When it comes to the FIELD study, what is...is

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1 Future Lipidology ISSN: (Print) (Online) Journal homepage: When it comes to the FIELD study, what is...is James McKenney To cite this article: James McKenney (2006) When it comes to the FIELD study, what is...is, Future Lipidology, 1:3, To link to this article: Copyright 2006 Future Medicine Ltd Published online: 18 Jan Submit your article to this journal Article views: 92 Full Terms & Conditions of access and use can be found at

2 PRIORITY PAPER EVALUATION When it comes to the FIELD study, what is...is James M McKenney Virginia Commonwealth University, National Clinical Research, 2809 Emerywood Parkway, Suite 140, Richmond, VA 23294, USA Tel.: ; Fax: ; jmckenney@ncrinc.net Keywords: CHD risk, outcome studies, pharmacotherapy, risk benefit decisions, Type2diabetes Evaluation of: The FIELD 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 366, (2005). The presentation of the fenofibrate intervention and event lowering in diabetes (FIELD) study last November at the American Heart Association s Annual Scientific Meeting and the subsequent publication in the Lancet represent a seminal moment in the life of fenofibrate and perhaps the entire class of fibrate lipid altering agents. The reaction to the findings of this study was at least disappointing if not worrying. How do we interpret these results? What do they teach us? How should they be applied to the care of diabetic patients, or any dyslipidemic patient for that matter? How do we make decisions regarding which triglyceride lowering agent to use, fenofibrate, gemfibrozil or niacin? Given the results of FIELD, should we be using fenofibrate at all? It shall be the goal of this commentary to critically review the findings of this pivotal study, to glean as much understanding from it as possible and to determine the implications of the study to health professionals and patients. The FIELD study results The fenofibrate intervention and event lowering in diabetes (FIELD) study was a 5-year multicenter, randomized, placebo controlled, two-arm parallel study in 9795 patients with Type 2 diabetes mellitus testing the hypothesis that long-term treatment with fenofibrate will reduce coronary morbidity and mortality [1]. Patients were required to have an initial plasma total cholesterol between 116 and 252 mg/dl ( mmol/l) and either a total cholesterol high-density lipoprotein cholesterol (HDL-C) ratio of at least 4.0 or a plasma triglyceride between 89 and 442 mg/dl ( mmol/l). Patients were not to be taking lipid-lowering drug therapy, including a statin, at study entry. Those with impaired renal function, chronic liver disease or symptomatic gallbladder disease were excluded. These criteria resulted in a study patient population that was 63% male with a mean age of 63 years and the following mean lipid profile: total cholesterol 195 mg/dl (5.03 mmol/l), HDL-C 43 mg/dl (1.10 mmol/l), low-density lipoprotein cholesterol (LDL-C) 119 mg/dl (3.07 mmol) and triglycerides 153 mg/dl (1.73 mmol/l). The investigators reported that approximately half (52%) had a triglyceride level above 150 mg/dl (1.7 mmol/l) and approximately half (59%) had a HDL-C less than 40 mg/dl (<1.03 mmol/l) if male or 50 mg/dl (<1.29 mmol/l) if female. Few (9%) smoked, 56% had hypertension (mean blood pressure [BP] of the population was 140/82 mmhg) and 22% had a prior history of cardiovascular disease (CVD). All patients meeting entrance criteria completed a 4-week dietary modification period, followed by a 6-week single-blind placebo treatment period and a 6-week single-blind fenofibrate 200 mg/day treatment period; 408 patients were dropped during the active run-in period for unclear reasons. A total of 9795 patients were randomized to fenofibrate 200 mg/day or matching placebo with breakfast and were followed at 4 6 month intervals for 5 years. Importantly, their primary care physician was at liberty to adjust usual care treatments, including the addition of lipid-altering drug therapy, during the course of the study. The primary study outcome, coronary heart disease (CHD), death and nonfatal myocardial infarction (MI), was reduced 11% (hazard ratio [HR] 0.89 [ ]; p = 0.16) (Table 1). This outcome occurred in 6% of placebo-treated patients and 5% of fenofibrate-treated patients during the 5-year study. Nonfatal MI alone was reduced 24% (HR 0.76 [ ]; p = 0.01). Some of the secondary outcomes were reduced significantly with fenofibrate, including a composite end point termed total cardiovascular (CV) events (i.e., CV death, nonfatal MI, stroke and revascularization procedures), coronary revascularization and all revascularizations (Table 1). Stroke was not reduced significantly (p = 0.36). Based on these results, 70 patients would have to be treated for 5 years with fenofibrate 200 mg/day to prevent one or more CV events in one patient. The reduction in total CV events with fenofibrate was not significantly / Future Medicine Ltd ISSN Future Lipidol. (2006) 1(3),

3 PRIORITY PAPER EVALUATION McKenney different in subjects with triglycerides levels above or below 150 mg/dl, HDL-C above or below 40 mg/dl in men, above or below 50 mg/dl in women, with or without hypertension or with or without the metabolic syndrome. Total CV events were reduced significantly in patients with no prior history of CV disease (19%; p = 0.001) but not in those with a prior CV history (p = 0.85). Total mortality, CV mortality and CHD mortality increased 11 19%; none of these s reached statistical significance. In summary, as the title of this commentary suggests, what is, is. Treatment with fenofibrate for 5 years in a huge population of CHD risk equivalent Type 2 diabetic patients, failed to produce a significant reduction in CHD death and nonfatal MI, the benchmark outcome used as the primary outcome measure in practically all of the statin trials. It did demonstrate a significant reduction in total CV events, but only in patients with no prior CHD history. It was also associated with increasing rates of total, CV and CHD mortality, which, while statistically insignificant, did not trend lower. Some explanations for study results So what went wrong? The investigators point their blame, with good reason, at the initiation of nonstudy lipid-lowering therapy during the study [1]. Of patients allocated to fenofibrate 19% (944 of 4895), and 36% of patients allocated to placebo (1776 of 4900) started other lipid lowering therapy during the course of the study. In approximately 93% of cases, this other therapy was a statin. The initiation of other lipid-lowering therapy was more likely to occur in patients receiving placebo, in those with prior CHD history and in those with higher total and LDL-C levels (apparently, the patients primary care physicians were not prohibited from obtaining lipid profiles during the study nor were they blinded to these results, a usual requirement in outcome trials). When the other lipid-lowering therapy was started, 26% of placebo patients and 38% of fenofibrate patients discontinued their assigned study drug. In other words, drop-out study treatment and drop-in other treatment was not balanced between study arms and the drop-in treatment, it appeared to be selectively started in those with highest CHD risk and highest cholesterol levels. In this manner, the integrity of the random allocation of blinded treatments in FIELD was irrevocably jeopardized, thus destroying the homogeneity of study treatment arms and the tenets upon which standard statistical evaluations are based. The authors did conduct a prespecified analysis, which adjusted for the new lipid treatments and found that fenofibrate was associated with a significant 19% reduction in CHD events (p = 0.01) and a 15% reduction in total CV events (p = 0.004). They warn, however, that due to the nonrandomized comparison, these results should be interpreted cautiously. How does FIELD compare with other fibrate outcome trials? One of the first observations one can make regarding the FIELD study, in comparison with other fibrate outcome trials, is that the s in lipid levels during the course of the study were not typical (Table 2). LDL-C levels were reduced initially by 12% (at 4 months) but only 6% by Table 1. Results of the FIELD study. Placebo (n = 4900) Fenofibrate (n = 4895) Hazard ratio (+ 95% CI, p value) Primary outcomes Coronary events 288 (6%) 256 (5%) 0.89 ( , p = 0.16) CHD mortality 93 (2%) 110 (2%) 1.19 ( , p = 0.22) Nonfatal MI 207 (4%) 158 (3%) 0.76 ( , p = 0.01) Secondary outcomes Total CV disease 683 (14%) 612 (13%) 0.89 ( , p = 0.035) CV mortality 127 (3%) 140 (3%) 1.11 ( , p = 0.41) Total mortality 323 (7%) 356 (7%) 1.11 ( , p = 0.18) Total stroke 175 (4%) 158 (3%) 0.90 ( , p = 0.43) Coronary revascularizations 364 (7%) 290 (6%) 0.79 ( , p = 0.003) All revascularizations 471 (10%) 380 (8%) 0.80 ( , p = 0.001) CHD: Coronary heart disease; CI: Confidence interval; CV: Cardiovascular; FIELD: Fenofibrate and event lowering in diabetes; MI: Myocardial infarction. 276 Future Lipidol. (2006) 1(3)

4 When it comes to the FIELD study, what is...is PRIORITY PAPER EVALUATION Table 2. Fibrate outcome studies. Study N Rx T. Chol mean FIELD 9795 F 195 (-7%) DIAS 418 F 216 (-10%) HHS 4081 G 270 (-8%) VA-HIT 2531 G 175 (-4%) BIP 3090 B 212 WHO Study CDP 3892 C 250 (-6.4%) LDL-C mean 119 (-6%) 131 (-6%) 189 (-8%) 112 (0%) 148 HLD-C mean 43 (+1%) 39 (8%) 47 (11%) 32 (6%) 35 (18%) TG mean 153 (-22%) 222 (-28%) 175 (-35%) 160 (-31%) 145 (-21%) Relative in CHD events -11% p= % -34% p< % p= % p=0.26 C (-9%) -20% p < (-16%) -7% (NS) 0% (NS) Relative in total mortality 11% p = % 7% -11% p = % (p = 0.62) +27.6% (p <0.05) Relative in CHD mortality 19% p = 0.22 Ref. [1] NR [2] -26% [3] -22% p = % (p = 0.61) +12.5% (p >0.05) -8% (NS) B: Bezafibratre; BIP: Bezafibrate infarction prevention; C: Clofibrate; CDP: Chemo/dietary prevention; DIAS: Diabetes atherosclerosis intervention study; F: Fenofibrate; FIELD: Fenofibrate and event loweing in diabettes; G: Gemfibrozil; HHS: Helsinki heart srudy; VA-HIT: Veterans affairs high-density lipoprotein intervention trial. [4] [5] [6] [7] study end. HDL-C levels were raised 5% initially but only 1.2% by study end; and the reduction in triglyceride levels fell from an initial 29% reduction to a 22% reduction at study end. This probably reflects discontinuations of study drug and nonadherence. Surprisingly, however, the effect of the statin therapy initiation during the course of the study, which would have been expected to lower total and LDL-C further, does not appear to have occurred. Perhaps this means that patients discontinued the statin therapy soon after starting it, but the FIELD report provides no information on adherence to these other therapies. Compared with the lipid s reported in other fibrate outcome trials (Table 2), the s in the FIELD trial were inferior. The results in the diabetes atherosclerosis intervention study (DIAS), a small angiographic study utilizing fenofibrate 200 mg/day, report superior effects [2]. The difference in lipid s were also especially evident in the two studies employing gemfibrozil 1200 mg/day, the Helsinki Heart Study (HHS) [3], VA-HIT [4], and the one study employing bezafibrate 400 mg/day [5], especially with regard to HDL-C and triglyceride levels. Based on the relationship between decrements in LDL-C and CHD events observed in epidemiological trials and now affirmed by the statin, bile acid sequestrant and ileal bypass outcome trials, one would expect an approximate 1% reduction in coronary events for every 1% lowering in LDL-C. Additionally, based on epidemiological trials and affirmed by the two gemfibrozil outcome trials [3 4], one would expect a 1 2% reduction in CHD events for approximately every 1% increase in HDL-C. Based on this formula, the approximate reduction in major CHD events in FIELD would be predicted to be 16 22%, based on 4-months of lipid data and 8 9% based on study end data. The actual result was a reduction of 11% which probably reflects more precisely the mean lipid s over the course of the study. Table 2 also illustrates that significant reductions in major CHD events (CHD death and nonfatal MI) was obtained only in the two gemfibrozil studies (HHS [3] and VA-HIT [4]) and one of the two clofibrate studies [6]. In three of the fibrate outcome studies, a post hoc analysis showed that CHD event reduction was accentuated and reached significance in the subpopulation of study patients with high triglyceride and low HDL-C levels [5,8,9]. For example, in the HHS, a Table 3. Mortality with fibrate therapy. Fibrate studies (n = 17) Risk ratio (95% CI) Effect on total mortality 1.00 ( ) Effect on cardiac mortality 0.93 ( ) Effect on non-cv 1.13 ( ) mortality CI: Confidence interval; CV: Cardiovascular

5 PRIORITY PAPER EVALUATION McKenney LDL-C/HDL-C ratio of greater than 5 and a triglyceride level of over 200 mg/dl defined the population receiving the greatest benefit from gemfibrozil, a 75% lowering in CHD events [8]. In the bezafibrate infarction prevention (BIP) trial, patients with a HDL-C less than 35 mg/dl and a triglyceride level of 200 mg/dl or greater achieved the greatest reduction with bezafibrate, a 42% significant reduction in major CHD events [5]. In fact, these observations suggest that fibrates should be used and studied in patients with high triglyceride/low HDL-C syndromes. However, as revealed in Table 2, rarely have mean triglyceride levels been over 200 mg/dl (defined as high by National Cholesterol Education Program s Adult Treatment Panel [NCEP ATP III]) in any of the fibrate outcome trials. Conversely, LDL-C levels are frequently as high as those found in statin trials; this was the case in FIELD as triglyceride levels were barely in the borderline high range. Perhaps it is not so surprising that total CV events in FIELD were no different in patients with triglyceride levels above or below 150 mg/dl (3.7 mmol/l). The most disturbing result of FIELD was the increase in total, CV and CHD mortality. While this increase was not statistically significant, the trend was clearly in the wrong direction. FIELD is not alone in this regard. As seen in Table 2, increases in total and/or CHD mortality were also reported in the HHS with gemfibrozil [3], in the BIP study with bezafibrate [5] and in the WHO study with clofibrate [6], thus raising the question of whether this may be a class effect. This observation was strengthened further by a recent meta-analysis of 17 fibrate trials all containing a control group, using random allocation to treatment arms and continuing for at least 6 months [10]. The results show that fibrate therapy had a negligible effect on total mortality (i.e., no reduction) and a significant 13% increase in noncv mortality (Table 3) [10]. These observations alone require more study before fenofibrate or other fibrates are used widely. Managing coronary heart disease risk in patients with Type 2 diabetes Without question, based on the evidence, statins are the drug of choice for the management of CHD risk in patients with Type 2 diabetes mellitus (Table 4). They provide superior reduction in CHD and stroke risk. Recently, in the collaborative atorvastatin in diabetes study (CARDS), treatment of 2838 patients with Type 2 diabetes with atrovastatin 10 mg/day for 3.9 years was shown to reduce CHD death and nonfatal MI by 37% (p = 0.001); acute coronary syndromes by 36%; coronary revascularizations by 31%; strokes by 48% and death from any cause by 27% (p = 0.059) [12]. In a prespecified analysis, treatment of 5963 diabetic patients in the large HPS with simvastatin 40 mg/day for 5 years was associated with a 27% reduction in CHD death and nonfatal myocardial infarction (p = ), 24% reduction in strokes (p = 0.01) and a 17% reduction in revascularization procedures (p = 0.02) [11]. No information is provided on mortality outcomes. Two of four other large statin outcome trials reported a significant reduction in CHD events in diabetic cohorts per post hoc analyses (Table 4). There are far fewer outcome studies in Type 2 diabetes patients evaluating fibrate treatment. In the largest study of its kind in diabetic patients, FIELD failed to demonstrate significant reductions in CHD death and nonfatal MI or in mortality rates, although it did show reductions in nonfatal MI and revascularization procedures (Table 1) [1]. The VA-HIT substudy, in which male diabetic subjects with a prior CHD history and HDL-C lower than 40 mg/dl (l.0 mmol/l), were treated with gemfibrozil 1200 mg/day for 5 years, reported a significant 32% reduction in CHD events (p = 0.004), a 41% reduction in CHD death (p = 0.02) and a 40% reduction in stroke (p = 0.046) (Table 4) [14]. Therefore these results stand in contrast to the FIELD study results. Part of the explanation for this may be the high CHD risk present in the VA-HIT subjects, due mainly to the inclusion of exclusively male subjects with low HDL-C levels and prior CHD. FIELD included approximately 40% women and patients mostly with no prior CHD history (80%) who were selected mostly on the basis of high cholesterol levels. A recent evaluation of pioglitazone mg/day in 5238 patients with Type 2 diabetes (43% of whom were taking a statin) in the PROactive study reported a nonsignificant reduction in the primary composite end point and a weakly significant 16% reduction (p = 0.027) in the composite end point of total mortality, nonfatal MI and stokes (Table 4) [13]. These data support the NCEP ATP III recommendations for managing CHD risk in patients with Type 2 diabetes [19]. Due to their high near term and lifetime risk of CHD events, they were identified as a CHD risk equivalent by 278 Future Lipidol. (2006) 1(3)

6 When it comes to the FIELD study, what is...is PRIORITY PAPER EVALUATION Table 4. Outcome studies in patients with Type 2 diabetes mellitus. Study N Rx T. Chol LDL-C HLD-C TG Placebo CHD event rate (%) Placebo CV event rate (%) CHD risk* reduction Ref. FIELD 9795 F % (p = 0.16) HPS-DM 5963 S % (p <0.0001) CARDS 2838 A % (p = 0.001) PROactive 5238 Pio % (p = 0.027) VA-HIT 769 G NR % (DM) (p = 0.004) ASCOT 2532 A NR -16% (p = 0.43) 4S 483 S NR -42% p = 0.001) CARE 586 P % (p = 0.05) LIPID 1077 P % (p = 0.11) [1] [11] [12] [13] [14] [15] [16] [17] [18] *CHD death, nonfatal MI, CHD death, nonfatal MI, strokes. A: Atorvstatin; ASCOT: Anglo-Scandinavian cardiac outcomes trial; CARDS: Collaborative atorvastatin in diabetes study; CARE: Cholesterol and recurrent events; CHD: Coronary heart disease; Chol: Cholesterol; CV: Cardiovascular; F: Fenofibrate; FIELD: Fenofibrate and event loweing in diabettes; G: Gemfibrozil; HDL-C: High-density lipoprotein cholesterol; HPS-DM: Heart protection study in diabetics; LDL-C: Low-density lipoprotein cholesterol; P: Pravastatin; Pio: Pioglitazone; S: Simvastatin; TG: Triglyceride; VA-HIT: Veterans affairs high-density lipoprotein intervention trial. ATP III, which means that simply being a diabetic patient even without evidence of CHD is alone sufficient to be considered high risk and treated with the same intensity as if they had experienced a coronary event. The treatment goal for these patients is an LDL-C under 100 mg/dl (2.58 mmol/l). However, as HPS has taught us, high risk patients, including those with diabetes, who have an untreated LDL-C under 100 mg/dl benefit from statin therapy [20]. Therefore, NCEP ATP III recommends the option of treating diabetic patients to a LDL cholesterol goal of under 100 mg/dl or if their baseline LDL-C is under 100 mg/dl, lowering the LDL-C by at least 30 40%. Should the diabetic patient also have evidence of atherosclerotic vascular disease, multiple CHD risk factors (especially smoking), or the metabolic syndrome, NCEP recommends that a more aggressive LDL-C goal of under 70 mg/dl may be considered. As supported by the evidence, these goals are best achieved by a statin with sufficient LDL-C lowering efficacy to achieve these treatment goals and, for those already under 100 mg/dl, sufficient efficacy to produce a minimal 30 40% reduction, preferably more. For patients who do not achieve LDL-C goals with statin monotherapy, combination therapy is an option. Thus, the addition of other LDL-C lowering drugs to the statin, such as a bile acid sequestrant, cholesterol absorption inhibitor, or niacin may be considered. For patients who achieve their LDL-C goal but have a triglyceride over 200 mg/dl, the NCEP ATP III recommends that a second goal be established that is defined by non-hdl-c and set 30 mg/dl higher than the LDL-C goal [19]. These patients often have high very low-denisty lipoprotein (VLDL) remnant cholesterol levels, small dense LDL particles, low HDL-C, and high particle concentration/number. Here is where therapy with a fibrate or niacin is preferred. Not only can these products add to the LDL-C lowering of the statin (niacin generally more than fibrates) but they can also help lower non-hdl and remnant cholesterol levels, shift small dense LDL to larger particles, raise HDL-C levels and help reduce particle numbers. Since this is how fibrates are most often indicated for use in the clinical setting, it is also the context in which they should be evaluated in outcome studies. Thus, an improved design for FIELD would have been the 279

7 PRIORITY PAPER EVALUATION McKenney addition of randomly assigned fenofibrate or placebo to ongoing stable statin therapy for all study patients. Furthermore, the study should be conducted only in patients who have an elevated triglyceride level (and optionally also a low HDL-C level). This is really where those who constructed the FIELD study failed. It was not designed to address the clinically relevant question: does the addition of fenofibrate on a background of statin therapy in high-risk diabetic patients with high triglyerides add CHD risk reduction? It really is a shame to have spent so much time and money conducting such a flawed study. Fortunately, a study is underway in the USA and Canada to help address this critical clinical question. The action to control cardiovascular risk in diabetes (ACCORD) study, sponsored by the US National Heart, Lung and Blood Institute, intends to enroll 10,000 patients with Type 2 diabetes and hypertension or dyslipidemia who will be followed for years. Patients who have elevated LDL-C and triglycerides and a low HDL-C will receive a less intense treatment with simvastatin 20 mg/day versus a more intense treatment with simvastatin 20 mg/day plus a fibrate. The primary end point will be nonfatal MI, nonfatal stroke and CV death. The study is scheduled to be completed by Until the results of ACCORD are available, only weak evidence-based justification exists to begin or continue fenofibrate therapy for CHD risk reduction. Fenofibrate is still useful as a triglyceride lowering treatment for patients with very high triglyceride levels (> 500 mg/dl or 12.9 mmol/l). Gemfibrozil has stronger support from randomized clinical outcome trials, but presents a significant drug interaction problem in combination with a statin. Niacin also has stronger support mainly from the CDP [7], which demonstrated CHD risk reduction in the 5-year trial and a mortality reduction 10 years after the trial was ended. Unfortunately for fenofibrate and the FIELD study, this is what is, at least for the moment. Disclosure James M McKenney, Pharm.D. is a member of the Speakers Bureau for AstraZeneca, KOS Pharmaceuticals, Merck & Co., Pfizer Inc., Reliant Pharmaceuticals, Schering-Plough and Takeda; serves as a consultant to AstraZeneca, KOS Pharmaceuticals, Microbia, Pfizer Inc., and Sankyo Pharma; and has received research grant support from AstraZeneca, GlaxoSmithKline, KOS Pharmaceuticals, Merck & Co., Reliant Pharmaceuticals, F. Hoffmann-La Roche Pharmaceuticals, Pfizer Inc., Schering-Plough and Takeda. Bibliography 1. The FIELD 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 366, (2005). 2. Diabetes Atherosclerosis Intervention Study Investigators: Effect of fenofibrate on progression on coronary-artery disease in Type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 357, (2001). 3. Frick MH, Elo O, Haapa K et al.: Helsinki Heart Study: Primary-prevention trial with gemfibrozil in middle-age men with dyslipidemia. Safety of treatment, s in risk factors, and incidence of coronary heart disease. N. Engl. J. Med. 317, (1987). 4. Rubins HB, Sander JR, Collins D et al. for the Veteran Affairs High Density Lipoprotein Cholesterol Intervention Trial Study Group: Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N. Engl. J. Med. 341, (1999). 5. The BIP study group: Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. The Bezafibrate Infarction Prevention (BIP) Study. Circulation 102, (2000). 6. Report from the Committee of Principal Investigators: A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Br. Heart J. 40, (1978). 7. The Coronary Drug Project Research Group: Clofibrate and niacin in coronary heart disease. JAMA 231, (1975). 8. Manninen V, Tenkanen L, Koskinen P et al.: Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment. Circulation 85, (1992). 9. Robins SJ, Collins D, Wittes JT et al. for the VA-HIT Study Group: Relation of gemfibrozil treatment and lipid levels with major coronary events. VA-HIT: a randomized controlled trial. JAMA 285, (2001). 10. Studer M, Briel M, Leimenstoll B, Glass TR, Bucher HC: Effects of different antilipidemic agents and diets on mortality. A systematic review. Arch. Intern. Med. 165, (2005). 11. Heart Protection Study Collaborative Group: MRC/BHF heart protection study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet 361, (2003). 12. Colhoun HM, Betteridge DJ, Durrington PN et al. on behalf of the CARDS investigators: Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 364, (2004). 13. Dormandy JA, Charbonnel B, Eckland DJA et al. on behalf of the PROactive investigators: Secondary prevention of macrovascular events in patients with Type 2 diabetes in the PROactive Study (PROspective pioglitazone Clinical Trial in macrovascular Events): a randomised controlled trial. Lancet 366, (2005). 14. Rubins HB, Robins SJ, Collins D et al. for the VA-HIT Study Group: Diabetes, plasma insulin, and cardiovascular disease. Subgroup analysis from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT). Arch. Intern. Med. 162, (2002). 280 Future Lipidol. (2006) 1(3)

8 When it comes to the FIELD study, what is...is PRIORITY PAPER EVALUATION 15. Sever PS, Dahlof B, Poulter NR et al. for the ASCOT investigators: Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid lowering arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 361, (2003). 16. Haffner SM, Alexander CM, Cook TJ et al. for the Scandinavian Simvastatin Study Group: Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels. Subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch. Intern. Med. 159, (1999). 17. Keech A, Colquhoun D, Best J et al.: For the LIPID study group: Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose. Diabetes Care 26, (2003). 18. Goldberg RB, Mellies MJ, Sacks FM et al. for the CARE investigators: Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels. Subgroup analyses in the cholesterol and recurrent events (CARE) trial. Circulation 98, (1998). 19. Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III): Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106, (2002). 20. Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet 360, 7 22 (2002). Affiliation James M McKenney Virginia Commonwealth University, National Clinical Research, 2809 Emerywood Parkway, Suite 140, Richmond, VA 23294, USA Tel.: ; Fax: ; jmckenney@ncrinc.net 281