Insulin glargine improves glycemic control and quality of life in type 2 diabetic patients on hemodialysis

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1 ORIGINAL ARTICLE JN EPHROL 25( DOI: /jn Insulin glargine improves glycemic control and quality of life in type 2 diabetic patients on hemodialysis Masao Toyoda, Moritsugu Kimura, Naoyuki Yamamoto, Masaaki Miyauchi, Tomoya Umezono, Daisuke Suzuki Division of Nephrology and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa - Japan Abstract Background: Diabetic patients on hemodialysis often experience severe hypoglycemia during intensive insulin therapy using conventional neutral protamine hagedorn (NPH) or nonintensive therapy with premixed insulin. Insulin glargine can simulate normal basal insulin secretion. We investigated the efficacy and safety of switching from NPH to glargine in type 2 diabetes patients on hemodialysis. Methods: Hemodialysis patients who were being treated with NPH-based basal-bolus insulin therapy, regular insulin, NPH insulin or premixed insulin were switched to glargine. The target early morning fasting blood glucose (FBG) level was 110 mg/dl. Any increase in glargine dose was coupled with a reduction in the dose of any regular or rapid-acting insulin analogue as far as possible while maintaining a constant daily insulin dose. FBG,, daily insulin dosage, percentage of basal insulin dose in total daily insulin dose, body weight and incidence of hypoglycemic events were evaluated during the study period. Quality of life (QOL) was measured with a short questionnaire. Results: improved significantly during the observation period after switching. The daily insulin dose was reduced from 20.1 ± 15.2 to 18.1 ± 15.1 U/day, although the change was not statistically significant. FBG decreased significantly from ± 58.7 to ± 27.7 mg/dl. Body weight measured after dialysis did not change, and there were no changes in hemoglobin or hematocrit. The frequency of hypoglycemic episodes decreased significantly. QOL reports with switching to glargine were improved compared with those before switching. Conclusion: The results suggest that glargine is useful, can improve QOL of diabetic patients on hemodialysis, and achieve better glycemic control than NPH. Key words: Type 2 diabetes, Hemodialysis, Hypoglycemia, Insulin glargine Introduction Diabetic nephropathy often advances to end-stage renal disease, and this complication has become the most common reason for initiation of dialysis in Japan. Insulin therapy is required in patients with diabetic nephropathy after the initiation of hemodialysis because most oral glucose-lowering agents are contraindicated due to the risk of severe hypoglycemia or other adverse reactions (1, 2). Even when insulin fails to control of blood glucose levels adequately, patients often experience persistent severe hypoglycemia during intensive insulin therapy (basal-bolus insulin therapy) using conventional neutral protamine hagedorn (NPH) or nonintensive therapy with premixed insulin. These hypoglycemic episodes seem to be due to the low renal degradation of insulin in renal failure, with subsequent excessive prolongation of the peak effect of insulin preparations and/or impairment of gluconeogenesis in the fasting or hypoglycemic state under hemodialysis. Many clinical reports showed that 989

2 Toyoda et al: Efficacy of glargine in hemodialysis patients the combination of once-daily basal insulin (NPH or longacting insulin analogue) and mealtime bolus insulin (regular insulin or rapid-acting insulin analogue) therapy was superior to a conventional 1-2 times of administration of NPH or premixed insulin therapy. Moreover, a recent study also reported the efficacy and safety of the new basal insulin analogue (3). Since the blood glucose-lowering action of recombinant insulin glargine does not show a distinct peak (4), conversion from NPH to glargine could reduce the development of hypoglycemic episodes and improve quality of life (QOL) in hemodialysis patients. The present study was designed to study the efficacy of glargine and to analyze the effect of switching from NPH to glargine on the clinical outcomes and safety in patients with type2 diabetes on hemodialysis. Methods Hemodialysis patients who were being treated with NPHbased basal-bolus insulin therapy, regular insulin, NPH insulin or premixed insulin at our hospital between October 2007 and June 2009 were switched to glargine (Tabs. I TABLE I CLINICAL CHARACTERISTICS OF THE 14 PATIENTS STUDIED Sex (M/F) 10/4 Age (years) 66.2 ± 10.7 Time on dialysis (years) 6.8 ± 4.5 Time since diagnosis of diabetes (years) 27.0 ± 8.6 Height (cm) ± 6.0 Body weight (kg) 58.6 ± 12.4 Systolic blood pressure (mm Hg) ± 16.2 Diastolic blood pressure (mm Hg) 66.2 ± 10.7 Hemoglobin (mg/dl) 9.7 ± 0.5 Hematocrit (%) 30.1 ± 1.6 Fasting blood glucose (mg/dl) ± 58.7 (%) 7.1 ± 1.0 Data are means ± SD. and II). The study was approved by the ethics committee of the Tokai University School of Medicine, and fully informed consent was obtained from all participants. When the insulin regimen was changed from 2 or more daily injections, to once daily glargine injection, the daily insulin dose was reduced to about 80% of that before switching. When basal-bolus insulin therapy with NPH was switched to glargine, the daily insulin dose was also reduced to about 80% of that before conversion. The dose was adjusted based on data obtained by self-monitoring of blood glucose (SMBG) after safety confirmation. The target early morning fasting blood glucose (FBG) level was 110 mg/ dl. Any increase in the glargine dose required reduction of the dose of any regular insulin or rapid-acting insulin analogue, as far as possible, while maintaining a constant daily insulin dose. The content and timing of meals, the number of hemodialysis sessions and the procedure and duration of each dialysis session were not changed throughout the study period. The initial glucose concentration in the dialysate was 100 mg/dl, and this was not changed after switching to glargine. The dialyzer membranes were standardized to avoid potential differences in insulin clearance across different dialyzer types. Changes from the time of switching to 3 months afterwards were analyzed for glycosylated hemoglobin ( ), the daily insulin dose, percentage of basal insulin dose in total daily insulin dose, and the frequency of hypoglycemic episodes. was measured by HPLC according to the standard method of the Committee for Standardization of Diabetes-Related Laboratory Testing of the Japanese Diabetes Society (JDS). Then is estimated as National Glycohemoglobin Standardization Program (NGSP) equivalent value calculated by the formula (%) = (JDS) (%) + 0.4%, according to the recommendations of the Japan Diabetes Society (5). Body weight was measured as the dry weight at the completion of dialysis. The weekly number of hypoglycemic episodes represented the sum of all episodes of hypoglycemic symptoms plus blood glucose level of 60 mg/dl by SMBG. We also assessed the changes in QOL, using a short questionnaire with 5 questions. Data are expressed as means ± SD. Statistical analysis was performed using the Wilcoxon signed-rank test. A p value <0.05 was considered statistically significant. Results After switching to glargine, improved significantly during the 3-month observation period (from 7.1% ± 1.0% 990

3 JN EPHROL 25( TABLE II CHANGES OF INSULIN THERAPY Patient no. 0 months 3 months Av. all patients TD 20.1 ± 15.2 TD 18.1 ± 15.1 (N.S.) B% 58.8 ± 34.6 B% 79.1 ± 25.3 (p=0.0284) 1 30R: TU 12, B% 70 G: TU 10, B% N: TU 32, B% 100 G: TU 22, B% R: TU 9, B% 0 G: TU 13, B% R: mix: TU 22, B% 45 R: G: TU 26, B% 46 5 R: TU 16, B% 0 G: TU 13, B% R: N: TU 18, B% 44 A: G: TU 18, B% 44 7 A: N: TU 13, B% 46 A: G: TU 13, B% 54 8 N: TU 10, B% 100 G: TU 8, B% R: N: TU 56, B% 29 A: G: TU 60, B% N: TU 2, B% 100 G: TU 3, B% A: N: TU 24, B% 67 A: G: TU 18, B% mix: TU 8, B% 70 G: TU 4, B% R: R: TU 46, B% 52 A: G: TU 37, B% N: TU 14, B% 100 G: TU 8, B% 100 Insulin injection times are expressed as before breakfast - before lunch - before dinner - at bed time (e.g., G: refers to glargine 8 U at bed time; R: refers to regular 4 U at breakfast, 6 U at lunch, 2 U at dinner). A = aspart; Av. = average; B% = percentage of basal insulin units in total daily insulin units; G = glargine; N = neutral protamine hagedorn; NS = not significant; 30R = premixed human insulin 30/70; 30mix = premixed insulin aspart 30; R = regular; TD = total daily insulin dose; TU = total daily insulin units; U = units. 991

4 Toyoda et al: Efficacy of glargine in hemodialysis patients hypoglycemic episodes that required hospitalization. As the data in Table IV from only 12 patients shows, we can improve the QOL of patients by switching to glargine. Discussion Fig. 1 - Serial changes in mean glycosylated hemoglobin ( ; National Glycohemoglobin Standardization Program [NGSP]) throughout the study period. to 6.8% ± 0.7%; p=0.0203) (Fig. 1). The daily insulin dose was reduced from 20.1 ± 15.2 U/day to 18.1 ± 15.1 U/day, although the change was not statistically significant (Tabs. II and III; Fig. 2). The percentage of basal insulin dose in total daily insulin dose was significantly increased from 58.8% ± 34.6% to 79.1% ± 25.3% (Tab. II). FBG decreased significantly from ± 58.7 mg/dl to ± 27.7 mg/ dl. Switching to glargine did not change the body weight measured after dialysis, and there were no changes in hemoglobin and hematocrit levels (Tab. III). The frequency of hypoglycemic episodes decreased significantly from 1.83 ± 2.25 episodes/week before switching, to 0.08 ± 0.28 episodes/week at 3 months (p=0.018). There were no severe TABLE III CHANGES IN DAILY INSULIN DOSE AND CLINICAL PARAMETERS Daily insulin dose (U/day) Fasting blood glucose (mg/dl) 0 months 3 months p Value 20.1 ± ± 15.1 NS ± ± 27.7 <0.001 Body weight (kg) 58.6 ± ± 12.7 NS Hemoglobin (mg/dl) 9.7 ± ± 0.5 NS Hematocrit (%) 30.1 ± ± 1.6 NS Data are means ± SD. NS = not significant. Ample evidence suggests that tight glycemic control prevents the onset or slows the progression of diabetic microvascular complications in diabetic patients free of renal failure. The Japanese Diabetes Society has established the following targets in the management of (NGSP values): a value <6.2% is excellent and 6.2%-6.9% is good. Thus, should at least be maintained below 6.9%. Many studies have shown that poor glycemic control influences the prognosis after initiation of dialysis. However, there have been a few recent reports about the effect of glycemic control after starting dialysis (6, 7). Oomichi et al (8) reported that (NGSP values) 8.0% was associated with poor prognosis in diabetic patients on hemodialysis. Unlike previous studies that analyzed at the time of starting hemodialysis, these findings strongly suggest the importance of tight glycemic control during maintenance hemodialysis. However, tight glycemic control with insulin may be associated with unstable blood glucose levels (9). Unexpected hypoglycemia often occurs in dialysis patients during basal-bolus insulin therapy despite careful adjustment of their insulin dose. This is due to 3 main factors: (i) prolongation of the elimination half-life of insulin associated with decreased renal degradation and excretion (9); (ii) impairment of gluconeogenesis by the kidneys and (iii) weak gastric peristalsis in diabetic patients on dialysis, with prolongation of stomach food retention, resulting in delays in glucose absorption. These factors mean that many patients need to sacrifice tight glycemic control to avoid the risk of hypoglycemia and a decrease in QOL. In the present study, switching of basal insulin from NPH to glargine in patients on various insulin regimens, such as basal-bolus insulin therapy, led to a significant improvement in without increasing the frequency of hypoglycemic episodes. In fact, switching to glargine significantly reduced hypoglycemic episodes and improved, as well as improving QOL (Tab. IV). Two or more daily injections of insulin were switched to once-daily glargine in 6 out of 14 patients (42.9%). Since the frequency of daily injections influences the psychological burden on diabetic patients, switching to glargine was considered to contribute to the improvement in QOL (Tab. IV). Administration of recombinant human erythropoietin (EPO) for renal anemia is reported to increase erythrocyte turn- 992

5 JN EPHROL 25( Fig. 2 - Changes of parameters in each patient. = glycosylated hemoglobin. TABLE IV RESULT OF THE QUESTIONNAIRE CONCERNING QUALITY OF LIFE 1. How was it to change to glargine from previous insulin treatment? Easier Unchanged More difficult 75.0% (n=9) 25.0% (n=3) 0 2. How is your hypoglycemia compared with that with your previous insulin treatment? Decreased Unchanged Increased 50.0% (n=6) 50.0% (n=6) 0 3. Has there been any change in your being active and positive using glargine, which has a low risk of hypoglycemia? More active Unchanged Less active 50.0% (n=6) 50.0% (n=6) 0 4. How is your glycemic control, after changing to glargine from your previous insulin treatment? Satisfied Unchanged Worse 66.7% (n=8) 33.3% (n=4) 0 5. Do you want to go back to the previous insulin treatment? No, I don t No preference Yes, I do 91.7% (n=11) 8.3% (n=1) 0 993

6 Toyoda et al: Efficacy of glargine in hemodialysis patients over, and these changes reduce the exposure of erythrocytes to blood glucose. Thus, glycemic control in dialysis patients may be incorrectly assessed if it is evaluated by alone (10). For this reason, many authors have reported that glycated albumin (GA) is a better indicator of glycemic control than for diabetic patients on hemodialysis. However, measurement of GA was not common at the time when this study was conducted. No significant changes were recorded during the follow-up period with respect to the dose of EPO, hemoglobin or hematocrit. This study was designed to evaluate individual changes in glycemic control by analyzing changes in up to 3 months after switching to glargine, and no problems were found with regard to evaluation of the changes in. The results showed improvement in without a significant increase in the daily insulin dose. Since adequate basal insulin secretion was stimulated by switching from NPH to glargine, allowing basal insulin to be sufficiently replenished, the nocturnal excursions of blood glucose were also safely controlled in patients who had experienced nocturnal hypoglycemia with NPH. In fact, Riddle et al (11) increased the dose of NPH or glargine administered before bedtime to patients with type 2 diabetes who were not on dialysis in whom the target FBG was 100 mg/dl. They found a significantly higher incidence of hypoglycemia in the NPH group than in the glargine group despite similar final FBG and levels (12). In addition, since stabilization of FBG can reduce the use of regular insulin or rapid-acting insulin analogues, such a mechanism may simultaneously reduce hypoglycemic episodes and improve. In the present study, was significantly improved by approximately 0.3%, although the total daily insulin dose was not increased, but the percentage of basal insulin dose in total daily insulin dose was significantly increased. The main reason for this observation is probably related to the improvement in the average FBG to <130 mg/dl without hypoglycemia. It is generally known that normalization of postprandial blood glucose response by supplementing endogenous secretion with bolus insulin will increase insulin sensitivity, resulting in improvement of FBG (12, 13). Moreover, some reports have indicated that the opposite is also true i.e., that the improvement of FBG can contribute to the normalization of postprandial blood glucose (14). The results of this study also suggest that improvement of FBG level contributed to the improvement in postprandial blood glucose levels. Since we did not measure postprandial blood glucose precisely in this study, we cannot reach any conclusion and need to await the results of further investigations. Weight gain associated with improvement of glycemic control by conventional basal-bolus insulin therapy was reported in many studies including the United Kingdom Prospective Diabetes Study (UKPDS) (15). A possible mechanism leading to such weight gain is that hypoglycemia induced by a relative insulin overdose may require supplementation of carbohydrates or additional food intake (15). In our study, there was no significant weight gain. A number of previous studies have shown that glargine significantly suppresses weight gain compared with NPH (16), so an appropriate diet and switching to glargine (which allows better glycemic control without hypoglycemia) may have suppressed supplementary food intake and improved without changing body weight in our patients. Our study has certain limitations. First, the study design was an uncontrolled study. Second, the study included only a small number of patients, who were followed for a relatively short period. A long-term study with a larger sample size is necessary. In addition to studies in Japanese patients, similar studies of European and American patients who have different dietary habits (such as differences of carbohydrate intake) are also necessary. In conclusion, the present study demonstrated that administration of glargine to Japanese patients with type 2 diabetes on hemodialysis resulted in improvement of, without increasing the frequency of hypoglycemic episodes. These results imply that glargine can improve the QOL of diabetic patients, as well as achieve better glycemic control than NPH. Financial support: No financial support was received. Conflict of interest statement: None declared. Address for correspondence: Daisuke Suzuki, MD, PhD Division of Nephrology and Metabolism Department of Internal Medicine Tokai University School of Medicine Isehara-Kanagawa , Japan daisuke@is.icc.u-tokai.ac.jp 994

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