Diabetes and cardiovascular mortality: the impact of sex
Authors: Anna Norhammar
Journal: The Lancet Diabetes & Endocrinology (2018)

Over the past 20 years, sex-specific aspects have gained increasing interest in the cardiology field, with campaigns such as the Go Red for Women movement.1Mosca L Hammond G Mochari-Greenberger H et al.Fifteen-year trends in awareness of heart disease in women: results of a 2012 American Heart Association national survey.Circulation. 2013; 127: 1254-1263Crossref PubMed Scopus (264) Google Scholar The main purpose of such campaigns has been to improve awareness and knowledge of the symptoms and causes of cardiovascular disease, which is one of the most common causes of death among women. Although cardiovascular outcomes have improved, mortality rates are still unsatisfactorily high.1Mosca L Hammond G Mochari-Greenberger H et al.Fifteen-year trends in awareness of heart disease in women: results of a 2012 American Heart Association national survey.Circulation. 2013; 127: 1254-1263Crossref PubMed Scopus (264) Google Scholar Clinical recommendations specific to women for the prevention of cardiovascular disease, such as those produced by the American Heart Association (AHA),2Mosca L Benjamin EJ Berra K et al.Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association.Circulation. 2011; 123: 1243-1262Crossref PubMed Scopus (1242) Google Scholar highlight the importance of systematic sex-differentiated analyses beyond standard interaction analyses to improve knowledge of different mechanisms, cardiovascular risk profiles, disease patterns, and treatment effects in men and women.2Mosca L Benjamin EJ Berra K et al.Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association.Circulation. 2011; 123: 1243-1262Crossref PubMed Scopus (1242) Google Scholar Diabetologists have long been aware that women with diabetes have an especially high risk of cardiovascular complications. In 1974, Kannel and colleagues reported that women with diabetes had a four times higher risk and that men with diabetes had a two times higher risk of cardiovascular complications and mortality compared with women and men without diabetes, respectively, and that the risk of heart failure in women with diabetes was around four to six times higher than in women without diabetes.3Kannel WB Hjortland M Castelli WP Role of diabetes in congestive heart failure: the Framingham study.Am J Cardiol. 1974; 34: 29-34Summary Full Text PDF PubMed Scopus (1615) Google Scholar, 4Garcia MJ McNamara PM Gordon T Kannel WB Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow-up study.Diabetes. 1974; 23: 105-111Crossref PubMed Scopus (1444) Google Scholar, 5Kannel WB McGee DL Diabetes and cardiovascular disease. The Framingham study.JAMA. 1979; 241: 2035-2038Crossref PubMed Scopus (3688) Google Scholar Since women generally develop cardiovascular disease later in life than men, the age-adjusted relative risk is higher in women than in men, but some evidence suggests that diabetes confers a higher absolute risk in women than it does in men, irrespective of the type of diabetes.6Peters SA Huxley RR Woodward M Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858,507 individuals and 28 203 coronary events.Diabetologia. 2014; 57: 1542-1551Crossref PubMed Scopus (383) Google Scholar, 7Huxley RR Peters SA Mishra GD Woodward M Risk of all-cause mortality and vascular events in women versus men with type 1 diabetes: a systematic review and meta-analysis.Lancet Diabetes Endocrinol. 2015; 3: 198-206Summary Full Text Full Text PDF PubMed Scopus (213) Google Scholar Also, after cardiovascular events such as acute coronary syndromes and heart failure, and despite extensive use of modern treatments, prognosis is much worse among women with diabetes than among women without diabetes; although the prognoses for women and men with diabetes are similar.8Ritsinger V Hero C Svensson AM et al.Characteristics and prognosis in women and men with type 1 diabetes undergoing coronary angiography: a nationwide registry report.Diabetes Care. 2018; 41: 876-883Crossref PubMed Scopus (9) Google Scholar, 9Johansson I Dahlström U Edner M et al.Risk factors, treatment and prognosis in men and women with heart failure with and without diabetes.Heart. 2015; 101: 1139-1148Crossref PubMed Scopus (33) Google Scholar Why women with diabetes have an increased risk of cardiovascular events is not completely understood—suggested explanations include a higher risk-factor burden, more extensive coronary artery disease, and lower use of evidence-based treatments among women than among men, as well as hormonal imbalances, early menopause, suboptimal treatment targets, and atypical symptoms, including silent ischaemia.10Norhammar A Schenck-Gustafsson K Type 2 diabetes and cardiovascular disease in women.Diabetologia. 2013; 56: 1-9Crossref PubMed Scopus (83) Google Scholar In The Lancet Diabetes & Endocrinology, Sarah Lewington and colleagues11Prospective Studies Collaboration and Asia Pacific Cohort Studies CollabroationSex-specific relevance of diabetes to occlusive vascular and other mortality: a collaborative meta-analysis of individual data from 980 793 adults from 68 prospective studies.Lancet Diabetes Endocrinol. 2018; (published online May 8.)http://dx.doi.org/10.1016/S2213-8587(18)30079-2Google Scholar investigate, via a meta-analysis of individual data from 68 prospective studies, how diabetes affects occlusive vascular and other mortality in men and women, and whether the increased risk seen in women can be explained by different levels of traditional cardiovascular risk factors. The investigators used data from almost 1 million adults (of whom about 42% were women) from 68 prospective population studies across different global regions with 9·8 million person-years of follow-up. The investigators report that, after controlling for major vascular risk factors, diabetes roughly doubled the risk for occlusive vascular mortality (mainly ischaemic heart disease and ischaemic stroke) among men (death rate ratio [RR] 2·10, 95% CI 1·97–2·24), but tripled the risk among women (3·00, 2·71–3·33; heterogeneity p<0·0001). Although the researchers found that diabetes conferred an increased risk of mortality for all age groups studied, and more so in women than in men, the risk conferred by diabetes was especially high among women aged 35–59 years, with a nearly six times higher occlusive vascular death rate in this age group. However, the death RRs for cancer mortality were considerably smaller (overall death RR 1·17, 95% CI 1·10–1·23) than for vascular causes, and did not differ between men and women with diabetes. This finding suggests that the increased mortality risk for women with diabetes is specifically associated with cardiovascular disease. However, it is important to note that absolute vascular death rates were higher for men with diabetes than for women with diabetes, but since women without diabetes have the best prognosis, diabetes confers a higher relative risk among women than among men. The investigators further explored the effect of different levels of traditional cardiovascular risk factors, including blood pressure, cholesterol, and BMI, which showed continuous log-linear associations with occlusive vascular mortality that were similar in people with and without diabetes; therefore, the relative increase in cardiovascular risk for women with diabetes compared with men with diabetes was not explained by differences in these risk factors. Two major messages should be taken from this work. First, diabetes is an important risk factor in younger women that attenuates the cardiovascular protection associated with female sex in the general population. Second, differences in traditional cardiovascular risk factors do not explain the relative excess risk of occlusive vascular disease associated with diabetes in women compared with men, highlighting that further research is needed to understand the mechanisms involved and to better target and individualise prevention strategies. Some limitations of the study include the paucity of data on more specific causes of vascular mortality, such as heart failure—a common and severe complication of diabetes reported more often among women than among men.3Kannel WB Hjortland M Castelli WP Role of diabetes in congestive heart failure: the Framingham study.Am J Cardiol. 1974; 34: 29-34Summary Full Text PDF PubMed Scopus (1615) Google Scholar Another limitation is that the data are quite old, so might not be representative of people diagnosed with diabetes more recently. However, analyses from more contemporary cohorts reveal the same risk patterns, with a higher relative risk among women with diabetes than men with diabetes,12Shah AD Langenberg C Rapsomaniki E et al.Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1·9 million people.Lancet Diabetes Endocrinol. 2015; 3: 105-113Summary Full Text Full Text PDF PubMed Scopus (673) Google Scholar including in cohorts with established cardiovascular disease.8Ritsinger V Hero C Svensson AM et al.Characteristics and prognosis in women and men with type 1 diabetes undergoing coronary angiography: a nationwide registry report.Diabetes Care. 2018; 41: 876-883Crossref PubMed Scopus (9) Google Scholar, 9Johansson I Dahlström U Edner M et al.Risk factors, treatment and prognosis in men and women with heart failure with and without diabetes.Heart. 2015; 101: 1139-1148Crossref PubMed Scopus (33) Google Scholar What can be done for women with diabetes now and in the future? Some high-risk individuals can be identified with easily accessible information, such as a history of gestational diabetes, pre-eclampsia, early menopause, and heredity cardiovascular diseases. Patients should be informed that atypical symptoms of myocardial ischaemia (eg, tiredness, sickness, tachycardia, breathlessness) could be more common in people with diabetes, and especially in women with diabetes, and might be misinterpreted as hypoglycaemia. Furthermore, diabetes societies should perhaps consider emulating the AHA and other cardiology societies with an updated set of sex-specific recommendations, not only addressing pregnancy in diabetes, but also sex-specific cardiovascular risks, prevention strategies, and gaps in knowledge for further research. Increased knowledge on risk profiles and patterns of cardiovascular complications among women with diabetes can further improve individualised treatment—eg, if stroke is the major complication, treatment with a drug that reduces the likelihood of stroke should be prioritised, whereas if heart failure is the major complication, treatment with a drug that reduces the likelihood of heart failure should be prioritised. Notably, at least in interaction analyses, the cardiovascular benefit associated with sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in recent cardiovascular outcome trials13Zinman B Wanner C Lachin JM et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7211) Google Scholar, 14Marso SP Daniels GH Brown-Frandsen K et al.Liraglutide and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2016; 375: 311-322Crossref PubMed Scopus (4230) Google Scholar seems to be similarly apparent in women and men with established cardiovascular disease. In depth sex-difference-oriented analyses from such randomised trials and real-world studies could reveal if patterns of cardiovascular complications, causes of mortality, and treatment effects differ between men and women with diabetes. Finally, regarding lifestyle changes, women and men with diabetes might have different preferences, compliance, and responses—this area is also in need of further research. Meanwhile, Lewington and colleagues have helped to highlight that sex remains an important factor in the assessment of cardiovascular risk in patients with diabetes. This online publication has been corrected. The corrected version first appeared at thelancet.com/diabetes-endocrinology on June 19, 2018. This online publication has been corrected. The corrected version first appeared at thelancet.com/diabetes-endocrinology on June 19, 2018. I have received research support from the Swedish Heart-Lung Foundation and the Kamprad Family Foundation, and have received honoraria for expert group participation from AstraZeneca, Merck Sharp & Dohme, Eli Lilly, Novo Nordisk, and Boehringer Ingelheim. Sex-specific relevance of diabetes to occlusive vascular and other mortality: a collaborative meta-analysis of individual data from 980 793 adults from 68 prospective studiesIndependent of other major vascular risk factors, diabetes substantially increased vascular risk in both men and women. Lifestyle changes to reduce smoking and obesity and use of cost-effective drugs that target major vascular risks (eg, statins and antihypertensive drugs) are important in both men and women with diabetes, but might not reduce the relative excess risk of occlusive vascular disease in women with diabetes, which remains unexplained. Full-Text PDF Open AccessCorrection to Lancet Diabetes Endocrinol 2018; 6: 517–19Norhammar A. Diabetes and cardiovascular mortality: the impact of sex. Lancet Diabetes Endocrinol 2018; 6: 517–19—In the sentence "Notably, at least in interaction analyses…", the references cited should be 13 and 14. This correction has been made to the online version as of June 19, 2018, the printed Comment is corrected. Full-Text PDF Open Access