Research Article| Volume 156, 107816, October 2019

Comorbid depression and risk of cardiac events and cardiac mortality in people with diabetes: A systematic review and meta-analysis



      To examine the association of comorbid occurrence of diabetes and depression with risk of cardiovascular endpoints including cardiovascular mortality, coronary heart disease and stroke.

      Research design and methods

      A systematic review and metaanalysis. We searched PUBMED/MEDLINE, Medscape, Cochrane Library, CINAHL, EMBASE and Scopus databases assessing cardiac events and mortality associated with depression in diabetes up until 1 December 2018. Pooled hazard ratios were calculated using random- effects models.


      Nine studies met the inclusion criteria. The combined pooled hazard ratios showed a significant association of cardiac events in people with depression and type 2 diabetes, compared to those with type 2 diabetes alone. For cardiovascular mortality the pooled hazard ratio was 1.48 (95% CI: 1.185, 1.845), p = 0.001, for coronary heart disease 1.37 (1.165, 1.605), p < 0.001 and for stroke 1.33 (1.291, 1.369), p < 0.001. Heterogeneity was high in the meta-analysis for stroke events (I-squared = 84.7%) but was lower for coronary heart disease and cardiovascular mortality (15% and 43.4% respectively). Meta-regression analyses showed that depression was not significantly associated with the study level covariates mean age, duration of diabetes, length of follow-up, BMI, sex and ethnicity (p < 0.05 for all models). Only three studies were found that examined the association of depression in type 1 diabetes, there was a high degree of heterogeneity and data synthesis was not conducted for these studies.


      We have demonstrated a 47.9% increase in cardiovascular mortality, 36.8% increase in coronary heart disease and 32.9% increase in stroke in people with diabetes and comorbid depression. The presence of depression in a person with diabetes should trigger the consideration of evidence-based therapies for cardiovascular disease prevention irrespective of the baseline risk of cardiovascular disease or duration of diabetes.
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        • Abdoli S.
        • Hardy L.R.
        • Hall J.
        The complexities of “struggling to live life”.
        The Diabetes Educator. 2017; 43: 206-215
        • Knowler W.C.
        • Barrett-Connor E.
        • Fowler S.E.
        • et al.
        Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
        New England J Med. 2002; 346: 393-403
        • Feng X.
        • Astell-Burt T.
        Impact of a type 2 diabetes diagnosis on mental health, quality of life, and social contacts: a longitudinal study.
        BMJ Open Diabetes Res Care. 2017; 5
        • Lloyd C.E.
        • Pambianco G.
        • Orchard T.J.
        Does diabetes-related distress explain the presence of depressive symptoms and/or poor self-case in individuals with Type I diabetes?.
        Diabet Med. 2010; 27: 234-237
        • Ali S.
        • Stone M.A.
        • Peters J.L.
        • et al.
        The prevalence of co-morbid depression in adults with Type 2 diabetes: a systematic review and meta-analysis.
        Diabet Med. 2006; 23: 1165-1173
        • Khaledi M.
        • Haghighatdoost F.
        • Feizi A.
        • et al.
        The prevalence of comorbid depression in patients with type 2 diabetes: an updated systematic review and meta-analysis on huge number of observational studies.
        Acta Diabetol. 2019; 56: 631-650
        • Lin E.B.
        • Heckbert S.R.
        • Rutter C.M.
        • et al.
        Depression and increased mortality in diabetes: unexpected causes of death.
        Ann Family Med. 2009; 7: 414-421
        • Milani R.V.
        • Lavie C.L.
        Behavioral differences and effects of cardiac rehabilitation in diabetic patients following cardiac events.
        Am J Med. 1996; 100: 517-523
        • van Dooren F.
        • Nefs G.
        • Schram M.
        • et al.
        Depression and risk of mortality in people with diabetes mellitus: A systematic review and meta-analysis.
        PLoS One. 2013; 8: 1-11
        • Park M.
        • Katon W.
        • Wolf F.M.
        Depression and risk of mortality in individuals with diabetes: a meta-analysis and systematic review.
        Gen Hosp Psychiatry. 2013; 35: 217-225
        • Zhang X.
        • Norris S.
        • Gregg E.
        • et al.
        Depressive symptoms and mortality among persons with and without diabetes.
        Am J Epidemiol. 2004; 161: 652-660
        • Coleman S.M.
        • Katon W.
        • Lin E.
        • et al.
        Depression and death in diabetes; 10-year follow up of all cause and cause specific mortality in a diabetic cohort.
        Psychosomatics. 2013; 54: 428-436
        • Egede L.E.
        Effect of depression on self-management behaviors and health outcomes in adults with type 2 diabetes.
        Curr Diabetes Rev. 2005; 1: 235-243
        • Bruce D.G.
        • Davis W.A.
        • Starkstein S.E.
        • et al.
        A prospective study of depression and mortality in patients with type 2 diabetes: the Fremantle Diabetes Study.
        Diabetologia. 2005; 48: 2532-2539
        • Pan A.
        • Lucas M.
        • Sun Q.
        • et al.
        Increased mortality risk in women with depression and diabetes mellitus.
        Arch Gen Psychiatry. 2011; 68: 42-50
        • Song J.W.
        • Chung K.C.
        Observational studies: cohort and case-control studies.
        Plast Reconstr Surg. 2010; 126: 2234-2242
      1. Wells GA, Shea B, O’Connell, D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses, 2012.

        • Modesti P.A.
        • Reboldi G.
        • Cappuccio F.P.
        • et al.
        Panethnic differences in blood pressure in Europe: a systematic review and meta-analysis.
        PLoS One. 2016; 11: e0147601
      2. Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available:

        • Higgins J.P.T.
        • Thompson S.G.
        • Deeks J.J.
        • et al.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • Egger M.
        • Smith D.
        • Schneider M.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • StataCorp
        Stata Statistical Software: Release 14.
        StataCorp LP, College Station, TX2015
        • Spitzer R.L.
        • Kroenke K.
        • Williams J.B.
        Validation and utility of a self report version of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire.
        JAMA. 1999; 282: 1737-1744
        • Melchior L.A.
        • Huba G.J.
        • Brown V.B.
        • et al.
        A short depression index for women.
        Educ Psychol Meas. 1993; 53: 1117-1125
        • Gudex C.
        • Kind P.
        The QALY toolkit. Centre for Health Economics.
        University of York, York1989
        • Robins L.N.
        • Helzer J.E.
        • Croughan J.
        National Institute of Mental Health Diagnostic Interview Schedule: Its history, characteristics and validity.
        Arch Gen Psychiatry. 1981; 38: 381-389
        • Cummings D.M.
        • Kirian K.
        • Howard G.
        • et al.
        Consequences of comorbidity of elevated stress and/or depressive symptoms and incident cardiovascular outcomes in diabetes: results from the reasons for geographic and racial differences in stroke (REGARDS) Study.
        Diabetes Care. 2016; 39: 101-108
        • Bruce D.G.
        • Davis W.A.
        • Dragovic M.
        • et al.
        Comorbid anxiety and depression and their impact on cardiovascular disease in type 2 diabetes: The Fremantle Diabetes Study Phase II.
        Depression Anxiety. 2016; 33: 960-966
        • Clouse R.E.
        • Lustman P.
        • Freedland K.
        • et al.
        Depression and coronary heart disease in women with diabetes.
        Psychosom Med. 2003; 65: 376-383
        • Lin E.B.
        • Rutter C.M.
        • Katon W.
        • et al.
        Depression and advanced complications of diabetes: a prospective cohort study.
        Diabetes Care. 2010; 33: 264-269
        • Sullivan M.D.
        • O’Connor P.
        • Feeney P.
        • et al.
        Depression predicts all-cause mortality. Epidemiological evaluation from the ACCORD HRQL substudy.
        Diabetes Care. 2012; 35: 1708-1715
        • Novak M.
        • Mucsi I.
        • Rhee C.
        • et al.
        Increased risk of incident chronic kidney disease, cardiovascular disease, and mortality in diabetic patients with comorbid depression.
        Diabetes Care. 2016; : 1-8
        • Ting R.
        • Lau E.
        • Ozaki R.
        • et al.
        High risk for cardiovascular disease in Chinese type 2 diabetic patients with major depression- A 7-year prospective analysis of the Hong Kong Diabetes Registry.
        J Affect Disord. 2013; 149: 129-135
        • Martin-Subero M.
        • Kroenke K.
        • Diez-Québécois R.
        • et al.
        Depression as measured by PHQ-9 versus clinical diagnosis as an independent predictor of long-term mortality in a prospective cohort of medical in-patients.
        Psychosom Med. 2017; 79: 273-282
        • Hofmann M.
        • Köhler B.
        • Leichsenring F.
        • et al.
        Depression as a risk factor for mortality in individuals with diabetes: a meta-analysis of prospective studies.
        PLoS One. 2013; 21: 8
        • Roy T.
        • Lloyd C.E.
        Epidemiology of depression and diabetes: A systematic review.
        J Affect Disord. 2012; 142: 8-12
        • Lavie C.J.
        • Menezes A.R.
        • De Schutter A.
        • et al.
        Impact of cardiac rehabilitation and exercise training on psychological risk factors and subsequent prognosis in patients with cardiovascular disease.
        Can J Cardiol. 2016; 32: 365-373
        • Kachur S.
        • Menezes A.R.
        • De Schutter A.
        • et al.
        Significance of comorbid psychological stress and depression on outcomes after cardiac rehabilitation.
        Am J Med. 2016; 129: 1316-1321
        • De Schutter A.
        • Lavie C.
        • Milani R.V.
        Relative importance of comorbid psychological symptoms in patients with depressive symptoms following phase II cardiac rehabilitation.
        Postgrad Med. 2011; : 72-78
        • Monster T.B.M.
        • Johnsen S.P.
        • Olsen M.L.
        • et al.
        Antidepressants and risk of first-time hospitalization for myocardial infarction: a population-based case-control study.
        Am J Med. 2004; 117: 732-737
        • Tata L.J.
        • West J.
        • Smith C.
        • et al.
        General population based study of the impact of tricyclic and selective serotonin reuptake inhibitor antidepressants on the risk of acute myocardial infarction.
        Heart. 2005; 91: 465-471
        • Cohen H.W.
        • Gibson G.
        • Alderman M.H.
        Excess risk of myocardial infarction in patients treated with antidepressant medications: association with use of tricyclic agents.
        Am J Med. 2000; 108: 2-8
        • Blanchette C.M.
        • Simoni-Wastila L.
        • Zuckerman I.H.
        • et al.
        A secondary analysis of a duration response association between selective serotonin reuptake inhibitor use and the risk of acute myocardial infarction in the aging population.
        Ann Epidemiol. 2008; 18: 316-321
      3. Coupland C, Dhiman P, Morriss R. et al. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ 2011; 343: 1–15.