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Practical Diabetes Care, 3rd Ed., Excerpt #34: Lipids Part 4 of 6

David Levy, MD, FRCP



Diet therapy

Always considered the mainstay of dyslipidemia management, significant reductions in LDL levels are difficult to achieve with diet except with long-term adherence to a regimen that most Western people would consider punitive. Changing the fatty acid constituents of diets to decrease w-6 fatty acids while substantially increasing w-3 fatty acids, for example through the Mediterranean diet (see Chapter 5), which is high in cis-monounsaturated fats and w-3 fatty acids, may not substantially change the conventional lipid profile but may have important effects on cardiovascular and cancer outcomes, and is easier to incorporate long term into contemporary diets than the conventional advice on measures largely designed to reduce LDL levels by decreasing saturated fat intake (Box 12.2). Patients with very marked hypertriglyceridemic syndromes, often genetic in origin (see below), should have primary diet therapy, as drug therapy may be relatively ineffective; modest reductions in weight and BMI, low alcohol intake and increased moderate exercise may have significant effects on the underlying non-alcoholic fatty liver disease that seems to drive the excessive VLDL secretion.



Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is rate-limiting in hepatic cholesterol synthesis. Lower intrahepatocyte cholesterol levels upregulate LDL receptors and enhance plasma clearance of LDL. Although the major effect of the statins is to lower LDL-cholesterol, the longer-acting, more powerful agents (atorvastatin and rosuvastatin) have a significant effect on triglyceride and HDL levels (Table 12.3). Whether these effects, or their powerful (but not always predictable) effects on lowering high-sensitivity CRP, contribute to their consistently beneficial effects on macrovascular events is less clear; statins are effective in reducing cardiovascular events in people with low HDL levels, and the clinical benefits of atorvastatin are seen at high doses, even though it is the only statin that tends to show an inverse relation between dose and HDL levels. The early secondary prevention statin studies (e.g. 4S, CARE and LIPID) recruited few diabetic subjects, and it was not clear initially whether they benefited to the same extent as non-diabetic subjects (the effectiveness of LDL lowering by statins in diabetes was not in question; the doubts included their lower initial LDL levels, the heterogeneity of the diabetes population and the relatively poor response of the lipid profile of the metabolic syndrome to statin treatment). However, from 2004, with the publication of the ‘primary prevention’ diabetes CARDS study, it became clear that statins reduced relative risks of cardiovascular events by a similar or even greater amount than in non-diabetes subjects, and also conferred higher absolute risk reductions. RCTs and guidelines are consistent in recommending a target LDL of 2 mmol/L (80 mg/dL)  in  all  type  2  diabetic  patients.  The  questions  remaining are whether attaining lower or even much lower LDL levels is of benefit in those with and without overt cardiovascular disease, what that LDL level should be, and whether combination treatment further improves the outlook (see below).


Dose–response  relationships

Low starting doses of statins result in large reductions in LDL (10 mg of simvastatin, atorvastatin and rosuvastatin reduce LDL by about 25, 35 and 45% respectively). Thereafter doubling the dose further reduces LDL by only 4–6%, a small reduction that might not be apparent considering the variability of routine clinical testing (see Box 12.1). Using doses intermediate between the tablet strengths available is therefore not logical. Since statin side-effects are dose-related, the highest doses carry an increased risk of side-effects while they may not be reliable in achieving target LDL. However, when low- and high-dose atorvastatin (10 and 80 mg daily) were compared in the TNT study (2005), the (expected) 16% LDL difference between the two groups was associated with a 20% lower risk of cardiovascular events (absolute risk reduction 2%). The risk of persistent liver function test abnormalities was greater with the high dose, though the absolute risk was low; not all studies show a dose-related side- effect profile for atorvastatin. Southeast Asian and South Asian patients develop higher circulating statin levels than white subjects for a given drug and dose, and starting doses can be lower. This is reflected in clinical trials, where very low doses (e.g. simvastatin 10 mg daily) are often effective, and in clinical practice, where the most powerful statin, rosuvastatin, should be started at 5 mg daily, and the highest recommended dose is 20 mg in these ethnic groups (Table 12.4).

Analyses of many statin trials over a long period confirm the close relationship between achieved LDL and vascular events, whichever statin is used. Importantly, an analysis of TNT found that high dose atorvastatin (80 mg) not only reduced the risk of a first event, but also subsequent events up to the fifth. Using the standard measure in clinical trials – reducing the occurrence of first events – therefore substantially underestimates the total burden of cardiovascular events prevented [7]. In contrast to blood pressure studies, the majority of lipid trials are not treat-to-target, use fixed doses of specific statins, and retrospectively establish target LDL levels. The ideal approach would therefore be to match the statin to the required LDL reduction, and then rapidly change the dose to achieve target LDL. (As an example, simvastatin 40 mg will reduce LDL by about 40%; a patient with a baseline LDL above 3.2 mmol/L is unlikely to achieve the target LDL of 2.0 mmol/L). However, the significant cost difference between generic simvastatin and the other agents means that most guidelines suggest starting with simvastatin and only changing to other drugs if there are side-effects or an inadequate response. The situation will change as patents expire on other statins. In practice, because LDL will remain stable indefinitely on statin treatment as long as the medication is taken, it is worthwhile investing some time achieving target LDL.

Morning or evening dosing?

Cholesterol is mostly synthesized at night when dietary intake is low, and therefore the effect of statins is thought to be greater if they are taken in the evening. In small studies with simvastatin, LDL levels were about 10% lower with night-time dosing. However, drugs are generally taken more reliably in the morning, and since compliance is so important with statin treatment, reliable morning tablet-taking is preferable to intermittent evening dosing. The long-acting agents atorvastatin and rosuvastatin are equally effective whenever they are taken. Alternate day rosuvastatin 20 mg is nearly as effective as 10 mg daily.

Practical approach to statin treatmentPDCChapt12Table12.4

Dose titration does not occur in practice, and most patients continue to take the dose on which they were started, but until we can routinely prescribe potent statins, active dose titration and changes of statin preparation are important in order to achieve target levels. After a change of statin or a dose, LDL will stabilize within 6 weeks, so it should be possible to establish a well-tolerated effective regimen in most patients within a few months. UK clinical guidelines do not specify in detail the practical place of statins other than simvastatin. The following is a possible strategy for secondary prevention.

  1. Trial of simvastatin up to 40 mg or maximum tolerated dose (since most of the effect is seen with 10 or 20 mg, it is worthwhile starting with these lower doses, especially in patients anxious about statins and in those with pre-existing musculoskeletal symptoms).
  2. If target LDL is not reached, trial of atorvastatin up to 40 mg (80 mg with caution).
  3. If still not at target, trial of rosuvastatin up to 40 mg daily (20 mg in South Asian and Southeast Asian patients).
  4. If still not at target, add ezetimibe 10 mg daily.
  5. If titration of a statin is limited by side-effects, use ezetimibe as monotherapy or add-on to maximum tolerated statin.

Adverse effects

Statins are worldwide the most widely prescribed drugs. More than 20 years of clinical experience confirms them also as some of the safest, but their massive usage has highlighted the burden of adverse effects. However, they are often carelessly prescribed with medications known to interact with them, some combinations resulting in increased plasma levels that increase the risk of adverse effects [8].

Muscle side-effects

The spectrum of muscle side-effects is wide, and their mechanism not known. Fulminating rhabdomyolysis, associated with gross elevations of CK (>10 000 U/L) is usually idiosyncratic and occurs within 3 months of starting statin treatment. Drug–drug interactions account for about half of cases, and renal impairment and hypothyroidism are also suspected contributory factors. Rhabdomyolysis can present with muscle weakness, and not always muscle pain and tenderness. Much feared, and undoubtedly 30–40 times more common in statin-treated patients compared with the general population, it is still extremely rare. Much more common and variable is myopathy or myalgia, neither reliably associated with increased CK levels. Myopathy with elevated CK levels is probably dose-related, for example there is a fourfold increased risk in patients taking simvastatin 80 mg daily compared with those taking 20–40 mg daily; also uncommon, its incidence is between 0.1 and 0.2%. Minor myalgia is common; for example, in the HPS, almost one-third of patients in the placebo and simvastatin-treated groups reported minor muscle aches and pains. These and other ‘minor’ symptoms commonly reported with statins (gastrointestinal symptoms, headache, functional impairment and flu-like symptoms) are apt to be dismissed as having a doubtful causal link to statin treatment, but they are lifelong treatments and should not be discounted so lightly. Review drug interactions; if there are none, stop the statin and suggest a rechallenge. The patient’s view is paramount. Trying another agent is worthwhile, though there is scant data on the value of this manoeuvre. Stereotyped symptoms on taking more than one agent should be a signal to discontinue further attempts at instituting long-term treatment, though dogged persistence with multiple agents, with a misplaced emphasis on the life-saving as opposed to the risk- reducing properties of statins, is depressingly common. Try other strategies (see below). CK levels are often measured for various reasons in asymptomatic patients and statins consequently not prescribed. It is safe to use statins in patients with asymptomatic elevations in CK up to five times the upper limit of the reference range.

Liver side-effects

Significant elevations in transaminases (more than three times upper limit of normal on two occasions separated by days or a few weeks) are about 10 times more common at the highest doses of statins than at the lowest. They usually occur within the first 3 months of treatment, in about 0.6 per 1000 clinical trial participants, and nearly always resolve after discontinuing the statin. Liver failure is very rare, and occurs at a rate no higher than that in the general population. Baseline checks of liver function, repeated 2–3 months after starting treatment, are still recommended, and caution required in patients with more than threefold elevation of alanine aminotransferase/aspartate aminotransferase. The background rate of liver function abnormalities in type 2 patients is high, and careful selective monitoring is needed. However, there is increasing evidence for the safety of statins in patients in non-alcoholic fatty liver disease, and expert opinion is that cardiovascular benefits outweigh hepatic risks in patients with stable chronic liver disease.

Drug interactions (Table 12.5)

The importance of drug interactions with statins is not fully appreciated in routine practice. All statins undergo extensive first-pass metabolism by liver cytochrome (P450/CYP) systems, and therefore circulating levels are markedly influenced by concomitant drug therapy that also relies on this system for metabolism. Enzyme-inducing drugs will reduce statin levels, enzyme-inhibiting drugs will increase statin levels. Increased levels are associated with a greater risk of muscle side-effects. Unfortunately, it is not known whether ‘minor’ side-effects are increased when statins are prescribed with CYP inhibitors. In patients taking complex antiretroviral or immunosuppressive drug regimens, consider using pravastatin, fluvastatin or rosuvastatin rather than simvastatin; careful discussion with pharmacist colleagues is needed.

There is a striking increase in muscle side-effects in patients taking statin–fibrate combinations. Gemfibrozil appears to be the chief  culprit, but it was little used in the UK in any case. It should be considered obsolete. Myopathy/myositis is not increased when fenofibrate is combined with a statin, but the clinical indications for using the combination are now much less compelling, and other drug combinations are probably more clinically effective in patients with mixed or insulin-resistant dyslipidemias (see below). There is much interest in the interaction between statins and grapefruit juice. Grapefruit juice inhibits CYP3A4 and increases systemic exposure to statins. Taking a glass of standard grapefruit juice every day modestly increases plasma simvastatin and atorvastatin levels, but pravastatin has no effect, as it is not metabolized by the CYP3A4 pathway. Large quantities of grapefruit juice should not be part of the dietary portfolio of people with diabetes in any case (one suggestion is that more than 1 L a day could be clinically significant), but a regular small intake is of no clinical consequence. The non- dihydropyridine CCBs diltiazem and verapamil are mild-to-moderate CYP3A4 inhibitors. Clinically, statin side-effects do not seem to be more common when atorvastatin or simvastatin are combined with these agents, but bear in mind the possibility.




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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)