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Fibrates: old drugs with a new role in type 2 diabetes prevention?


Robert Elkeles British Journal of Diabetes & Vascular Disease 2011 11: 4 DOI: 10.1177/1474651410397245 The online version of this article can be found at: http://dvd.sagepub.com/content/11/1/4

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Fibrates: old drugs with a new role in type 2 diabetes prevention?


ROBERT ELKELES
Abstract
he incidence of type 2 diabetes is increasing throughout the world resulting in a huge growth in demands on health services. Despite advances in treatment, complications still occur. Prevention of type 2 diabetes or delaying its onset is therefore a desirable goal. In trials, lifestyle measures have been partially successful but continuing adherence is difficult. A number of drugs have been tried with varying success. Those people who develop type 2 diabetes have been found to have a more atherogenic lipid profile and to be more insulin resistant, than those who do not, and at increased cardiovascular risk. Fibrates, which are safe and cheap, could help to correct these abnormalities at an early stage and reduce cardiovascular risk. They would seem a suitable option for prevention of type 2 diabetes. Evidence is presented to suggest that the fibrates, in particular bezafibrate, could have a role in prevention of type 2 diabetes in those at high risk and that a randomised trial would seem justified. Br J Diabetes Vasc Dis 2011;11:4-9. Key words: bezafibrate, diabetes prevention, fibrates, type 2 diabetes

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

The Author(s), 2011. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav

10.1177/1474651410397245

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Figure 1. Mechanism of action of fibrates

Table 1. PPAR-mediated gene regulation by fibrates

Mechanism of action of fibrates

Target gene Apolipoprotein CIII Lipoprotein lipase

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

Apolipoprotein AI Apolipoprotein AII ABCA1

Activated PPAR/RXR Lipoprotein metabolism Cellular cholesterol homeostasis Fatty acid metabolism

PPRE/target genes

Inflammation

Fatty acid binding protein Acyl CoA synthetase

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

Effects of fibrates on blood glucose and insulin resistance


In small, randomised placebo controlled studies both bezafibrate and gemfibrozil have been shown to reduce both fasting and postprandial blood glucose in type 2 diabetic patients.7-9 The SENDCAP study was set up to find out whether bezafibrate had any effect on cardiovascular outcomes in type 2 diabetes.10 In this study, 117 male and 47 female type 2 diabetic patients were randomised to receive either bezafibrate or
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE

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.

Effects on serum lipids and lipoprotein metabolism


In general most studies have shown that fibrates reduced plasma triglyceride concentration by 3050% and increase HDL
5

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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.

Table 2. Fibrate trials of cardiovascular outcomes involving type 2 diabetic patients

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

Effects on cardiovascular outcomes


The effects of fibrates on cardiovascular outcomes have been somewhat overshadowed by the striking results found with statins. However, before the advent of statins, the Helsinki Heart Study, which was a primary prevention study in middleaged dyslipidaemic men, showed that in comparison with a placebo group those treated with gemfibrozil had significantly fewer coronary events.15 This beneficial effect on risk reduction was most marked in those with obesity, those with the highest serum triglycerides and those with the lowest HDL cholesterol. Gemfibrozil-induced serum lipid changes in the diabetic patients in this study were similar to those in non-diabetic subjects and also reduced CHD incidence.16 The BIP study was a secondary intervention study designed to determine the effects of bezafibrate on CHD. Although overall the study was negative, in those with hypertriglyceridaemia (plasma triglycerides > 2.25 mmol/L) there was a significant (39%) reduction in coronary events.17 In contrast the VAHIT was a secondary intervention study using gemfibrozil in men selected for low HDL cholesterol and normal LDL cholesterol. Those treated with gemfibrozil had significantly fewer events and a reduction in coronary mortality.18 Similar results were found for those who had type 2 diabetes. The SENDCAP study was probably the first, though small, prospective study to investigate the effects of lipid modification on cardiovascular outcomes specifically in type 2 diabetes.10 Type 2 diabetic patients were randomised to bezafibrate 400 mg or placebo daily and followed for a mean period of 3 years. The primary outcome was change in carotid intima media thickness. Although there was no significant difference in the progress of ultrasonically measured arterial disease, in those treated with bezafibrate there was a significant reduction in the combined incidence of Minnesota-coded probable ischaemic changes on the resting ECG and of documented MI. DAIS was a double-blind placebo-controlled study using fenofibrate in the actively treated participants to find out whether correcting lipid abnormalities typically seen in type 2 diabetes would alter the progression of angiographically measured coronary artery disease.19 The fenofibrate-treated group had significantly less angiographic progression than the placebo group. There was also a 23% reduction in clinical events in the fenofibrate treated group but the study was not powered to be a clinical event study. The FIELD study was a large prospective study of the effects of fenofibrate on cardiovascular events in type 2 diabetes. Overall, fenofibrate failed to reduce the

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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.

The rationale for early intervention to prevent type 2 diabetes


A significant problem in prevention of cardiovascular complications of type 2 diabetes is that at diagnosis people with type 2 diabetes are already at greatly increased risk of CHD and stroke.24 Even people with IGT or IFG have about a two-fold increased risk for developing CVD events compared with those with normal blood glucose levels.25 The DECODE study analysed 10 prospective European cohort studies including 15,388

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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.

Previous interventions to prevent type 2 diabetes


Intervention with lifestyle measures of diet and exercise was shown by Tuomilehto et al. to reduce the incidence of type 2 diabetes in people with IGT by 58% over a period of 3.2 years35 and by 43% in the Da Qing study in a Chinese population.36 In the Diabetes Prevention Program, in people with either IFG or IGT, lifestyle advice or metformin reduced the incidence of type 2 diabetes by 58%, and 31% respectively compared to placebo over 2.8 years follow-up.37 The STOP-NIDDM study38 the alphaglucosidase inhibitor acarbose, reduced incidence of new diabetes in those with IFG by 25% over 3.3 years. It is noteworthy that 25% of subjects given acarbose withdrew from the study, mainly due to gastrointestinal side effects. Another approach to prevention has been to reduce insulin resistance pharmacologically in those with IFG or IGT. In the DREAM39 study 5,269 people with IFG or IGT were randomised to receive either rosiglitazone or placebo. The composite endpoint was incident diabetes or death. Rosiglitazone substantially reduced the incident type 2 diabetes. Cardiovascular event rates were similar in the two groups but there was an increase in those developing heart failure in the rosiglitazone group.

Could fibrates have a role in prevention of type 2 diabetes?


As mentioned above, those who develop type 2 diabetes have been found to be more insulin resistant, have higher triglycerides and lower HDL-cholesterol those who do not. Furthermore, at diagnosis of type 2 diabetes cardiovascular disease is already present. Therefore intervention at an early stage in those with IFG or IGT with an agent which could correct these metabolic abnormalities and in addition reduce blood glucose and risk of cardiovascular events could make sense where lifestyle measures are not effective. The fibrates seem to fit these requirements better than other classes of drugs. The effect of bezafibrate on the progression of IFG to type 2 diabetes was studied in 303 participants aged 4274 years with coronary artery disease over 6.2 years. New onset diabetes was recorded in 54% of subjects given placebo and 42% given bezafibrate, a significant reduction in incidence.40 In a retrospective cohort study from the General Practice Research Database in the UK, individuals chronically exposed to bezafibrate were compared with those exposed to other fibrates for incident type 2 diabetes.41 Those on bezafibrate had a lower incidence of type 2 diabetes than those on other fibrates. In a post-hoc analysis those on bezafibrate also showed a lower incidence of progression to oral antidiabetic agents or progression to use of insulin. Gemfibrozil has not been widely used in the UK and there may be interactions between it and the statins. For a trial of prevention of type 2 diabetes, the choice would seem to lie

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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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12. Taniguchi A, Fukushima M, Sakai M et al. Effects of Bezafibrate on insulin sensitivity and insulin secretion in non-obese Japanese type 2 diabetic patients Metabolism 2001;50:477-80. 13. Tenenbaum A, Fisman EZ, Boyko V et al. Attenuation of progression of insulin resistance in patients with coronary artery disease by Bezafibrate. Arch Intern Med 2006;166:737-41. 14. Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999; 141:498-511. 15. Frick MH, Elo O, Haapa K et al. The Helsinki Heart Study; primary prevention trial with gemfibrozil in middle aged men with dyslipidaemia safety or treatment changes in risk factors and incidence of coronary heart disease. N Engl J Med 1987;317:1237-45. 16. Koskinen P, Manttarri M, Manninen V et al. Coronary heart disease in NIDDM patients in the Helsinki Heart Study. Diabetes Care 1992; 15:820-5. 17. The BIP Study Group. Secondary prevention by raising HDL-cholesterol and reducing triglycerides in patients with coronary heart disease. The Bezafibrate Infarction Prevention (BIP) study. Circulation 2000;102: 21-7. 18. Rubins HB, Robins SJ, Collins D et al. for the Veterans Affairs HighDensity Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410-8. 19. The Diabetes Atherosclerosis Intervention Study Investigators. Effect of Fenofibrate on progression of coronary artery disease in type 2 diabetes. The Diabetes Atherosclerosis Intervention Study. Lancet 2001;357: 905-10. 20. The FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366: 1849-61. 21. Rajamani K, Colman PG, Li LP et al. On behalf of the FIELD study investigators. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a pre-specified analysis of a randomised controlled trial. Lancet 2009;373:1780-8. 22. The ACCORD Study Group. Effects of combination lipid therapy in Type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74. 23. Jun M, Foote C, Lv J et al. Effects of fibrates on cardiovascular outcomes : a systematic review and meta-analysis. Lancet 2010;375: 1875-84. 24. Laakso M, Lehto S. Epidemiology of macrovascular disease in diabetes. Diabetes Rev 1997;5:294-315. 25. Coutinho M, Gerstein HC, Wang Y Yusuf S. The relationship between glucose and incident cardiovascular events: a metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 1999;22:233-40. 26. Abdul-Ghani MA, Tripathy D, DeFronzo RA. Contributions of b-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose Diabetes Care 2006; 29:1130-9. 27. Laakso M, Sarlund H, Mykkanen L. Insulin resistance is associated with lipid and lipoprotein abnormalities in subjects with varying degrees of glucose tolerance Arteriosclerosis 1990;10:223-31. 28. Laakso M, Sarlund H, Salonen R et al. Asymptomatic atherosclerosis and insulin resistance Arterioscl Thromb 1991;7:217-26. 29. Howard G, OLeary DH, Zaccaro D et al. Insulin sensitivity and atherosclerosis Circulation 1996; 93:1809-17. 30. Hanley AJG, Williams K, Stern MP, Haffner SM. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care 2002; 25:1177-84. 31. Bonora E, Kiechl S Willeit J et al. Insulin resistance as estimated by homeostasis model assessment predicts incident symptomatic cardiovascular disease in Caucasian subjects from the general population: the Bruneck Study. Diabetes Care 2007;30:318-24. 32. Haffner SM, Stern MP, Hazuda HP et al. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart

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37. Diabetes Prevention Program Research Group. Reduction in in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403. 38. Chiasson JL, Josse RG, Gomis R et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial Lancet 2002; 359:2072-7. 39. The DREAM Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096-1105. 40. Tenenbaum A, Motro M, Enrique Z et al. Effect of bezafibrate on incidence of type 2 diabetes mellitus in obese patients. Eur Heart J 2005; 26:2032-8. 41. Flory JH, Ellenberg S, Szapary PO et al. Antidiabetic action of Bezafibrate in a large observational database. Diabetes Care 2009;32:547-51.

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