Interventions to manage CVD risk include:
In addition to lifestyle modification, all people at high absolute CVD risk should be treated with both antihypertensive medication and lipid-lowering medication (refer below), unless contraindicated or clinically inappropriate.1
GPs should set individual treatment targets for patients, balancing the benefits and risks of interventions. For example, the CVD risk associated with lipid and blood pressure levels is continuous; hence, specific targets are somewhat arbitrary and should be used as a guide to treatment, not as mandatory goals. It’s important to understand that there might be small absolute benefits required to reach suggested goals. However, any reduction in risk factor values will be associated with some benefit.1
When developing a management plan for patients, refer to the National Vascular Disease Prevention Alliance’s Guidelines for the management of absolute cardiovascular disease risk.1
Lifestyle changes in nutrition, physical activity and smoking status underpin a general practice approach to CVD risk minimisation. Lifestyle changes show excellent cost-effectiveness in lowering the burden of disease and remain the basis for the management of all CVD risk levels.8,9
In people with type 2 diabetes and obesity (average BMI 36 kg/m2), the Look AHEAD study found that a lifestyle intervention that focused on weight loss improved glycated haemoglobin (HbA1c) and quality of life, but did not significantly reduce risk of cardiovascular morbidity or mortality.10
For further information, refer to the section ‘Lifestyle interventions for management of type 2 diabetes’.
Lowering blood pressure reduces cardiovascular events and all-cause mortality in people with type 2 diabetes. While no difference is noted between different classes of blood pressure–lowering therapy for CVD outcomes, there is clear evidence that in people with type 2 diabetes, antihypertensive therapy with an angiotensin receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEI) decreases the rate of progression of albuminuria, promotes regression to normoalbuminuria and may reduce the risk of decline in renal function. Combining an ARB and an ACEI is not recommended.1,11
Blood pressure targets
The target level for optimum blood pressure is controversial. A number of international guidelines have changed their blood pressure targets to <140/90 mmHg,3,12 while others remain at <130/80 mmHg.13 Some suggest that low targets such as <130/80 mmHg could be appropriate for people at high risk of CVD, if achievable without undue treatment burden.12
Considering these guidelines, the RACGP recommends a blood pressure target of <140/90 mmHg for people with diabetes, with lower targets considered for younger people and those at high risk of stroke, as long as the treatment burden is not high.
For secondary prevention of CVD, the target blood pressure for people with diabetes and microalbuminuria or proteinuria (emergent chronic kidney disease) remains <130/80 mmHg. As always, treatment targets should be individualised and people with diabetes monitored for side effects from the use of medications to achieve lower targets.
GPs should consider treatable secondary causes of raised blood lipids before commencing pharmacotherapy.
Statins remain the clear first-line choice when commencing pharmacotherapy. The results from several systematic reviews are consistent, and suggest that people with diabetes gain at least similar benefits as people without diabetes. The data clearly demonstrate that statin therapy results in a significant decrease in coronary artery disease morbidity and mortality in type 2 diabetes for those at high CVD risk.1,14,15 This benefit is in contrast to the contentious effects of improved glycaemic control in CVD risk management.
Statin use for primary prevention of CVD
Statins are indicated for people with diabetes at high absolute risk of CVD, at any cholesterol level.1
Statin use for secondary prevention
Statin therapy is recommended for all patients with CVD (unless exceptional circumstances apply).
Other lipid-lowering medications
The evidence for using lipid-lowering medications other than statins to decrease the risk of coronary artery disease is still accumulating.
Ezetimibe has been studied in the IMPROVE-IT trial in people with diabetes and existing acute coronary syndrome. Compared with a statin alone, ezetimibe combined with a statin showed an absolute risk reduction of 5.5% (40% versus 45.5%) for the composite primary endpoint of cardiovascular death, major coronary events or non-fatal stroke over seven years.16
Thus, in adults, ezetimibe combined with a statin (simvastatin) in diabetes patients with acute coronary syndrome may provide additional low-density lipoprotein cholesterol (LDL-C) lowering (if >1.8 mmol/L on statin therapy) and CVD risk reduction.
Nicotinic acid, bile-acid resins and fibrates
These agents have been suggested as alternatives for people who cannot tolerate statins.
Nicotinic acid (niacin) has been shown in one trial to reduce CVD outcomes, although the study was done in a cohort of people without diabetes.17 More recent trials have not confirmed this initial result. The use of nicotinic acid, in particular, as well as gemfibrozil and cholestyramine is limited by a high rate of adverse effects.
The role of fibrates (fenofibrate, gemfibrozil) to decrease CVD is contentious. Fibrates, preferably fenofibrate, should be commenced in addition to a statin or on their own (for those intolerant to statin) when fasting triglycerides are ≥2.3 mmol/L, or HDL-C is low.2
Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9)
PCSK9 are injectable lipid-lowering agents, some of which have restricted Therapeutic Goods Administration (TGA) and Pharmaceutical Benefits Scheme (PBS) approval for use in select high-risk patients. Long-term outcome studies on safety are needed. For more information, refer to the websites for the TGA and the PBS.
It is not usually recommended that antiplatelet therapy (eg aspirin, clopidogrel) be used in primary prevention of CVD. For secondary prevention, the strong positive effects in the conditions outlined in the ‘Recommendations’ need to be weighed against individual patient risks.
Glucose-lowering medications (novel non-glycaemic effects)
In populations with existing CVD, cardiovascular outcome trials have been conducted for newly developed diabetes drugs to demonstrate, primarily, cardiovascular safety and various secondary non-glycaemic endpoints. Some trials did include people with multiple risk factors for CVD. The trials were not glycaemic efficacy trials.
Summary of outcomes
Refer to the individual trial designs and outcomes for specific drug effects.
Sodium glucose co-transporter 2 (SGLT2) inhibitors
A 2019 meta-analysis of the cardiovascular outcomes trials showed that SGLT2 inhibitors led to:18
- 11% reduction in major adverse cardiovascular events, seen only in those with established CVD, but not those without CVD
- 23% reduction in CVD death or hospitalisation for heart failure in those with or without atherosclerotic disease or heart failure.
Future clinical trials are focused on specific non-glycaemic benefits in heart failure (with or without diabetes) and renal outcomes. The exact mechanism of action on CVD and heart failure has not been fully elucidated.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs)
A 2018 meta-analysis showed that GLP-1 RAs led to:19
- 10% reduction in primary endpoints for major adverse cardiovascular outcomes
- 13% reduction in cardiovascular mortality
- 12% reduction in all-cause mortality.
Non-significant effects were demonstrated on fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospital admission for unstable angina, and hospital admission for heart failure.
The exact mechanism of action has not been fully elucidated.
Dipeptidyl peptidase-4 inhibitors (DPP-4i)
Recent meta-analyses for DPP-4i showed:20–22
- safety, but non-significant benefits for cardiovascular outcomes in those with high risk for cardiovascular events or with established CVD
- statistically non-significant 5% increased risk of hospitalisation for heart failure.
Meta-analyses of randomised clinical trials for sulfonylureas have shown:
- no excess cardiovascular risks associated with this class23,24
- lower all-cause and cardiovascular mortality associated with gliclazide and glimepiride compared with glibenclamide.25