Atorvastatin and Micronized Fenofibrate Alone and In

Emerging Treatment and Technologies ORIGINAL ARTICLE

Atorvastatin and Micronized Fenoﬁbrate Alone and in Combination in Type 2 Diabetes With Combined Hyperlipidemia

1 3 VASILIOS G. ATHYROS, MD DIMOKRITOS S. DEMITRIADIS, MD ombined hyperlipidemia (CHL), a 2 ATHANASIOS A. PAPAGEORGIOU, MD ATHANASIOS G. KONTOPOULOS, MD, FACC, highly atherogenic lipid disorder 1 3 VALASIA V. ATHYROU, BSC FESC C characterized by increased LDL cholesterol, elevated triglycerides (TGs), and low HDL cholesterol, is not rare in patients with type 2 diabetes (1). Moreover, metabolic abnormalities, such as predom- OBJECTIVE — This study evaluated the effect of a atorvastatin-fenofibrate combination on inance of small dense LDL particles (2) lipid profile, in comparison to each drug alone, in patients with type 2 diabetes and combined hyperlipidemia (CHL). and increased glycation of LDL (3), raise the atherogenic risk in these patients. Gly- RESEARCH DESIGN AND METHODS — A total of 120 consecutive patients, who cemic control appears to improve but not were free of coronary artery disease (CAD) at entry, were studied for a period of 24 weeks. These normalize these abnormalities (4). Statins patients were randomly assigned to atorvastatin (20 mg/day, n ϭ 40), micronized fenofibrate or fibrates can be used in this setting. St- (200 mg/day, n ϭ 40), or a combination of both (atorvastatin 20 mg/day plus fenofibrate 200 atins have been shown to reduce athero- mg/day, n ϭ 40). The effect of treatment on LDL cholesterol, triglycerides (TGs), HDL choles- sclerosis-related morbidity and mortality terol, apolipoprotein A-I and B, lipoprotein(a), and plasma fibrinogen (PF) was recorded. More- in patients with diabetes (5,6). On the over, the percentage of patients that reached the American Diabetes Association treatment goals and the estimated CAD risk status were calculated. other hand, fibrates are drugs that can de- crease TG concentrations and elevate RESULTS — No patient was withdrawn from the study because of side effects. The atorva- HDL cholesterol, thus reducing cardio- statin-fenofibrate combination reduced total cholesterol by 37%, LDL cholesterol by 46%, TGs vascular morbidity and mortality (7,8). by 50%, and PF by 20%, whereas it increased HDL cholesterol by 22% (P Ͻ 0.0001 for all). Recent studies (9,10) showed that statin These changes were significantly better than those of both monotherapies. Of the patients on or fibrate monotherapies can improve the drug combination, 97.5% reached the LDL cholesterol treatment goal of Ͻ100 mg/dl, 100% lipid profile in patients with type 2 diabe- reached the desirable TG levels of Ͻ200 mg/dl, and 60% reached the optimal HDL cholesterol Ͼ tes and CHL; however, these affect differ- levels of 45 mg/dl. These rates were significantly higher than those of both monotherapies. ent aspects of lipoprotein (LP) Combined treatment reduced the 10-year probability for myocardial infarction from 21.6 to 4.2%. metabolism. Hence, it is difficult to mod- ify the lipid profile of patients with type 2 CONCLUSIONS — The atorvastatin-fenofibrate combination has a highly beneficial effect diabetes and CHL using monotherapy on all lipid parameters and PF in patients with type 2 diabetes and CHL. It improved patients’ with either a statin or a fibrate, according CAD risk status significantly more than each drug alone. to the recent suggestions of the American Diabetes Association (ADA) (11). Diabetes Care 25:1198–1202, 2002 An effective therapeutic approach of CHL in nondiabetic patients is a statin- fibrate combination (12–19). This regimen has not been widely adopted because of the concern about side effects, mainly ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● myopathy, reported with the lovastatin- gemfibrozil combination (20). This has From the 1Lipid Out-patient Clinic, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece; the 2Second Propedeutic Department of Internal Medicine, Aristotelian University, Hippocration Hospital not been confirmed by studies using other Thessaloniki, Greece; and the 3Division of Cardiology, Aristotelian University, Hippocration Hospital, Thes- statin-fibrate combinations (12–19). The saloniki, Greece. recently reported problems with cerivas- Address correspondence and reprint requests to Vasilios G. Athyros, MD, 15 Marmara St., Thessaloniki, tatin, when combined with gemfibrozil, 551 32, Greece. E-mail: [email protected]. Received for publication 10 November 2001 and accepted in revised form 2 March 2002. seem to be related mainly to the toxicity of Abbreviations: ADA, American Diabetes Association; apo, apolipoprotein; BIP, Bezafibrate Infarction cerivastatin, because most deaths due to Prevention; CAD, coronary artery disease; CARDS, Collaborative Atorvastatin Diabetes Study; CHL, com- myopathy-rhabdomyolysis reported in bined hyperlipidemia; CK, creatine kinase; Lp, lipoprotein; FIELD, Fenofibrate Intervention and Event the U.S. were associated with mono- Lowering in Diabetes; PF, plasma fibrinogen; 4S, Scandinavian Simvastatin Survival Study; TC, total cholesterol; TG, triglyceride; VA-HIT, Veterans Affairs High-Density Lipoprotein Intervention Trial. therapy rather than with combination A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion therapy. factors for many substances. The present open-label prospective

1198 DIABETES CARE, VOLUME 25, NUMBER 7, JULY 2002 Athyros and Associates

Table 1—Demographic characteristics and baseline values of measured parameters of the Statistics patients with type 2 diabetes and combined hyperlipidemia in the three treatment groups Results are reported as the means Ϯ SD. ANOVA, with 95% CIs, was used to com- Atorvastatin Fenofibrate Combination pare values within and between the treat- group group group ment groups. Differences were considered to be significant at P Ͻ 0.05. Mean per- n 40 40 40 cent changes of the LP and apo values Sex (M/F) 23/17 22/18 23/17 were also calculated. For all forms of sta- Age (years) 57 (44–67) 58 (48–69) 58 (50–68) tistical analysis, SPSS version 8.0 (SPSS, Hypoglycemic treatment (oral/insulin) 16/24 18/22 17/23 Chicago, IL) was used. Ϯ Ϯ Ϯ HbA1c (%) 8.1 0.2 8.0 0.3 8.1 0.2 Duration of diabetes (years) 8.6 Ϯ 1.6 8.9 Ϯ 1.8 8.5 Ϯ 1.6 RESULTS — All 120 patients con- Data are n, median (range), or means Ϯ 1 SD. cluded the study: 68 men and 52 women, with an age range of 44–69 years (median 58). At baseline, there were no significant randomized parallel study was under- combination of both (atorvastatin 20 mg/ differences in the demographic character- taken to investigate the hypothesis that day plus micronized fenofibrate 200 mg/ istics of the three treatment groups (Table combination therapy with atorvastatin day, n ϭ 40). Lipid profile assessment as 1). and micronized fenofibrate will be more well as physical and laboratory investiga- effective than each drug alone in tackling tion for drug-induced adverse effects Adverse effects multiple lipid coronary artery disease were performed every month. Hypogly- No significant adverse events were re- (CAD) risk factors in patients with type 2 cemic or other concurrent treatments recorded. There was a nonsignificant in- diabetes and CHL. mained unchanged throughout the study. crease in serum transaminase values in patients on combination treatment. These RESEARCH DESIGN AND remained under the threefold level of the METHODS — The study included Assessments upper normal limit. No patient presented 120 consecutive patients with type 2 dia- After an overnight fast, TC, TG, and uric myalgia or creatine kinase (CK) levels Ͼ betes and CHL, who were free of CAD at acid were assessed by an Olympus AU 10-fold from pretreatment values. CK baseline, with fairly adequate glycemic 560 autoanalyzer, using respective re- was increased with combination therapy control. The inclusion criteria were no agents (Olympus Diagnostica, Clare, Ire- at a higher level than with both mono- previous hypolipidemic treatment, HbA1c therapies, but it remained within the nor- Ͻ land). LDL cholesterol was calculated by 8.5%, and laboratory findings of CHL. the Friedewald formula (in mg/dl) [LDL mal range. No patient was withdrawn CHL was defined as total cholesterol (TC) cholesterol ϭ TC Ϫ (TG/5 ϩ HDL cho- from the study because of side effects. Ͼ220 mg/dl (5.7 mmol/l), LDL choles- Ͼ lesterol)]. Apo B and A-I values were as- terol 130 mg/dl (3.4 mmol/l), TG from sessed by the immunoprecipitin method Glycemic control and lipid 200 mg/dl (2.3 mmol/l) to 399 mg/dl (4.5 parameters with the Technicon RA-1000 autoana- mmol/l), HDL cholesterol Ͻ40 mg/dl HbA remained unchanged throughout lyzer (Technicon-Swords, Dublin, Ire- 1c (1.04 mmol/l), and apolipoprotein (apo) the study in all groups. Combined treat- land), using the apo B and apo A-I B Ͼ150 mg/dl. Patients were on the Na- ment had a beneficial effect on all lipid reagents, respectively (Incstar, Stillwater, tional Cholesterol Expert Panel step 2 hy- parameters. It reduced TC and LDL cho- polipidemic diet for 6 weeks, during MN). Lp(a) levels were measured using a lesterol significantly more than atorvasta- which time they received a placebo tablet monoclonal anti–Lp(a) antibody tech- tin, whereas it had a better effect on TG daily. After that, if they still met the inclu- nique and enzyme-linked immunoassay and HDL cholesterol than micronized fe- sion criteria, they continued participating (Terumo Medical, Elkron, MD). Plasma nofibrate (Table 2). Lp(a) levels were not in the study. Fertile women were ex- fibrinogen (PF) was assessed with the affected by all three regimens. cluded. In all patients, normal liver and Clauss method, using the fibrin titer test renal function was established. The study Fibrindex (Ortho Diagnostic, Raritan, PF and uric acid protocol received ethical approval, and NJ). Atorvastatin had a neutral effect on PF informed consent was obtained by all par- levels. Fenofibrate and drug combination ticipants before enrolment. reduced PF significantly (21 and 20%, re- Estimated risk for myocardial spectively; P Ͻ 0.001 vs. baseline and P Ͻ Study design infarction 0.01 vs. atorvastatin) (Table 2). Uric acid Patients were randomized into three The risk for myocardial infarction within was reduced by atorvastatin and drug groups, using the Random Number Gen- the next 10 years, using the PROCAM risk combination (Table 2). eration, Discrete Uniform, Stat Graphics calculator suitable for men and post- version 4.0 (Statistical Graphics, Prince- menopausal women (21 and online at Treatment goals ton, NJ) method, and they were assigned http://www.chd-taskforce.de/), was cal- According to the ADA recommendations to active treatment for 24 weeks with ator- culated in all patients at baseline and dur- (11), the goal for LDL cholesterol of Ͻ100 vastatin (20 mg/day, n ϭ 40), micronized ing monotherapy or combination mg/dl (2.4 mmol/l), the desirable TG lev- fenofibrate (200 mg/day, n ϭ 40), or a treatment. els of Ͻ200 mg/dl (2.6 mmol/l), and the

DIABETES CARE, VOLUME 25, NUMBER 7, JULY 2002 1199 Atorvastatin plus fenoﬁbrate in type 2 diabetes

Table 2—Baseline values of measured parameters of the patients with type 2 diabetes and combined hyperlipidemia in the three treatment groups and effect of treatment

Atorvastatin Group Fenofibrate Group Combination Group Baseline Treatment Effect Baseline Treatment Effect Baseline Treatment Effect TC 252 Ϯ 17 174 Ϯ 10* Ϫ31 253 Ϯ 17 213 Ϯ 14* Ϫ16 255 Ϯ 19 159 Ϯ 7*† Ϫ37 TGs 278 Ϯ 24 195 Ϯ 22* Ϫ30 281 Ϯ 24 167 Ϯ 15* Ϫ41 278 Ϯ 23 139 Ϯ 12*† Ϫ50 LDL cholesterol 161 Ϯ 15 97 Ϯ 7* Ϫ40 163 Ϯ 15 140 Ϯ 15* Ϫ15 163 Ϯ 16 89 Ϯ 6*† Ϫ46 HDL cholesterol 34.6 Ϯ 3.2 37.7 Ϯ 4.5* 9 34.8 Ϯ 3.4 40.3 Ϯ 4.38 16 35.1 Ϯ 3.5 43 Ϯ 4.3*‡ 22 Apo A-I 124 Ϯ 10 127 Ϯ 9 3 124 Ϯ 10 132 Ϯ 11* 6 124 Ϯ 9 138 Ϯ 9*† 12 Apo B-100 169 Ϯ 18 117 Ϯ 11* Ϫ31 172 Ϯ 22 135 Ϯ 17* Ϫ14 170 Ϯ 18 101 Ϯ 19*† Ϫ41 Lp(a) 18.4 Ϯ 3.7 18.8 Ϯ 4.3 2 20.1 Ϯ 5.2 19.5 Ϯ 4.7 Ϫ4 19.2 Ϯ 4.1 19.4 Ϯ 4.4 1 Fibrinogen 379 Ϯ 30 369 Ϯ 34 Ϫ3 382 Ϯ 25 302 Ϯ 21* Ϫ21 380 Ϯ 30 306 Ϯ 25*‡ Ϫ19 Data are means Ϯ 1 SD (in mg/dl) or %. *P Ͻ 0.0001 vs. baseline; ‡P Ͻ 0.05 vs. atorvastatin; †P Ͻ 0.05 vs. both monotherapies. To convert data from mg/dl to mmol/l, divide TC and LDL and HDL cholesterol values by 38.7 and TGs by 88.6. optimal HDL cholesterol levels of Ͼ45 in this group of patients with type 2 dia- tion in coronary mortality (42%) was in- mg/dl (1.2 mmol/l) was reached with betes and CHL. However, both mono- duced by a 35% reduction in LDL combination therapy by significantly therapies were not able to induce the cholesterol by simvastatin, in comparison more patients than with both monothera- maximum global change in patients’ CAD to placebo, in the 4S (22). In this study, pies, with atorvastatin being the second risk profile. Conversely, combined ther- patients with diabetes in the original re- best in reaching the LDL cholesterol goal apy had a concurrent beneficial effect on port (n ϭ 202 with the old ADA criteria) and fenofibrate in reaching TG and HDL all lipid parameters, changing the CAD were benefited more (55% reduction in cholesterol targets (Table 3). risk status of these patients from high to coronary mortality) than nondiabetic pa- low. Until now, the effects of statins and tients (5). Even with the new (1997) ADA Estimated risk for myocardial fibrates in patients with type 2 diabetes diagnostic criteria, the benefit was greater infarction and CHL were compared in a competitive in patients with diabetes (n ϭ 483) or im- The probability of having a myocardial manner. Results of this paper suggest that paired glucose tolerance (n ϭ 678) than infarction within the next 10 years in all the combination treatment seems to be in nondiabetic patients (23). The LDL patients at baseline was calculated at the optimal therapeutic approach. cholesterol reduction seen in the present 21.6%. With atorvastatin this was re- The landmark survival trials with stat- study, by combined therapy and atorva- duced to 7.5% (P Ͻ 0.0001 vs. baseline, ins (the Scandinavian Simvastatin Sur- statin, were greater than in the 4S. Hope- P Ͻ 0.05 vs. fenofibrate), and with feno- vival Study [4S], Cholesterol and fully, this will translate into analogous fibrate it was reduced to 10.9% (P Ͻ Recurrent Events [CARE] study, and clinical benefit. 0.0001 vs. baseline), whereas with com- Long-Term Intervention with Pravastatin The two hypolipidemic drugs used in bination therapy it was reduced to 4.2% in Ischemic Heart Disease [LIPID] trial for the present study have complementary (P Ͻ 0.05 vs. both monotherapies and secondary as well as the West of Scotland modes of action. Atorvastatin is a potent P Ͻ 0.0001 vs. baseline) (Table 3). Coronary Prevention Study [WOSCOPS] inhibitor of hydroxymethylglutaryl-CoA for primary CAD prevention) showed that reductase, which decreases LDL choles- CONCLUSIONS — Both atorvastatin considerable reduction in LDL cholesterol in plasma by upregulating LDL re- and fenofibrate significantly improved terol levels induces clear clinical benefit ceptor activity (24). It has been shown the lipid profile, each in different aspects, for high-risk patients. The biggest reduc- that atorvastatin significantly reduced cir- culating levels of all major LDL subspe- Table 3—Percentage of patients reaching lipid targets set by the ADA and percent probability cies: light, intermediate, and dense (25); for myocardial infarction within the next 10 years as estimated with the PROCAM CAD however, in terms of absolute LP mass, calculator (21) the reduction in small dense LDL particles and atherogenic LDL particles, character- istic of CHL, was predominant (26). Ator- Micronized Combination vastatin also reduces the secretion of apo Baseline Atorvastatin fenofibrate therapy B–containing LPs. This is believed to ac- n 120 40 40 40 count for its TG-lowering effect (27), ADA LDL cholesterol goal 0 80*† 5* 97.5*‡ which is more profound at higher doses TG desirable levels 0 75* 92.5*§ 100*‡ (28,29). Effects on apo E, C-II, and C-III HDL cholesterol optimal levels 0 17.5* 30*§ 60*‡ and a dose-dependent reduction in cho- 10-year probability for 21.6 7.5*† 10.9* 4.2*‡ lesteryl ester transfer protein activity by myocardial infarction atorvastatin have also been suggested Data are %. *P Ͻ 0.0001 vs. baseline; †P Ͻ 0.05 vs. fenofibrate; ‡P Ͻ 0.05 vs. both monotherapies; §P Ͻ (26). Fenofibrate activates peroxisome 0.05 vs. atorvastatin. proliferator–activated receptors (30),

1200 DIABETES CARE, VOLUME 25, NUMBER 7, JULY 2002 Athyros and Associates which induce an increase in LP lipase ac- induced an increase of HDL cholesterol in early stages, and it will take them a few tivity, a reduction in apo C-III, an increase and a reduction in TG levels significantly years to provide evidence on which to in apo A-I, as well as a reduction in cho- higher than that of the VA-HIT and the base medical treatment of diabetic dyslip- lesterol ester transfer protein activity (31). BIP trial. Hopefully, they will translate idemia. In the meantime, there is an ur- These result in TG level reduction, redis- into analogous clinical benefit. gent necessity to have an effective drug tribution of LDL particle size, and an HDL PF, an independent predictor of myo- regimen at hand for patients with type 2 cholesterol increase. The significant re- cardial infarction in both sexes (33), re- diabetes and CHL. Data from the present duction of apo B, with “low or normal” mained unaffected by atorvastatin and study suggest that the atorvastatin- LDL cholesterol, seen in this study with was significantly reduced by fenofibrate fenofibrate combination may serve this atorvastatin, fenofibrate, and mainly with and drug combination. Whether atorva- purpose. their combination is indicative of a bene- statin affects fibrinogen concentrations ficial increase in LDL particle size (15). has been a matter of debate. The overall Study limitations Statins should be the basis of treat- impression is that atorvastatin does not The study was placebo controlled only in ment in diabetic dyslipidemia because affect fibrinogen concentration if a con- regard to baseline assessments, but not they exhibit an excellent effect in reduc- trolled study design is used (34–36). during the active treatment period being high LDL cholesterol, the main en- Atorvastatin did not have any adverse ef- cause of ethical issues, and it was not dou- emy, but they also display their pleotropic fect on Lp(a) levels. This is consistent with ble blind for practical reasons. The study effects, which are valuable in high-risk the findings of a recent study (34). The was underpowered to prove the safety of patients. It has been shown that the beneficial effect of atorvastatin on uric the atorvastatin-fenofibrate combination. higher doses of statins may be moderately acid levels has recently been reported (37). effective at reducing TG levels (although The literature on statin-fibrate combi- Summary not necessarily at raising HDL levels) and nations in patients with type 2 diabetes The atorvastatin-fenofibrate combination thus may reduce the need for combina- and CHL is limited. Until now, only two is a very effective therapeutic approach of tion therapy (11). Nonetheless, with the studies addressing this issue have been patients with type 2 diabetes and CHL. It use of high doses of statins, the LDL levels published. One study (38) combining has a clear beneficial effect on all lipid may be reduced to Ͻ80 mg/dl, and there simvastatin (20 mg/day) and bezafibrate parameters and PF concentrations. These is no safety data at such low LDL levels (400 mg/day) had moderate results in properties reduce CAD risk, expand the (11). Besides, statin-fibrate combinations terms of TC (Ϫ23%) and LDL cholesterol spectrum of therapeutic choices, and en- seem superior than high dosages of statins (Ϫ29%) reduction, although drug combi- hance the individualization of hypolipi- because they normalize all aspects of the nation significantly reduced TG levels by demic treatment in patients with type 2 lipid profile and further improve CAD 42% and increased HDL cholesterol by diabetes. risk status. The fibrate induced addi- 25%. Of the 148 patients from this study, tional, but moderate, LDL cholesterol re- 2 presented myopathy. An older study duction, especially by fenofibrate (17), (39) compared gemfibrozil alone versus References and the substantial reduction in TG lev- placebo and, in a second phase, versus the 1. Farnier M, Picard S: Diabetes: statins, fibrates, or both? Curr Atheroscler Rep els, the shift to a less-dense and thus less- combination of gemfibrozil plus lova- 3:19–28, 2001 atherogenic LDL particle profile, as well statin in 16 patients with type 2 diabetes. 2. Packard C, Caslake M, Shepherd J: The as the significant increase in HDL choles- Most of the patients (10) presented TG role of small, dense low density lipopro- terol levels (32) substantially improve the levels Ͼ500 mg/dl, despite good glycemic tein (LDL): a new look. Int J Cardiol 74 efficacy of combination treatment. The control. Differences in study populations (Suppl. 1):17S–22S, 2000 Veterans Affairs High-Density Lipopro- do not permit comparison of our out- 3. Bucala R, Makita Z, Vega G, Grundy S, tein Intervention Trial (VA-HIT) (8) comes with those of the latter study. Our Koschinsky T, Cerami A, Vlassara H: showed that treatment with gemfibrozil findings are consistent with those of an- Modification of low density lipoprotein resulted in a significant elevation in HDL other study (17) combining atorvastatin by advanced glycation end products con- cholesterol and a reduction in TGs in pa- with fenofibrate in nondiabetic patients tributes to the dyslipidemia of diabetes and renal insufficiency. Proc Natl Acad Sci tients with borderline TG at entry, with with severe CHL. USA91:9441–9445, 1994 no change in LDL cholesterol, that coin- There are two ongoing trials on dia- 4. Stern MP, Mitchell BD, Haffner SM, Ha- cided with a significant reduction in the betic dyslipidemia: Fenofibrate Interven- zuda HP: Does glycemic control of type-2 CAD event rate (22%). On the other tion and Event Lowering in Diabetes diabetes suffice to control diabetic dyslip- hand, in a subgroup of patients (n ϭ 459) (FIELD), with micronized fenofibrate, idemia? A community perspective. Diabe- of the Bezafibrate Infarction Prevention and the Collaborative Atorvastatin Diabe- tes Care 15:638–644, 1992 (BIP) trial (7) with elevated baseline TG tes Study (CARDS), with atorvastatin. The 5. Pyo¨ra¨la¨ K, Pedersen TR, Kjekshus J, levels (Ͼ200 mg/dl), treatment with Lipids in Diabetes Study (LDS), with mi- Faergeman O, Olsson AG, Thorgeirsson bezafibrate induced a significant reduc- cronized fenofibrate and cerivastatin G: Cholesterol lowering with simvastatin tion in the primary study end points alone or in combination, was prematurely improves prognosis of diabetic patients with coronary heart disease: a subgroup (40%), which were related to significant terminated because of the withdrawal of analysis of the Scandinavian Simvastatin reductions in TG and increases in HDL cerivastatin. The FIELD and CARDS trials Survival Study (4S). 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