Trends and New Insights in Cardiovascular Complications of Diabetes

Quick Takes

  • Despite the increasing prevalence of diabetes, the rate of complications in patients with diabetes is thought to be declining.
  • We discuss findings from a study by Davis et al. of 13,995 Australian participants with and without diabetes from two sequential, longitudinal, observational cohorts called FDS1 and FDS2.
  • The rates of major cardiovascular complications and death has declined in Australian patients with and without diabetes in the 15-year period between FDS1 and FDS2.
  • The gap in absolute cardiovascular event rates narrowed by 50% between the two phases, when comparing patients with and without diabetes.

The worldwide prevalence of diabetes mellitus continues to increase sharply, with conservative estimates suggesting that 642 million patients will be afflicted by the disease in 2040 (as compared to 30 million in 1964).1 This poses a heavy burden on healthcare systems in both resource-rich and resource-poor settings. Indeed, in the US, the estimated economic costs of diabetes have already increased 26% from 2012 to 2017, with recent data suggesting a cost of $327 billion.2 This figure is expected to increase exponentially over the coming decades. In addition, the negative impact on patient quality of life is incalculable often due to the multiple complications of diabetes including cardiovascular disease, stroke, visual impairment, lower extremity amputation and renal disease.

Initial data suggest that despite an increase in prevalence of diabetes, the rate of diabetes-related complications is on the decline.3,4 However, these studies are limited in their analysis due to variance in individual patient characteristics, misclassification of outcome measures, and loss of patients upon follow up. Further barriers include a lack of standardization in treatment and even lack of uniformity in making the diagnosis.5 As such, there is an urgent need to properly quantify the complication of diabetes. Davis et al. have studied the trends in long term complications among patients with diabetes mellitus to help bridge these knowledge gaps.6

This paper uses data from two longitudinal observational studies from Western Australia: the Fremantle Diabetes Study Phases I (FDS1) and II (FDS2).7 Participants with diabetes were enrolled from zip-code restricted geographical areas from hospitals, clinics, and primary care lists between 1993-1996 for FDS1 and between 2008-2011 for FDS2. Each patient had four age, sex, postcode matched participants without diabetes. In total, FDS1 enrolled 1,291 participants with diabetes mellitus and 5,159 participants without, while FDS2 enrolled 1,509 participants with diabetes mellitus and 6,036 participants without. Adjudication of outcomes was performed at annual or biennial visits using standardized definitions of albuminuria, peripheral sensory neuropathy, retinopathy, coronary artery disease, stroke, and peripheral artery disease.

Results showed that the 5-year incidence rates (IR) among patients with diabetes were universally lower in FDS2 than in FDS1 including all-cause mortality, cardiovascular mortality, fatal and nonfatal myocardial infarction (MI), fatal and nonfatal stroke, hospitalization for heart failure, and hospitalization for lower-extremity amputation. The incidence rate ratios (IRR) comparing FDS2 and FDS1 participants were also less than one, except for hospitalization for lower extremity amputation, suggesting a strong trend toward lower complications rates among the FDS2 participants. Notably, even for lower extremity amputations, there was a trend towards decline but this outcome had the fewest number of events and 95% confidence intervals were wide. A trend towards lower rates was also noted among matched participants without diabetes, except for stroke and amputation outcome measures. The study also confirmed the higher rates of negative sequelae of the disease by comparing IRRs and incidence rate differences between participants with and without diabetes. Yet, between FDS1 and FDS2, the rate of absolute events among patients with diabetes for MI, stroke, lower extremity amputation, heart failure, decreased as compared to those without diabetes. The exception was all-cause mortality where age at death in FDS2 was 1.7 years later in participants without diabetes as compared with the difference of 0.7 years in FDS1. Specifically, when comparing the FDS1 and FDS2 cohorts, patients without diabetes had an increase of 3.6 years in life expectancy up to 78.9 years, as compared to an increase of 2.5 years up to 77.1 years in patients with diabetes. This overall increase in life expectancy may be due to aggressive risk factor modification, but there is a clear reduction in effect among patients with diabetes, suggesting there is scope for improvement in bridging this gap.

In the Cox models, phase of study and presence of diabetes were strong predictors for all outcomes. Using the FDS2 participants without diabetes as baseline, the hazard ratios for all outcome measures were highest among FDS1 participants with diabetes. In the Cox model adjusted for age as timeline, sex, Charlson Comorbidity Index, and time from recruitment of first participant in each phase to study entry for each participant/matched person, particularly interesting findings were noted for hazard ratios in regard to all-cause mortality and cardiovascular disease mortality.8 Patients with diabetes from FDS1 had hazard ratios of 2.57 (95% CI: 2.16-3.05) for all-cause mortality and 6.33 (95% CI: 4.80-8.33) for cardiovascular disease specific mortality, as compared to reference patients without diabetes from FDS2.

These data suggest more intensive control of diabetes in the FDS2 population and a subsequent reduction in complications. Indeed, participants in FDS2 tended to be diagnosed at a younger age and had subsequently longer disease duration, had more intensive management of their diabetes with higher rates of insulin use (with or without oral agents or non-insulin injectables), lower systolic blood pressures, lower serum lipid levels and higher glomerular filtration rates. This investigation suggests a consistent and largely uniform decrease in major complications of diabetes mellitus in this West Australian population. Simultaneously, this study notes a decrease in major cardiovascular outcomes and mortality in the general population without diabetes.

The authors correctly identified that more stringent definitions of diabetes between the two FDS phases may have led to the inclusion of participants with relatively lower cardiovascular risk in FDS2, which may explain the improved outcomes in the second phase. Secondly, the gap in all-cause mortality between FDS2 and FDS1 despite reductions in cardiovascular mortality suggest a shift in cause of death among patients with diabetes away from cardiovascular disease to non-cardiovascular disease. For example, this is supported by emerging literature which links higher rates of malignancies in patients with diabetes.9,10,11

This excellent work by Davis et al. takes a rigorous approach to identifying trends in diabetes related complications. By leveraging data from two well-designed and well-adjudicated studies, this study gives strong support to the prior literature which suggests a reduction in major complications of diabetes such as cardiovascular, disease, stroke and diabetic nephropathy.3,4 The explanation for this decline is likely multifactorial and involves aggressive screening measures, standardization of treatment and nation-wide initiatives targeting population health.12,13,14 While these results certainly are promising, the increase in prevalence of diabetes may yet still lead to an increase in the absolute number of diabetes-related cardiovascular complications. Further, the persistently higher rates of MI, heart failure, lower extremity amputation and cardiovascular mortality in patients with diabetes as compared to those without diabetes, suggest that much more efforts need to be taken to control the burden of diabetes-related complications.

References

  1. Ogurtsova K, da Rocha Fernandes JD, Huang Y, et al. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract 2017;128:40-50.
  2. American Diabetes Association. Economic costs of diabetes in the U.S. in 2017. Diabetes Care 2018;41:917-28.
  3. Gregg EW, Li Y, Wang J, et al.  Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med 2014;370:1514-23.
  4. Gregg EW, Cheng YJ, Srinivasan M, et al.  Trends in cause-specific mortality among adults with and without diagnosed diabetes in the USA: an epidemiological analysis of linked national survey and vital statistics data. Lancet 2018;391:2430-40.
  5. Grant P. Management of diabetes in resource-poor settings. Clin Med (Lond) 2013;13:27-31.
  6. Davis WA, Gregg EW, Davis TME. Temporal trends in cardiovascular complications in people with or without type 2 diabetes: the Fremantle diabetes study. J Clin Endocrinol Metab 2020;105:dgaa215.
  7. Davis TME, Bruce DG, Davis WA. Cohort profile: the Fremantle Diabetes Study. Int J Epidemiol 2013;42:412-21.
  8. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373-83.
  9. George SM, Mayne ST, Leitzmann MF, et al. Dietary glycemic index, glycemic load, and risk of cancer: a prospective cohort study. Am J Epidemiol 2009;169:462–72.
  10. Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer: a consensus report. Diabetes Care 2010;33:1674-85.
  11. Abudawood M. Diabetes and cancer: a comprehensive review. J Res Med Sci 2019;24:94.
  12. Shortus TD, McKenzie SH, Kemp LA, Proudfoot JG, Harris MF. Multidisciplinary care plans for diabetes: how are they used? Med J Aust 2007;187:78-81.
  13. Spijkerman AMW, Adriaanse MC, Dekker JM, et al. Diabetic patients detected by population-based stepwise screening already have a diabetic cardiovascular risk profile. Diabetes Care 2002;25:1784-89.
  14. Narayan KMV, Zhang P, Williams D, et al. How should developing countries manage diabetes? CMAJ 2006;175:733.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Acute Heart Failure

Keywords: Metabolic Syndrome X, Diabetes Mellitus, Cardiovascular Diseases, Proportional Hazards Models, Quality of Life, Diabetic Nephropathies, Peripheral Arterial Disease, Coronary Artery Disease, Glomerular Filtration Rate, Albuminuria, Confidence Intervals, Follow-Up Studies, Blood Pressure, Cause of Death, Risk Factors, Diabetes Complications, Heart Failure, Amputation, Hospitalization, Myocardial Infarction, Stroke, Delivery of Health Care, Primary Health Care, Outcome Assessment (Health Care), Neoplasms, Reference Standards, Retinal Diseases, Lower Extremity, Vision Disorders, Comorbidity, Administration, Oral, Insulins, Lipids


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