Patients with type 2 diabetes mellitus have a 2-4-fold increased risk for death and cardiovascular disease.2 Atherosclerotic cardiovascular disease (coronary artery disease, cerebrovascular disease, peripheral artery disease) is the most important cause of morbidity and mortality in diabetes and there are several pathophysiological mechanisms contributing to atherosclerotic disease.3

Diabetic patients with CVD should consider an ACE-inhibitor or ARB therapy to reduce the risk of further cardiovascular events.

Diabetes independently is a significant risk factor for atherosclerosis, and then hypertension and dyslipidaemia are common co-morbidities of diabetes, which are significant risk factors. Diabetes is also a risk factor for the development of heart failure which can be secondary to a myocardial infarction or secondary to hypertension but diabetes on its own is an independent risk factor for heart failure. Rates of heart failure hospitalisations are at least two-fold increased as compared to non-diabetic people.

Risk enhancing factors independent of diabetes itself:

  1. A long duration of diabetes (>10 years in type 2 and >20 years in type 1)
  2. Albuminuria
  3. eGFR < 60 ml/min
  4. Retinopathy
  5. Neuropathy
  6. Ankle-brachial Index (ABI) <0.9.

There are now two issues in the context of this increased cardiovascular risk: to reduce atherosclerotic risk the well-known cardiovascular risk factors need to be treated with evidence-proven therapies and the second issue is whether treatment of glycaemia or specific drugs can reduce the risk of atherosclerotic cardiovascular disease.

Cardiovascular risk reduction in diabetes by treatment of traditional risk factors:

There are two new documents that will be summarised: 2019 ACC/AHA Guideline on the primary prevention of cardiovascular disease specifically the section on diabetes3 and the Standards of Care in diabetes: 2019 section on cardiovascular disease and risk management.4

A comprehensive patient-centred approach that can address all aspects of a patient’s lifestyle, habits and an estimated risk of future Atherosclerotic Cardiovascular Disease (ASCVD) is the first step in deciding on management and pharmacotherapy. A team-based care approach is recommended and a shared-decision strategy to discuss the best option and strategy to reduce the risk of ASCVD.

Recommendation in diet: Increase intake of vegetables, fruit, legumes, nuts, whole grains and fish. (Mediterranean type). Avoid refined carbohydrates. Weight loss and increased physical activity (at least 150 minutes per week of moderate activity) is recommended. Important is to constantly check the adherence of patients to these recommendations.

Hypertension treatment:

Hypertension remains the risk factor with the largest impact on morbidity and mortality globally. Worldwide the treatment and control of blood pressure remains inadequate. Patients with elevated blood pressure ≥ 140/90 mmHg should have blood pressure confirmed using multiple readings on separate days and if uncertain whether hypertension is present, it is recommended to do 24-hour ambulatory readings. All patients with confirmed hypertension should monitor their blood pressure at home (home BP measurements) to evaluate the response on therapy, the control of blood pressure and it may improve patient adherence.

As a minimum, blood pressure should be lowered to a target of < 140/90 mmHg. Those who can tolerate a goal of 130/80 mmHg it is not unreasonable to aim for this lower target and such lower levels is suggested by meta-analyses. Lower targets than 130/80 mmHg may not offer robust benefits. Antihypertensive therapy with lower baseline levels and lower attained goal reduces the risk of stroke, retinopathy and albuminuria while ASCVD and heart failure outcomes are less evident.

Individualising blood pressure targets are encouraged based on the patient risk profile and their participation by way of autonomous decision. Considering the potential adverse effects of hypertension therapy such as hypotension, syncope, falls, acute kidney injury and electrolyte abnormalities should also be part of the discussion with patients. The drugs that can be used in diabetes include ACE-inhibitors, ARB’s, thiazide-like diuretics and dihydropyridine calcium channel blockers. For those with albuminuria, ACE-inhibitors or ARB’s should be included in the treatment regime. Beta-blockers should not be used unless there was a prior myocardial infarction or heart failure with reduced ejection fraction.

In most patients a combination of antihypertensive drugs will be necessary to control blood pressure. A single-pill combination is preferred as it is associated with improved compliance and step one in the treatment for all hypertensive patients are recommended by the 2018 European Society of Hypertension. Renin-angiotensin Blockers (ACE-I and ARB) are commonly combined with a diuretic or a calcium channel blocker.

Combining an ACE-inhibitor and an ARB should not be used as there is minimal benefit and much harm. In hypertension in pregnancy, there is a lack of randomised clinical trials on how to precisely treat hypertension. During pregnancy ACE-inhibitors, Angiotensin-receptor blockers (ARB’s) and spironolactone are contra-indicated as they cause foetal damage. Diuretics are also not recommended but can be considered in late pregnancy for volume control if necessary. Safe drugs are methyldopa, labetalol and long-acting nifedipine.

Lipid management:

It is reasonable to obtain a lipid profile with the first consultation and then, if under the age of 40 years, every five years repeat the lipid profile.

For patients with diabetes of all ages and established ASCVD or a 10-year risk > 20% a high-intensity statin should be used. (Atorvastatin 40-80 mg and Rosuvastatin 20-40 mg). If a goal of LDL-cholesterol of < 1.8 mmol/l is not reached on high-intensity statin at maximum dose, adding ezetimibe or a PCSK-9 inhibitor should be considered. For diabetic patients younger than 40 years of age, if there are other cardiovascular risk factors, a moderate-intensity statin should be used. (Atorvastatin 10-20 mg; Rosuvastatin 5-10 mg; Simvastatin 20-40 mg; Pravastatin 40-80 mg; Lovastatin 40 mg; Fluvastatin XL 80 mg).

For patients 40-75 years of age without ASCVD and LDL levels ≥ 4.9 mmol/l, start a moderate-intensity statin without calculating 10-year risk. In those diabetic patients with multiple cardiovascular risk factors, it is reasonable to use a high-intensity statin to reduce LDL-levels
by > 50%.

Assess adherence and percentage response to LDL-cholesterol lowering medications and life-style changes with repeat lipid profile after 4-12 weeks of statin therapy or dose adjustments and then repeated 3-12 months as needed.

Statin therapy is contra-indicated in pregnancy.

For patients with fasting triglycerides of > 5.7 mmol/l consider treating to reduce the risk of pancreatitis with diet, lifestyle fish oil and fibric derivatives and statin therapy. Combining a statin and niacin is not recommended given the lack of efficacy in randomised clinical trials.

Antiplatelet therapy:

Aspirin in a dose of 75 to 162 mg daily is recommended for diabetic patients who survived an ASCVD event (secondary prevention) as the benefit outweighs the harm. This recommendation is similar than for non-diabetic patients. With documented aspirin allergy, clopidogrel 75 mg per day is used to replace aspirin.

Dual anti-platelet therapy with aspirin plus clopidogrel for one year is reasonable after an acute coronary syndrome. Aspirin therapy as a primary prevention therapy may have less benefit and increased bleeding risk and such therapy, with low ASCVD risk should not routinely be started but this risk-benefit ratio should be discussed with the patient.

In those patients without established cardiovascular disease but who have many cardiovascular risk factors and a large 10-year risk, aspirin therapy is not unreasonable as the benefit may be more than the harm. Routine aspirin therapy for every diabetic patient without an increased cardiovascular risk is not encouraged.

Smoking:

Cessation of smoking is a well-established and very effective therapy in reducing the risk of atherosclerotic cardiovascular disease. All efforts should be undertaken to assist patients to stop smoking.

Diabetic patients with cardiovascular disease:

Consider an ACE-inhibitor or ARB therapy to reduce the risk of further cardiovascular events. Those patients, who had a prior myocardial infarction, also consider using a beta-blocker for two years after the event. All other well-established secondary cardiovascular prevention therapies will apply. In patients with heart failure, metformin can still be used provided the eGFR remains above 30 ml/min. Metformin should be stopped when the diabetic patient with heart failure is unstable or being admitted to hospital with acute heart failure.

Patients with established cardiovascular disease should be considered for sodium-glucose-cotransporter inhibitors (SGLT-2-I) as these drugs were shown to reduce heart failure and some also reduce mortality. Similarly, the use of GLP1-RA can be used in high risk patients as it reduces MACE but not heart failure.

Antihyperglycemic therapies to reduce cardiovascular outcomes:

SGLT2-Inhibitors:

Empagliflozin in the randomised clinical trial, EMPA-REG, assessed the effect of this drug versus placebo on cardiovascular outcomes in diabetic patients with established cardiovascular disease.5 Over a mean of 3.1 years, the composite outcome of myocardial infarction, stroke and cardiovascular death were reduced by Empagliflozin 10.5% vs. 12.1% absolute reduction (NNT of 63).

This result was driven by an absolute risk reduction by empagliflozin of cardiovascular death of 3.7% vs 5.9%. (NNT of 45). All these risk reductions were statistically significant with narrow confidence intervals. The risk of incident heart failure hospitalisation was also significantly reduced in these diabetic patients (2.7% vs. 4.1% NNT 71).

In the DECLARE-TIMI-58 trial, dapagliflozin was tested in a randomised clinical trial vs placebo over a mean of 4.2 years in diabetic patients of whom 40.6% had established cardiovascular disease and 59.4% had only multiple cardiovascular risk factors without established cardiovascular disease.6 MACE (major adverse cardiovascular events) were not significantly reduced but hospitalisation for heart failure was significantly reduced by 0.8% absolute reduction and NNT 125.

In a meta-analysis of 34 222 patients using SGLT2-Inhibitors, MACE was significantly reduced but benefit only occurred in patients with established cardiovascular disease.7 In the interpretation of this meta-analysis it was concluded that SGLT2 inhibitors have moderate benefit on major cardiovascular events that seem confined to patients with established atherosclerotic cardiovascular disease. The SGLT2-Inhibitors have robust benefits on reducing hospitalisations for heart failure and progression of renal disease regardless of existing atherosclerotic disease or a history of heart failure.

Glucagon-like peptide receptor agonists (GLP1-RA):

In another meta-analysis of 42 920 patients with diabetes, the GLP1-RA reduced the risk of MACE significantly but restricted to those patients with established cardiovascular disease. The GLP1-RA did not reduce heart failure hospitalisations, but they did reduce the risk of worsening kidney disease including macroalbuminuria but they did not reduce the risk of worsening eGFR, end-stage renal disease or renal death like the SGLT2-Inhibitors have shown.8

AUTHOR: Prof James Ker

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Conclusion

1. Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus.
2. Hypertension and dyslipidemia are common co-morbidities in patients with type 2 diabetes mellitus.
3. Reducing the risk of atherosclerotic cardiovascular disease is the major focus, and the traditional cardiovascular disease risk factors need to be treated according to well-established guidelines. Significant benefit is seen in reducing blood pressure and LDL-cholesterol
4. There are two new classes of antihyperglycemic drugs that also reduce significantly the risk of cardiovascular disease and renal disease. These drugs are the SGLT2-inhibitors and the GLP1-RA. Meta-analyses for these two classes are available.