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REVIEW
Robert Elkeles
Abbreviations and acronyms ACCORD Apo BIP CHD CVD DAIS DECODE DREAM ECG FIELD Action to Control Cardiovascular Risk in Diabetes apoprotein Bezafibrate Infarction Prevention Study coronary heart disease cardiovascular disease Diabetes Atherosclerosis Intervention Study Diabetes Epidemiology Collaborative Criteria in Europe Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication electrocardiogram Effects of Long-term Fenofibrate Therapy on Cardiovascular Events in People with Type 2 Diabetes Mellitus homeostasis model assessment insulin resistance high-density lipoprotein International Diabetes Federation impaired fasting glucose impaired glucose tolerance Insulin Resistance Atherosclerosis Study low-density lipoprotein lipoprotein lipase myocardial infarction oral glucose tolerance test peroxisome proliferator activated receptor St Marys Ealing Northwick Park Diabetes Cardiovascular Prevention Study Study to Prevent NIDDM Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Study very low-density lipoprotein
Introduction
Type 2 diabetes now affects 2.8 million people in the UK and its incidence both here and worldwide is increasing with IDF predicting a 54% increase by 2030 to give a global prevalence of 438.4 million.1,2 People with type 2 diabetes are at greatly increased risk from CVD as well chronic renal failure, retinopathy and neuropathy. People with IFG and IGT are at high risk of developing type 2 diabetes3 but also are at increased risk of CVD.4 Current methods of treating type 2 diabetes are still inadequate and it has not been possible to eliminate the risk of
Department of Metabolic Medicine, Imperial College Healthcare, St Marys Hospital, London, UK. Correspondence to: Professor Robert Elkeles Department of Metabolic Medicine, Imperial College Healthcare, St Marys Hospital, Praed Street, London, W2 1NY, UK. Tel: +44 (0)20 3312 6037; Fax: +44 (0)020 3312 1563 E-mail: robert.elkeles@imperial.nhs.uk
HOMA-IR HDL IDF IFG IGT IRAS LDL LPL MI OGTT PPAR- SENDCAP STOP-NIDDM VAHIT VLDL
10.1177/1474651410397245
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Function of gene product Inhibitor of VLDL clearance Lipolysis, TGRL HDL formation, reverse cholesterol transport HDL formation, reverse cholesterol transport Cellular cholesterol efflux/HDL formation Cellular fatty acid uptake Fatty acid activation, acyl CoA esters Fatty acid oxidation Fatty acid synthesis Blood clotting Acute prase reactant Fatty acid metabolism Adhesion molecule
Gene expression
Fibrate
PPAR
Activated PPAR/RXR Lipoprotein metabolism Cellular cholesterol homeostasis Fatty acid metabolism
PPRE/target genes
Inflammation
Haemostasis
Reproduced with from Chapman MJ. Fibrates: therapeutic review. Br J Diabetes Vasc Dis 2006;6:11-21.
b-oxidation pathway Acetyl CoA carboxyrase Fibrinogen C-reactive protein, interleukin6 Cyclooxygenase 2 VCAM-1
complications. It would therefore be highly desirable to prevent its occurrence or at least delay its onset. Type 2 diabetes is associated with both peripheral insulin resistance and impaired beta cell function. Insulin resistance is present for many years before the onset of type 2 diabetes5 and it is possible that intervention at an early stage could delay onset or reduce the incidence of type 2 diabetes. Could fibrate drugs have a role in the prevention of type 2 diabetes? They have been widely used to modify plasma lipids. Their mode of action is to activate the nuclear receptor PPAR (figure 1). PPAR modulates the transcription of genes involved in the synthesis of apo-CIII and fatty acids while increasing the expression of genes involved in the synthesis of apoA-V and LPL and those involved in fatty acid oxidation (table 1). The results of these actions are to decrease the production and to increase the removal of triglyceride rich lipoproteins thereby reducing circulating triglyceride concentration. The increased apoA-I and apoA-II gene expression and LPL activity also result in increased HDL formation. These and the other effects of fibrates on inflammation, coagulation and haemostasis have been well described.6 Less well known are their effects on blood glucose and insulin resistance.
Key: HDL = high-density lipoprotein; TGRL = triglyceride-rich lipoproteins; VLDL = very low-density lipoprotein; PPAR = peroxisome proliferator activated receptor. Adapted from Chapman (2003)3 Reproduced with permission.6
placebo. After a median of 3.5 years, there was a small rise in fasting blood glucose in the placebo group but no change in the bezafibrate treated group. The bezafibrate group also showed a small fall in insulin resistance as measured by HOMA-IR.11. In non-obese Japanese type 2 diabetic patients treatment with bezafibrate 400 mg daily for 3 months was associated with a reduction in fasting blood glucose, serum insulin and in insulin resistance measured by HOMA-IR.12 The BIP study was set up to study the effect of bezafibrate on the combined incidence of non-fatal MI or death from CHD in people who had sustained a previous MI. They received either bezafibrate 400 mg daily or placebo. Over a two-year period there were significant rises in serum insulin and HOMAR-IR in the placebo group but no significant changes in the bezafibrate group. Thus, bezafibrate was able to attenuate the rise in insulin resistance over time found in the placebo group.13.
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cholesterol by 1015% although there is considerable variation in the size of these effects.14 The effects of the fibrates on LDL cholesterol are variable. LDL-cholesterol may be decreased by up to 10%. However, in those with significantly elevated triglycerides an increase in LDL-cholesterol may be found. This is presumably due to increased LPL activity which increases the conversion of VLDL to LDL. However, in these subjects the particle size of LDL is increased to the larger more buoyant variety, which is thought to be less atherogenic.
Study Helsinki Heart Study SENDCAP (St Marys Ealing Northwick Park Diabetes Cardiovascular Prevention Study) VA-HIT (Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Study) DAIS (Diabetes Atherosclerosis Intervention Study) FIELD (Effects of Long-term Fenofibrate Therapy on Cardiovascular Events in People with Type 2 Diabetes Mellitus) ACCORD (Action to Control Cardiovascular Risk in Diabetes)
References 15,16 10 18 19 20
22
number of coronary events or total mortality.20 However, there was a 24% reduction in non-fatal MIs, a significant reduction in total CVD events and reduced progression of albuminuria and retinopathy. The lack of effect on mortality may have been due to the large numbers given statins in the placebo group. In a pre-specified analysis it was also associated with reduction in lower limb amputation rate.21 The much awaited ACCORD study investigated whether combination therapy with a statin plus fibrate as compared with statin alone would reduce risk of CVD in patients with type 2 diabetes who were at high risk from CVD.22 This showed that fenofibrate given in addition to statin did not lead to any reduction in mortality. However, in the subgroup with high triglycerides and low HDL cholesterol the primary outcome rate was 12.4% in the fenofibrate group compared with 17.3% in in the placebo group; this failed to reach statistical significance. The main fibrate cardiovascular outcome studies in type 2 diabetes are listed in table 2. A recent large meta-analysis identified 18 trials with data from 45,058 subjects including 2,870 major cardiovascular events.23 Fibrate therapy produced a 10% reduction for major cardiovascular events and a 13% reduction in coronary events There was no benefit for stroke or cardiovascular or all-cause mortality. Thus, overall, fibrates do seem to have a modest effect in reducing cardiovascular outcomes especially in those with the metabolic syndrome or type 2 diabetes.
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men and 7,126 women.4 There appeared to be a linear relationship between blood glucose concentration and CVD mortality even within the normal glucose range. Both IGT and IFG are associated with insulin resistance.26 Insulin resistant subjects tend to have higher total and VLDL triglyceride and lower HDL cholesterol than more insulin sensitive subjects,27 a pattern thought to be atherogenic and common in type 2 diabetes. There is evidence to implicate insulin resistance in the genesis of atherosclerosis. Insulin-mediated glucose disposal was measured in healthy individuals using euglycaemic hyperinsulinaemic clamps and ultrasound of the carotid and femoral arteries to detect asymptomatic atherosclerosis. Those with asymptomatic atherosclerosis showed a 20% decrease in insulin sensitivity compared with those without.28 Furthermore, in IRAS a significant negative association was found between insulin sensitivity as measured by the frequently sampled glucose tolerance test and carotid intima media thickness.29 There is also considerable evidence that insulin resistance is associated with cardiovascular disease. In the San Antonio Heart Study, Mexican and non-Hispanic white residents underwent baseline examination with HOMA-IR measurements. During the follow-up period a significant association was found between HOMA-IR and risk of cardiovascular events after adjustment for multiple covariates.30 In the Bruneck population study in Italy, HOMA-IR estimated insulin resistance was associated with subsequent symptomatic cardiovascular disease independently of all classical and several non-traditional risk factors.31 There is evidence that insulin resistance and associated cardiovascular risk factors are present many years before the onset of type 2 diabetes. In the San Antonio cohort,32 those who converted to type 2 diabetes had higher total and LDL cholesterol, triglyceride and serum triglyceride, lower HDL cholesterol and fasting glucose, insulin, 2-h glucose, body mass index and blood pressure than those who did not develop type 2 diabetes. When those with IGT at baseline were excluded those who converted to type 2 diabetes still had a more atherogenic pattern of risk factors including lower HDL cholesterol at baseline. In a group of Pima Indians studied prospectively with OGTT and hyperinsulinaemic clamp studies at baseline, insulin resistance was the strongest predictor of conversion to type 2 diabetes.33 In the 7-year follow up of the San Antonio Heart Study, those who converted to type 2 diabetes had significantly higher body mass index, waist circumference triglyceride blood pressure and lower HDL cholesterol than non-converters.34 Thus, it would appear that the seeds of increased cardiovascular risk characteristic of type 2 diabetes are sewn long before the onset of the level of hyperglycaemia at which type 2 diabetes is diagnosed. This led Haffner to postulate that, unlike microvascular complications, for which the clock starts ticking with the onset of clinical diabetes, for macrovascular disease precipitating events may begin decades earlier. Haffner has called this the ticking clock hypothesis.32 It therefore seems reasonable to
suggest that intervention at this early so-called pre-diabetic stage to reduce insulin resistance and modify the atherogenic lipid profile could have a role in prevention not only of type 2 diabetes but also its associated cardiovascular complications. The fibrate group of drugs could provide just such a mechanism.
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Key messages
Delaying onset or prevention of type 2 diabetes is an important aim The fibrate drugs, in particular bezafibrate: reduce blood glucose and insulin resistance improve the atherogenic lipid profile A trial of bezafibrate to prevent type 2 diabetes is justified
between bezafibrate or fenofibrate. Bezafibrate is inexpensive, has a good safety record, and has been shown to have beneficial effects on blood glucose and insulin resistance in addition to its well described effects on improving the atherogenic lipid profile. These effects taken together might be able to prevent or delay the onset of type 2 diabetes and to reduce cardiovascular risk in those at high risk for developing type 2 diabetes.
Conclusion
There seems to be a reasonable case for a randomised control trial of bezafibrate to delay the onset of, or to prevent, type 2 diabetes in those at high risk.
References
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