.66 | 1.79 (0.36 to 8.76) | 0.46 |
| Insulin | 1.10 (0.52 to 2.34) | 0.78 | 1.15 (0.39 to 3.33) | 0.78 | 1.43 (0.11 to 17.64) | 0.77 |
| No. consultations general practitioner (n to 1) | ||||||
| 0 | Ref | 0.95 | Ref | 0.33 | Ref | 0.49 |
| 1–4 | 1.02 (0.38 to 2.71) | 2.04 (0.59 to 7.08) | 1.80 (0.20 to 15.7) | |||
| 5 or more | 0.94 (0.36 to 2.47) | 1.27 (0.39 to 4.15) | 2.99 (0.38 to 23.2) | |||
| Sex of general practitioner (male/female) | 1.13 (0.66 to 1.96) | 0.63 | 1.68 (0.78 to 3.62) | 0.17 | 9.00 (0.19 to 4.20 | 0.89 |
| Endocrinologist (n–1) | 1.43 (0.70 to 2.88) | 0.31 | 0.93 (0.36 to 2.43) | 0.89 | 1.42 (0.13 to 14.69) | 0.76 |
| Cardiologist (n–2) | 0.87 (0.53 to 1.43) | 0.59 | 0.92 (0.48 to 1.77) | 0.81 | 2.40 (0.61 to 9.42) | 0.20 |
Imputed multivariate analysis stratified by the number of antihypertensive treatment classes delivered
ALD: Serious long-term illness for which reimbursement from the national health insurance funds is 100%.
ACR, albumin-creatinine ratio; ALD, affections de longue durée; eGFR, estimated glomerular filtration rate; LDL, low density lipoprotein; RAS, renin–angiotensin–system.
The interaction between RAS-inhibitor treatment, sex of individuals with diabetes and the GP’s sex was not significant (p=0.75).
Among individuals without coronary heart disease (CHD), women received RAS inhibitors significantly less often than the men (75.1% vs 88.1%; p<0.001), while this difference was not significant for those with CHD (79.5% vs 84.2%, p=0.42) (online supplemental appendix 1). The interaction between RAS-inhibitor treatment, sex and coronary disease was not significant (p=0.33).
Discussion
Principal results
Our study shows that women with diabetes appear to be prescribed RAS inhibitors significantly less often than men with diabetes. When we examined the delivery of RAS inhibitors according to the number of antihypertensive classes prescribed, the women with diabetes always had RAS inhibitors less often than men in both single-drug and two-drug therapy, but this result was no longer found in individuals receiving 3 or more classes of antihypertensive drugs.
In our sample of patients with diabetes treated with antihypertensives, the systolic blood pressure of women was significantly lower than that of men, although the literature about hypertension control generally shows higher systolic blood pressure among women with diabetes.9 Thus, the hypertension of the women with diabetes in our sample was not controlled more poorly than that of the men with diabetes.
The proportion of women filling a prescription for at least one antihypertensive treatment did not differ from that of men. But regardless of the number of antihypertensive classes delivered, the women with diabetes in our sample had RAS inhibitors delivered significantly less often than men—a finding also reported regularly in the diabetes literature12 14 as in the general population.24 We also showed that the delivery of antihypertensive treatments differed according to the number of antihypertensive classes delivered: in single-drug and two-drug therapy, women were prescribed fewer RAS inhibitors than the men. It is only at the stage of therapy by three or more drugs that there is no longer any difference in RAS-inhibitor prescriptions between men and women. This result suggests that RAS inhibitors, which are recommended as first-line or second-line antihypertensive therapy according to current guidelines,12 25 are prescribed less frequently to women than to men as initial or second-line antihypertensive treatment. Thus, the maintenance of single-drug or two-drug antihypertensive therapy over several years may be detrimental to young women with early-onset hypertension, who have been shown to be at particularly high relative risk of cardiovascular mortality.8
The reasons for the lower prescription rate of RAS inhibitors among women than men are not at all clear. Among the possible explanations, we note prescription biases due to the higher frequency of cardiovascular disease observed among men—a situation in which a RAS inhibitor is often recommended.22 23 Moreover, we found no association between the prescription of RAS inhibitors and the GP’s sex, whereas some authors have shown that female doctors perform better than male doctors in the prevention of cardiovascular disease.26,29
Among the patients in our study treated with three or more drug classes, almost all the men and women with and men were treated with RAS inhibitors, with no significant difference between women and men. This result fails to support the hypothesis that women tolerate RAS inhibitor class less well than men (a hypothesis frequently used to explain their underprescription to women). Nonetheless, among patients on ACE inhibitors, coughing was twice as frequent among women as men, which is consistent with our findings that women are more likely than men to use an ARB2 than an ACE inhibitor.30 Replacement of the ACE inhibitor treatment by an ARB2 that does not present this adverse effect is recommended when coughing accompanies an ACE inhibitor, and it is during this change that another drug class, less appropriate in single-drug or two-drug therapy, might be added. Another hypothesis is that when chronic hypertension preceded the diabetes diagnosis, the initial antihypertensive treatment, which is not necessarily a RAS inhibitor, is not modified by the onset of diabetes, especially if this treatment is well tolerated and the treatment objective is attained. Finally, pregnancy, when RAS inhibitor use is contraindicated, is not relevant to the women with diabetes in our population, whose mean age was 61 years. However, this hypothesis may still be worth exploring in a separate study specifically designed to address whether the possibility of pregnancy influences RAS prescription in younger women with diabetes.
In our multivariate model not stratified by the number of antihypertensive treatments, CHD appears to impede the prescription of RAS inhibitors. This unexpected result may be explained by the fact that patients with this specific form of heart disease receive, especially as a single-drug therapy, beta blockers more often than those without CHD. Accordingly, for the same number of antihypertensive treatment classes, patients with CHD are at greater risk of not receiving a RAS inhibitor. The analyses stratified by antihypertensive classes confirmed this hypothesis: CHD was inversely associated with the delivery of a RAS inhibitor in single-drug therapy, became positively associated with it in two-drug therapy, and the difference no longer appeared significant in three-drug (or more) therapy.
We note the surprisingly frequent prescription of beta-blocking treatments to this group, given that it can mask the hypoglycaemia induced by some antidiabetes treatments. The first inclusions date back to 2012—more than a decade ago. These results may thus be due to old guidelines that placed beta-blockers at the same level as other drug classes for treating chronic hypertension in France.31 The same trend in the distribution of antihypertensive drug classes in diabetes was observed over the same period in Sweden.24 Beta-blockers may also be indicated as a disease-modifying drug for migraine headaches, which are more frequent among women than men.32 This may be one reason that beta-blockers rank second among the classes delivered in single-drug therapy to women who have CHD (for which beta blocker treatment is recommended) less often than men do.
Finally, we note that in two-drug therapy, women receive inappropriate combinations of drugs significantly more often than men, such as beta-blockers and diuretics or calcium channel blockers and diuretics, or calcium channel blockers and beta-blockers rather than the combinations recommended for two-drug therapy in various guidelines that combine a RAS inhibitor with either a calcium channel blocker or a diuretic.33
Strengths and limitations
We were able to consider numerous types of data: socioeconomic, clinical, laboratory and insurance reimbursements. On the other hand, although the majority of individuals reported having arterial hypertension, we cannot be certain that the delivery of an antihypertensive treatment always corresponded to the presence of chronic hypertension, as several situations justify the prescription of a class of antihypertensives in patients without chronic hypertension: migraines, heart failure, CHD and kidney disease. Nonetheless, these situations may not modify the meaning/direction of our results because, except for migraines, these diseases are less common among the women with diabetes in our sample and justify the prescription of a RAS inhibitor.
In our multivariate analysis, we did not differentiate ACE inhibitors from ARB2 as they are recommended indiscriminately and considered interchangeable because of their similar efficacy. It should moreover be noted that the evidence about the superiority of RAS inhibitors over other antihypertensive classes for reducing cardiovascular or total morbidity and mortality in patients with diabetes is discordant.4 34
In our multivariate analysis stratified by three or more antihypertensive drugs, the vast majority of individuals received a RAS inhibitor, and ORs could not be calculated for some explanatory variables because the number of individuals in certain categories was too small. We performed a sensitivity analysis without these variables, and our results were unchanged.
A final limitation is that we do not have patients’ HbA1c readings. Nonetheless, diabetes control is not directly associated with the choices of antihypertensive treatment.
Perspectives
An analysis of the trajectory of antihypertensive treatments delivered before and after the onset of diabetes enabled us to test the hypothesis that antihypertensive treatments of women with diabetes receiving single-drug or two-drug therapy reflect the prescriptions of antihypertensives before this onset.
Future analyses using the CONSTANCES cohort may explore whether sex differences in antihypertensive treatment translate into differential cardiovascular or renal outcomes.
Conclusions
Women with diabetes treated with antihypertensives are prescribed a RAS inhibitor less often than the men when they receive single-drug and two-drug therapy. This finding suggests a suboptimal use of RAS inhibitors at the initiation of chronic hypertension treatment among women with diabetes—a situation that may persist for several years. The women with diabetes, especially the youngest among them, have a relative risk of death by cardiovascular disease higher than men with diabetes. Our results suggest that physicians, whatever their sex, must pay more attention to their care of women with diabetes, especially in primary prevention, to put an end to the difference in management of cardiovascular risk factors by sex and to reduce the cardiovascular morbidity and mortality of women with diabetes.
Supplementary material
Acknowledgements
The authors thank the team of the Epidemiological Population Cohorts Unit in France (UMS 011—Inserm, Universités Paris Cité, Paris Saclay, Versailles Saint-Quentin), which designed and manages the Constances cohort. They also acknowledge the French national health insurance fund (Caisse nationale d’assurance maladie, CNAM) and its health examination centres for collecting a large part of the data, as well as the French national old-age insurance fund (Caisse nationale d’assurance vieillesse, CNAV) for their contribution to the establishment of the cohort, and ClinSearch for performing data quality control.
None of these funding sources played any role in the study design, data collection and analysis, or the decision to publish the findings.
Footnotes
Funding: The Constances cohort is supported and funded by the French national health insurance fund (Caisse nationale d’assurance maladie, CNAM). Constances is recognised as a 'National infrastructure in biology and health' and receives funding from the French national research agency (grant ANR-11-INBS-0002). The cohort is also marginally funded by private sector companies, notably from the healthcare industry, within the framework of public–private partnerships.
Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2024-092205).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Ethics approval: The authors certify that all procedures performed in the study complied with the ethical standards of the relevant national and institutional committees on human experimentation and with the 1975 Declaration of Helsinki, as revised in 2008. All procedures were approved by the Institutional Review Board (IRB) of the National Institute of Health and Medical Research (Inserm) (Opinions No. 01-011 and No. 21-842) and authorised by the French data protection authority (Commission nationale de l’informatique et des libertés, CNIL) (Authorisation No. 910486). The biobank received a favourable opinion from the Research ethics committee (Comité de protection des personnes) (CPP Sud Est I, Opinions No. 2018-32) and was authorised by the CNIL (Authorisation No. DR-2-2018-137). All participants provided written informed consent at inclusion. This analysis was conducted in accordance with the scientific objectives approved for the CONSTANCES project.
Data availability free text: The data used in this study are not publicly available. Access can be granted on approval of a research proposal by the Constances cohort international scientific committee and provided the project meets the legal requirements set by the French data protection authority (Commission nationale de l’informatique et des libertés, CNIL) under the General data protection regulation (GDPR). The use of cohort data is governed by the Constances cohort access charter. The data access procedure is available on the Constances cohort website (https://www.constances.fr: Home 〉 Scientific area 〉 Access to Constances)
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Data availability statement
Data may be obtained from a third party and are not publicly available.
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