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The Impact of Uncontrolled Diabetes on Overall Cardiovascular Health

Naveed Sattar, MD
Glasgow, Scotland, United Kingdom 
01/17/2021

Looking back at the history of diabetes management in high-income countries, we can see a number of advances. Striking among them is the change in mortality risk. In the 1970s, at a time before intensive glucose control or multiple risk factor management was widely practiced, the mortality risk of people with diabetes was 116% (95% confidence interval, 87 to 148%) higher compared to individuals who did not have the disease.1 Since then, mortality risk among patients with diabetes has declined to a comparative rate of 30 to 50% higher than their unaffected counterparts, with the risk being even lower in some countries. 

This decline has been driven largely by reductions in cardiovascular mortality over time with sizeable reductions in rates of myocardial infarctions and stroke.2 Contributing factors include improvements in disease management–including earlier diabetes diagnosis and better glycaemic control, as well as progressively more aggressive targeting of LDL-cholesterol and blood pressure levels3,4 and better secondary prevention measures. However, increased life expectancy in people with type 2 diabetes, along with the growing problem of obesity in many countries, has resulted in a higher diabetes prevalence of type 2 across the globe.4 This development leads us to an evolving challenge in the management of the disease: addressing the multiple comorbidities (e.g., ischemic heart disease, heart failure, peripheral vascular disease, kidney damage, etc.) that arise in patients who are living longer with type 2 diabetes.

It has recently been argued that for many patients, type 2 diabetes pathogenesis is driven by the progressive gain of ectopic fat into key organs such as the liver and pancreas.5 Even before frank diabetes develops, ectopic fat contributes to the emergence of several risk factors such as hyperlipidaemia or hypertension. This collectively explains the heightened cardiovascular risk already evident in the pre-diabetes phase, before frank hyperglycemia manifests.6 In many ways, we can say that whilst type 2 diabetes is diagnosed using glycaemic criteria, it is a state of uncontrolled cardiometabolic risk stemming from several dysregulated pathways linked to ectopic fat excesses. 

As frank diabetes develops, not only does atherothrombotic risk increase further, but so do risks of heart failure and renal complications as alterations in haemodynamic pathways place additional stress on the kidneys and the heart.7 Obesity (and related excess calorie and salt intake) are likely contributors to the haemodynamic dysregulation that characterises type 2 diabetes, including hyperinsulinemia. It is now clear from different drug treatments (e.g., glitazones which increase heart failure risk), that people with type 2 diabetes may be highly sensitive to fluid shifts.

The DiRECT trial provides further proof of the role of obesity and ectopic fat in diabetes.8 In many patients, low-calorie diets and meaningful weight loss (around 10kg on average) resulted in diabetes remission, with parallel improvements in cardiovascular risk factors, findings corroborated in the DIADEM-I trial.9 Furthermore, a growing body of evidence supports lifestyle interventions in preventing conversion to diabetes in those at high risk; newer tools in the prevention and early treatment of type 2 diabetes are now available.

A look at patients with type 2 diabetes and younger age of onset reminds us just how toxic the disease can be. In our review of data from the Swedish National Diabetes Registry, we found that those who developed type 2 diabetes at 20-30 years of age lost more than a decade of life expectancy, whereas those who develop diabetes after 80 years of age, lose no years as a result of the disease.10 This difference in life years lost (and in lifetime vascular risks) is in large part due to greater incidence of obesity (and some associated risk factors) in younger patients with diabetes relative to older people who develop the disease.11 As obesity levels rise worldwide, an increasing number of young people will develop type 2 diabetes; therefore we need to focus on earlier and more effective risk factor management in order to prevent rapid development of vascular and other complications in this population. The emergence of newer drugs for type 2 diabetes that lessen the risk of atherosclerotic cardiovascular disease (ASCVD) and cardiorenal complications represents a marked advance, especially since these agents help patients reduce their weight and lower their blood pressure. As we continue to meet the challenge of managing our patients with diabetes and associated cardiovascular conditions – a challenge that is set to become harder after the COVID pandemic passes – it is encouraging to note that the toolbox of treatments is expanding. 

Be sure to join my colleagues and me in further discussion of this topic during the upcoming webinar, Reaching Therapeutic Goals in Type 2 Diabetes: New Options. We look forward to learning more about your experience and perspective on cardiovascular risk and comorbidities in your patients with type 2 diabetes. What patterns are you seeing in your younger patients versus older ones? Have you had success with lifestyle interventions and/or the use of newer type 2 diabetes medications? Please let us know in the comments section below. 

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References

  1. Rao Kondapally Seshasai S, Kaptoge S, Thompson A, et al. Emerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011Mar 3;364(9):829-841. doi: 10.1056/NEJMoa1008862. Erratum in: N Engl J Med. 2011 Mar 31;364(13):1281. 
  2. Gregg EW, Sattar N, Ali MK. The changing face of diabetes complications. Lancet Diabetes Endocrinol. 2016 Jun;4(6):537-47. doi: 10.1016/S2213-8587(16)30010-9. Epub 2016 May 4. 
  3. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet. 2009 May 23;373(9677):1765-72. doi: 10.1016/S0140-6736(09)60697-8. 
  4. Chan JCN, Lim LL, Wareham NJ, et al. The Lancet Commission on diabetes: using data to transform diabetes care and patient lives. Lancet. 2021 Dec 19;396(10267):2019-2082. doi: 10.1016/S0140-6736(20)32374-6. Epub 2020 Nov 12. Erratum in: Lancet. 2021 Dec 19;396(10267):1978. 
  5. Taylor R, Al-Mrabeh A, Sattar N. Understanding the mechanisms of reversal of type 2 diabetes. Lancet Diabetes Endocrinol. 2019 Sep;7(9):726-736. doi: 10.1016/S2213-8587(19)30076-2. Epub 2019 May 13. Erratum in: Lancet Diabetes Endocrinol. 2019 May 22.
  6. Welsh C, Welsh P, Celis-Morales CA, et al. Glycated hemoglobin, prediabetes, and the links to cardiovascular disease: Data from UK biobank. Diabetes Care. 2020 Feb;43(2):440-445. doi: 10.2337/dc19-1683. Epub 2019 Dec 18. 
  7. Sattar N, McGuire DK. Pathways to cardiorenal complications in type 2 diabetes mellitus: A need to rethink. Circulation. 2018 Jul 3;138(1):7-9. doi: 10.1161/CIRCULATIONAHA.118.035083. 
  8. Lean ME, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2018 Feb 10;391(10120):541-551. doi: 10.1016/S0140-6736(17)33102-1. Epub 2017 Dec 5. 
  9. Taheri S, Zaghloul H, Chagoury O, et al. Effect of intensive lifestyle intervention on bodyweight and glycaemia in early type 2 diabetes (DIADEM-I): an open-label, parallel-group, randomised controlled trial. Lancet Diabetes Endocrinol. 2020 Jun;8(6):477-489. doi: 10.1016/S2213-8587(20)30117-0. 
  10. Sattar N, Rawshani A, Franzén S, et al. Age at diagnosis of type 2 diabetes mellitus and associations with cardiovascular and mortality risks. Circulation. 2019 May 7;139(19):2228-2237.  doi: 10.1161/CIRCULATIONAHA.118.037885.
  11. Wright AK, Welsh P, Gill JMR, Kontopantelis E, Emsley R, Buchan I, Ashcroft DM, Rutter MK, Sattar N. Age-, sex- and ethnicity-related differences in body weight, blood pressure, HbA1c and lipid levels at the diagnosis of type 2 diabetes relative to people without diabetes. Diabetologia. 2020 Aug;63(8):1542-1553. doi: 10.1007/s00125-020-05169-6. Epub 2020 May 21.