Dr Nqoba Tsabedze, academic and clinical head, division of Cardiology, Department of Internal Medicine, recently presented on this important topic. This webinar was made possible by Eli Lilly.
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The following article is based on Dr Tsabedze’s presentation.
The prevalence of type 2 diabetes mellitus (T2D) is increasing. Globally, 424.9 million people were living with diabetes in 2017. This will rise to 628.6 million by 2045. Cardiovascular death rates are higher among adults with diabetes when compared to those without diabetes.
Macro and microvascular complications of T2D:
- Sexual dysfunction
- Sensory impairment (peripheral neuropathy)
- Stroke (cerebrovascular disease)
- Heart disease (cardiovascular disease)
- Bacterial and fungal infections of the skin
- Severe hardening of the arteries (atherosclerosis)
- Autonomic neuropathy (including slow emptying of the stomach and diarrhoea)
- Necrobiosis lipoidica
- Poor blood supply to lower limbs (peripheral vascular disease)
- Visual impairment: diabetic retinopathy, cataract and glaucoma
- Kidney disease (diabetic nephropathy).
Life expectancy is markedly reduced in patients with T2D. Macrovascular risk factors in patients with diabetes results in an increased incidence of cardiovascular disease (CVD) and mortality in this population.
The risk of CVD depends on the duration of diabetes. CVD risk at the point of diagnosis or conversion to diabetes in the majority of individuals is largely determined by conventional CVD risk factors. After this point, the elevation in glucose into the diabetic range enhance CVD risk gradually over time, so that by 8-10 years duration, patients have attained a coronary heart disease (CHD) risk equivalent state.
Diabetes confers significant cardiovascular risk in both women and men. A combination of diabetes and a history of myocardial infarction (MI) further increases the risk.
Comorbidities commonly seen in patients with T2D that further increase CV risk include the following risk factors
- Central obesity
Diabetes is a major risk factor for CVD-related mortality and morbidity. Providing patient-centred care is essential to effective diabetes management.
Treatment goals for T2D are to prevent or delay complications and maintain quality of life through:
- Empathic, individualised patient-centred care
- Stepwise approach, with metformin and comprehensive lifestyle management as foundational therapy
- Treatment pathways should consider key patient characteristics, especially CV comorbidity.
Primary prevention of CVD: Pharmacological approaches
Primary prevention refers to adjusting modifiable risk factors to prevent the onset of disease.
CVD prevention aims to prevent the onset of disease. Secondary prevention focuses on early disease detection before critical and permanent damage occurs, and allows healthcare practitioners to treat patients and secure quality of life.
The REWIND study recruited 371 sites from August 2011-August 2013. It involved 9901 participants in 24 countries on six continents.
One of the research questions was: Is dulaglutide (1.5mg once weekly) superior to placebo in reducing major adverse cardiac events (MACE) in people with T2D who have CV risk factors or established CVD, receiving standard of care?
It found that dulaglutide 1.5mg significantly reduced MACE in a broad population of people with T2D receiving standard of care.
Similar benefits were seen irrespective, in:
- Patients with or without prior CVD
- Men and women
- Patients with higher and lower BMI
- Patients with higher and lower HbA1c.
Dulaglutide therapy for a median of 5.4 years also durably reduced the following:
- HbA1c reduced by approximately 0.6%
- Weight reduced by 1.5kg
- Systolic blood pressure was reduced by 1.7mmHg.
Although more gastrointestinal adverse events were experienced with dulaglutide, it was generally well-tolerated and taken for 82% of follow uptime.
Current guidelines place greater focus on patient-related issues such as CVD. Comprehensive lifestyle and metformin continue to be the preferred first-line therapy for all people with diabetes.
To avoid clinical inertia, reassess and modify treatment regularly (3-6 months).
Indicators of high-risk or established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD) or heart failure (HF).
Approach for glucose-lowering medication in T2D management according to American Diabetes Association, European Association for the Study of Diabetes:
Metformin and comprehensive lifestyle (including weight management and physical activity).
Indicators of high risk or established ASCVD, CKD or HF:
If ASCVD predominates: In patients with established ASCVD or with indicators of high ASCVD risk, Glucagon-like peptide-1 receptor agonists (GLP-1 RA) with proven CVD benefit or Sodium-glucose cotransporter 2 inhibitors (SGLT2i) with proven CVD benefit if (estimated glomerular filtration rate (eGFR) is adequate is recommended.
Indicators of high ASCVD risk are age ≥55 years and left-ventricular hypertrophy or coronary, carotid, lower extremity artery stenosis >50%.
If HF or CKD predominates: In patients particularly with heart failure with reduced ejection fraction (HFrEF) (left ventricular ejection fraction [LVEF] <45%), SGLT2i are preferred with evidence of reducing HF in cardiovascular outcomes trials (CVOTs) if eGFR is adequate.
SGLT2i are preferred in patients with CKD, specifically eGFR 30 60ml, with evidence of reducing CKD progression in CVOTs.
If SGLT2i is not tolerated or contraindicated or eGFR is less than adequate, GLP-1 RA with proven CV benefit is recommended.
GLP-1 receptor agonist recommendations: ADA/EASD Consensus 2020
For patients with T2D and established atherosclerotic CV disease (such as those with prior myocardial infarction, ischaemic stroke, unstable angina with ECG changes, myocardial ischaemia on imaging or stress test, or revascularisation of coronary, carotid or peripheral arteries) where MACE is the gravest threat, the level of evidence for MACE benefit is greatest for GLP-1 receptor agonists.
To reduce the risk of MACE, GLP-1 RAs can also be considered in patients with T2D 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 <60ml min–1 [1.73 m]–2 or albuminuria.
Diabetes is a major risk factor for CVD. Although the FDA guidance aimed to ensure CV safety of new glucose-lowering therapies for T2D, some of the CVOTs have demonstrated potential for secondary prevention of CVD: EMPA-REG OUTCOME, CANVAS and LEADER, Harmony Outcomes.
Studies of new glucose-lowering therapies have a focus on primary prevention, such as the REWIND Trial.