Endocrine Journal 2010, 57 (7), 579-586

Or i g i n a l

Efficacy and safety of mitiglinide in diabetic patients on maintenance hemodialysis

Masanori Abe, Kazuyoshi Okada, Takashi Maruyama, Noriaki Maruyama and Koichi Matsumoto

Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan

Abstract. Mitiglinide is a rapid- and short-acting insulinotropic receptor ligand and features rapid hypoglycemic action. To date, no prospective study has evaluated the use of mitiglinide in diabetic patients receiving hemodialysis (HD). In this study we evaluated the efficacy and safety of mitiglinide in diabetic patients on HD. Following an 8-week baseline period, we enrolled a study population of poorly controlled diabetic HD patients who had mean

hemoglobin (Hb)A1c levels greater than 6.5% at baseline and who were not receiving injection therapy. Patients were administered mitiglinide, 15 mg for those who were younger than 70 years and 7.5 mg for those who were 70 years and older, daily with each meal for the first 8 weeks. Subsequently, the doses were titrated by dose-doubling to a maximum of 30 mg/day if no adverse effects appeared. The efficacy was determined by monitoring glycemic control (plasma glucose,

HbA1c, and glycated albumin levels). Safety and tolerance were determined by monitoring clinical and laboratory parameters during the 24-week study period. The average final dose of mitiglinide was 20.0 ± 8.6 mg daily. Mitiglinide

was effective in reducing not only HbA1c and glycated albumin but also fasting plasma glucose levels from week 4 after the start of treatment. The agent was also effective in reducing triglyceride levels. No serious adverse effects such as hypoglycemia or liver impairment were observed in any patient. However, we could not completely rule out the possibility of a hypoglycemic episode, including silent hypoglycemia due to autonomic neuropathy, and therefore further clinical studies are required. It is necessary to adjust the dose of mitiglinide according to the status of glycemic control or hypoglycemic symptoms of individual patients. Although mitiglinide was effective as a treatment for diabetic patients on HD therapy, it should be initiated at a lower dose in the HD population, compared with the general population of diabetic patients. Mitiglinide can be safely used for diabetic patients on HD, if careful attention is paid to hypoglycemia.

Key words: Glycemic control, Hemodialysis, Mitiglinide, Type-2 diabetes

Numerous with different mechanisms of ac- tients receiving hemodialysis (HD) therapy. tion are being used with the aim of improving glyce- Mitiglinide is a rapid- and short-acting insulinotro- mic control, and drugs with different pharmacologic pic SU receptor (SUR) ligand, which is a benzylsuc- profiles are employed in the management of type 2 di- cinic acid derivative that was developed in Japan. Its abetes. Therapeutic options for patients with type 2 rapid hypoglycemic action is unlike that of SU agents diabetes and end-stage renal disease (ESRD) are lim- [2-4]. It alleviates postprandial hyperglycemia and as ited because a reduced glomerular filtration rate re- a result improves glycemic control [5]. Because the sults in the accumulation of certain drugs and/or their concentration of mitiglinide in the blood rapidly ris- metabolites [1]. Conventional oral hypoglycemic es after oral administration then quickly disappears, it agents, such as sulfonylurea (SU), are not suitable due is unlikely that the will exert hypoglycemic ef- to the risk of prolonged hypoglycemia; furthermore, fects early in the morning and between meals. In ad- is contraindicated. Therefore, in order to dition to mitiglinide, two other insulinotropic SUR li- achieve good glycemic control, insulin injection ther- gands, and , are in clinical use; apy remains the mainstay of treatment in diabetic pa- however, mitiglinide shows selective action on the ATP-dependent K+ channel (Kir6.2/SUR1) of pancre- Received Oct. 30, 2009; Accepted Apr. 5, 2010 as K09E-318 atic β-cells and the affinity to Kir6.2/SUR1 is stronger Released online in J-STAGE as advance publication May 13, 2010 (mitiglinide > repaglinide > nateglinide) [6]. These Correspondence to: Masanori Abe, MD, Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon results suggest that mitiglinide acts specifically on University School of Medicine, 30-1, Oyaguchi Kami-chou, Itabashi- pancreatic β-cells to induce secretion of insulin and ku, Tokyo 173-8610, Japan. E-mail: [email protected] has few unwanted effects on the cardiovascular sys- 580 Abe et al. tem. Therefore, as mitiglinide is rarely accompanied was 22.3 ± 3.2 kg/m2. The primary renal diagnosis in by hypoglycemia, it is an attractive therapeutic op- all patients was diabetic nephropathy due to type 2 di- tion even in the HD population in Japan. is abetes mellitus. Exclusion criteria were infectious dis- an α-glucosidase inhibitor (α-GI) that reduces or de- ease, thyroid disease, malignant tumors, and treatment lays carbohydrate digestion by competitive enzyme with steroids. inhibition at the ciliated border of the small intestine. Also, α-GI is rarely accompanied by hypoglycemia Design and is administered without dose adjustments in the The study was designed as a prospective, open- HD population [7]. On the other hand, the National label study that consisted of a pretreatment observa- Kidney Foundation Kidney Disease Outcomes Quality tion period of 8 weeks and a 24-week treatment pe- Initiative (NKF-K/DOQI) guidelines recommended riod. During the 8-week observation period, a fixed that α-GIs including voglibose are to be avoided [8]. dose of conventional anti-diabetic agents (voglibose Furthermore, mitiglinide is not currently used in the and/or ) was administered orally. Eligible US. Thus, recommended oral antidiabetic agents dif- patients who met the inclusion criteria during the ob- fer between countries. servation period then continued conventional therapy In light of this, we decided to evaluate the efficacy at the same dose and additionally received oral (po) and safety of mitiglinide in Japanese diabetics on HD. mitiglinide 5 mg three times a day (tid) immediately Mitiglinide has yet to be adequately studied in patients (within 5 min) before each meal. Elderly patients (>70 receiving HD, but clinical trials have been conducted in years old) received mitiglinide 2.5 mg tid po imme- diabetic patients with relatively normal kidney function. diately before each meal. Thereafter, if HbA1c after 8 No prospective study has evaluated the use of mitiglinide weeks of continuous mitiglinide administration did not in combination with an α-GI and/or pioglitazone in dia- reach the target value (<6.5%), the dose of mitiglinide betic patients receiving HD. This is very important for was increased to 10 mg tid from week 8. In elderly diabetics on HD, as mitiglinide may become the anti-di- patients, the dose of mitiglinide was increased to 5 mg abetic therapy of choice if its safety and efficacy can be tid from week 8. On the other hand, if the physician confirmed. judged that mitiglinide 5 mg (or 2.5 mg for elderly pa- tients) tid presented a safety problem, the dose could Methods be reduced to 2.5 mg tid (or 2.5 mg twice a day (bid) for elderly patients). Patients continued their regular Subjects medications, such as antihypertensives, recombinant The study participants were Japanese patients with human erythropoietin, phosphate binders, and lipid- aged >20 years who did not show ad- lowering agents, during the study period. The baseline equate glycemic control (defined as mean hemoglo- characteristics and medications are shown in Table 1. bin (Hb)A1c levels over the last 2 months of between >6.5% and <9.0%) and who were not receiving insu- Study evaluations lin injection therapy despite receiving treatment for HbA1c, glycated albumin (GA), and fasting plasma >8 weeks with conventional therapy (dietary therapy glucose levels were measured once monthly as indi- alone or voglibose and/or pioglitazone). ces of glycemic control. Levels of Hb, total bilirubin Thirty-one chronic diabetic HD patients (male/fe- (T-bil), asparate aminotransferase (AST), alanine ami- male: 22/9) were selected from those undergoing HD notransferase (ALT), lactate dehydrogenase (LDH), three times weekly for 4-hour sessions at the blood alkaline phosphatase (ALP), γ-glutamyl transpeptidase purification unit of our hospital. All of the patients (γ-GTP), total (T-chol), high-density lipo- had oliguria or anuria. The local ethics committee of protein (HDL), triglyceride (TG), total protein (TP), our hospital approved the study protocol, and all par- and albumin (Alb) were measured by routine clinical ticipants gave their written informed consent. The chemistry procedures using commercial kits. Body study protocol was designed in accordance with the weight before and after dialysis, to assess the inter- Declaration of Helsinki. The mean patient age was dialytic weight gain, BMI, cardiothoracic ratio (CTR) 67.0 ± 8.1 years and the mean duration of HD was by chest X-ray, and predialysis systolic and diastolic 22.6 ± 8.1 months. The mean body mass index (BMI) blood pressures were also measured. Fasting blood Efficacy of mitiglinide in HD patients 581

Table 1 Baseline characteristics and medications tient. The glucose concentration of the dialysate was Variables 100 mg/dL. Heparin was used at 2600–5000 units per Number of patients 31 4-hour HD session for anticoagulation. The volume Gender (male/female) 22/9 of ultrafiltration was maintained on the basis of clini- Age (years) 67.0 ± 8.1 cal dry weight during each session. Hemodialysis duration (months) 22.6 ± 8.1 Body mass index (kg/m2) 22.3 ± 3.2 Statistical analysis Fasting plasma glucose (mg/dL) 168 ± 20 Results are expressed as mean ± SD. Statistical sig- Hemoglobin A1c (%) 6.9 ± 0.6 Glycated albumin (%) 26.0 ± 3.9 nificance was tested using the paired t-test for paramet- Medication (n) ric data and the Wilcoxon signed-rank test for nonpara- Conventional antidiabetic agents metric data. Comparisons of categorical data between Voglibose 10 groups were performed using the chi-square test. Pioglitazone 7 Statistical significance was established at a level of p < Dietary modification alone (without 16 0.05. medication) RAS blockers 16 Statins 8 Results RAS, renin-angiotensin system. Dose of mitiglinide Subjects who were younger than 70 years (n=18) samples were obtained before the start of HD treat- were given an initial dose of 15 mg/day. The remain- ment. All variables were evaluated monthly for 8 ing subjects who were 70 years and older (n=13) were weeks before and 24 weeks during the mitiglinide initially given 7.5 mg/day. The dose was doubled treatment period. stepwise to ascertain the safety of the drug. Upon confirmation of the absence of adverse effects 8 weeks Safety after the start of mitiglinide therapy, the dose was in- At each visit, subjects were questioned with regard creased to a maximum of 30 mg/day in a total of 12 to compliance (diet, medication), concomitant medi- subjects (39%). The mitiglinide doses was reduced cation, and adverse events. Safety assessments were from the baseline dose in the four subjects at week 24; performed throughout the study. Adverse events were 15 mg/day tid to 10 mg/day bid in three subjects and graded by intensity (mild, moderate, severe). Serious 7.5 mg/day to 5 mg/day bid in one subject. The aver- adverse events were defined as medical events that re- age final dose of mitiglinide was 20.0 ± 8.6 mg/day sulted in death, hospitalization, or significant disability (0.35 ± 0.14 mg/kg/day). or incapacity. Patient withdrawal from the study was The final dose of mitiglinide was lower in patients considered if an allergy or intolerance to the drug ap- with fasting plasma glucose levels at baseline of less peared during the study, if either the serum transami- than 160 mg/dL (n = 13; 15.2 ± 7.6 mg/day) compared nase or creatine kinase concentration increased to more with those with a baseline level of more than 160 mg/ than double the upper limit of the normal range, or fol- dL (n = 18; 23.3 ± 7.6 mg/day) (p = 0.012). lowing the development of any condition that, in the opinion of the investigators, might have posed a risk to Glycemic control the patient or confounded the results of the study. As shown in Fig. 1, there was a significant decrease

in HbA1c levels at 4 weeks after the start of mitiglinide HD procedure therapy, and the levels continued to decrease through- In all patients, the HD procedure was performed for out the 24-week period of treatment. Fig. 2 shows 4 hours at a blood flow rate of 200 mL/min and a di- that there was a significant decrease in GA levels at 4 alysate flow rate of 500 mL/min. HD was performed weeks after the start of mitiglinide therapy, and the lev- using dialysers containing high-flux membranes such els continued to decrease throughout the 24-week pe- as polysulphone, polyester-polymer alloy, or cellulose riod of treatment. Fig. 3 shows similar data for fasting triacetate. The surface area of the dialyser membrane plasma glucose; the levels were significantly decreased was selected according to the body weight of the pa- at 4 weeks after the start of mitiglinide therapy and 582 Abe et al.

Table 2 Variables measured in this study At baseline At study end p-value Systolic blood pressure (mmHg) 145 ± 11 145 ± 12 0.44 Diastolic blood pressure (mmHg) 79 ± 8 79 ± 9 0.88 Hemoglobin (g/dL) 10.9 ± 1.0 11.0 ± 0.9 0.38 EPO dose (U/week) 4274 ± 2535 3895 ± 2425 0.36 Total protein (g/dL) 6.7 ± 0.6 6.7 ± 0.5 0.65 Albumin (g/dL) 3.7 ± 0.4 3.8 ± 0.4 0.21 Total bilirubin (mg/dL) 0.28 ± 0.07 0.27 ± 0.07 0.50 AST (U/L) 14.3 ± 7.0 12.3 ± 5.2 0.08 ALT (U/L) 11.9 ± 6.9 11.1 ± 6.1 0.46 LDH (U/L) 187 ± 34 181 ± 31 0.18 ALP (U/L) 270 ± 69 246 ± 64 0.0024 γ-GTP (U/L) 19.4 ± 7.0 19.4 ± 7.9 0.96 Total cholesterol (mg/dL) 165 ± 36 157 ± 25 0.08 HDL (mg/dL) 44.9 ± 14.9 45.1 ± 14.5 0.82 Triglyceride (mg/dL) 151 ± 82 108 ± 59 0.0006 Body mass index (kg/m2) 22.2 ± 3.3 22.3 ± 3.2 0.12 Dry weight (kg) 56.4 ± 10.9 56.5 ± 10.7 0.83 CTR (%) 47.8 ± 2.4 47.7 ± 2.4 0.19 Interdialytic weight gain (kg) 2.2 ± 0.6 2.1 ± 0.6 0.0001 ALP, alkaline phosphatase; ALT, alanine aminotransferase ; AST, aspartate aminotransferase; CTR, cardiothoracic ratio; EPO, erythropoietin; LDH, lactate dehydrogenase; γ-GTP, γ-glutamyl transpeptidase; HDL, high-density lipoprotein cholesterol.

Table 3 Characteristics of monotherapy group and combination group at the end of the study

Monotherapy group Combination group p-value n (male/female) 16 (12/4) 15 (10/5) 0.62 Age (years) 68.5 ± 8.2 65.5 ± 8.0 0.23 Duration of hemodialysis (months) 21.1 ± 6.9 24.3 ± 9.2 0.28 Body mass index (kg/m2) 21.9 ± 3.0 22.4 ± 3.6 0.65

Change in hemoglobin A1c (%) −1.1 ± 0.4 −1.2 ± 0.5 0.52 Change in glycated albumin (%) −4.6 ± 2.0 −5.6 ± 2.5 0.26 Change in fasting plasma glucose (mg/dL) −38 ± 23 −36 ± 18 0.46 Mitiglinide dose (mg/day) 16.1 ± 7.8 23.8 ± 8.1 0.01 Mitiglinide dosage (mg/kg/day) 0.27 ± 0.11 0.43 ± 0.13 0.001 continued to decrease for 24 weeks. However, although there were no significant changes

in the indices of glycemic control (reduction in HbA1c, Lipid control GA, and fasting plasma glucose levels), the dose of Fasting serum triglyceride levels decreased from mitiglinide was significant lower in the monotherapy 151 mg/dL at baseline to 108 mg/dL at 24 weeks. group, as shown in Table 3. There were no significant changes in total cholesterol or HDL-cholesterol (Table 2). Adverse effects and metabolic effects Systolic and diastolic blood pressures were not sig- Subgroup analysis nificantly different after the start of mitiglinide thera- When subjects were subdivided into (1) mitiglin- py. Although no statistically significant changes were ide monotherapy group (n=16) and (2) combination observed in BMI, dry weight, CTR, or total protein or therapy (mitiglinide plus voglibose and/or pioglita- serum albumin levels, there was a significant reduc- zone) group (n=15), there were no significant differ- tion in interdialytic body weight gain (Table 2). ences in age, sex distribution, duration of HD, or BMI. As shown in Table 2, there were no significant dif- Efficacy of mitiglinide in HD patients 583

Fig. 1 Changes in hemoglobin (Hb)A1c level during treatment Fig. 2 Changes in glycated albumin (GA) level during treatment

Fig. 3 (a) Changes in mean fasting plasma glucose levels during treatment (b) Changes in fasting plasma glucose levels in each subject at baseline and at the end of the study ferences in Hb or the erythropoietin dose throughout CYP2C9 (70%) and CYP3A4 (30%) [11]. However, the 24 weeks of treatment. None of the patients ex- metabolites of repaglinide and nateglinide have insulin hibited significant adverse effects such as symptomat- secretion properties. Therefore, their half-time is pro- ic hypoglycemia or liver dysfunction. Only ALP lev- longed in patients with renal impairment and this re- el was significantly decreased at the end of the study sults in hypoglycemic episodes. By contrast, metabo- compared with baseline levels. lism of mitiglinide is different from that of repaglinide and nateglinide [12]. Although mitiglinide is metabo- Discussion lized in the kidney and liver, and predominantly me- Three rapidly acting insulin secretagogues, nateglin- tabolized to glucuronic acid conjugate (74%) and hy- ide, repaglinide, and mitiglinide, are currently in clini- droxide (<25%), these metabolites have little insulin cal use because of their rapid onset of action result- secretory activity [13]. Therefore, it is considered that ing in improvement in hyperglycemia. Repaglinide is the likelihood of hypoglycemia is low with mitiglin- metabolized in the liver by the cytochrome P450 en- ide, even in patients with renal impairment, compared zymes, principally CYP2C8 and CYP3A4 [9, 10]. In with repaglinide and nateglinide. The time of maxi- vitro data demonstrated that nateglinide is predomi- mum concentration and the half-life of mitiglinide in nantly metabolized by cytochrome P450 isoenzymes patients receiving HD are approximately 0.41 and 11.7 584 Abe et al. hours, respectively. Because the half-life of mitiglin- group. Furthermore, because some patients had im- ide is 1.48 and 3.22 hours in patients with normal kid- proved glycemic control even with twice daily admin- ney function and stage 3 chronic kidney disease, re- istration, the lower dose of mitiglinide was considered spectively, close attention must be paid to excessive to be clinically useful in patients with HD. Therefore, blood glucose reduction when mitiglinide is given to the initial dose of mitiglinide was required to be low- patients with renal impairment. In the present study, er in the HD population. It is necessary to adjust the there were a few incidences of hypoglycemia even dose of mitiglinide according to the status of glyce- though the dose of mitiglinide was low compared mic control or hypoglycemic symptoms of individual with other clinical studies in patients with normal kid- patients. However, in the present study, plasma glu- ney function [14-16]. Mitiglinide is intended to lower cose levels were measured only at pre-HD time points, postprandial glucose levels because its effect on insu- which were expected to be the time points of lowest lin secretion is rapid and short; however, fasting plas- mitiglinide blood concentration. Because we could ma glucose levels were significantly decreased in the not completely rule out the possibility of a hypogly- present study. This suggests that appropriate blood cemic episode, including silent hypoglycemia due to glucose levels can be maintained even at a low dose autonomic neuropathy, further clinical studies are re- of mitiglinide not only during the postprandial period quired. but also before meals, due to the prolonged half-life We found that the overall incidence of adverse of mitiglinide in patients with HD compared with the events was similar between the mitiglinide monother- half-life in those with normal kidney function. The fi- apy and mitiglinide combination groups; combina- nal dosage of mitiglinide was lower for patients with tion therapy with voglibose or pioglitazone did not in- a fasting plasma glucose levels at baseline of less than crease the incidence of adverse events. Because there 160 mg/dL compared with those with baseline levels was also no clear difference in the incidence of hypo- above 160 mg/dL. This might explain why few pa- glycemic symptoms among the groups, combination tients had a hypoglycemic episode in the fasting state. therapy did not increase the risk of onset of hypogly- If the initial fasting plasma glucose levels were low- cemia. Although in combination therapy with insu- er than 160 mg/dL, mitiglinide should be initiated at linotropic SUR ligands and deriva- a lower dose in order to avoid hypoglycemia. Thus, tives, weight gains of about 2–6 kg from baseline have it was considered that mitiglinide not only improved been reported in patients with normal kidney function

HbA1c, the overall glycemic control index in type 2 di- [17-19], we found no significant changes in the dry abetes, but also effectively improved fasting plasma weight even in patients treated combined with piogli- glucose in patients with HD. tazone. In contrast, interdialytic weight gain was sig- Kaku et al. [15] reported that mitiglinide effective- nificantly reduced at the end of the study compared with ly improves glycemic control in patients with type baseline. This finding is thought to be due to allevia- 2 diabetes with normal kidney function who are in- tion of dipsesis, and thus a reduction in water intake, adequately controlled by pioglitazone monotherapy. as a result of the improvement of hyperglycemia with Subjects were first treated with pioglitazone 15–30 mitiglinide therapy. Furthermore, triglyceride levels mg/day plus dietary modification for 4 weeks then were reduced by mitiglinide treatment. This finding randomly assigned to receive additional mitiglinide was considered to be a secondary effect of improved (5 or 10 mg) or placebo tid for a further 16 weeks. plasma glucose levels, because firstly glycemic con-

HbA1c was reduced by 0.02 ± 0.60% in the pioglita- trol (fasting plasma glucose, HbA1c, and GA levels) zone monotherapy group and by 0.45 ± 0.77% and 0.67 was improved, and then triglyceride levels were sig- ± 0.59% in the mitiglinide 5 and 10 mg combination nificantly reduced from week 16 without changes in groups, respectively (both p < 0.001 vs. pioglitazone dietary habits or changes in clinical dry weight, total monotherapy group). In the present study, the dose of protein, serum albumin, or serum urea nitrogen levels. mitiglinide was 20.0 ± 8.6 mg daily, which was lower Our study is limited by the relatively small sample than in the subjects with normal kidney function [14- size, the short period of treatment, and the lack of a 16]. Furthermore, in our monotherapy group, a lower control group. Moreover, further longitudinal, double- dose of mitiglinide was required to maintain adequate blind, comparative multicenter clinical trials should glycemic control compared with the combination be conducted in a larger number of patients in order Efficacy of mitiglinide in HD patients 585 to further clarify the effect and safety of mitiglinide In conclusion, we found that mitiglinide is effective in the HD population. Furthermore, the participants for the treatment of diabetic patients on HD therapy. of the present study were considered to have relative- It is worth considering administration of mitiglinide ly mild type 2 diabetes, because fasting plasma glu- before choosing insulin injection therapy for patients cose levels were significantly and rapidly improved. who require glycemic control. Mitiglinide might have Therefore, it is likely that insulin secretion was main- the potential to reduce the number of Japanese pa- tained in these subjects. In our study, we noted that tients with type 2 diabetes on HD who ultimately re- mitiglinide significantly improved glycemic con- quire insulin injection therapy. Long-term follow-up trol, triglyceride level, and interdialytic weight gain of patients undergoing HD treatment with mitiglinide even when administered only for a short duration. is necessary to confirm the effects of glycemic control Therefore, we believe that this agent may be beneficial on the progression of cardiovascular complications for diabetic patients on HD. and the prognosis in diabetic HD patients.

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