Atherosclerotic CVD (ASCVD) – in particularly stroke, myocardial infarction (MI), peripheral vascular disease and HF – is the main cause of morbidity and disability-adjusted life years in patients with T2DM.⁹

T2DM doubles, and in some cases triples, the risk of MI and stroke, relative to age and gender-matched controls. The absolute risks of ASCVD in patients with T2DM depends on multiple variables:¹⁰

• Age
• Gender
• Hypertension
• Lipid profile
• Smoking
• Duration of diabetes
• Presence of microvascular complications
• Use of specific risk lowering medications (eg statins).

A review of data from 2007-2017 by Einarson et al, which included data from more than 4.5 million participants with T2DM, found that globally, overall CVD affects about 32.2% of all persons with T2DM. CVD is a major cause of mortality among people with T2DM, accounting for approximately half of all deaths over the study period. Coronary artery disease and stroke were the major contributors.¹

What is the predominant manifestation of CVD in patients with T2DM?

Shah et al looked at the associations between T2DM and 12 initial manifestations of cardiovascular disease. Data from more than 1.8 million participants were analysed of which 1.8% (34 198) had T2DM. The follow-up period was 5.5 years and during this time, the researchers observed 113 638 first presentations of CVD. A total of 17.9% of participants with T2DM had a first CV presentation, the most common of which were peripheral arterial disease (PAD) (16.2%) and heart failure (HF) (14.1%). T2DM was positively associated with PAD, ischaemic stroke, stable angina, HF, and non-fatal myocardial infarction (MI), but was inversely associated with abdominal aortic aneurysm and subarachnoid haemorrhage, and not associated with arrhythmia or sudden cardiac death.²

The aim of the 2020 International Survey of the Occurrence of Cardiovascular Disease Among Patients With T2DM (CAPTURE) was to estimate the contemporary (2019) prevalence of established CVD in people with T2DM across 13 countries from five continents. In total, 9823 adults with T2DM managed in primary as well as specialist care, participated. Overall CVD prevalence was 34.8%, with most (85.8%) categorised as ASCVD (31.8%). Overall coronary heart disease prevalence was 17.7%, carotid artery disease was 8.4%, and cerebrovascular disease was 7.2%. The overall prevalence of HF was 2.4%, driven by a relatively low prevalence in China (0.2%). Prevalence estimates were similar across primary and specialist care settings. The researchers concluded that in 2019, about one in three adults with T2DM attending a primary or specialist healthcare visit, had established CVD.³

In the CAPTURE study patients were treated with GLP-1RAs such as semaglutide, and sodium-glucose cotransporter-2 inhibitors (SGLT-2is). The majority of guidelines now recommend early introduction of these agents as second-line therapy in combination with metformin in patients who are at high risk or have established CVD, noted Prof Ntsekhe.

The role of semaglutide in reduction of CVD in T2DM

Semaglutide has an extended half-life of about seven days, allowing for one weekly dosing.¹¹

Its efficacy and safety have been shown in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6). Patients (n=3297) with T2DM who were on a standard-care regimen, were randomised to receive once-weekly semaglutide (0.5mg or 1mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of CV death, non-fatal MI, or non-fatal stroke. At baseline, 83% of participants had established CVD, chronic kidney disease (CKD), or both. The primary outcome occurred in 6.6% of the semaglutide group and 8.9% of those in the placebo group. Non-fatal MI occurred in 2.9% of the participants receiving semaglutide and in 3.9% of those receiving placebo. Non-fatal stroke occurred in 1.6% of participants in the semaglutide group and 2.7% in the placebo group. Rates of death from CV causes were similar in the two groups. The team concluded that in patients with T2DM who were at high CV risk, the rate of CV death, non-fatal MI, or non-fatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo.⁴

Prof Ntsekhe noted that the majority of patients in the study had established CVD – either past MI or stroke. But what are the implications for patients who were considered high risk, but did not have a history of CVD?

In a posthoc analysis of SUSTAIN-6, Leiter et al grouped participants according to gender, age (50-65 years and > 65 years), and CV risk profile at baseline (prior MI or stroke versus no prior MI or stroke, and established CVD versus CV risk factors alone, including participants with CKD). Time to major adverse cardiovascular events (MACE) and its individual components (CV death, non-fatal MI, nonfatal stroke), hospitalisation for unstable angina or HF, and revascularisation (coronary and peripheral) were analysed for all subgroups. Additional analyses were performed for gender and age to investigate change from baseline in HbA1c and body weight, as well as tolerability. A total of 41.5% of participants had a history of MI or stroke and 76.8% had established CVD. Compared with placebo, semaglutide reduced the risk of the first occurrence of MACE and each MACE component consistently across all subgroups (gender, age, and baseline CV risk profile). Revascularisations, HbA1c and body weight were also reduced consistently across all subgroups compared with placebo.⁵

In this post-hoc analysis of SUSTAIN 6, once-weekly semaglutide versus placebo reduced the risk of MACE in all subjects included in the trial, regardless of gender, age, or baseline CV risk profile, stressed Prof Ntsekhe.

The findings of this study have important implications. Fang et al showed that even in developed countries such as the United States, diabetes care – specifically the effective management of CVD risk factors and reductions – needs to improve. Newer agents like semaglutide offer major opportunities for better patient care and outcomes, said Prof Ntsekhe.

Fang et al evaluated trends in diabetes treatment and control in American adults (1999-2018). Data from the National Health and Nutrition Examination Survey (NHANES) were analysed. Diabetes control improved from 1999 to the early 2010s among participants but subsequently stalled and declined. Between 2007-2010, and 2015-2018, the percentage of adult NHANES participants with diabetes in whom glycaemic control (<7%) was achieved declined from 57.4% to 50.5%. After major improvements in lipid control (non–high-density lipoprotein cholesterol level, <2.8mmol/L) in the early 2000s, minimal improvement was seen from 2007–2010 (52.3%) to 2015–2018 (55.7%). From 2011–2014 to 2015–2018, the percentage of participants in whom blood-pressure control (<140/90mmHg) was achieved decreased from 74.2% to 70.4%. The percentage of participants in whom all three targets were simultaneously achieved plateaued after 2010 and were 22.2% in 2015–2018. The percentages of participants who used any glucose-lowering medication or any blood-pressure-lowering medication were unchanged after 2010, and the percentage who used statins plateaued after 2014. After 2010, the use of combination therapy declined in participants with uncontrolled blood pressure and plateaued for those with poor glycaemic control.⁶

• Take-home messages
• The burden of diabetes is high and growing – particularly in geographical regions such as sub-Saharan Africa.
• The burden of CVD in patients with T2DM is high with ASCVD predominating as the main manifestation,
• It is important to view diabetes as a cardiometabolic disease rather than a disorder of dysglycaemia.
• Early use of once-weekly semaglutide provides an opportunity to improve CVD outcomes beyond traditional risk factor control.

REFERENCES:

1. Einarson TR, Acs A, Ludwig C, et al. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017. Cardiovasc Diabetol, 2018.
2. Shah 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. Alguwaihes A, Arenas Leon JL, Bayram F, et al. CAPTURE: a cross-sectional study of the contemporary (2019) prevalence of cardiovascular disease in adults with type 2 diabetes across 13 countries. https://www.easd.org/virtualmeeting/home.html#!resources/capture-a-cross-sectional-study-of-the-contemporary-2019-prevalence-of-cardiovascular-disease-in-adults-with-type-2-diabetes-across-13-countries-6443597c-6a85-4a9e-8895-8e97f8f0c390
4. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. NEJM, 2016.
5. Leiter LA, Bain SC, Hramiak I, et al. Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial. Cardiovasc Diabetol, 2019.
6. Fang M, Wang D, Coresh J, et al. Trends in Diabetes Treatment and Control in U.S. Adults, 1999–2018. NEJM, 2021.
7. Cho NH, Shaw JE, Karuranga S, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract, 2018.
8. Centres for Disease Control and Prevention. Diabetes Fast Facts. https://www.cdc.gov/diabetes/basics/quick-facts.html
9. Wang CC, Hess CN, Hiatt WR, et al. Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes – Mechanisms, Management, and Clinical Considerations. Circulation, 2016.
10. American Diabetes Association. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes. Diabetes Care, 2019.