Treating patients with low high-density lipoprotein cholesterol: choices, issues and opportunities

Three clinical trials have recently focused on the benefits of lipid-regulating therapy in populations with normocholesterolaemia and low high-density lipoprotein (HDL)-cholesterol. Two secondary prevention studies (Veterans Affairs HDL-Cholesterol Intervention Trial [VA-HIT] and Bezafibrate Infarction Prevention [BIP] trial) testified to the efficacy of fibrates in decreasing cardiovascular events, particularly in patients with coexisting risk factors, including hypertriglyceridaemia. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) demonstrated that a statin could decrease acute coronary events in patients with isolated low HDL-cholesterol in a primary prevention setting. The absolute risk reduction in coronary events in the VA-HIT study compares favourably with those reported from the statin-based Cholesterol and Recurrent Events (CARE) and Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) trials. The absolute risk reduction in AFCAPS-TexCAPS is similar to that in West of Scotland Coronary Pravastatin Study (WOSCOPS). Recommendations are given concerning lifestyle and pharmacological management of low HDL-cholesterol. Optimal management also requires review of current treatment targets for HDL-cholesterol and triglycerides levels.     

Cardiovascular disease with diabetes or the metabolic syndrome: should statins or fibrates be first line lipid therapy?

PURPOSE OF REVIEW: Subgroups with diabetes or with features of the metabolic syndrome have been increasingly highlighted in large clinical endpoint trials with lipid therapy. This review will focus on the results of trials with statins or fibrates and examine the strength of the evidence for major cardiovascular event reduction with each kind of therapy in these high-risk subgroups that typically have low-to-moderate levels of LDL cholesterol. RECENT FINDINGS: Of six statin trials in populations with moderately increased LDL cholesterol only one, the Heart Protection Study, has shown that statin therapy will significantly reduce the major coronary heart disease events of non-fatal myocardial infarction or coronary heart disease death in diabetes. None of these trials has shown that statins have a particular predilection for reducing cardiovascular events in individuals with higher levels of body weight or other features of the metabolic syndrome. There are far fewer trial data with fibrates than with statins. However, the Veterans Affairs High Density Lipoprotein Intervention Trial has shown that a fibrate can significantly reduce major cardiovascular events, most particularly coronary heart disease death, in those with diabetes as well as those without diabetes who have insulin resistance. Indeed, all fibrate trials show that this therapy appears to selectively benefit the individual with obesity and features of the metabolic syndrome. SUMMARY: Based principally on evidence from the Veterans Affairs High Density Lipoprotein Intervention Trial and the cumulative experience with statins, trial data would thus far suggest that the patient with a modest increase in LDL cholesterol who has diabetes or features of the metabolic syndrome might be likely to achieve more substantial cardiovascular benefit from fibrate than from statin therapy.     

Which is the best lipid-modifying strategy in metabolic syndrome and diabetes: fibrates, statins or both?

Although less clinical intervention studies have been performed with fibrates than with statins, there are evidences indicating that fibrates may reduce risk of cardiovascular events. The potential clinical benefit of the fenofibrate will be specified by the ongoing Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, which rationale, methods and aims have been just published. Controlled clinical trials show similar or even greater cardiovascular benefits from statins-based therapy in patient subgroups with diabetes compared with overall study populations. Therefore, statins are the drug of first choice for aggressive lipid lowering actions and reducing risk of coronary artery disease in these patients. However, current therapeutic use of statins as monotherapy is still leaving many patients with mixed atherogenic dyslipidemia at high risk for coronary events. A combination statin/fibrate therapy may be often necessary to control all lipid abnormalities in patients with metabolic syndrome and diabetes adequately, since fibrates provide additional important benefits, particularly on triglyceride and HDL-cholesterol levels. Thus, this combined therapy concentrates on all the components of the mixed dyslipidemia that often occurs in persons with diabetes or metabolic syndrome, and may be expected to reduce cardiovascular morbidity and mortality. Safety concerns about some fibrates such as gemfibrozil may lead to exaggerate precautions regarding fibrate administration and therefore diminish the use of the seagents. However, other fibrates, such as bezafibrate and fenofibrate appear to be safer and better tolerated. We believe that a proper co-administration of statins and fibrates, selected on basis of their safety, could be more effective in achieving a comprehensive lipid control as compared with monotherapy.     

Role for fibrate therapy in diabetes: evidence before FIELD

PURPOSE OF REVIEW: Diabetic dyslipidaemia, among the main factors contributing to vascular risk in type 2 diabetes, is characterized by hypertriglyceridaemia, low HDL-cholesterol and increased prevalence of small dense LDL particles. Because fibrates have positive effects on triglycerides, HDL-cholesterol and LDL particle size, they may be an appropriate treatment for diabetic dyslipidaemia. Statins have been shown to diminish significantly the risk for coronary disease in patients with type 2 diabetes, and so what are the real effects of fibrates on cardiovascular risk in type 2 diabetes? RECENT FINDINGS: Although statins reduce the incidence of coronary disease in type 2 diabetes, data from clinical trials demonstrate 'residual' cardiovascular risk in these patients treated with statins. Clinical trials with fibrates show that they are particularly effective in reducing cardiovascular risk in patients with type 2 diabetes/metabolic syndrome and in those exhibiting the lipid abnormalities typical of diabetic dyslipidaemia (elevated triglycerides, low HDL-cholesterol). SUMMARY: Data on the effects of fibrates on cardiovascular risk in diabetes were obtained from subgroup analyses. Thus far, the only study performed specifically in patients with type 2 diabetes is the angiographic Diabetes Atherosclerosis Intervention Study which demonstrated a significant reduction in progression of atherosclerosis in patients receiving fenofibrate, but it was not powered to analyse the effects of fibrates on clinical outcomes. This is why the Fenofibrate Intervention and Event Lowering in Diabetes study is needed; it will provide robust data on the ability of fibrates to reduce cardiovascular risk in patients with type 2 diabetes.     

Anti-atherogenic effects of fibrates in type 2 diabetes

Type 2 diabetes is an increasing cause of premature coronary heart disease. Several trials with lipid-modifying therapy have included sufficient numbers of diabetics to indicate that treatment of diabetic dyslipidaemia with either fibrates or statins reduces the risk of future coronary events in such patients. However, until recently no reported study had been designed specifically to investigate the effects of intervening in patients with type 2 diabetes. The Diabetes Atherosclerosis Intervention Study (DAIS) is an angiographic study in which 418 diabetic subjects were randomized to micronised fenofibrate or placebo groups. After 3 years of treatment, the fenofibrate group had a significantly reduced rate of progression of coronary atherosclerosis. This study, when considered with the results of other studies that have included diabetics, has important implications for the treatment of diabetic dyslipidaemia. The evidence that is currently available supports a place for both fibrates and statins, either as monotherapy or in combination, in the treatment of diabetic dyslipidaemia.     

Hypertriglyceridemia, the coronary heart disease risk marker "solved"

Both epidemiological and intervention studies have shown that hypertriglyceridemia is a significant cardiovascular risk factor. The large variation of the triglyceride values is explained by the influence of several modifying factors, which are difficult to standardise. Therefore hypertriglyceridemia should be considered rather as risk marker, than risk factor. The measurement of the apolipoprotein CIII level, which is a more stable parameter of the triglyceride rich lipid particles, is now becoming more widespread. This parameter is also able to substitute the assessment of the small dense LDL form that has a controversial significance. The clinical benefit of reduction of triglyceride concentration and the accompanying increase of HDL cholesterol level by fibrates, in the prevention of the coronary heart disease (CHD) events, have been demonstrated in several prospective, placebo-controlled trials. The VA-HIT study, enrolling the largest number of patients, has shown that fibrates have another effect, presumably influencing the insulin resistance independently of lipid levels that is also able to reduce the CHD events.     

Fenofibrate therapy and cardiovascular protection in diabetes: recommendations after FIELD

PURPOSE OF REVIEW: The aim of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was to provide valuable information on the ability of fibrates to reduce cardiovascular risk in type 2 diabetes. The purpose of this review is to analyse results from FIELD and to see whether they may lead to modify the recommendations for treatment of diabetic dyslipidemia. RECENT FINDINGS: In FIELD, fenofibrate therapy was associated with a nonsignificant 11% reduction in the primary endpoint (coronary heart disease death, nonfatal myocardial infarction), corresponding to a significant 24% reduction in nonfatal myocardial infarction (P = 0.010) and a nonsignificant 19% increase in CHD mortality. Fenofibrate reduced CHD events only in patients in primary prevention, but not in secondary prevention. Fenofibrate treatment was associated with less albuminuria progression and less retinopathy needing laser treatment. SUMMARY: FIELD's results are somewhat disappointing. The relatively low cardiovascular risk population from FIELD and the 'pollution' by statin therapy may not totally explain the weak results of fenofibrate in the reduction in CHD events. The significant increase in plasma homocysteine observed with fenofibrate could partly explain not only the higher number of venous thrombotic events, but also the poor effect of fenofibrate in reducing clinical outcomes, more particularly in patients with previous cardiovascular disease.     

Protecting the heart: a practical review of the statin studies

The aim of this review of the landmark HMG-CoA reductase inhibitors (statins) studies is to enable the clinician to draw practical lessons from these trials. The Scandinavian Simvastatin Survival Study (4S) established the importance of treating the hypercholesterolemic patient with established cardiovascular heart disease. The West of Scotland Coronary Prevention Study (WOSCOPS) showed the benefit of treating healthy hypercholesterolemic men who were nevertheless at high risk of developing cardiovascular heart disease in the future. The Cholesterol and Recurrent Events (CARE) study, a secondary prevention trial, proved the benefit of treating patients with myocardial ischemia and cholesterol levels within normal limits. This conclusion was confirmed by the Long-term Intervention With Pravastatin in Ischemic Disease (LIPID) study, another secondary prevention study that enrolled patients with a wide range of cholesterol levels (4-7 mmol/dL), into which the large majority of patients would belong. The importance of treating patients with established ischemic heart disease (IHD), and those at high risk of developing cardiovascular heart disease, regardless of cholesterol level, was being realized. The Air Force/Texas Coronary Artery Prevention Study (AFCAPS/TexCAPS) then showed that treatment can reduce adverse cardiovascular events even in the primary prevention of patients with normal cholesterol levels. The Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) trial showed that hypocholesterolemic therapy is useful in the setting of an acute coronary syndrome, while the Atorvastatin Versus Revascularisation Treatment (AVERT) study showed that aggressive statin therapy is as good as angioplasty in reducing ischemic cardiac events in patients with stable angina pectoris. Finally, the Heart Protection Study (HPS) randomized more than 20,000 patients, and the value of statins in reducing adverse cardiovascular events in the high-risk patient, including the elderly, women, and even in those with low cholesterol levels, is beyond doubt. The emphasis is now on the risk level for developing cardiovascular events, and treatment should target the high-risk group and not be dependent on the actual cholesterol level of the patient. It is interesting to compare the large amount of data on the value and safety of the statins with the much more limited and less convincing data on antioxidant vitamins.     

The safety and efficacy of achieving very low LDL-cholesterol concentrations with high dose statin therapy

PURPOSE OF REVIEW: The benefits of lipid lowering with statins are established in patients with or at risk for coronary artery disease. Recent trials with high doses of potent statins have examined treating to very low levels of LDL-cholesterol. Concerns have been raised about the safety of this strategy. This review examines the safety and efficacy of treating to very low LDL-cholesterol. RECENT FINDINGS: Four clinical trials, Treating to New Targets (TNT) and Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) in stable coronary artery disease and Aggrastat to Zocor (A to Z) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT)-TIMI 22 following acute coronary syndromes, have examined intensive statin therapy compared to moderate statin therapy. These trials and a meta-analysis demonstrated that intensive statin therapy reduces cardiovascular events. Subsequent analyses from these trials suggest that very low levels of LDL-cholesterol can be achieved safely and may improve clinical outcomes. A note of caution regarding hemorrhagic events following stroke with intensive statin therapy was raised by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) trial despite impressive reductions in cardiovascular events. SUMMARY: A growing body of evidence suggests progressive benefit for lowering LDL-cholesterol aggressively with intensive statin therapy in coronary artery disease. Future trials will be needed to define whether there is a level of LDL-cholesterol beyond which further benefit is not seen or safety concerns emerge.     

Glycemia Management and Cardiovascular Risk in Type 2 Diabetes: An Evolving Perspective

ObjectiveTo review recent glycemia trials focused on reducing cardiovascular disease (CVD) risk in patients with type 2 diabetes and to describe how the results of these studies have altered our approach to the management of glycemia in patients with diabetes.MethodsResults of some of the previous as well as recent trials, including the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease (ADVANCE), and Veterans Affairs Diabetes Trial (VADT), are reviewed.ResultsThe results demonstrate that the establishment of glycemia (hemoglobin A1c) goals in patients with type 2 diabetes aimed at reducing CVD events is complex, should be highly individualized, and should probably be varied depending on the duration of diabetes as well as the presence or absence of CVD and microvascular complications.ConclusionResults of the ACCORD, ADVANCE, and VADT studies have considerably increased our knowledge and refined our approach to establishing glycemia goals in patients with type 2 diabetes. In patients with recently recognized diabetes with no prior CVD events, glycemic control to normal or near-normal levels appears to be effective in preventing CVD events and mortality. In patients with established diabetes (8 to 10 or more years) and recognized CVD, however, glycemic control to normal or near-normal levels does not reduce the risk of further CVD events or mortality. Importantly, strict control of all known risk factors for CVD and microvascular complications by aggressive management of hypertension, dyslipidemia, and glycemia, use of aspirin, and cessation of smoking in patients with type 2 diabetes has proved to be highly beneficial. (Endocr Pract. 2008;14:639-643)     

Fibric acid derivatives in cardiovascular disease prevention: results from the large clinical trials

PURPOSE OF REVIEW: Results from five large placebo-controlled trials with second-generation fibrates have shown varying success in reducing cardiovascular events. This review focuses on a number of extended analyses from these trials that may relate to the success or failure of fibrate therapy and indicate who might likely benefit from this therapy. RECENT FINDINGS: Results have been far from uniform and several trials have been adversely impacted by high off-trial statin use. Collective evidence suggests, however, that fibrates have optimum cardiovascular benefit in diabetes or other manifestations of insulin resistance. Much of this evidence comes from posttrial analysis in subgroups with more sharply defined clinical characteristics than in the overall trial population. Analyses also suggest that different fibrates have a different range of favorable clinical properties, that the cardiovascular benefit of fibrates may not be readily measured or mostly predicted by changes in traditional lipid measurements, and that other nonlipid properties of fibrates as peroxisome proliferator-activated receptor agents might explain some of the benefit of these drugs. SUMMARY: Results of major clinical endpoint trials with fibrates, although not uniformly positive, provide substantial evidence for a selective therapeutic role of these drugs in cardiovascular event reduction in diabetes or insulin resistance.     

Cardiovascular outcomes among participants with diabetes in the recent large statin trials

PURPOSE OF REVIEW: Despite their increased cardiovascular risk and its continuous relationship with cholesterol, until recently only diabetic patients with marked dyslipidaemia were routinely offered lipid-lowering therapy. The secondary prevention statin trials led to more widespread cholesterol lowering in patients with coronary disease and diabetes. Here we review the results of recent randomized trials, which included substantial numbers of patients with diabetes and no vascular disease. RECENT FINDINGS: The MRC/BHF Heart Protection Study included 5963 participants with diabetes, of whom 2912 had no history of vascular disease at baseline. Patients were randomized to 40 mg simvastatin daily or matching placebo for 5 years, which, on average, reduced LDL by 1.0 mmol/l compared with placebo. Highly significant reductions of about one-quarter in major vascular events were seen both overall and in different types of patient with diabetes, including those with average and below average lipid levels. Recent data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial and the Anglo-Scandinavian Cardiac Outcomes Trial support these findings and are consistent with these effects. SUMMARY: Good quality, randomized trials including substantial numbers of patients with diabetes show that such patients obtain the same proportional benefit as other groups studied. Given their increased cardiovascular risk, these findings argue for a simple strategy of considering routine statin therapy for patients with type 2 diabetes and adult patients with type 1 diabetes, irrespective of lipid levels. As generic statins become available this could have a greater impact on the burden of cardiovascular disease in diabetes than restricted and targeted therapy.     

Statin action favors normalization of the plasma lipidome in the atherogenic mixed dyslipidemia of MetS: potential relevance to statin-associated dysglycemia

The impact of statin treatment on the abnormal plasma lipidome of mixed dyslipidemic patients with metabolic syndrome (MetS), a group at increased risk of developing diabetes, was evaluated. Insulin-resistant hypertriglyceridemic hypertensive obese males (n = 12) displaying MetS were treated with pitavastatin (4 mg/day) for 180 days; healthy normolipidemic age-matched nonobese males (n = 12) acted as controls. Statin treatment substantially normalized triglyceride (−41%), remnant cholesterol (−55%), and LDL-cholesterol (−39%), with minor effect on HDL-cholesterol (+4%). Lipidomic analysis, normalized to nonHDL-cholesterol in order to probe statin-induced differences in molecular composition independently of reduction in plasma cholesterol, revealed increment in 132 of 138 lipid species that were subnormal at baseline and significantly shifted toward the control group on statin treatment. Increment in alkyl- and alkenylphospholipids (plasmalogens) was prominent, and consistent with significant statin-induced increase in plasma polyunsaturated fatty acid levels. Comparison of the statin-mediated lipidomic changes in MetS with the abnormal plasma lipidomic profile characteristic of prediabetes and T2D in the Australian Diabetes, Obesity, and Lifestyle Study and San Antonio Family Heart Study cohorts by hypergeometric analysis revealed a significant shift toward the lipid profile of controls, indicative of a marked trend toward a normolipidemic phenotype. Pitavastatin attenuated the abnormal plasma lipidome of MetS patients typical of prediabetes and T2D.     

Pharmacologic prevention of both restenosis and atherosclerosis progression: AGI-1067, probucol, statins, folic acid and other therapies

PURPOSE OF REVIEW: In this article, the authors intend to provide an update on clinical trials of pharmacologic prevention of restenosis after percutaneous coronary interventions, placed in the perspective of the use of orally administered therapy for the prevention of atherosclerosis progression and clinical events. RECENT FINDINGS: AGI-1067, the mono-succinic acid ester of probucol, is a phenolic antioxidant member of a novel class of agents termed v-protectants. It has strong antioxidant properties equipotent to those of probucol and antiinflammatory properties. It inhibits gene expression of VCAM-1 and MCP-1 and has been effective at preventing atherosclerosis in all tested animal models including the non-human primate. In the Canadian Antioxidant Restenosis Trial (CART) 1, AGI-1067 and probucol improved lumen dimensions at the site of percutaneous coronary intervention. AGI-1067 also improved luminal dimensions of non-intervened coronary reference segments in the Canadian Antioxidant Restenosis Trial, which suggests a direct antiatherosclerosis effect. Probucol reduced post-percutaneous coronary intervention restenosis and progression of carotid atherosclerosis in other clinical trials. Although statins reduce atherosclerotic events, they do not appear to have a significant effect on restenosis. The failure of folate therapy to protect against restenosis in the Folate After Coronary Intervention Trial (FACIT) occurred despite significant reductions in homocysteine levels. SUMMARY: Prevention of both post-percutaneous coronary intervention restenosis and atherosclerosis progression with a pharmacologic agent such as AGI-1067 may be an attractive treatment paradigm. Two important trials that test the antioxidant/antiinflammatory hypothesis are ongoing with AGI-1067: the Canadian Atherosclerosis and Restenosis Trial 2, which assesses its value for the reduction of both atherosclerosis progression and post-percutaneous coronary interventions restenosis, and the Aggressive Reduction of Inflammation Stops Events (ARISE) trial which is evaluating its effects on cardiovascular events.     

Apolipoprotein A5, a crucial determinant of plasma triglyceride levels,is highly responsive to peroxisome proliferator-activated receptor alpha activators

The recently discovered APOA5 gene has been shown in humans and mice to be important in determining plasma triglyceride levels, a major cardiovascular disease risk factor. apoAV represents the first described apolipoprotein where overexpression lowers triglyceride levels. Since fibrates represent a commonly used therapy for lowering plasma triglycerides in humans, we investigated their ability to modulate APOA5 gene expression and consequently influence plasma triglyceride levels. Human primary hepatocytes treated with Wy 14,643 or fenofibrate displayed a strong induction of APOA5 mRNA. Deletion and mutagenesis analyses of the proximal APOA5 promoter firmly demonstrate the presence of a functional peroxisome proliferator-activated receptor response element. These findings demonstrate that APOA5 is a highly responsive peroxisome proliferator-activated receptor alpha target gene and support its role as a major mediator for how fibrates reduce plasma triglycerides in humans.     

Hypertriglyceridemia Is Independently Associated with Renal,but Not Retinal Complications in Subjects with Type 2 Diabetes: A Cross-Sectional Analysis of the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study

Objective

Atherogenic dyslipidemia seems to play a major role in microvascular complications and in residual microvascular risk after statin therapy, which reduces triglycerides up to 40%. We assessed whether raised TG levels are associated with an increased burden from microvascular complications in patients with type 2 diabetes.

Methods

Subjects from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study (n=15,773) were divided in 4 groups depending on whether they had plasma triglycerides below (NTG, 67.8%) or above (HTG, 32.2%) 1.7 mmol/L and were (42.4%) or not on (57.6%) statin therapy. Estimated GFR (eGFR) was calculated from serum creatinine, albuminuria was measured by immunonephelometry or immunoturbidimetry, and retinopathy was evaluated by fundus examination.

Results

HTG subjects, either with or without statin, had higher prevalence of albuminuria, reduced eGFR and chronic kidney disease (CKD), especially the albuminuric forms, but not of retinopathy, than NTG subjects. In contrast, cardiovascular disease and advanced DR were more prevalent in subjects on statin than in those not, independently of triglyceride levels. Logistic regression analysis confirmed that HTG, without or with statin, was independently associated with micro and macroalbuminuria, mildly to severely reduced eGFR, and all CKD phenotypes, but not with retinopathy. The adjusted odd ratios for CKD increased linearly for every 0.26 mmol/L increase (approximately one decile) in triglyceride levels. The increase was higher with increasing severity of albuminuria, eGFR loss and CKD phenotype as well as in subjects receiving than in those not receiving statin treatment.

Conclusions

Triglycerides are associated with CKD, but not retinopathy in subjects with type 2 diabetes, independently of statin treatment. These data point to a possible role of hypertriglyceridemia in the development of CKD, though it remains to be demonstrated that diabetic individuals might benefit from triglyceride reduction with statins and eventually with combination therapy with fibrates.

Trial Registration

www.ClinicalTrials.gov NCT00715481     

Hypertriglyceridemia and the fibrate trials

Epidemiological studies published since 1996 have established that hypertriglyceridemia can predict risk of cardiovascular disease in a manner statistically independent of HDL cholesterol. Nevertheless, the relationship of concentrations of plasma triglycerides to risk of cardiovascular disease remains less than straightforward, partly because triglycerides are carried in lipoproteins of different atherogenicity, partly because hypertriglyceridemia is associated with non-lipid atherogenic and thrombogenic processes. For example, the association of highest risk of cardiovascular disease to moderate rather than to severe hypertriglyceridemia can be understood in terms of the distribution of triglycerides between different classes of plasma lipoproteins. It is counter-intuitive to most clinicians, however, and hence it can result in the misdirection of clinical efforts including drug therapy.Fibrates lower plasma triglycerides, and raise HDL, efficiently and with few immediate side-effects. Central to their mode of action is activation of certain nuclear receptors in cells. There is no necessary connection, however, between that fascinating biochemistry and clinical benefit as defined by reductions in rates of death by coronary artery disease. A review of trials of cholesterol-lowering by diet and drugs, published between 1966 and 1996, included 12 trials of therapy with fibrates or placebo in more than 21000 patients. Overall, these trials indicated no benefit in terms of reduction in risk of coronary deaths. The period since 1996 has seen the publication of four additional trials of treatment of 6144 patients with fibrates or placebo. Two of them were major trials. The VA-HIT was very encouraging, because treatment with gemfibrozil produced a signficant reduction in the combined incidence of fatal and non-fatal coronary events. There was no significant reduction in coronary deaths, however. The results of BIP were frankly disappointing, because they demonstrated no significant effect of treatment with bezafibrate on either the primary end-point of the trial or on rates of coronary death.Clinical indications for the use of fibrates can obviously not be based on biochemical insights, however intriguing in their own right, but they have also not been satisfactorily defined by the randomized clinical trials published to date. Hope remains, however, that some clarification will result from ongoing trials of fibrate treatment of patients with type II diabetes.     

Reassessment of cardiovascular risk in diabetes

PURPOSE OF REVIEW: To review recent trials and reassess cardiovascular risk in people with diabetes. RECENT FINDINGS: Recent clinical trials have tended to focus on lower-risk participants with diabetes who have had event rates considerably lower than participants in the early lipid trials. Statin studies have generally shown benefit in those without cardiovascular disease and at lower levels of low-density lipoprotein cholesterol. Results of fibrate and glitazone studies have been mixed; the question of benefit among statin-treated patients remains unanswered. Investigators failed to confirm the benefits of glucose control observed in the original Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction study possibly due to study design issues. Epidemiologic follow-up of the Diabetes Control and Complications Trial showed sustained benefit of glucose control. A number of studies have shown the benefit of inpatient control of blood glucose. We await the results of ongoing blood pressure trials and other ongoing trials, which should provide much new information. A conceptual model of cardiovascular risk for people with diabetes mellitus based on the UK Prospective Diabetes Study outcomes model is discussed. SUMMARY: The majority of adults with diabetes have a substantially greater risk compared with those without diabetes and a small percentage has very high risk. A minority of individuals may have considerably lower 10-year risk.     

Lifestyle intervention to prevent diabetes: intensive and cost effective

PURPOSE OF REVIEW: Type 2 diabetes is a major cause of morbidity and mortality, and despite treatment advances appears to be increasing in incidence. Since individuals at risk for the disease are usually identifiable in the prediabetic phase of impaired glucose tolerance, early intervention might prevent diabetes and hence its complications from developing. Obesity and sedentary living are powerful determinants of diabetes, and thus lifestyle change is a logical approach to prevention of this disease. Recent clinical trials have now tested the effectiveness of this intervention and form the basis for this review. RECENT FINDINGS: Three clinical trials have demonstrated that, compared with usual care, lifestyle intervention significantly reduced progression rates to diabetes in prediabetic individuals. Each trial incorporated individualization and repeated long-term contacts with facilitators, in which dietary and physical activity goal setting and behavior modification were central themes. Progression to diabetes was reduced in the Da Qing study by approximately 40%, in the Finnish Diabetes Prevention Study by 58% and in the Diabetes Prevention Program by 58%. The Diabetes Prevention Program included a cost-benefit unit that estimated the per capita costs of the lifestyle intervention to exceed that of the usual care group by Dollars 3540, which translated to a cost of Dollars 15,700 per case of diabetes prevented. Lifetime cost-utility analysis demonstrated an overall cost of Dollars 1100 per quality-adjusted life year. SUMMARY: These findings make the case for translation of research findings to healthcare systems. Although there is more to be learned about effective strategies in clinical practice, it seems clear that the intervention needs to incorporate individualization and long-term interaction with trained facilitators.     

Efficacy of Standard and Intensive Statin Treatment for the Secondary Prevention of Cardiovascular and Cerebrovascular Events in Diabetes Patients: A Meta-Analysis

Aims

To estimate the efficacy of standard and intensive statin treatment in the secondary prevention of major cardiovascular and cerebrovascular events in diabetes patients.

Methods

A systematic search was conducted in Medline over the years 1990 to September 2013. Randomized, double-blind, clinical trials comparing a standard-dose statin with placebo or a standard-dose statin with an intensive-dose statin for the secondary prevention of cardiovascular and cerebrovascular events in diabetes patients were selected. Trial and patient characteristics were extracted independently by two researchers. The combined effect on the composite primary endpoint was measured with a fixed-effect model. Potential publication bias was examined with a funnel plot.

Results

Five trials were included in the analysis comparing standard-dose statins with placebo with a total of 4 351 participants. Four trials were included for comparing standard-dose with intensive-dose statins, including 4 805 participants. Compared with placebo, standard-dose statin treatment resulted in a significant relative risk (RR) reduction of 15% in the occurrence of any major cardiovascular or cerebrovascular event (RR 0.85, 95% CI 0.79–0.91). Compared with standard-dose statin treatment, intensive-dose statin treatment resulted in an additional 9% relative risk reduction (RR 0.91, 95% CI 0.84–0.98).

Conclusion

Treatment with standard-dose statins to prevent cardiovascular or cerebrovascular events in diabetes patients with manifest cardiovascular disease results in an estimated 15% relative risk reduction and intensive-dose statin treatment adds 9%. If proven cost-effective, more intensive statin treatment should be recommended for diabetes patients at high cardiovascular risk.