Cardiovascular Risk and the Management of Dyslipidaemia
Cardiovascular Risk and the Management of Dyslipidaemia in Patients with Type 2 Diabetes Mellitus
Managing cardiovascular risk in type 2 diabetes
(See Strength of Recommendations Taxonomy (SORT) for explanation of Grade A-C)
| SEMDSA 2017 Recommendations |
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Type 2 diabetes is considered a coronary artery disease risk equivalent and dyslipidaemia as well as other cardiovascular risk factors should be looked for and aggressively treated in every patient with diabetes
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A |
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In most diabetic subjects, the risk is due to LDL that contributes the bulk of total cholesterol but hypertriglyceridaemia may also contribute to atherosclerotic cardiovascular risk and may in some cases cause pancreatitis. Hypertriglyceridaemia of 10 to 15mmol/L requires urgent intervention to diet and diabetes control to avoid pancreatitis
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B |
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Lowering LDL-cholesterol, particularly with statin therapy, reduces the risk of major cardiovascular events
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A |
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Statins are the first-line agents for lowering LDL-cholesterol levels
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A |
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Achieving the LDL-cholesterol level is the primary goal of therapy
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A |
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Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for all patients with type 2 diabetes who:
Have existing cardiovascular disease (i.e. ischaemic heart disease, cerebrovascular disease or peripheral vascular disease) Have chronic kidney disease (eGFR < 60 ml/minute/1.73m2). Are either older than 40 years of age or have diabetes of longer than 10 years’ duration, with one or more additional cardiovascular risk factor, i.e. hypertension, cigarette smoker, low HDL-cholesterol level, family history of early coronary heart disease, and any albuminuria |
A |
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Monitor LDL-cholesterol 3 months after therapy is instituted or therapy adjusted and then annually once at target
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C |
INTRODUCTION
Although hyperglycaemia is the most obvious feature of type 2 diabetes mellitus it is conceptually useful to think of type 2 diabetes as a vasculopathic disorder that damages both small (microvascular) and large (macrovascular) vessels. Dyslipidaemia is a major contributor to macrovascular disease, or atherosclerosis, which accounts for up to 70% of all diabetic mortality.
Type 2 diabetes is therefore considered a coronary artery disease risk equivalent and dyslipidaemia as well as other cardiovascular risk factors should be looked for and aggressively treated in every patient with diabetes.1
MANAGING CARDIOVASCULAR RISK IN TYPE 2 DIABETES
The risk of CVD for people with type 2 diabetes is increased two to three fold in men and three to five fold in women compared with people without diabetes.2 Abnormal glucose metabolism (dysglycaemia) that does not meet diagnostic criteria for diabetes is already associated with increased cardiovascular risk. Outcomes following myocardial infarction, stroke or revascularisation are also worse in patients with diabetes compared to non-diabetic individuals.
Atherosclerosis is often accelerated, severe and diffuse in diabetes. Chronic hyperglycaemia is an additional risk factor for atherosclerosis in patients with diabetes and adds to the well-known standard risk factor burden of race, gender, hypertension, dyslipidaemia, smoking, social deprivation and obesity.3 Table I summarises the traditional modifiable risk factors for CVD and the recommended target values in diabetes.
ESTIMATING CVD RISK IN TYPE 2 DIABETES
Risk scoring in diabetes is useful in obtaining more accurate numeric risk estimates, but is generally not needed for deciding whether to start lipid-lowering therapy or not as diabetes is considered to be a coronary risk equivalent and therapy is therefore indicated in almost all cases.4,5 The ACC/AHA guidelines also recommend more aggressive lipid-lowering therapy if the individuals calculated risk is high.6
THE METABOLIC SYNDROME
The metabolic syndrome, or insulin resistance syndrome, has become one of the major public health challenges worldwide7. Over the past few decades the prevalence has increased exponentially, affecting up to 25% of Western populations. This increase has paralleled the global epidemic of obesity.
The metabolic syndrome increases the risk of developing diabetes approximately fivefold, and doubles the risk of atherosclerotic cardiovascular disease.6 Features characteristic of the syndrome include abdominal obesity, atherogenic dyslipidaemia (elevated serum triglyceride and lowered HDL cholesterol), hypertension and elevated fasting glucose. Other ancillary conditions may include the polycystic ovarian syndrome (PCOS), non-alcoholic fatty liver disease (NAFLD) and sleep apnoea.
Criteria for the diagnosis of the metabolic syndrome are shown in Table II. The presence of three of the five listed criteria is sufficient to make a diagnosis of the metabolic syndrome. Drug treatment specifically targeted at any one of criteria 2-5 makes that criterion positive even if the measured variable falls below the cutoff. Population- and country-specific definitions of elevated waist circumference are provided in Table III.
Pharmacotherapy may play a role in the management of the metabolic syndrome, but lifestyle change, namely diet adjustment, weight loss and regular exercise, are the cornerstone of therapy. Lifestyle change can delay, or even prevent, the onset of type 2 diabetes in patients with the metabolic syndrome (Refer to: Prevention and delay of type 2 diabetes mellitus). Statins are also frequently used in subjects with the metabolic syndrome. With statin therapy, the risk of developing diabetes is increased by a rate of 0.1% per year. However most people aged 50 years or older have a 10-year risk of a cardiovascular event exceeding 10%.
Combining information from 13 individual studies (involving a total of 91 140 patients) showed that treating 255 patients with statins for 4 years led to one extra case of diabetes mellitus, whereas 5.4 cardiovascular events were prevented. Therefore the cardiovascular benefit of statin therapy far exceeds the risk of developing diabetes.8
Table I: CVD risk factors and targets for patients with type 2 diabetes
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Traditional CVD risk factors
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Targets
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| Cigarette smoking | Cessation | |
| Dyslipidaemia | ||
| Total cholesterol | <4.5 mmol/L | |
| LDL cholesterol | <1.8 mmol/L | |
| HDL cholesterol | > 1.0 mmol/L (men) >1.2 mmol/L (women) |
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| Triglycerides | <1.7 mmol/L | |
| Obesity | Waist circumference | <94 cm (men); <90 cm (men of South Asian descent) <80 cm (women) |
| Body mass index | <25 kg/m2 | |
| Hypertension | Systolic blood pressure | <140 mmHg |
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Diastolic blood pressure
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<90 mmHg |
LDL = low density lipoprotein; HDL = high density lipoprotein
Table II: Harmonised criteria for the clinical diagnosis of the metabolic syndrome7
| Measure | Categorical cut points |
| Elevated waist circumference |
Population- and country- specific definitions (Table III) |
| Elevated triglycerides§ |
≥ 1.7 mmol/l |
| Reduced HDL cholesterol§ |
Men < 1.0 mmol/l Women < 1.3 mmol/l |
| Elevated blood pressure§ | Systolic ≥ 130 mmHg and/or Diastolic ≥ 85 mmHg |
Elevated fasting glucose§ |
≥ 5.6 mmol/l |
§If the patient is receiving treatment directed at this variable, the criterion is counted as positive.
Table III: Population- and relevant country-specific definitions of elevated waist circumference
| Men |
Women |
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| Sub-Saharan Africa | ≥ 94 cm | ≥ 80 cm |
| Europid | ≥ 94 cm | ≥ 80 cm |
| Asian | ≥ 90 cm | ≥ 80 cm |
| Chinese | ≥ 85 cm | ≥ 80 cm |
DIABETIC DYSLIPIDAEMIA
Atherosclerosis accounts for up to 70% of all diabetic mortality in white, mixed race and Asian patients. Atherosclerosis is still uncommon in black patients, but is on the increase. Lipid disturbances are common in diabetes and are an important contributor to the high incidence of vascular disease. Lipid abnormalities should therefore be looked for and treated in every patient with diabetes.
The most frequently encountered lipid disturbances in type 2 diabetes are mildly to moderately increased serum triglycerides and decreased HDL cholesterol. Moderate triglyceride elevation (2-5 mmol/L) usually indicates that the concentration of remnant lipoproteins (partially metabolised VLDL and chylomicrons) is increased. Remnant lipoproteins are highly atherogenic. LDL cholesterol levels are often not very elevated but the LDL particles tend to be small and dense.
Thus the LDL-C concentration may be misleading as there will be more LDL particles for any given cholesterol concentration. Measuring apolipoproteinB (apoB) reflects the total number of atherogenic lipid particles. Non-HDL-C (calculated as TC-HDLC) reflects all cholesterol carried in atherogenic lipid particles and provides similar, but not identical,information to apoB measurements.
Although elevated LDL-C is not the major lipid abnormality in patients with type 2 diabetes, clinical trials have clearly demonstrated that reduction of LDL-C particularly with statin treatment reduces the risk for major cardiovascular events9 (Level A).
Patients with poorly controlled type 1 diabetes often have elevated triglyceride and, to a lesser extent, cholesterol levels. In well-controlled patients, the levels of total cholesterol, triglycerides and LDL cholesterol are similar to those of nondiabetic individuals. Individuals with diabetic renal disease, both microalbuminuria and frank proteinuria, have higher total cholesterol, LDL cholesterol and triglyceride levels, and lower HDL cholesterol levels.
LDL-C is the primary target of lipid-lowering therapy. The focus on LDL-C is supported by results of large, controlled clinical trials that have demonstrated that LDL-C lowering with statins will reduce the risk of major cardiovascular events and reduce all-cause mortality. Importantly the benefits of statin therapy are independent of the baseline LDL-C value.
Although lowering triglycerides, as a surrogate for remnant lipoprotein cholesterol, and increasing HDL-C are both intuitively appealing and biologically plausible interventions clinical trials thus far (nicotinic acid, fibrates, cholesterol ester transfer protein inhibitors) have failed to demonstrate cardiovascular event rate reductions. Further research is ongoing in this area.
The ideal lipid profile of a patient with diabetes is:
| Total cholesterol | < 4.5 mmol/l |
| LDL cholesterol | < 1.8 mmol/l |
| HDL cholesterol | > 1.0 mmol/l in men, and > 1.2 mmol/l in women |
| Triglycerides | < 1.7 mmol/l |
MONITORING SERUM LIPIDS
At the first visit, the total cholesterol and triglyceride levels should be checked. If either is elevated, a fasting lipogram (10 hour fast) should be performed (i.e. total cholesterol, triglycerides, HDL cholesterol and calculated LDL cholesterol). If the laboratory is able to measure LDL-C directly it is not essential for patients to fast, but the non-fasting state should be taken into account when interpreting triglyceride levels. In patients with hypertriglyceridaemia, triglycerides may vary markedly according to the composition and timing of the last meal and fasting triglycerides are best for serial comparisons.
If the results of the fasting lipogram are satisfactory, this test should be repeated annually. If the levels are unsatisfactory, the test should be repeated in three months, after the patient has been following an appropriate lipid-lowering diabetic diet, weight reduction has been encouraged, glucose control has been established, and lipid-lowering therapy has been instituted, or the dose of lipid lowering therapy has been adjusted.
NON-PHARMACOLOGICAL THERAPY
Diet is the cornerstone of therapy. Severe hypertriglyceridaemia (TG > 10 – 15 mmol/L) usually responds particularly well to dietary triglyceride restriction. All diabetic patients should receive standard advice on healthy eating habits and preferred food choices as also discussed in the chapter on medical nutrition therapy.
- Calories: The calorie content of the diet must be adjusted to achieve ideal body weight. Even moderate weight loss (e.g. 5-10%) can be of great value in improving dyslipidaemia and glycaemia.
- Fats: There is limited evidence on the ideal macronutrient composition of the diet in patients with diabetes. The type of fat consumed is probably more important than the total amount of fat in patients without severe hypertriglyceridaemia.
Mediterranean style diets high in monounsaturated fatty acids have been shown to improve glycemic control, lipid parameters and outcomes in patients with type 2 diabetes. Trans fats should be avoided because of their proven negative effect on cardiovascular outcomes, while saturated fat intake should be limited to less than 7% of total caloric intake.
The consumption of oily fish should be encouraged. Routine prescription of omega-3 supplements for the primary or secondary prevention of cardiovascular disease is not supported by randomised controlled trials. Omega-3 supplements in sufficiently high doses (2-4 g/day) can decrease moderately elevated triglycerides.
- Fibre: The fibre content of the diet should be increased aiming for an intake of around 14 g per 1000 kcal consumed.
- Alcohol: In the presence of obesity and/or hypertriglyceridaemia,alcohol should be avoided. Otherwise, alcohol should be restricted to maximally one (in females) or two (in males) units per day.
Poor metabolic control is a contributor to diabetic dyslipidaemia, and it is important to ensure that the glycaemic control is adequate. Adequate glycaemic control is particularly important in patients with severe hypertriglyceridaemia (TG>10 -15 mmol/L) where it is the most common secondary precipitating factor.10 In patients with severe hypertriglyceridaemia and poorly controlled diabetes initiation or intensification of insulin therapy should not be delayed.
Secondary causes of hyperlipidaemia (e.g. hypothyroidism, renal disease, medications [corticosteroids, retinoic acid derivatives,protease inhibitors, oestrogen, sirolimus and others] and alcohol abuse) must always be excluded.
PHARMACOLOGICAL THERAPY
- Achieving the recommended LDL-cholesterol level is the primary goal of therapy. Statins are the first-line agents for lowering LDL cholesterol in patients with diabetes. In patients unable to achieve LDL cholesterol goals on the maximum dose of a highly potent statin (i.e. atorvastatin or rosuvastatin), or in those unable to tolerate a sufficiently potent statin dose, combination therapy of a statin with ezetimibe should be considered. There is now also outcome evidence for the clinical utility of statin + ezetimibe combinations from the recently published IMPROVE-IT trial.11
- The addition of a fibrate or another triglyceride-lowering drug may be considered if triglyceride levels remain > 2 mmol/l, but only after reaching the LDL-cholesterol target with a statin. However, ideally these patients should be referred for specialist assessment as there is currently considerable uncertainty regarding optimal lipid management in diabetes beyond LDL cholesterol lowering. Clinical trials conducted to date do not support triglyceride reduction as a means to reduce CVD risk in diabetic subjects. Similarly there is little evidence to show that raising HDL-C with drug therapy reduces cardiovascular risk.
- Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for all patients with type 2 diabetes who:
- Have existing cardiovascular disease (i.e. ischaemic heart disease, cerebrovascular disease or peripheral vascular disease).
- Have chronic kidney disease (eGFR < 60 ml/minute/1.73m2).
- Are either older than 40 years of age or have had diabetes for longer than 10 years, with one or more additional cardiovascular risk factor, i.e. hypertension, cigarette smoker, low HDL-cholesterol level, family history of early coronary heart disease, and any albuminuria.
- Drug interactions should always be considered when prescribing a statin. For example, simvastatin should not be co-prescribed with most antiretroviral agents, and only low doses of simvastatin should be used with calcium-channel blockers. Simvastatin 80 mg/day should not be newly initiated in any patients.12
- In diabetic patients at lower risk (i.e. those without established cardiovascular disease or chronic kidney disease, or those younger than 40 years of age or who have diabetes of less than 10 years’ duration without additional cardiovascular risk factors), a targeted approach should be followed. Statin therapy should be considered if the LDL cholesterol is > 1.8 mmol/l.
- Specialist referral should occur when triglyceride levels are > 5 mmol/l in the controlled diabetic, or > 15 mmol/l before treatment.
HMG-CoA reductase inhibitors or Statins (e.g. simvastatin, atorvastatin, rosuvastatin, pravastatin, fluvastatin).
The statins are powerful cholesterol-lowering agents and are generally the lipid-lowering therapy of choice in diabetics. Statins lower serum cholesterol by 16-65%. Statin treatment in type 2 diabetes has been shown to markedly reduce the risk of cardiovascular events and improve survival. Statins do not fully address all the abnormalities found in diabetic dyslipidaemia (low HDL cholesterol and high triglycerides) but their use is supported by extensive safety and efficacy data.9 Statins are safe in renal failure.
Fibric acid derivatives (e.g. bezafibrate, fenofibrate, gemfibrozil).
Fibrates are indicated when there is severe hypertriglyceridaemia ( > 10-15 mmol/l) to reduce the risk of acute pancreatitis. Combination therapy with statins in those with moderate hypertriglyceridaemia, low HDL cholesterol and adequately controlled LDL cholesterol has intuitive appeal but lacks a definite evidence base. Specialist consultation is advised before initiating a statin + fibrate combination. Fibrate doses must be reduced in patients with renal failure. Gemfibrozil should not be used in combination with a statin.
Cholesterol absorption inhibitors
Ezetimibe is a selective inhibitor of cholesterol uptake by the gastrointestinal tract. Ezetimibe lowers LDL cholesterol by 15-20%, and can be used in combination with statin therapy if LDL-cholesterol goals are not achieved with statin therapy alone.
Bile acid sequestrants (e.g. cholestyramine)
Bile acid sequestrants should be used with caution in the management of diabetic dyslipidaemia, as they can worsen hypertriglyceridaemia (especially if the baseline triglycerides are elevated) which may secondarily lower HDL-cholesterol levels.
Niacin
Lowers triglycerides, lipoprotein(a), LDL cholesterol and increases HDL cholesterol. Niacin administration at higher doses leads to flushing as well as gout and can raise blood glucose; adjustments to treatment of dysglycaemia may be required. Niacinamide (nicotinamide) does not result in flushing but does not lower cholesterol. Trial evidence does not support the use of niacin for cardiovascular risk reduction in diabetic subjects.
Newer therapies
The role of proprotein convertase subtilisin/kexin type 9 (PCSK9)-inhibitor therapy, microsomal triacylglycerol transfer protein (MTP) inhibitor or cholesterol ester transfer protein (CETP) inhibitor therapy for the management of diabetic dyslipidaemia remains uncertain. These agents may have a role in the future if they are found to reduce cardiovascular risk in diabetic patients.
Authors: Derick J Raal, Dirk J Blom and Adrian D Marais
Editors: Aslam Amod and Nazeer A Mohamed
References
- The Emerging Risk Factors Collaboration. Association of cardiometabolic multimorbidity with mortality. JAMA 2015;314(1): 52-60
- Low Wang CC, Hess CN, Hiatt WR. et al. Clinical Update. Cardiovascular disease in diabetes mellitus. Circulation 2016;133:2459-2502
- Mazzone T, Chait A, Plutzky J. Cardiovascular disease in type 2 diabetes mellitus: insights from mechanistic studies. Lancet 2008:371:1800-1809.
- Task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J.2011;32(14):1769-1818.
- Garder AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm-2016 Executive Summary. Endocrine Practice 2016;22(1): 84-113
- Fox CS, Golden SH, Anderson C, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence. A scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2015;38:1777-1803
- Alberti KGMM, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome. Circulation. 2009;120:1640-1645.
- Shah RV, Goldfine AB. Statins and risk for new-onset diabetes mellitus. Circulation 2012;121:e282-284.
- Cholesterol Treatment Trialists’ (CTT) collaborators. Efficacy of cholesterol lowering therapy in 18 686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371:117-125.
- Hogue JC, Lamarche B, Tremblay AJ, et al. Evidence of increased secretion of apolipoprotein B-48-containing lipoproteins in subjects with type 2 diabetes. JLipid Res 2007;48:1336-1342
- Cannon CP, Blazing MA, Giugliano AP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372:2387-2397
- Egan A, Colman E. Weighing the benefits of high-dose simvastatin against the risk of myopathy. N Engl J Med. 2011;364(4): 285-287.