Editor's Note: Commentary based on Huxley RR, Peters SAE, 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;3:198-206.

Background

It is known that type 1 diabetes leads to premature death. Type 1 diabetes, unlike other autoimmune diseases, affects both males and females equally. Although women generally have lower mortality than men, Huxley et al. examined mortality rates for those with type 1 diabetes to see if this gender protection extends to mortality in those with type 1 diabetes. Prior studies have shown that women often have inadequate control of diabetes compared to men. Although some small studies have shown that women with type 1 diabetes have higher mortality, this paper was the first meta-analysis to quantify sex differences in all-cause as well as cause-specific events and mortality in those with type 1 diabetes.

Methods

A meta-analysis of studies was performed that reported sex-specific standardized mortality ratio (SMR) or hazard ratios associated with type 1 diabetes for either all-cause mortality or various other outcomes. This analysis examined within-sex excess mortality due to type 1 diabetes. A random effects meta-analysis with inverse variance weighting was performed to obtain sex-specific pooled SMRs for all-cause mortality, or mortality from cardiovascular (CVD) disease, renal disease, cancer, accident or suicide, as well incident coronary heart disease (CHD) and stroke. Subgroup analyses were done by baseline year of data collection, by region, by duration of study follow-up, by age of study participants, type of study design, and by quality of study.

Results

Data from 214,114 individuals with type 1 diabetes from a total of 26 studies was pooled. The pooled women-to-men ratio of SMR for all-cause mortality was 1.37 (95% CI 1.21-1.56); for incident stroke the SMR was similar, 1.37 (95% CI 1.03-1.81), for fatal CVD, 1.86 (95% CI 1.62-2.15), and for renal disease 1.44 (95% CI 1.02-2.05). For incident CHD, the SMR was 2.54 (95% CI 1.80-3.60). There were no sex differences in mortality for cancer, accident, or suicide. Subgroup analysis showed no significant sources of between study heterogeneity.

Conclusion

When compared to men with type 1 diabetes, women with type 1 diabetes had two times the risk of fatal and nonfatal cardiovascular events, as well as 40% greater excess risk for all-cause mortality.

Commentary/Perspective

Individuals with type 1 diabetes are known to have shorter life expectancy; however, Huxley and his colleagues have now shown that excess risk of mortality is much greater in women with type 1 diabetes compared to men with type 1 diabetes. In this paper, Huxley et al. have extended the evidence for sex-based differences in outcomes from their prior work in type 2 diabetes mellitus to type 1 diabetes. The sex differences in mortality seem to be even more significant in type 1 diabetes, with 37% increase in all-cause mortality and a staggering twofold higher incidence of fatal and non-fatal cardiovascular disease. As with type 2 diabetes, the greater relative risk from type 1 diabetes in women compared to men may be from several important sex-specific contributing factors. One of these underlying factors may be related to undertreatment, difficulties with insulin management, and worse glycemic control in girls and women with type 1 diabetes.^2,3 In addition to undertreatment, biological factors including disturbance in the hypothalamic-pituitary-ovarian axis in young women may contribute to higher levels of hyperglycemia.⁴ Finally, it is known that women with versus without diabetes have greater endothelial dysfunction, more fibrinolysis and thrombosis, and higher blood pressure than men with versus without diabetes.⁵ These treatment and biological differences may contribute to the greater relative risk in women compared to men for all-cause mortality, CVD events and CVD mortality. This growing evidence of sex differences should be used to improve not only the precision of risk prediction models for this population but also the quality of care.

To improve this gender disparity in mortality, more resources need to be invested in providing personalized strategies for glycemic control in girls and women with type 1 diabetes. In addition to glycemic control, sex differences in the management of risk factors of CVD need to be addressed on a population level. For instance, a health system response could incorporate gender-specific process measures into physician performance feedback, such as measures of sex-specific glycemic control, sex-specific cardiovascular disease risk factor treatment, and sex-specific risk factor target achievement to aid in not only identifying but also reducing gender disparities in type 1 diabetes treatment and outcomes.

References

1. Huxley 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;3:198-206
2. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ 2006;332:73-78.
3. ME Larkin, J-Y Backlund, P Cleary, et al. Disparity in management of diabetes and coronary heart disease risk factors by sex in DCCT/EDIC. Diabet Med 2010;27:451-8.
4. Arrais RF, Dib SA. The hypothalamus-pituitary-ovary axis and type 1 diabetes mellitus: mini review. Hum Reprod 2006;21:327-37.
5. Wannamethee SG, Papacosta O, Lawlor DA, et al. Do women exhibit greater differences in established and novel risk factors between diabetes and non-diabetes than men? The British Regional Heart Study and British Women's Heart Health Study. Diabetologia 2012;55:80-7.

Keywords: Accidents, Achievement, Biological Factors, Blood Glucose, Blood Pressure, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Fibrinolysis, Follow-Up Studies, Hyperglycemia, Incidence, Insulins, Life Expectancy, Mortality, Premature, Neoplasms, Process Assessment, Health Care, Risk, Risk Factors, Sex Characteristics, Stroke, Suicide, Thrombosis

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