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BMJ Clin Evid. 2008; 2008: 0610.
Published online 2008 June 9.
PMCID: PMC2907966

Diabetes: managing dyslipidaemia

Jigisha Patel, MRCP PhD, Chadburn Lecturer

Abstract

Introduction

Dyslipidaemia is a major contributor to the increased risk of heart disease found in people with diabetes. An increase of 1 mmol/L LDL-C is associated with a 1.57-fold increase in the risk of coronary heart disease (CHD) in people with type 2 diabetes. A diagnosis of diabetic dyslipidaemia requiring pharmacological treatment is determined by the person's lipid profile and level of cardiovascular risk.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions for dyslipidaemia in people with diabetes? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: anion exchange resins, combined treatments (for lipid modification), ezetimibe, fibrates, fish oil (for lipid modification), intensive multiple intervention treatment programmes (for lipid modification), nicotinic acid (for lipid modification), and statins.

Key Points

Dyslipidaemia is characterised by decreased circulating levels of high-density lipoprotein cholesterol (HDL-C) and increased circulating levels of triglycerides and low-density lipoprotein cholesterol (LDL-C).

  • Dyslipidaemia is a major contributor to the increased risk of heart disease found in people with diabetes.
  • An increase of 1 mmol/L LDL-C is associated with a 1.57-fold increase in the risk of CHD in people with type 2 diabetes.
  • A diagnosis of diabetic dyslipidaemia requiring pharmacological treatment is determined by the person's lipid profile and level of cardiovascular risk. The classification of cardiovascular risk and lipid targets for drug treatment differ between the USA and the UK, and the rest of Europe. We used the United Kingdom Prospective Diabetes Study (UKPDS) risk calculator to estimate 10-year cardiovascular risk, and categorised a 15% or more risk as "higher risk", and 15% or less as "lower risk" according to the UK clinical guidelines. We found no RCTs of a solely lower-risk population, although some studies were excluded because of insufficient data to calculate risk. In clinical practice, most people with diabetes are increasingly considered at high cardiovascular risk, regardless of the presence or absence of other risk factors.

Statins are highly effective at improving cardiovascular outcomes in people with diabetes.

  • Statins reduce cardiovascular mortality in people with type 2 diabetes with and without known CVD, and regardless of baseline total and LDL-C concentrations.
  • Different statins seem to have similar efficacy at reducing LDL-C.

Combining statins with other treatments (such as ezetimibe or a fibrate) seems to reduce LDL-C more than statin treatments alone.

  • Combinations could be useful in people with mixed dyslipidaemia where one drug fails to control all lipid parameters.

Fibrates seem to have a beneficial effect on cardiovascular mortality and morbidity by reducing triglyceride levels.

  • In people with mixed dyslipidaemia, statins may also be required.

Intensive-treatment programmes involving multiple interventions (people seen by a nurse every 4-6 weeks) seem better at reducing cholesterol than usual-care programmes.

Fish oils may reduce triglyceride levels, but also seem to increase LDL-C levels, making them of limited benefit to most diabetic patients.

Nicotinic acid seems effective at increasing HDL-C and may reduce triglycerides. However, in clinical practice, nicotinic acid alone is not the preferred treatment for hypertriglyceridaemia, but may be used in combination with a statin in people with mixed dyslipidaemia, or in those unable to tolerate fibrates.

  • Nicotinic acid seems to increase the incidence of flushing, particularly in female patients.

We don't know whether anion exchange resins or ezetimibe are useful in treating dyslipidaemia in people with diabetes, but they could be used in combination with a statin if the statin alone fails to achieve lipid targets.

About this condition

Definition

The term dyslipidaemia is used to describe a group of conditions in which there are abnormal levels of lipids and lipoproteins in the blood. Abnormalities of lipid metabolism are present in people with both type 1 and type 2 diabetes. The nature of these abnormalities is complex, but the core components of diabetic dyslipidaemia are elevated circulating levels of triglycerides and decreased circulating levels of high-density lipoprotein cholesterol (HDL-C). In addition, the number of small, dense lipoprotein particles is raised. Consequently — although the cholesterol content of these particles may be low — small, dense low-density lipoprotein cholesterol (LDL-C) is raised. Total cholesterol and LDL-C may be normal if glycaemic control is adequate. Triglycerides and cholesterol are the main lipids of interest. The main classes of lipoprotein considered in this review are low-density lipoproteins (LDL) and high-density lipoproteins (HDL). Diagnosis: A diagnosis of diabetic dyslipidaemia requiring drug treatment is determined by the person's lipid profile and level of cardiovascular risk. The classification of cardiovascular risk and lipid targets for drug treatment differ between the USA and the UK,and the rest of Europe. While it is accepted that people with diabetes are at high risk of CVD, in the UK and USA this high-risk group is stratified further to target those most likely to benefit from treatment. However, the European guidelines on CVD prevention classify as all high risk people with type 2 diabetes, and with type 1 diabetes and microalbuminuria. Treatment targets for the UK and USA and the rest of Europe are shown in table 1 . These targets apply to people with type 2 diabetes. It is acknowledged that in the USA, there is a case for offering drug treatment at lower lipid levels in people at high cardiovascular risk. In the USA, an "optional" goal for LDL-C of 1.81 mmol/L (70 mg/dL) is considered in people with high cardiovascular risk;and the Canadian Diabetic Association recommends a goal for LDL-C of 2.0 mmol/L or less in similarly high-risk people. Although these targets apply to people with type 2 diabetes, in clinical practice they are often extrapolated to people with type 1 diabetes. Population: For this review, we have included studies of adults with type 1 and type 2 diabetes, including those with concurrent hypertension, and we have used UK (NICE) guidelines to determine level of risk. The UKPDS (United Kingdom Prospective Diabetes Study) tool, which includes data from people with diabetes, was used to calculate level of cardiovascular risk only. Subpopulations are described in detail in the description of individual studies where appropriate. Studies in children were excluded. Studies of adults with diabetes and microalbuminuria or nephropathy are covered in a separate review (see review on diabetic nephropathy).

Table 1
Target thresholds for pharmacological treatment of diabetic dyslipidaemia in the UK and USA.

Incidence/ Prevalence

Type 1 diabetes mellitus: In people with well-controlled type 1 diabetes, the incidence of dyslipidaemia is comparable to that in the general population. However, there are no detailed data on the incidence and prevalence of dyslipidaemia in people with type 1 diabetes. Type 2 diabetes mellitus: Dyslipidaemia is common in people with type 2 diabetes. A survey of 498 adults with type 2 diabetes (representing a projected population size of 13,369,754 in the US adult general population) estimated that over 70% of people have an LDL-C greater than the US treatment goal of less than 2.6 mmol/L (less than 100 mg/dL; some have estimated this figure at greater than 80%). Over half of men and two thirds of women have an HDL-C level below US recommended goals of greater than 1.0 mmol/L, while over half of men and women have elevated triglyceride levels. Only 28.2% of people with diabetes were taking lipid-modifying drugs, and only 3% were controlled to US targets for all lipids.

Aetiology/ Risk factors

In people with diabetes mellitus, insulin insufficiency or insulin resistance can have an effect on lipid metabolism. Type 1 diabetes mellitus: Little is understood about the cause of dyslipidaemia in people with type 1 diabetes. In poorly controlled type 1 diabetes, and in nephropathy, the typical cluster of abnormalities seen in diabetic dyslipidaemia does occur, and is associated with a much greater cardiovascular risk than in people without diabetes. Type 2 diabetes mellitus: Impaired insulin action may not be the only cause of dyslipidaemia. Central/visceral obesity may increase the amount of free fatty acids released into the portal circulation, increasing hepatic triglyceride production, while high-fat meals — typical of a Western diet — may exacerbate postprandial hypertriglyceridaemia. Impaired insulin action in people with type 2 diabetes is thought to result in the loss of suppression of lipolysis (the breakdown of triglycerides into free fatty acids and glycerol) in adipose tissue. This leads to an increased release of free fatty acids into the portal circulation and, consequently, increased delivery of free fatty acids to the liver. This leads to increased production of triglycerides by the liver and a decreased production of HDL-C. In addition, there is impaired clearance of triglycerides from the circulation. This resulting hypertriglyceridaemia alters the activity of other enzymes, which leads to the formation of small, dense LDL particles, and increased catabolism of HDL.

Prognosis

CVD is 2-6 times more frequent in people with diabetes than in people without diabetes, and progresses more rapidly when it occurs. Overall, it is the most common cause of death in people with diabetes, with at least 50% of deaths in type 2 diabetes caused by CHD. Dyslipidaemia is one of the major contributors to this increased cardiovascular risk. Lipid abnormalities are important predictors of CHD in people with type 2 diabetes. High LDL-C, high triglycerides, and low HDL-C have all been reported as predictors for cardiovascular risk. A 1.57-fold increase in CHD risk has been reported to be associated with a 1 mmol/L increase in LDL-C, and a 15% decrease in risk with a 0.1 mmol/L increase in HDL-C concentration.

Aims of intervention

To reduce cardiovascular mortality and morbidity; to reduce all-cause mortality; to improve lipid profile; and to minimise adverse effects of treatment.

Outcomes

Primary outcomes: Reduction in cardiovascular morbidity and mortality (including MI, stroke, PVD); a clinically significant improvement in lipid profile as opposed to achieving "target values" per se; quality of life; adverse effects of treatment including muscle events (myalgia, myositis, myopathy); changes in glycaemic control; renal failure; changes in liver enzymes (in clinical practice, an elevation of liver enzymes of at least 3 times the upper limit of normal, or creatine kinase of at least 10 times the upper limit of normal, would warrant stopping treatment). Secondary outcomes: All-cause mortality; change in any other risk factor for macrovascular disease.

Methods

BMJ Clinical Evidence search and appraisal June 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2007, Embase 1980 to June 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 2. Additional searches were done using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 individuals. We did not exclude on the basis of loss to follow-up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded, unless blinding was impossible. Studies that compared different intervention options without a placebo arm, but using a double dummy design, were included. We also searched for cohort studies and case control studies on specific harms of interventions. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. Cardiovascular risk stratification: In the UK and USA, cardiovascular risk determines whether people are offered pharmacological treatment. We have, therefore, stratified the evidence in a similar way. For this review, we have used the UK (NICE) guidelines to determine level of risk. For each RCT, we categorised the study group as "lower risk" or "higher risk". Studies which stated that the study group had a history of CVD were automatically categorised as higher risk. RCTs where no history was reported, but where patient demographics and baseline lipids were available, were categorised according to the estimated 10-year cardiovascular risk (using the UKPDS risk calculator). Those with a risk of greater than 15% were categorised as higher risk, and those with a risk of less than 15% as lower risk. The UKPDS risk calculator takes into account: duration of diabetes, sex, ethnicity, smoking, systolic blood pressure, HbA1C, total cholesterol, HDL-C, and the presence or absence of atrial fibrillation. The minimum factors used to determine risk were sex, smoking status, systolic blood pressure, and baseline total cholesterol and HDL-C. Ethnicity, HbA1c, and duration of diabetes were included if this information was reported. Most trials assessing the clinical effects of lipid-lowering treatment do not record the presence or absence of atrial fibrillation: this factor was therefore assumed to be absent in the calculation of cardiovascular risk. RCTs were excluded if the authors did not report the presence or absence of a history of manifest CVD, and where the minimum required risk factors as stated above were not recorded. We found no RCTs in people categorised as lower risk. We excluded some studies because the authors did not report sufficient data to calculate risk, and these may have included lower-risk populations. Clinical significance criteria for determining changes in lipid profiles: For the outcome of lipid modification, only studies which either reported the proportion of people reaching treatment targets, or which showed a decrease from baseline for LDL-C of 30% or more, or an increase in HDL-C of 5% or more, or a decrease in triglycerides of 30% or more, or a decrease in total cholesterol 20% or more, were considered clinically significant and included. These criteria for clinical significance were based on the findings of large lipid-intervention trials, where a change in lipid parameters was associated with a clinically beneficial effect on cardiovascular morbidity and mortality. Adverse effects: Adverse events of interest were muscle effects (myalgia, myositis, and myopathy), change in glycaemic control, an increase in liver enzymes greater than three times the upper limit of normal, an increase in creatine kinase greater than 10 times the upper limit of normal, and any increase in creatinine. RCTs, cohort and case control studies, and phase IV studies addressing the adverse effects of interest were included. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table
GRADE evaluation of interventions for dyslipidaemia in diabetes

Glossary

High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Notes

Diabetic nephropathy

Diabetes: prevention of cardiovascular events

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2008; 2008: 0610.
Published online 2008 June 9.

Statins

Summary

CARDIOVASCULAR EVENTS Statins compared with placebo: Statins may be more effective at preventing primary and secondary composite outcomes of major coronary events (including coronary artery disease death, non-fatal MI, or myocardial revascularisation procedures) especially in people without a history of CVD ( low-quality evidence ). Atorvastatin compared with placebo: Atorvastatin is more effective at reducing cardiovascular events in people with diabetes and hypertension but without a history of CVD ( moderate-quality evidence ). CHANGE IN LIPID PROFILE Simvastatin compared with placebo: Simvastatin is more effective at 6–24 weeks at improving triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol ( high-quality evidence ). Pravastatin compared with placebo: Pravastatin may be more effective at 24 weeks at improving total cholesterol and triglyceride levels (low-quality evidence). Atorvastatin compared with placebo: Atorvastatin is more effective at 30 weeks at improving triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol in people with type 2 diabetes (moderate-quality evidence).

Benefits

We found one systematic review (search date 2004) and two subsequent RCTs in people with diabetes at higher risk of macrovascular complications, which compared statins versus placebo for the outcomes of cardiovascular morbidity and mortality (see table 2 ). We also found five RCTs comparing statins versus placebo for the outcome of change in lipid profile (see table 3 ).

Table 2
RCTs assessing the effects of statins on cardiovascular outcomes.
Table 3
RCTs evaluating the lipid-modifying effects of statins.

Statins versus placebo for cardiovascular mortality and morbidity:

One systematic review (search date 2004; 4 primary prevention RCTs; 6 secondary prevention RCTs; and 2 primary and secondary prevention RCTs) found that, compared with placebo, statins (pravastatin, simvastatin, atorvastatin, lovastatin, and fluvastatin) significantly reduced cardiovascular risk in both primary and secondary prevention (see table 2 ). The primary outcome measured was a composite outcome of major coronary events (defined as coronary artery disease death, non-fatal MI, or myocardial revascularisation procedures). Secondary outcomes were listed as coronary artery disease death, non-fatal MI, myocardial revascularisation procedures, stroke, and changes in blood lipid profile. The review did not report changes in lipid profile in detail. The review carried out subgroup analyses for individual secondary outcomes. It found that statins significantly reduced incidence of stroke and myocardial revascularisation procedures compared with placebo, but the difference between groups in non-fatal MI and death from CHD did not reach significance (see table 2 ). None of the RCTs included in the review was solely in people with diabetes. The results presented are from pooled diabetes-specific data. The review found similar relative risk reductions for a major coronary event in primary and secondary prevention in people with diabetes (see table 2 ), but it found a significantly higher difference in absolute risk for major coronary event in secondary prevention (risk difference for major coronary events: primary prevention; –0.02, 95% CI –0.04 to 0.00, P = 0.1; secondary prevention; –0.07, 95% CI –0.11 to –0.03, P = 0.0003); these analyses include people treated with gemfibrozil (a fibrate). The characterisation of people with diabetes included in these large intervention trials is poor. This may have implications for the generalisability of results.

Simvastatin versus placebo for cardiovascular mortality and morbidity:

We found no systematic review or RCT assessing the effects of simvastatin on cardiovascular mortality and morbidity. We found three RCTs comparing simvastatin versus placebo for the outcome of change in lipid profile, all of which found significant improvements in lipid levels in people taking simvastatin (see table 3 ).

Pravastatin versus placebo for cardiovascular mortality and morbidity:

We found no systematic review or RCT assessing the effects of pravastatin on cardiovascular mortality and morbidity. We found one RCT comparing pravastatin versus placebo for the outcome of change in lipid profile, which found that pravastatin significantly improved total cholesterol and triglycerides compared with placebo (see table 3 ).

Atorvastatin versus placebo for cardiovascular mortality and morbidity:

We found two subsequent RCTs, both of which found that atorvastatin significantly reduced cardiovascular events in people with diabetes but no previous CVD. The first RCT found that, compared with placebo, atorvastatin 10 mg daily significantly reduced cardiovascular events at 3.9 years in people with type 2 diabetes without CVD (see table 2 ). The trial was stopped 2 years early because of the large treatment effect reported. CVD was defined as history of MI, angina, coronary vascular surgery, cerebrovascular disease, significant PVD defined as that warranting surgery, or high low-density lipoprotein cholesterol (LDL-C). Cardiovascular events were defined as fatal and non-fatal MI, unstable angina, resuscitated cardiac arrest, coronary revascularisation, and fatal and non-fatal stroke. The second RCT comparing atorvastatin versus placebo did a subgroup analysis of 2532 people with type 2 diabetes. The RCT found that, compared with placebo, atorvastatin 10 mg daily significantly reduced the incidence of total cardiovascular events and procedures at 3.3 years in people with diabetes and hypertension, but with no history of CHD, and in people with with cholesterol concentrations that were not markedly elevated (see table 2 ). Participants were required to have at least three of the following risk factors: male sex, age at least 55 years, microalbuminuria or proteinuria, smoking, ratio of plasma total cholesterol to high-density lipoprotein cholesterol 6 or greater, a premature family history of CHD, left ventricular hypertrophy, other specified abnormalities on electrocardiogram, previous stroke, or transient ischaemic attack. We found one RCT comparing atorvastatin versus placebo for the outcome of change in lipid profile (see table 3 ).

Harms

Statins:

The systematic review gave no information on adverse effects. Detailed data were not reported. RCTs found that statins may be associated with musculoskeletal adverse effects and may cause elevations of alanine transaminase, aspartate aminotransferase, liver enzymes, and creatine kinase, although results differed among RCTs (see table 2 and table 3 ). The review did not comment on adverse effects among different ethnic groups in the included trials. A drug safety alert has been issued on the increased risk of haemorrhagic stroke associated with high doses of atorvastatin in people with recent stroke.

Comment

We found no systematic review or RCTs evaluating effects of statins and placebo on outcomes such as quality of life, or change in other risk factors for macrovascular disease. For the surrogate outcome of lipid modification, we defined the size of change in lipid parameters that would qualify as clinically significant, and used this as an inclusion criterion for this review. Our criteria for clinical significance were based on the findings of large lipid-intervention trials where a change in lipid parameters was associated with a beneficial effect on cardiovascular morbidity and mortality. We excluded four RCTs where statistically significant changes in lipid parameters with statins failed to meet our criteria for clinical significance (see methods).

Clinical guide:

Statins reduce cardiovascular mortality in people with type 2 diabetes with and without known CVD. This benefit is present in people without elevated baseline total cholesterol and LDL-C concentrations. Different statins seem similarly effective at reducing LDL-C. Statins seem well tolerated with infrequent serious adverse effects. In UK clinical practice, statins are increasingly used to achieve cholesterol targets lower than those recommended by NICE guidelines, in people with both type 1 and type 2 diabetes at high risk of cardiovascular complications. Some physicians favour starting statin treatment regardless of baseline cholesterol or LDL-C, if the cardiovascular risk is regarded as high enough on an individual patient basis. We found no studies evaluating the effect of statins compared with placebo in people with lower risk of cardiovascular complications. However, some studies were excluded because the authors did not report sufficient data to calculate risk, and these may have included lower-risk populations. Although we found no direct evidence of a beneficial effect of statins in people classified as at lower risk, in clinical practice, most people with diabetes are increasingly considered at high cardiovascular risk, regardless of the presence or absence of other risk factors. Therefore, people classified as “at lower risk of macrovascular complications” may be offered statin treatment at a cholesterol level lower than that recommended by NICE guidelines (e.g. some will start statin treatment in people aged over 40 years with a cholesterol level of greater than 4.0 mmol/L [154 mg/dL]).

Substantive changes

Statins One systematic review on the effects of statins added; benefits and harms data enhanced; categorisation unchanged (Beneficial). The review found that, compared with placebo, statins (pravastatin, simvastatin, atorvastatin, lovastatin, and fluvastatin) significantly reduced cardiovascular risk in both primary and secondary prevention.

2008; 2008: 0610.
Published online 2008 June 9.

Combined treatments

Summary

CHANGE IN LIPID PROFILE Statin plus ezetimibe compared with statin alone: A statin plus ezetimibe may be more effective at improving lipid profiles at 6–8 weeks ( moderate-quality evidence ). Statin plus fibrate compared with statin alone: Fluvastatin plus fenofibrate may be more effective at improving lipid profiles in people with type 2 diabetes, a history of MI (more than 2 years), and dyslipidaemia ( low-quality evidence ). NOTE We found no clinically important results about the effects of combined treatment compared with monotherapy on cardiovascular morbidity and mortality, quality of life, and changes in other risk factors for macrovascular disease.

Benefits

We found no systematic review or RCTs comparing combined treatment versus monotherapy for the outcomes of: cardiovascular morbidity and mortality, all-cause mortality, quality of life, and changes in other risk factors for macrovascular disease. We found three RCTs comparing combined treatments versus monotherapy for the outcome of change in lipid profile (see table 4 ).

Table 4
RCTs evaluating the lipid-modifying effects of combination treatment.

Statin plus ezetimibe versus statin alone:

Two RCTs found that, compared with statin plus placebo, statin plus ezetimibe significantly improved lipid profile at 6–8 weeks in people with diabetes (see table 4 ). In the first RCT (191 people with type 2 diabetes, 53% of the statin-plus-placebo group and 46% of the statin-plus-ezetimibe group had CHD), about 34% of the statin-plus-placebo group and 23% of the statin-plus-ezetimibe group were taking simvastatin, and 36% of the statin-plus-placebo group and 42% of the statin-plus-ezetimibe group were taking atorvastatin. Other statins included in this study were lovastatin, pravastatin, fluvastatin, and cerivastatin.The second RCT included people with diabetes, metabolic syndrome, or neither condition (see table 4 ). The RCT carried out a subgroup analysis of people with only type 2 diabetes (1163 people). Atorvastatin was the most frequently used statin (39%), followed by simvastatin (29%), and pravastatin (22%). Fluvastatin and lovastatin were also included. Efficacy analyses were based on ITT population (included all randomised patients with baseline and at least one post-baseline measurement).

Statin plus fibrate versus statin alone:

One RCT (43 people) found that, compared with fluvastatin plus placebo, fluvastatin plus fenofibrate significantly improved lipid profile in people with type 2 diabetes, dyslipidaemia, and history of CHD (see table 4 ). CHD was defined as a history of MI more than 2 years before study entry.

Harms

Statin plus ezetimibe versus statin alone:

One RCT found no significant increase in liver enzymes and creatine kinase with statin plus ezetimibe compared with statin alone. The proportion of people who stopped treatment because of adverse effects was small, and similar in both groups (3%).The second RCT found a similar proportion of people reporting drug-related adverse effects for the two groups (see table 4 ). The proportion of people stopping treatment because of drug-related adverse effects was similar for the two groups (see table 4 ). The RCT found no significant difference between treatment groups in percentage of patients (included patients with metabolic syndrome and neither syndrome) exceeding predefined limits of change in liver enzymes (alanine and aspartate transaminase) and in muscle creatine kinase (see table 4 ).

Statin plus fibrate versus statin alone:

One RCT reported that two people in the fluvastatin plus fenofibrate group and one person in the fluvastatin plus placebo alone group withdrew because of myalgia.

Comment

Clinical guide:

In clinical practice, a combination of statin plus ezetimibe may be used in people with diabetes at higher cardiovascular risk if a statin alone fails to lower cholesterol adequately. A combination of statin and fibrate may be used in people with mixed dyslipidaemia where one drug fails to control all lipid parameters. In these cases, a statin may be given first, and a fibrate added to treat any remaining hypertriglyceridaemia.

Substantive changes

Combined treatments One RCT on the effects of adding ezetimibe to statins added; benefits and harms data enhanced; categorisation unchanged (Likely-to-be-beneficial). The RCT found that, compared with statin plus placebo, statin plus ezetimibe significantly improved lipid profile at 6 weeks in people with diabetes.

2008; 2008: 0610.
Published online 2008 June 9.

Fibrates

Summary

CARDIOVASCULAR EVENTS Bezafibrate compared with placebo: Bezafibrate may be more effective at reducing CHD event rates at 3 years in people with type 2 diabetes and no clinical history of CVD ( low-quality evidence ). Gemfibrozil compared with placebo: Gemfibrozil may be more effective at preventing primary and secondary major coronary events in men with type 2 diabetes ( very low-quality evidence ). Fenofibrate compared with placebo: Fenofibrate may be no more effective at reducing total CVD events (first occurrence of non-fatal MI or death from coronary heart disease) in people with type 2 diabetes (low-quality evidence). CHANGE IN LIPID PROFILE Bezafibrate compared with placebo: Bezafibrate may be more effective at 3 years at reducing triglycerides and at increasing high-density lipoprotein cholesterol in people with type 2 diabetes with no clinical history of CVD (very low-quality evidence). Gemfibrozil compared with placebo: Gemfibrozil is more effective at 20–24 weeks at reducing triglyceride levels in people with type 2 diabetes ( moderate-quality evidence ).

Benefits

Bezafibrate versus placebo:

We found no systematic review but found one RCT. It found that, compared with placebo, bezafibrate 400 mg daily significantly reduced CHD event rate at 3 years in people with type 2 diabetes with no clinical history of CVD (see table 5 ). Bezafibrate also significantly reduced triglyceride concentration and increased high-density lipoprotein cholesterol (HDL-C) (see table 6 ). The results of the RCT for cardiovascular outcome should be interpreted with caution, as the primary aim of the study was to evaluate the effects of bezafibrate on progress of ultrasonically measured arterial disease: lipid-modifying effect and CHD morbidity were secondary end points in this study. CHD was assessed annually using history and a 12-lead ECG at rest and during exercise. The primary end point was intima–media thickness, a marker for generalised atherosclerosis.

Table 5
RCTs assessing the effects of fibrates on cardiovascular outcomes.
Table 6
RCTs evaluating the lipid-modifying effects of fibrates.

Gemfibrozil versus placebo:

We found one systematic review (search date 2004; 4 primary prevention RCTs; 6 secondary prevention RCTs; and 2 RCTs on primary and secondary prevention) that assessed the effects of lipid-lowering agents on predominantly cardiovascular outcomes. Two RCTs (three publications) identified by the review compared gemfibrozil (1200 mg daily) versus placebo. None of the RCTs included in the review was solely in people with diabetes. The results presented are from pooled diabetes-specific data. The review carried out a subgroup analysis for the comparison of gemfibrozil versus placebo for primary and secondary prevention of risk of cardiovascular events (see table 5 ). The review did not discuss the results from the meta-analysis of the effects of gemfibrozil separately. The analysis found that gemfibrozil significantly improved secondary prevention of major coronary events compared with placebo (see table 5 ). However, there was no difference between groups in primary prevention of major coronary events (see table 5 ). Primary outcome was a composite of major coronary events (defined as coronary artery disease death, non-fatal MI, and myocardial revascularisation procedures); secondary outcomes were listed as coronary artery disease death, non-fatal MI, myocardial revascularisation procedures, stroke, and changes in blood lipid profile: the review did not report changes in lipid profile in detail. A subgroup analysis of the RCT assessing the effects of gemfibrozil on secondary prevention and identified by the review was also reported separately. It found that, compared with placebo, gemfibrozil significantly reduced the risk of cardiovascular events (see table 5 ). A subgroup analysis of the RCT assessing the effects of gemfibrozil on primary prevention identified by the review for people with diabetes was reported separately. The analysis found that gemfibrozil reduced CHD incidence at 5 years in men with type 2 diabetes compared with placebo, but the difference between groups was not significant (see table 5 ). The authors of the RCT suggested that gemfibrozil may reduce the risk of MI in people with type 2 diabetes, but warned that this conclusion should be drawn with caution because of the small proportion of men with diabetes in the study. Two RCTs compared gemfibrozil 600 mg twice daily versus placebo for the outcome of change in lipid profile (see table 6 ). Both found a clinically significant decrease in triglyceride levels with gemfibrozil compared with placebo. One of the RCTs found that this significant decrease in triglyceride concentration was not linked to a change in low-density lipoprotein cholesterol or total cholesterol (LDL-C). HDL-C increased with both placebo and gemfibrozil, with no significant difference between groups (see table 6 ).

Fenofibrate versus placebo:

One RCT (9795 people with type 2 diabetes) found that, compared with placebo, fenofibrate 200 mg daily reduced total CVD events, non-fatal MI, and the need for revascularisation procedures (see table 5 ). There was an increase in CHD mortality with fenofibrate, although the difference between groups did not reach significance. The authors found that significantly more people taking placebo began treatment with statins; this may have masked a larger treatment benefit of fenofibrate. The RCT also found that, compared with placebo, fenofibrate significantly reduced the rate of progression to albuminuria, and the proportion of people who developed retinopathy requiring laser treatment.

Harms

Bezafibrate versus placebo:

The RCT gave no information on adverse effects.

Gemfibrozil versus placebo:

The systematic review and three RCTs gave no information on adverse effects. A fourth RCT found no differences between groups in liver enzymes, urea, or creatinine (significance not assessed; P values not reported).

Fenofibrate versus placebo:

The RCT found that people taking fenofibrate were at a greater risk of pancreatitis and a small increased risk of pulmonary embolism.

Comment

For the surrogate outcome of lipid modification, we defined the size of change in lipid parameters that would qualify as clinically significant, and used this as an inclusion criterion for this review. Our criteria for clinical significance were based on the findings of large lipid-intervention trials where a change in lipid parameters was associated with a beneficial effect on cardiovascular morbidity and mortality. We excluded one RCT where statistically significant changes in lipid parameters with bezafibrate failed to meet our criteria for clinical significance (see methods).

Clinical guide:

In UK clinical practice, fibrates are used in people with diabetes and higher cardiovascular risk to reduce circulating triglyceride concentrations in those with hypertriglyceridaemia, and in combination with a statin in people with combined dyslipidaemia where a statin alone fails to adequately reduce the triglyceride level.

Substantive changes

Fibrates One systematic review added for the comparison of gemfibrozil versus placebo; benefits enhanced; categorisation unchanged (Likely-to-be-beneficial). The analysis reported by the review found that gemfibrozil significantly improved secondary prevention of major coronary events compared with placebo, but there was no difference between groups in primary prevention of major coronary events.

2008; 2008: 0610.
Published online 2008 June 9.

Intensive multiple-intervention treatment programmes

Summary

CHANGE IN LIPID PROFILE Compared with standard care: Intensive intervention by a nurse-led hyperlipidaemia clinic may be more effective at achieving target total-cholesterol levels of less than 5.0 mmol/L (less than 193 mg/dL) in a mixed group of people with type 1 and type 2 diabetes and higher risk for macrovascular complications, but we don't know whether increased frequency of visits to a health professional or changes in medication are beneficial ( very low-quality evidence ).

Benefits

Intensive multiple-intervention treatment programmes versus standard care:

We found no systematic review evaluating effects of intensive multiple-intervention treatment programmes and standard care on cardiovascular mortality, quality of life, or other cardiovascular risk factors. We found one RCT which found that, compared with usual care, randomisation to a specialist nurse-led hyperlipidaemia clinic resulted in a reduction in total cholesterol to below target at 1.5-year follow-up (see table 7 ). In the RCT, the usual-care group was seen once by the diabetologist, and was reviewed in primary care as thought necessary by the primary-care physicians. The primary-care physicians were invited to 4-monthly education sessions where guidelines for the management of hypercholesterolaemia were discussed. The specialist nurse-led intervention group was given an individual action plan at their first visit with the specialist nurse, including a discussion of the benefits of treatment and lifestyle changes, drug actions, and potential adverse effects. This group was seen every 4–6 weeks until target cholesterol (less than 5.0 mmol/L [193 mg/dL]) was reached. At these visits, lifestyle modifications were reinforced and cholesterol-lowering medication was titrated according to response to treatment. Medications were “fibrate” or “statin”. Given that the nature of the intervention precluded any blinding, and the ethical restrictions to including a placebo arm, it is difficult to determine which aspect of the intervention (i.e. increased frequency of visits to a health professional or changes in medication) was beneficial.

Table 7
RCT assessing intensive multiple-intervention treatment programmes (for lipid modification).

Harms

Intensive multiple-intervention treatment programmes versus standard care:

We found no systematic review or RCTs evaluating adverse effects of intensive multiple-intervention treatment programmes and usual care on cardiovascular mortality, lipid modification, all-cause mortality, quality of life, or change in other risk factors for macrovascular disease. One RCT did not report adverse effects.

Comment

Clinical guide:

Intensive multiple-intervention treatment programmes in people with diabetes and higher risk for macrovascular complications would entail intensive management of modifiable CVD risk factors including dyslipidaemia, in addition to other interventions, such as glycaemic control and lifestyle management.

Substantive changes

No new evidence

2008; 2008: 0610.
Published online 2008 June 9.

Fish oils

Summary

CHANGES IN LIPID PROFILE Compared with control: Fish oils may be more effective at lowering triglyceride levels in hypertriglyceridaemic people, but may increase low-density lipoprotein cholesterol ( low-quality evidence ).

Benefits

Fish oils versus controls:

We found one systematic review (search date 2000) evaluating the effects of omega-3 triglycerides (eicosapentaenoic acid, docosahexaenoic acid) compared with vegetable oils (olive oil, linseed oil, safflower oil, corn oil) for cardiovascular morbidity and mortality, lipid profile, glycaemic control, and weight in people with type 2 diabetes. The review also included one RCT comparing fish oils versus saline. The review found no RCTs comparing fish oils versus control for the outcomes of cardiovascular morbidity and mortality. It found that, compared with control, fish oils significantly lowered triglyceride levels and increased low-density lipoprotein cholesterol (LDL-C). It found no significant difference in high-density lipoprotein cholesterol (HDL-C) between fish oils and control (see table 8 ). The review found limited evidence, based on indirect comparisons, of a higher reduction of triglycerides and greater increase in LDL-C with fish oils in people with pre-existing hypertriglyceridaemia than in people without pre-existing hypertriglyceridaemia (see table 8 ). Most people in the review were male with a duration of diabetes of 5–10 years, and treated with diet or oral hypoglycaemic agents. The doses of fish oils ranged from eicosapentaenoic acid 1.08–5.2 g, and docosahexaenoic acid 0.3–4.8 g. Any type of dietary supplementation with n-3 fatty acids was included. There were no restrictions on dose or formulation. The range of compounds used as controls included olive oil, safflower oil, and corn oil, all of which might be metabolised to n-3 fatty acids.

Table 8
RCT assessing fish oil (for lipid modification).

Harms

Fish oils versus controls:

The review found no significant difference in glycaemic control between fish oils and placebo. No other adverse outcomes were reported.

Comment

Clinical guide:

Although fish oils may reduce triglyceride concentration in people with hypertriglyceridaemia, this may be accompanied by an increase in LDL-C. In clinical practice, fish oils are not usually prescribed for people with diabetes and higher cardiovascular risk. People with normal triglycerides may be advised to increase their dietary fish oil consumption.

Substantive changes

No new evidence

2008; 2008: 0610.
Published online 2008 June 9.

Nicotinic acid group

Summary

CHANGES IN LIPID PROFILE Compared with placebo: Nicotinic acid in combination with a statin may be more effective at reducing triglyceride levels and at increasing high-density lipoprotein cholesterol in people with type 2 diabetes ( very low-quality evidence ). NOTE Nicotinic acid has been associated with flushing. We found no direct information about acipomix in the treatment of people with diabetes at risk of macrovascular complications.

Benefits

We found no systematic review evaluating effects of nicotinic acid and placebo on cardiovascular mortality, quality of life, all-cause mortality, or change in other risk factors for CVD.

Nicotinic acid versus placebo:

We found one RCT comparing the effects on lipid profile of nicotinic acid 1 g and 1.5 g versus placebo. The RCT found that, compared with placebo, nicotinic acid 1 g and 1.5 g significantly increased high-density lipoprotein cholesterol (HDL-C) at 16 weeks (146 people with type 2 diabetes, mean age: 61 ± 1.4 years in placebo group v 57 ± 1.4 years in 1 g group v 63 ± 1.6 years in 1.5 g group; HDL-C increased with 1 g and 1.5 g nicotinic acid, range: from 13–19% in 1 g group v 22–24% in 1.5 g group; P less than 0.05 compared with placebo). The RCT also found that nicotinic acid 1.5 g significantly reduced triglyceride concentration at 16 weeks compared with placebo (median % change range: 28–36%; P less than 0.05 compared with placebo). Nicotinic acid 1.5 g significantly decreased total cholesterol and low-density lipoprotein cholesterol (LDL-C), but these changes were small (6.1 ± 2.1% for total cholesterol and 7.1 ± 3.2% for LDL-C; P less than 0.05 compared with placebo). This study included people treated with diet alone, people treated with insulin and oral hypoglycaemics excluding thiazolidinediones, and people with stable coronary and cerebrovascular disease. About 59% of the placebo group, 40% of the nicotinic acid 1 g group, and 40% of the nicotinic acid 1.5 g group were also taking a statin.

Acipomix versus placebo:

We found no systematic review or RCTs comparing acipomix versus placebo, or comparing different doses for clinical outcomes of interest (cardiovascular mortality, lipid modification, all-cause mortality, quality of life, or change in other risk factors for macrovascular disease), in people with diabetes and higher risk of macrovascular complications.

Harms

Nicotinic acid versus placebo:

One RCT comparing nicotinic acid 1 g and 1.5 g versus placebo found a small increase in haemoglobin A1c at 16 weeks with nicotinic acid 1 g and 1.5 g (mean ± standard error, HbA1c: from 7.20 ± 0.14% at baseline to 7.40 ± 0.19% at 16 weeks with nicotinic acid 1 g v from 7.20 ± 0.11% at baseline to 7.50 ± 0.14% at 16 weeks with nicotinic acid 1.5 g v from 7.10 ± 0.12% at baseline to 7.10 ± 0.13% at 16 weeks with placebo; P value reported as not significant for placebo v nicotinic acid 1 g, P = 0.048 for placebo v nicotinic acid 1.5 g). The RCT reported a higher incidence of flushing with nicotinic acid compared with placebo (75% with nicotinic acid [1 g and 1.5 g] v 10% with placebo; absolute numbers and statistical data not reported). The proportion of people reporting any adverse event was not significantly different among treatment groups (69% with nicotinic acid 1 g v 77% with nicotinic acid 1.5 g v 73% with placebo; reported as non-significant, P value not reported). None of the people included in the trial had myopathy or an elevation in liver enzymes of three times the upper limit of normal or greater.

Acipomix versus placebo:

We found one cohort study evaluating adverse effects of acipomix in people with diabetes. The study found that, in 3009 people (52% female) with type 2 diabetes taking acipomix 250 mg twice daily (82%) or three times daily (18%) for at least 3 months, 263 (9%) people reported adverse events. In 165 (6%) people treatment was withdrawn. Higher doses were associated with a marginal increase in incidence of adverse events (212/2476 [9%] with twice-daily dose v 51/533 [10%] with 3 times-daily dose; statistical data not reported). A greater incidence of adverse events (predominantly flushing and pruritus) was found in female compared with male participants (177/1572 [11%] female v 86/1437 [6%] male). Acipomix was associated with an 8.5% reduction in HbA1c compared with before treatment (8.20 ± 0.04% before v 7.50 ± 0.04% after; P value reported as not significant).

Comment

For the surrogate outcome of lipid modification, we defined the size of change in lipid parameters that would qualify as clinically significant, and used this as an inclusion criterion for this review. Our criteria for clinical significance were based on the findings of large lipid-intervention trials where a change in lipid parameters was associated with a beneficial effect on cardiovascular morbidity and mortality. We excluded two RCTs where statistically significant changes in lipid parameters failed to meet our criteria for clinical significance (see methods).

Clinical guide:

Nicotinic acid seems effective at increasing HDL-C and may reduce triglycerides, but a significant proportion of people in the reported RCT were also taking statins. In clinical practice, nicotinic acid is not usually preferred treatment for hypertriglyceridaemia. However, it may be used in combination with a statin in people with mixed dyslipidaemia, and in those unable to tolerate a fibrate.

Substantive changes

No new evidence

2008; 2008: 0610.
Published online 2008 June 9.

Anion exchange resins

Summary

We found no direct information about whether anion exchange resins (colestyramine, colestipol) are better than no active treatment, or how different anion exchange resins, or different doses compare in the treatment of people with diabetes and high risk for macrovascular complications.

Benefits

We found no systematic review or RCTs comparing anion exchange resins (colestyramine, colestipol) versus placebo, or comparing different anion exchange resins, or different doses for clinical outcomes of interest (cardiovascular mortality, lipid modification, all-cause mortality, quality of life, or change in other risk factors for macrovascular disease) in people with diabetes and higher risk for macrovascular complications.

Harms

We found no RCTs.

Comment

Clinical guide:

In clinical practice, anion exchange resins are not usually preferred treatment for people with diabetes and higher cardiovascular risk. However, they may be used in combination with a statin where a statin alone fails to achieve lipid targets, or where the person is unable to tolerate a statin.

Substantive changes

No new evidence

2008; 2008: 0610.
Published online 2008 June 9.

Ezetimibe

Summary

We found no direct information about whether ezetimibe is better than no active treatment, or comparing different doses in the treatment of people with diabetes and high risk for macrovascular complications.

Benefits

We found no systematic review or RCTs comparing ezetimibe versus placebo, or comparing different doses for clinical outcomes of interest (cardiovascular mortality, lipid modification, all-cause mortality, quality of life, or change in other risk factors for macrovascular disease) in people with diabetes and higher risk for macrovascular complications. In clinical practice, ezetimibe is not usually preferred treatment, but it may be used in combination with a statin if a statin alone fails to achieve lipid targets.

Harms

We found no RCTs.

Comment

Clinical guide:

In clinical practice, ezetimibe is not usually preferred treatment for people with diabetes and higher cardiovascular risk. However, it may be used in combination with a statin where a statin alone fails to achieve lipid targets, or where the person is unable to tolerate a statin.

Substantive changes

No new evidence


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