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Practical Diabetes Care, 3rd Ed., Excerpt #35: Lipids Part 5 of 6

David Levy, MD, FRCP

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Statins in renal disease

See Chapter 8.

Ezetimibe

Ezetimibe is the first cholesterol absorption inhibitor, acting at a gastrointestinal cholesterol target now known to be Niemann–Pick C1-like protein, which is involved in the accumulation of free cholesterol. It lowers LDL-cholesterol, with minor effects on other lipids (see Table 12.3). Its mode of action is quite different from that of other lipid-lowering agents acting on the gut, for example the bile-acid sequestrants and the plant sterols/stanols.

The indications for ezetimibe are as follows.

  •  As add-on therapy to high-dose (or maximum-tolerated dose) statin where target LDL has not been reached.
  •  Where there is a poor response to statins: type 1 patients have high intestinal cholesterol absorption, and respond well to ezetimibe.
  •  As monotherapy when statins are not tolerated.
  •  In CKD (including pre-dialysis and dialysis patients), combined with low-dose simvastatin [9].

Ezetimibe acts synergistically with statins and, importantly, its LDL-lowering effect is constant and independent of baseline LDL. Individual responses to ezetimibe vary widely, but most studies show a mean LDL fall of about 15–18%. This drop is equivalent to the effect of three statin dosage steps (e.g. an eightfold increase in dose of simvastatin, from 10 to 80 mg), and therefore avoids the need for intensive statin dose titration, as it is well tolerated and does not add to the side-effect rate of statins. Concern about increased risks of cancer with ezetimibe has been allayed by careful analysis.

Enthusiasm for ezetimibe has been tempered by the results of three contentious RCTs, and the absence of hard endpoint studies.

  •  There was no reduction in CIMT in familial hypercholesterolemia over 2 years in the ENHANCE trial (2008), despite the expected additional 17% LDL lowering when added to existing maximum statin therapy. However, this result was not unexpected given the clinical circumstances.
  •  Ezetimibe with simvastatin also had no effect on echocardiographic measurements or operative intervention in aortic stenosis (SEAS, 2008), but again the outcome was not unexpected – even potent statins are ineffective in this condition.
  •  In the ARBITER-6 HALTS study (2009), niacin added to statin treatment reduced CIMT while ezetimibe had no effect, but the trial was stopped early, and this probably biased the outcome.

A more conventional study, IMPROVE-IT, due to finish in 2011, is using simvastatin 40 mg with or without ezetimibe in post-ACS patients [10].

In contrast to this controversy, studies dating back many years have shown consistent benefits from LDL lowering, whatever the method used. In clinical practice, ezetimibe remains valuable in secondary pre- vention and very high risk primary prevention patients. There is a single dose, 10 mg daily. No significant drug interactions are known. In small studies it is safe and effective when combined with fibrates or niacin, though these combinations are not licensed.

Fibric acid drugs

The fibrates (gemfibrozil, ciprofibrate, bezafibrate and fenofibrate) are PPAR-a agonist drugs with a broad spectrum of lipid actions, though their major clinical effects are to:

  •  increase HDL and decrease triglycerides;
  •  reduce fasting and postprandial levels of triglyceride-rich lipoproteins;
  •  shift LDL from the small dense pattern, thought to be atherogenic, to a larger more buoyant fraction.

Other than reducing triglycerides, the fibrates do not have effects that can be measured on a simple lipid profile, and in long-term studies they do not significantly reduce LDL (see Table 12.3).

The indications for the fibrates are:

  •  Hypertriglyceridemia, particularly where there is a risk or history of acute triglyceride-induced pancreatitis (e.g. triglycerides > 10 mmol/L, 890 mg/dL).
  •  After myocardial infarction in cautious combination with a statin where there is an insulin-resistant dyslipidemia.
  •  In patients with cardiovascular risk factors when there is a severe insulin-resistant dyslipidemia (e.g. HDL < 0.75 mmol/L, 30 mg/dL; triglycerides > 3.2 mmol/L, 284 mg/dL; ACCORD).
  •  Patients with retinopathy.

Fibrates were widely used as monotherapy until the introduction of the statins in the late 1980s, and a further series of clinical trials reported from the late 1990s onwards. The most unequivocally positive was the secondary prevention VA-HIT (1999), in which gemfibrozil reduced events in a group of post-myocardial infarction patients with low-normal LDL (mean 2.9 mmol/L, 113 mg/dL), mildly raised triglycerides (1.8 mmol/L, 160 mg/dL) and low HDL (0.8 mmol/L, 31 mg/dL). Greatest benefit was seen in subjects with diabetes or the insulin resistance syndrome. However, implementing the findings of this study in practice was difficult: gemfibrozil could not be safely combined with a statin in routine practice, and the results of studies of intensive post- myocardial infarction statin therapy were uniformly impressive.

Angiographic progression of atheroma was reduced by fenofibrate in the DAIS (2001). There have been two large recent primary prevention studies in diabetes, both using fenofibrate. FIELD (2005) was negative for its primary major cardiovascular end points, and several reasons have been cited. The baseline lipid profile was remarkably normal, and the effects of fenofibrate were limited to a 30% fall in triglycerides from a high-normal level of 1.7 mmol/L (150 mg/dL). The placebo group had a high rate of ‘drop in’ statin treatment. It may simply be that fenofibrate, in contrast to the other fibrates, is relatively ineffective, though safe, both as monotherapy and in combination with a statin. Much has been made of other benefits of fenofibrate seen in FIELD (e.g. significant reductions in laser-treated retinopathy and of below-ankle amputations) for which there are no mechanistic explanations, but may be related to the many non-lipid effects of fibrates, for example improvement in procoagulant and inflammatory states [11]. Of great interest, and confirming this unexpected outcome, ACCORD Eye also found that patients with some retinopathy at baseline had a lower risk of significant retinopathy progression if treated with fenofibrate (in addition to simvastatin).

The ACCORD lipid study (2010) was the first completed primary prevention study using combination simvastatin and fenofibrate treatment. The baseline lipid profile was again unremarkable and, apart from a lower HDL, was similar to VA-HIT (LDL 2.56 mmol/L, 100 mg/dL; HDL 0.97 mmol/L, 38 mg/dL; triglycerides 1.8 mmol/L,  162 mg/dL). By the end of the study (mean  follow-up  4.7  years)  only  triglycerides were significantly different in the fenofibrate group. There was no reduction in cardiovascular end points when compared with a group treated with simvastatin alone, but patients with the most severe insulin-resistant dyslipidemia (e.g. HDL < 0.75 mmol/L, 30 mg/dL; triglycerides > 3.2 mmol/L, 284 mg/dL) benefited, with a significant 10–13% risk reduction in major cardiovascular and coronary events [12]. This finding, that patients with the most atherogenic dyslipidemia, gain real benefit with fibrate treatment has now been replicated across several major studies, but most analyses have been post hoc, and it is difficult to draw firm messages for primary care teams.

In the light of the failure of these two definitive end-point studies, fibrates can no longer be considered to have a routine place in primary prevention or in high-risk patients. In post-myocardial infarction patients, combination therapy with a statin plus niacin has a stronger overall evidence base (see below). However, where dramatic triglyceride lowering to a safe level (i.e. < 5 mmol/L, 445 mg/dL) is required for reducing the risk of acute pancreatitis, the fibrates are more effective than either the potent statins or niacin (see below), neither of which should be used as initial treatment in patients with predominant hypertriglyceridemia. Patients with retinopathy that is progressing or not regressing could be considered for fibric acid treatment, especially if their lipid profile approximated that of the high-risk ACCORD subjects.

Gemfibrozil has the strongest evidence base of all the fibrates in clinical trials, but in practice modified-release bezafibrate (400 mg daily) is probably the fibrate of first choice where it is available, followed by fenofibrate (micronized, 160, 200 and 267 mg daily). Fibrates are renally excreted, and doses should be reduced according to eGFR (see British National Formulary, section 2.1.2); do not use fibrates where eGFR is below 15 mL/min.

Because of the general move away from fibric acid drugs, there is often no clear plan how to manage the many patients still taking them. Patients with a clear history of triglyceride-induced pancreatitis should not change therapy, but in others withdrawing the fibrate is safe and has little effect on the lipid profile so long as the statin is maintained. However, always carefully review the history for the initial indication(s).

Adverse effects

Non-specific side-effects are common, as with statins, but the risk of muscle side-effects is lower. Statistically significant increases in CK levels have been reported with fenofibrate. Serum creatinine can reversibly increase by up to 15% resulting from increased creatinine synthesis; if a fibrate is co-prescribed with an angiotensin-blocking agent, the cumulative effect on serum creatinine can be quite dramatic. Trial withdrawal of one or both agents can be reassuring. Combination statin–fibrate treatment must not be used in renal impairment.

References:

 

  1. Bulugahapitiya U, Siyambalapitiya S, Sithole J, Idris I. Is diabetes a coronary risk equivalent? Systematic review and meta-analysis. Diabetic Med 2009;26:142–8. PMID: 19236616.
  2. Purnell JQ, Hokanson JE, Marcovina SM, Steffes MW, Cleary PA, Brunzell JD. Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT. JAMA 1998;280:140–6. PMID: 9669786.
  3. Duntas LH, Wartofsky L. Cardiovascular risks and subclinical hypothyroidism: focus on lipids and new emerging risk factors. What is the evidence? Thyroid 2007;17:1075–84. PMID: 17900236.
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  9. Landray M, Baigent C, Leaper C et al. The second United Kingdom Heart and Renal Protection (UK-HARP-II) Study: a randomized controlled study of the bio- chemical safety and efficacy of adding ezetimibe to simvastatin as initial therapy among patients with CKD. Am J Kidney Dis 2006;47:385–95. PMID: 16490616.
  10. Cannon CP, Giugliano RP, Blazing MA etal. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J 2008;156:826–32. PMID: 19061694.
  11. Rajamani K, Colman PG, Li LP et al. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet 2009;373:1780–8. PMID: 19465233.
  12. Ginsberg HN, Elam MB, Lovato LC et al. Effects of combination lipid therapy in type 2 diabetes mellitus. ACCORD Study Group. N Engl J Med 2010;362:1563– 74. PMID: 20228404.
  13. Belalcazar LM, Reboussin DM, Haffner SM et al. Marine omega-3 fatty acid intake: associations with cardiometabolic risk and response to weight loss intervention in the Look AHEAD (Action for Health in Diabetes) study. Diabetes Care 2010;33:197–9. PMID: 19841042.
  14. Zhao XQ, Krasuski RA, Baer J et al. Effects of combination lipid therapy on coronary stenosis progression and clinical cardiovascular events in coronary disease patients with metabolic syndrome: a combined analysis of the Familial Atherosclerosis Treatment Study (FATS), the HDL-Atherosclerosis Treatment Study (HATS), and the Armed Forces Regression Study (AFREGS). Am J Cardiol 2009;104:1457–64. PMID: 19932775.
  15. Fazio S, Guyton JR, Polis AB et al. Long-term safety and efficacy of triple combination ezetimibe/simvastatin plus extended-release niacin in patients with hyperlipidemia. Am J Cardiol 2010;105:487–94. PMID: 20152243.

 

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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)