Influences of Statins on Glucose Tolerance in Patients with Type 2 Diabetes Mellitus

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1 Original Article 95 Influences of Statins on Glucose Tolerance in Patients with Type 2 Diabetes Mellitus Tatsuro Takano, Tadashi Yamakawa, Mayumi Takahashi, Mari Kimura, and Atsushi Okamura Department of Endocrinology and Diabetes Mellitus, Yokohama City University Medical Center, Yokohama, Japan. Drs Takano and Yamakawa contributed equally to this study Atorvastatin is frequently administered for the treatment of hypercholesterolemia associated with type 2 diabetes mellitus. However, a marked deterioration of glycemic control has been reported in some patients treated with atorvastatin. No study has been done to determine whether atorvastatin adversely affects glycemic control. In this study, we retrospectively compared an atorvastatin-treated group (Group A, n 76) with a -treated group (Group P, n 78) to examine the effects of the 2 statins on glycemic control from the onset of administration to 3 months thereafter. No change occurred in the antidiabetic drug dose in 62 patients of Group A and 68 patients of Group P. In those patients, arbitrary blood glucose levels increased from (mean SD) mg/dl to mg/ dl in Group A and from mg/dl to mg/dl in Group P. HbA1c increased from % to % in Group A and from % to % in Group P. The increase was significant only in Group A, and the extent of the increase was also significantly greater in Group A. These results suggest a predisposition to a deterioration of glycemic control in type 2 diabetic patients treated with atorvastatin. J Atheroscler Thromb, 2006; 13: Key words; Type 2 diabetes mellitus, Hyperlipidemia, Atorvastatin, Pravastatin, Glycemic control Introduction Address for correspondence: Tadashi Yamakawa, Department of Endocrinology and Diabetes, Yokohama City University Medical Center, 4-57 Urafunecho, Minami-ku, Yokohama , Japan. yamakat@urahp.yokohama-cu.ac.jp Received: June 23, 2005 Accepted for publication: January 10, 2006 Concern for the development of arteriosclerosis in type 2 diabetic patients requires clinicians to consider prevention of ischemic heart disease and cerebrovascular accidents. It also requires sufficient attention to complications from hyperlipidemia in this patient group. Patients with type 2 diabetes mellitus need life style changes, diet therapy, kinesitherapy and so on, but many require the administration of drugs as well. HMG-CoA reductase inhibitors are often selectively administered for the treatment of hypercholesterolemia associated with type 2 diabetes mellitus. The subanalysis of 4S 1), CARE 2), LIPID 3), and HPS 4) have provided evidence that the administration of or simvastatin inhibits the development of coronary disease, reduces mortality from heart disease, and reduces overall mortality in patients with type 2 diabetes mellitus. More recently, revisions to guidelines have established a new goal, a lower level of low-density lipoprotein (LDL) cholesterol than was previously considered necessary, to reduce the risk of developing cardiovascular disease. However, we frequently encounter patients for whom treatment with conventional drugs at accepted levels is insufficient to achieve the new goal. Atorvastatin, a liposoluble HMG-CoA reductase inhibitor, has a potent LDL-cholesterol-lowering effect and is frequently administered for the treatment of hypercholesterolemia associated with type 2 diabetes mellitus. In CARDS 5), a recently reported study, atorvastatin was shown to inhibit the development of cardiovascular events in diabetic patients. However in Japan, diabetic patients who showed a marked deterioration of glycemic control after the onset of atorvastatin administration have been reported, though no definitive study has been done to assess whether or

2 96 not the administration of atorvastatin adversely affects glycemic control. Since glycemic control is greatly influenced by lifestyle, the effects of atorvastatin on blood glucose might have been overlooked. To examine the effects of two statins, atorvastatin and, on blood glucose, we compared a group of 76 patients who received atorvastatin (Group A) with another group of 78 patients who recieved (Group P) with respect to changes in glycemic control from the onset of administration to 3 months thereafter. Subjects and Methods Patients with type 2 diabetes mellitus complicated by hyperlipidemia receiving a HMG-CoA reductase inhibitor at the Citizen s General Medical Center, Yokohama City University, School of Medicine were enrolled in this study. The patients in this study were those: who had received atorvastatin 10 mg from January 2000 to July 2003 and who had received 10 mg from April 2000 to July The decision to administer either atorvastatin or was made by the physician in charge; the drug considered more appropriate at that point was selected for each individual patient. Furthermore, patients whose HbA1c had changed more than 10% within the past 3 months were excluded. As shown in Fig. 1, HbA1c levels at baseline and 3 months before the initiation of the study were not significantly different between Group A and Group P. The patients were first examined to determine whether or not they required an increase or reduction in the dose of their antidiabetic drugs (insulin injections and oral hypoglycemic agents) for the first 3 months after the onset of the administration of atorvastatin or. Patients who required no change in drug dose during this observation period were examined and compared retrospectively with respect to time-course changes in arbitrary blood glucose level and in laboratory values, e.g., HbA1c, from the onset of the administration of atorvastatin or to 3 months thereafter. Subsequently, the number of subjects who were statistically analyzed in this study was 76 (34 males and 42 females, mean age 60.9 years) in Group A and 78 (34 males and 44 females, mean age 65.7 years) in Group P. The baseline characteristics of these patients are listed in Table 1. Although no significant difference was found between the two groups in age or body weight, a shift from other drugs occurred more frequently in Group A. Patients who were excluded from the study were those: who had dose changes in A glucose (mg/dl) B HbA1c (%) atorvastatin 0 atorvastatin 3M 0 their antidiabetic drugs, had their drug therapy modified within 3 months prior to the onset of the administration of atorvastatin or, underwent a first medical examination in our department and attended the diabetes education program for the first time, or were considered to have glycemic control affected by hospitalization or treatment. Furthermore, patients who had events that affected glycemic control, e.g., hospitalization and simultaneous development of other disorders during the 3-month observation period, were also excluded. In addition, medications known to influence glucose tolerance or lipid metabolism were neither added nor withdrawn during the 3M 3M Fig. 1. Changes in fasting plasma glucose (FPG) before and after treatment and HbA1c at 3 months before, baseline, and 3 months after initiation of the study. (A) FPG, (B) HbA1c. Values are the mean SD. Open bars represent the data before treatment and closed bars represent the data after treatment. P 0.001, P 0.01

3 97 Table 1. Baseline characteristics Gender Males Females Mean age Body Weight (kg) Prior treatment Drug naive others Treatment for Diabetes Diet only OHA insulin Other drugs ARB ACEi Calcium antagonist atrovastatin (n 76) study. Values are expressed as the mean SD, and the paired t-test and repeated measures ANOVA were used for statistical analyses. Results (n 78) P 0.01 ARB, angiotensin receptor blocker; ACEi, angiotensin-converting enzyme inhibitor. Variables are expressed as the number of patients, or mean SD. Increases or reductions in the antidiabetic drug dose for 3 months after the onset of the administration are shown in Table 2. During the 3-month observation period, in Group A, 11 patients required a dose increase, 1 patient required a dose reduction, and 2 patients required other modifications (patients for whom a dose reduction in insulin injection due to the addition of -GI made it difficult to assess a dose change). In Group P, 8 patients required a dose increase, 1 patient required a dose reduction, and 1 patient required other modifications. No significant difference was found between the groups of patients who required dose changes. Other medications which could possibly affect glucose metabolism, such as antihypertensive drugs, were not significantly different between the two groups (Table 1). No change occurred in the antidiabetic drug dose in 62 patients of Group A and 68 patients of Group P. In those patients, arbitrary blood glucose levels increased from mg/dl to mg/dl in Group A (P 0.001) and from mg/dl to Table 2. Changes in Doses of antidiabetic drugs during the study Antidiabetic drug increase No change reduction others Atorvastatin (n 60) Pravastatin (n 64) mg/dl in Group P. HbA1c increased from % to % in Group A (P 0.001) and from % to % in Group P (Fig.1). Only Group A showed significant increases in these variables. The extent of the increase was also significantly greater in Group A compared to Group P (P 0.01). Changes in plasma lipid and lipoprotein concentrations before and 3 months after the onset of the administration are shown in Table 3. Total cholesterol levels decreased from mg/dl to mg/ dl in Group A and from mg/dl to mg/dl in Group P. LDL-cholesterol levels also decreased, from mg/dl to mg/dl in Group A and from mg/dl to mg/ dl in Group P. All groups showed significant decreases (P ); however, the improvement in all the variables was greater in Group A than in Group P. Triglyceride levels decreased from mg/dl to mg/dl in Group A and from mg/ dl to mg/dl in Group P. HDL-cholesterol levels increased from mg/dl to mg/dl in Group A and from mg/dl to mg/ dl in Group P. No significant difference was found between the two groups. Furthermore, body weight increased from kg to kg in Group A and from kg to kg in Group P; there was no significant difference in body weight changes between the two groups. Total cholesterol and TG concentrations were higher in Group A, which possibly affected the blood glucose levels. Thus, we divided Group A into those patients whose total cholesterol or TG levels were the same as in Group P and those whose total cholesterol or TG levels were higher than in Group P. HbA1c values of the patients with higher total cholesterol levels increased significantly from % to % while those of the patients with the same total cholesterol levels increased significantly from % to %; there was no significant difference in the rate of increase between those groups. TG levels of the patients with higher TG concentrations increased sig-

4 98 Table 3. Changes in Plasma lipid and Lipoprotein Concentrations atorvastatin before after before after TC (mmol/l) TG (mmol/l) LDL-C (mmol/l) HDL-C (mmol/l) P nificantly from % to % and those with the same TG values also significantly increased from % to %. As described above, HbA increased in Group A regardless of the change in the total cholesterol or TG level. Discussion We examined the time course of changes in glycemic control for 3 months from the onset of the administration of atorvastatin or. There was no significant difference in increases or decreases in the antidiabetic drug dose. However, a review of patients with no change in antidiabetic drug dose revealed increases in arbitrary blood glucose and HbA1c levels only in the patients treated with atorvastatin. This was a retrospective study conducted for all patients who had initiated medication at a given time. This approach generated a bias between the two groups with respect to the presence or absence of antihyperlipidemic drug administration before the onset of atorvastatin or treatment. More patients in Group A had previously received other drugs. Among them, the largest number, 25, had shifted from treatment. Furthermore, 7 of those 25 patients required an increase in the antidiabetic drug dose after shifting to atorvastatin treatment, none received a dose reduction, and 1 was unable to be assessed. In 17 patients who had no increase or reduction in dose, HbA1c increased significantly (P 0.01) from the preadministration value of % to % at 3 months, and arbitrary blood glucose levels increased significantly (P 0.01) from mg/dl to mg/dl. We considered that these findings support the overall result that atorvastatin adversely affects glycemic control compared to. On the other hand, Group P included a relatively small number of patients who had been on other medications. Among them, the majority, 22, had shifted from cerivastatin to. We contemplated that there was possibly no overall deterioration in glycemic control in Group P because cerivastatin had affected glycemic control, and its discontinuation improved glycemic control in those who had shifted. We examined this possibility separately; however, arbitrary blood glucose levels varied from mg/dl to mg/dl, and HbA1c levels from % to %. Therefore, the non-significant statistical changes of this examination did not support the assertion. As shown in the results, total cholesterol and triglyceride levels were significantly higher in Group A than in Group P. A High TG level frequently accompanies insulin resistance 6). Therefore, high lipid levels possibly affected the blood glucose concentration. In order to eliminate the influence of lipids, we determined the changes in blood glucose and HbA1c by dividing Group A into 2: patients with higher total cholesterol and TG levels and patients with lower total cholesterol and TG levels. As a result, HbA1c increased in Group A regardless of changes in the total cholesterol or TG level. Therefore, we assume that total cholesterol and TG levels do not affect glucose metabolism even though they were significantly increased compared with Group P. WOSCOPS 7) indicated that decreased the number of new cases of diabetes mellitus by 30%. Therefore, one interpretation of the results of this study is that the administration of suppressed the deterioration of glycemic control, which occurs as part of the spontaneous course of common diabetes mellitus as observed in UKPDS 8) and other studies. Even though the observation period in this study was as short as 3 months, the data lead us to consider that the administration of atorvastatin itself provoked a deterioration of glycemic control. Some reports have documented the influences of atorvastatin on glycemic control. In the subanalysis of the ASCOT-LLA study, which compared 2 antihypertensive drugs in hypertensive patients, the atorvastatin group tended to include a greater number of new patients with diabetes mellitus compared to the placebo

5 99 group, although there was no statistically significant difference 9). In CARDS, a large-scale study examining the ability of atorvastatin to suppress the development of cardiovascular events in patients with type 2 diabetes mellitus, the mean follow-up survey of 4 years revealed an increase in HbA1c in the atorvastatin group from the preadministration value of 7.87% to 8.3%. The change appeared greater than in the placebo group which showed an increase from 7.81% to 8.1%. However, the study did not refer to the presence or absence of a statistically significant difference 5). Kanda, et al., administered atorvastatin and for 6 weeks to rats with streptozotocin-induced diabetes mellitus and conducted OGTT before and after the administration to examine and compare the deterioration of glucose tolerance. Consequently, they noted a significant deterioration in the atorvastatin group although there was no significant difference in insulin secretion 10). Patients who experienced an acute deterioration of glucose tolerance after the administration of atorvastatin have been reported sporadically 11, 12). In Japan, the package for atorvastatin describes a deterioration of glucose tolerance not observed with other statins. The mechanism by which atorvastatin affects glycemic control remains unknown. However, some studies were conducted with a similar liposoluble statin. A study using rat islet -cells 13) showed that the addition of simvastatin dose-dependently inhibited a glucose-induced increase in the intracellular calcium ion concentration and reported that the actual secretion of insulin also was inhibited; this inhibition was not observed with water-soluble. Furthermore, another study, in which adipose cells were pretreated with lovastatin to observe glucose uptake after the addition of insulin, reported that a decrease in GLUT4 lowered glucose uptake into the cell and that the addition of mevalonic acid recovered the uptake. On the other hand, Tanaka, et al., conducted a 12-week randomized study in which atorvastatin and placebo were administered to 20 patients each and reported that the administration of atorvastatin did not affect glucose tolerance 14). There have been other studies in Japan conducted on small numbers of patients. Whether or not a deterioration of glucose tolerance occurs due to the administration of atorvastatin is controversial. However, studies concluding that no deterioration of glycemic control occurred in the control group after a long-term clinical course included patients for whom the dose of antidiabetic drugs had been increased or reduced freely. Thus we attribute the diverse conclusions among repots to the fact that the effects of different conditions during the observation period must be considered in human studies because an extremely diversified range of factors influence blood glucose, which also is closely associated with lifestyle, especially diet and exercise. To explain the loss of glycemic control caused by atorvastatin after excluding these effects requires the study of a greater number of patients and clarification of the mechanism involved. Large-scale and other studies have indicated the importance of strict lipid control in diabetic patients to inhibit the development of cardiovascular events. Recent guidelines recommended lower target levels of LDL-cholesterol. Numerous studies have reported that the cholesterol-lowering effect of atorvastatin is potent. The present study provided similar results. Futhermore, there is a study showing that atorvastatin inhibits cardiovascular events. We expect that atorvastatin will continue to be prescribed for cholesterol lowering, however it is important to continue careful observation of the clinical course with respect to a deterioration of glucose tolerance when administering atorvastatin until conclusive evidence concerning its effects on blood glucose is forthcoming. 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