The main aim of the CAPTURE study was therefore to determine the prevalence of established CVD and its management in adults (n=9823) with T2DM across 13 countries (Australia, China, Japan, Czech Republic, France, Hungary, Italy, Argentina, Brazil, Mexico, Israel, Kingdom of Saudi Arabia, and Turkey).3
The authors report that the prevalence of CVD and atherosclerotic CVD (ASCVD) were 34.8% and 31.8%, respectively. The mean duration of T2DM in this cohort was 10.7 years. In essence this means that one out of every three participants were diagnosed with CVD.3
The authors also report that the majority of patients were sub-optimally treated despite the availability of effective therapies to reduce the risk of CVD.3
Reducing the risk of CVD
Numerous large CV outcomes trials (CVOTs) have investigated the safety and efficacy of glucagon-like-peptide 1 receptor agonist (GLP-1RA) or a sodium–glucose cotransporter 2 inhibitor (SGLT2i) to reduce major adverse CV events (MACE), hospitalisation for heart failure (HF), CV death or chronic kidney disease (CKD).2
In the 2016 Trial to Evaluate CV and Other Long-term Outcomes With Semaglutide in Subjects With T2DM (SUSTAIN-6) Marso et al randomised participants (n=3297) to semaglutide, a once-weekly GLP-1RA, and placebo. Participants who were on standard care received either once-weekly subcutaneous semaglutide (0.5mg or 1mg) or placebo for 104 weeks.2
The primary composite outcome was the first occurrence of CV death, nonfatal myocardial infarction (MI), or non-fatal stroke. At baseline, 83% of patients had established CVD, CKD, or both.2
The primary outcome occurred in 6.6% of participants in the semaglutide group and in 8.9% in the placebo group. Nonfatal MI occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo and nonfatal stroke occurred in 1.6% and 2.7%, respectively. Rates of death from CV causes were similar in the two groups.2
Oral semaglutide has been developed as a once-daily tablet, which may allay concerns about injections among some patients and clinicians and result in earlier initiation of GLP-1RA therapy.5
In the 2019 A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With T2DM (PIONEER 6), Husain et al investigated the CV outcomes of once-daily oral semaglutide in patients (n=3183) at high CV risk (age of ≥50 years with established CVD or CKD, or age of ≥60 years with CV risk factors only). The primary outcome in a time-to-event analysis was the first occurrence of a major adverse CV event (death from CV causes, nonfatal myocardial infarction, or nonfatal stroke). The trial was designed to rule out 80% excess CV risk as compared with placebo.4
Major adverse CV events occurred in 3.8% of patients in the oral semaglutide group and 4.8% in the placebo group.
Results for components of the primary outcome were as follows:4
- Death from CV causes: 0.9% in the oral semaglutide group and 1.9% in the placebo group
- Nonfatal MI: 2.3% and 1.9%, respectively
- Nonfatal stroke: 0.8% and 1%
- Death from any cause: 1.4% in the oral semaglutide group and 2.8% in the placebo group.
- Guidelines stress CV prevention as part of T2DM management
Updated international guidelines now recommend that CVD prevention form part of the management of patients with T2DM.5,6
The updated American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) consensus report contains three important changes, based on the results from these large CVOTs.5
These changes include:5
- Patients at high risk of CVD should be treated with a GLP-1RA or a sodium–glucose cotransporter 2 inhibitor (SGLT2i) to reduce major adverse CV events (MACE), hospitalisation for heart failure (HF), CV death or CKD. Decisions to treat these patients with either a GLP-1RA or SGLT2i should be considered independently of baseline HbA1c or individualised HbA1c targets
- To reduce risk of MACE, GLP-1RAs can also be considered in patients with T2DM without established CVD with indicators of high risk, specifically, patients aged 55 years or older with coronary, carotid or lower extremity artery stenosis >50%, left ventricular hypertrophy, eGFR <60 ml min–1 [1.73 m]–2 or albuminuria.
- SGLT2is are recommended in patients with T2DM and HF, particularly those with heart HF with reduced ejection fraction, to reduce hospitalisation, MACE and CV death. SGLT2is are also recommended for patients with CKD (eGFR 30 to ≤60 ml min−1 [1.73 m]−2 or urinary albumin-to-creatinine ratio >30 mg/g, particularly >300 mg/g) to prevent the progression of CKD, hospitalisation, MACE and CV death.
The 2021 American Diabetes Association (ADA) standard of care guidance recommend metformin (unless there are contraindications) and lifestyle changes as initial treatment. Additional and/or alternative agents may be considered in special circumstances, such as in individuals with established or increased risk of CV or renal complications.6
Several mechanisms through which GLP-1RAs mediate CV effects have been proposed. These include improved cardiac function and attenuating atherothrombosis, with the strongest evidence supporting an effect on atherosclerosis.7
Weight-loss reduces CV risks
Between 1980 to 2015, the prevalence of overweight globally has increased by almost 50% and that of obesity around 80%. It is estimated that for every 1% above healthy body mass index (BMI) values, the risk for CVD increases by about 4% in both men and women.8
The most recent American College of Cardiology/American Heart Association (AHA) guidelines (2019) on the primary prevention of CVD recommend that weight loss ≥5% of initial body weight is associated with moderate improvement in blood pressure, low density lipoprotein cholesterol, triglycerides, and glucose blood concentrations.9
Furthermore, state the authors of the guidelines, weight loss reduces or delays the development of T2DM in persons with obesity.9
Wilding et al recently showed that semaglutide in associated with lifestyle changes was associated with sustained, clinically relevant reduction in body weight in overweight or obese patients. The study enrolled 1961 adults with a BMI of ≥30 who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4mg) or placebo, plus lifestyle intervention.7
The primary endpoints were the percentage change in body weight and weight reduction of at least 5%. The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo, for an estimated treatment difference of −12.4 percentage points.7
More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more, 10% or more and 15% or more at week 68. The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group.7
Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo.7
Similar results were shown in patients with T2DM who were either overweight or obese. In the Semaglutide 2.4mg once a week in adults with overweight or obesity, and T2DM (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial, Davies et al (2021) enrolled adults with T2DM, a BMI of at least 27kg/m2 and HbA1c of between 7%–10%. Patients were recruited from 149 outpatient clinics in 12 countries including South Africa.10
Patients (n=1210) were randomly allocated (1:1:1) to subcutaneous injection of semaglutide 2.4mg, or semaglutide 1mg, or placebo once a week for 68 weeks, plus a lifestyle intervention.10
Primary endpoints were percentage change in bodyweight and achievement of weight reduction of at least 5% at 68 weeks for semaglutide 2.4mg versus placebo, assessed by intention to treat.10
Estimated change in mean bodyweight from baseline to week 68 was −9·6% with semaglutide 2.4mg and −3·4% with placebo. Estimated treatment difference for semaglutide 2.4mg versus placebo was −6.2 percentage points. At week 68, more patients on semaglutide 2.4mg than on placebo achieved weight reductions of at least 5%.10
REFERENCES:
1. Achwak M, Htira Y, Dridi M, et al. Weight gain and insulin therapy in patients with type 2 diabetes mellitus. Endocrine Abstracts (2021) 73 EP14. DOI: 10.1530/endoabs.73.EP104. Diabetes, Obesity, Metabolism and Nutrition, 2021.
2. Marso SP, Bain S, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. NEJM, 2016.
3. Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. NEJM, 2019.
4. Mosenzon O, Alguwaihes A, Leon JLA et al. CAPTURE: a multinational, cross-sectional study of cardiovascular disease prevalence in adults with type 2 diabetes across 13 countries. Cardiovascular Diabetology, 2021.
5. Buse JB, Wexler DJ, Tsapas A, et al. Correction to: 2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of diabetes (EASD). Diabetologia 63, 1667 (2020).
6. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2021. Diabetes Care, 2021;44(Suppl. 1):S111–S124.
7. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. NEJM, 2021.
8. Yannakoulia M and Panagiotakos D. Weight loss through lifestyle changes: impact in the primary prevention of cardiovascular diseases. Heart, 2021.
9. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation, 2019.
10. Davies M, Faerch L, Jeppesen OK, et al. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. The Lancet, 2021.
