David Levy, MD, FRCP
Screening for secondary causes of hyperlipidemia
Simple screening tests will identify most secondary causes of hyperlipidemia:
- liver function tests and gamma-glutamyltransferase;
- full blood count (mean corpuscular volume, alcohol);
- creatinine and electrolytes;
- urate (associated metabolic syndrome, especially hypertriglyceridemia);
- thyroid function.
Factors modifying lipid levels
Overt hypothyroidism (TSH ;:, 10 mU/L) reduces hepatic LDL clearance, and profound hypothyroidism can be associated with very high cholesterol levels, but in most cases even when total cholesterol is elevated (e.g. > 6.2 mmol/L, 240 mg/dL), expect only a modest reduction (~ 10%) after thyroxine treatment.
Subclinical hypothyroidism (TSH 5–10 mU/L) is not consistently associated with high cholesterol levels, though lipid profiles may improve with thyroxine treatment. There are no RCTs of thyroxine replacement and cardiovascular events in subclinical hypothyroidism, and treatment should be individualized . Both hypothyroidism and statin treatment can give rise to muscle symptoms. Resistance to statin treatment may be caused by any degree of hypothyroidism (the upper limit of normal for TSH is now considered to be as low as 4.5 mU/L). Repeat thyroid function tests periodically in dyslipidemic type 2 patients. There is still interest in thyromimetics in the treatment of dyslipidemia; the hepatic-specific eprotirome improves the lipid profile of statin-treated patients, though it slightly reduces HDL.
As proteinuria progresses, the lipid profile deteriorates, and is especially marked in nephrotic patients. High triglycerides and low HDL cholesterol, partly related to decreased apoA1 synthesis, are characteristic. Surprisingly, patients with renal failure tend to have total and LDL cholesterol levels that are lower than patients without renal failure. Dyslipidemia itself may impair renal function, for example abnormal LDL may increase angiotensin II and upregulate the AT1 receptor, and increased chylomicron remnants may cause vasoconstriction. Naturally, angiotensin blockade and intensive lipid-lowering treatment are both required in patients with any degree of renal impairment or proteinuria, but lipid lowering does not reduce cardiovascular events once renal impairment has progressed to ESRD, presumably because advanced calcific coronary artery and valvular heart disease is not helped by statin treatment (see below).
Effects of drugs used in diabetes
Only the glitazones have substantial effects on lipid profiles that may impact on cardiovascular outcomes. Pioglitazone has overall a beneficial effect. In particular HDL rises by about 9%, and triglycerides fall by 0.2–0.6 mmol/L (18–53 mg/dL), but LDL rises slightly. Other non-insulin agents are either lipid-neutral or have generally beneficial but minor effects that are not clinically significant compared with formal lipid-modifying treatment.
For information on beta-blockers and thiazide diuretics, see Chapter 11. Beta-blockers have occasionally been associated with severe hypertriglyceridemia and acute pancreatitis.
Primary therapeutic target: LDL-cholesterol
Who should have statins for LDL lowering?
This list, derived from UK guidelines for diabetes, is largely uncontentious .
- Those with clinical evidence of macrovascular disease: angina, myocardial infarction, revascularization, peripheral vascular disease, cerebrovascular disease including transient ischemic episodes.
- Treated hypertension.
- Microalbuminuria or macroalbuminuria (including those with previous microalbuminuria resolved by antiproteinuric and antihypertensive treatment).
- Impaired renal function (e.g. eGFR < 60 mL/min).
- Most diabetes patients over 50 years of age without additional cardiovascular risk factors.
There is insufficient evidence for universal statin treatment in the following groups, and judgement should be used in assessing individual risk:
- current smokers, irrespective of age (e.g. younger type 1 patients with no other cardiovascular risk factors);
- obesity (BMI > 30);
- metabolic syndrome.
Statin treatment in type 1 patients
Statin treatment should be individualized in type 1 patients under 50 years of age where there are no other cardiovascular risk factors and no microvascular complications. Uncomplicated patients under 40 probably do not require statin treatment. Microalbuminuric patients require statins, but there is nothing to guide us in the management of those with isolated retinopathy or neuropathy. These are rapidly expanding groups of patients, comprising possibly 5–10% of type 1 patients, for whom there is no evidence for the routine use of statin treatment. A meta-analysis of 1500 type 1 patients in RCTs between 1994 and 2005 found that the cardiovascular benefit of statins was similar to those with type 2 diabetes. However, nearly 40% had previous vascular events and hypertension, and their lipid profile was similar to that of the type 2 cohort (cholesterol 5.7 mmol/L, LDL 3.4 mmol/L, HDL 1.3 mmol/L, triglycerides 1.6 mmol/L), much more adverse than that of uncomplicated patients, for example those in the DCCT (see above) .
LDL targets for type 2 diabetes (Table 12.2)
The CARDS study (2005) established that maintaining LDL at about 2.0 mmol/L (80 mg/dL) reduced events in type 2 patients without known cardiovascular disease; this is an LDL level at which coronary and carotid atheroma probably stabilizes in those with established vascular disease (REVERSAL and ARBITER studies, respectively, using atorvastatin 80 mg daily). Coronary heart disease events fell within 6 months of starting treatment, and from 12 months until the end of the trial showed a consistent 37% relative risk reduction. Hypertensive patients in ASCOT-LLA also achieved an LDL of 2.1–2.2 mmol//L, with a substantial reduction in stroke; these and other RCTs support reducing LDL to 2.0 mmol/L in the general type 2 population. Unusually, epidemiological and clinical data agree on the log-linear relationship between LDL lowering and reduction in cardiovascular events, with no discernible plateau or J-shaped curve. Studies using angiographic measures of atheroma (e.g. ASTEROID, 2006) support LDL lowering to about 1.6 mmol/L (60 mg/dL), and to 1.7–1.8 mmol/L (66–70 mg/dL) in patients with ACS (PROVE-IT TIMI 22, 2004). Ultra-low LDL levels in the same trial (< 1.04 mmol/L and 1.04–1.55 mmol/L, 40–60 mg/dL) were associated with lower cardiac event rates than in other groups. There are no RCTs of these ultra-low LDL levels in either the general type 2 population or those with stable coronary disease, but they are attainable, do not seem to be associated with an increased risk of side-effects of the high doses of statins needed to achieve these levels (e.g. rosuvastatin 40 mg daily or atorvastatin 80 mg daily), and may well be justified in individuals at the very highest risk, for example people with stents or bypass grafts or who have evidence of extensive coronary artery disease or atheroma elsewhere .
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David Levy, MD, FRCP, Consultant Physician, Gillian Hanson Centre, Whipps Cross University Hospital; Honorary Senior Lecturer
Queen Mary University of London London, UK
This edition first published 2011, © 2011 by David Levy. 1st edition 1998 (Greenwich Medical Media/Cambridge University Press) 2nd edition 2006 (Altman Publications)