Diabetes is a global health problem. According to data. Premixed Insulin Analogue Compared with Basal-Plus Regimen for Inpatient Glycemic Control

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1 DIABETES TECHNOLOGY & THERAPEUTICS Volume 18, Number 11, 2016 ª Mary Ann Liebert, Inc. DOI: /dia ORIGINAL ARTICLE Premixed Insulin Analogue Compared with Basal-Plus Regimen for Inpatient Glycemic Control Abraham Edgar Gracia-Ramos, MD, MSc, 1 María del Pilar Cruz-Domínguez, MD, DSc, 2 Eduardo Osiris Madrigal-Santillán, DSc, 3 José Antonio Morales-González, DSc, 3 Eduardo Madrigal-Bujaidar, DSc, 4 and José Leopoldo Aguilar-Faisal, DSc 3 Abstract Background: No previous studies have investigated the use of a premixed insulin analogue in a hospital setting. Objective: To compare the efficacy and safety of treatment with premixed insulin analogue (insulin lispro mix 75/ 25, LM75/25) with the basal-plus regimen with insulin glargine in hospitalized patients with type 2 diabetes (T2D). Materials and Methods: A randomized clinical trial in hospitalized patients with T2D and glucose >140 mg/dl on admission was performed. A total of 54 patients were randomized to receive insulin LM75/25 or glargine. In both groups, a correction dose of lispro was administered before meals. Insulin dose was adjusted to obtain a mean blood glucose (BG) between 100 and 140 mg/dl. Results: Improvement in the mean BG after the first day of treatment was similar in both groups (P = 0.470). Glycemic control at the end of follow-up was similar between the group with insulin LM75/25 ( mg/dl) and insulin glargine ( mg/dl, P = 0.153). The aim of a BG concentration of <140 mg/ dl was obtained in 72% of the patients in the premixed insulin analogue group and 56% of patients in the basalplus group (P = 0.239). There was no difference in the frequency of hypoglycemia between groups (7 vs. 10, P = 0.529). Conclusion: Results of this trial indicate that the use of a premixed insulin analogue is as effective and safe as the basal-plus regimen to achieve glycemic control. Keywords: Hyperglycemia, Inpatient, Insulin lispro mix 75/25, Premixed insulin analogue, Type 2 diabetes. Introduction Diabetes is a global health problem. According to data from the International Diabetes Federation, *382 million people suffer from this disease worldwide. 1 In a hospital setting, it has been estimated that at least 20% of medical and surgical patients present diabetes. 2 Hyperglycemia in hospitalized noncritical patients, both diabetic and nondiabetic, is associated with an increased risk of complications, length of stay, disability, and death Adequate control of blood glucose (BG) level produces a reduction in complications Based on this, the American Diabetes Association (ADA), American Association of Clinical Endocrinologists (AACE), Endocrine Society, American Heart Association (AHA), American Association of Diabetes Educators (AADE), and European Society of Endocrinology and the Society of Hospital Medicine have recommended the treatment of hospital hyperglycemia through insulin administration with the therapeutic goal of maintaining a fasting BG level between 100 and 140 mg/dl and glucose at any time of day <180 md/dl. 16,17 The most recommended insulin application method consists of a basal-bolus regimen. This approach requires subcutaneous administration of basal insulin given once or twice daily in combination with prandial and corrective doses of rapid-action insulin before each meal Several observational and randomized controlled trials in 1 Departamento de Medicina Interna, Hospital de Especialidades, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Mexico City, Mexico. 2 División de Investigación en Salud, Hospital de Especialidades, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Mexico City, Mexico. 3 Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico. 4 Escuela Superior de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico. 705

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3 PREMIXED INSULIN ANALOGUE IN HOSPITAL SETTING 707 Table 1. Insulin Treatment Protocols (A) Insulin LM75/25 a regimen: Start total daily insulin dose: 0.2 U/kg of body weight when the admission BG concentration is mg/dl 0.3 U/kg of body weight when the admission BG concentration in between 201 and 400 mg/dl Give two-thirds of the total daily dose before breakfast and one-third before dinner (B) Basal-plus regimen with insulin glargine: Start total daily insulin dose: 0.15 U/kg of body weight when the admission BG concentration is mg/dl 0.2 U/kg of body weight when the admission BG concentration in between 201 and 400 mg/dl Give insulin glargine once daily at the same time of the day (C) In both groups: Discontinue oral antidiabetic drugs on admission Supplemental insulin: Give supplemental insulin lispro following the sliding scale protocol for BG >140 mg/dl Insulin adjustment: If mean BG during the day is between 100 and 140 mg/dl in the absence of hypoglycemia: no change If mean BG during the day is between 140 and 180 mg/dl in the absence of hypoglycemia: increase insulin TDD by 10% every day If mean BG during the day is >180 mg/dl in the absence of hypoglycemia: increase insulin TDD by 20% every day If mean BG during the day is between 70 and 99 mg/dl in the absence of hypoglycemia: decrease insulin TDD by 10% every day If a patient develops hypoglycemia (BG <70 mg/ dl), the insulin TDD should be decreased by 20% BG monitoring: Measure BG before each meal and at bedtime. Diet: Calculated to 25 calories/kg/day (carbohydrates 45%, fat 37%, protein 18%, sodium <2300 mg/ day). (D) Supplemental insulin scale BG (mg/dl) software, version 21. Graphics were prepared with SigmaPlot software, version Results Insulin dose > a Insulin LM75/25, insulin lispro mix 75/25. BG, blood glucose; TDD, total daily dose. From March 25, 2014, to September 26, 2014, a total of 2670 patients were hospitalized in the Department of Cardiology. Of these, 54 patients who met the inclusion criteria provided consent. From this group, 27 patients were randomized to receive insulin LM75/25 and 27 patients to receive basal-plus regimen with glargine. After randomization, two patients from each group were excluded because they received <24 h of insulin treatment. A total of 25 patients in the insulin LM75/25 group and 25 patients in the basal-plus group were included in the final analysis. Clinical characteristics of the study patients are shown in Table 2. There were no significant differences between groups in mean age, sex, body mass index, duration of diabetes, glycated hemoglobin (HbA1c), and length of hospital stay. In both groups, each patient had an average of two comorbid conditions with similar distribution. The admitting diagnoses in the insulin LM75/25 group were ischemic heart disease (80%) and valvular heart disease (20%), whereas the basal-plus regimen diagnoses included ischemic heart disease (72%), cardiac arrhythmia (12%), auricular myxoma (8%), valvular heart disease (4%), and heart failure (4%). None of the patients had a history of nephropathy, neuropathy, or retinopathy. The mean admission glucose for the insulin LM75/25 group was mg/dl and in the basal-plus group was mg/dl (P = 0.235). Changes in glycemic control during the hospital stay are shown in Table 3. Both Variable Table 2. Clinical Characteristics of Study Patients Insulin LM75/25 Basal-plus P No. of patients Gender, n (%) a Male 18 (72) 14 (56) Female 7 (28) 11 (44) Age (years) b BMI (kg/m 2 ) b Duration of diabetes c (years) HbA1c (%) c Serum creatinine (mg/dl) c Diabetes treatment before admission, n (%) Insulin 4 (16) 5 (20) d Insulin plus oral agents 5 (20) 4 (16) d Oral agent monotherapy 2 (8) 5 (20) d Multiple oral agents 14 (56) 11 (44) a Comorbid conditions, n (%) Obesity/overweight 22 (88) 17 (68) a Hypertension 14 (56) 16 (64) a Previous ischemic 13 (52) 12 (48) a heart disease Dyslipidemia 8 (32) 10 (40) a Other 4 (16) 8 (32) d Admitting diagnoses, n (%) Ischemic heart disease 20 (80) 18 (72) a Valvular heart disease 5 (20) 1 (4) d Cardiac arrhythmia 0 3 (12) Auricular mixoma 0 2 (8) Heart failure 0 1 (4) Hospital stay (days) b a Comparison of proportions by v 2 test. b Comparison between medians by Mann Whitney U test. c Comparison between means by Student s t test for independent samples. d Comparison of proportions by Fisher exact test. BMI, body mass index; HbA1c, glycated hemoglobin.

4 708 GRACIA-RAMOS ET AL. Table 3. Glycemic Control, Insulin Therapy, and Hospital Complications in Patients Treated with Insulin Lispro Mix 72/25 (LM75/25) and Basal-Plus Regimen Insulin LM75/25 Insulin glargine P Glycemic control Admission BG (mg/dl) a BG reading during therapy (mg/dl) After the 1st day a After the 2nd day a After the 3rd day a After the 4th day a After the 5th day a After the 6th day a BG at follow-up (mg/dl) a BG range at follow-up, n (%) mg/dl 18 (72) 14 (56) b >140 mg/dl 7 (28) 11 (44) BG difference between the beginning and the end a of treatment (mg/dl) BG registered at different times of the day (mg/dl) Fasting BG <0.001 a,c Before lunch BG a,c Before dinner BG a Bedtime a,c Total dose of insulin (U/kg) <0.001 a,c Patients with hypoglycemia d Hypoglycemic events b a Comparison between means by Student s t test for independent samples. b Comparison of proportions by v 2 test. c Value with significance level (P = 0.05). d Comparison of proportions by Fisher exact test. treatment regimens resulted in prompt and sustained improvement in mean daily BG concentration during the hospital stay, showing similar improvement in daily BG after the first day of therapy but without significant difference (Fig. 1). The percentage of subjects who achieved a mean BG between 70 and 140 mg/dl was higher in the insulin LM75/25 group (72%) than in the basal-plus group (56%); however, the difference was not statistically significant (P = 0.239). The mean BG concentration at the end of follow-up was mg/dl in the insulin LM75/25 group and mg/dl in the basal-plus group, but without significant difference (P = 0.153). The difference between the mean admission glucose and the mean BG at follow-up was mg/dl in the insulin LM75/25 regimen and mg/dl in the basal-plus regimen. These results were significant for each group (both groups with P < 0.001) but not when compared between groups (P = 0.086). According to the BG registered at different times of the day, when analyzing each of the groups, there was no difference in mean glucose in the group treated with insulin LM75/25, whereas in the group treated with insulin glargine, the glucose reported at breakfast was lower than that recorded before lunch and bedtime (Fig. 2). Compared with insulin LM75/25, treatment with the basal-plus regimen was associated with lower BG before breakfast ( vs mg/dl, P < 0.001) but was higher before lunch ( vs mg/dl, P = 0.047) and bedtime ( vs mg/dl, P = 0.002). There was no difference in BG before dinner between groups ( mg/dl in the insulin LM75/25 group and mg/dl in the insulin glargine group, P = 0.536). Total daily dose of insulin (U/kg) was higher in the insulin LM75/25 group ( U/kg) than in the basal-plus group ( U/kg; P < 0.001). There was no difference in the supplemental doses of insulin lispro during the hospital stay in both groups. Hypoglycemia (BG <70 mg/dl) occurred in four patients (16%) in both groups (P = 0.649). Of the 568 glucose readings in the insulin LM75/25 group, there were seven (1.2%) glucose values <70 mg/dl, whereas in the 532 glucose readings in the basal-plus regimen, there were 10 (1.9%) glucose values <70 mg/dl (P = 0.529). In both groups, no glucose values <40 mg/dl were recorded. In all cases, hypoglycemia was corrected with oral dextrose and no episodes were associated with adverse outcomes. Discussion This is the first randomized prospective trial comparing the efficacy and safety of a premixed insulin analogue (insulin lispro mix 25, 75% insulin lispro protamine suspension, 25% lispro) with basal-plus regimen with insulin glargine once daily plus corrective doses with lispro before meals in hospitalized patients with T2D. We observed similar improvements in glycemic control in both groups with no differences in the mean daily BG, number of BG readings within aim of treatment, and number of hypoglycemic events. Hyperglycemia in hospitalized patients is a common, serious, and costly healthcare problem. 22 Evidence from observational and interventional studies indicates that hyperglycemia in critical and noncritical illness is associated with an increased risk of complications such as infections,

5 PREMIXED INSULIN ANALOGUE IN HOSPITAL SETTING 709 FIG. 1. Changes in mean daily blood glucose concentration between patients treated with insulin lispro mix 75/25 (LM75/ 25) and basal-plus regimen with glargine (mean standard error). prolonged hospital stay, disability after hospital discharge, and death Randomized clinical trials in critically ill and noncritically ill patients have reported that improved glycemic control can reduce the number of hospital complications Based on this, clinical guidelines from professional organizations recommend the use of subcutaneous insulin as the preferred therapy for glycemic control in hospitalized patients in a non-icu setting The most recommended regimen is the basal-bolus insulin therapy. However, this regimen requires subcutaneous administration of basal insulin once or twice daily in combination with prandial and corrective doses of rapid-acting insulin given before meals. The complexity of this approach has limited its acceptance among physicians Another scheme is the basal-plus regimen, which consists of a single daily dose of basal insulin with supplemental (corrective) doses of rapidacting insulin analogues before meals. This has a similar efficacy and safety as the basal-bolus regimen. 30,31 However, the basal-plus scheme does not provide prandial coverage of insulin. Therefore, we tested the use of insulin LM75/25 with the hypothesis that use of a premixed insulin analogue is a convenient insulin regimen by providing bolus insulin with meals through a rapid-action component and by fulfilling basal insulin requirements through a protaminated slower release component, and may represent an alternative to the use of the basal-plus regimen in hospitalized subjects with T2D. In the current study, we found that treatment with premixed insulin analogue resulted in similar glucose control as the basal-plus regimen with a prompt and sustained improvement in mean daily BG after the first day of therapy, with a BG aim <140 mg/dl in >70% of patients. These results are similar to those reported in other studies. The basal-plus trial compared the efficacy and safety of a daily dose of glargine plus corrective doses with glulisine before meals against a standard basal-bolus regimen and sliding scale regular insulin in medical and surgical patients with T2D. There was a significant improvement in mean daily BG after the first day of therapy in the intervention groups ( mg/dl for the basal-plus group and mg/dl for the basal-bolus group, P = NS). BG aim of <140 mg/dl was achieved in less than half of those groups. 30 A recent study by Bellido et al. compared the efficacy and safety of a premixed human insulin regimen (30% regular insulin and 70% NPH insulin) twice daily with basal-bolus regimen (glargine once daily and glulisine before meals) in medical and surgical patients with T2D and reported a mean daily BG level after the first day of insulin treatment of and in the premixed human insulin and basal-plus regimens, respectively, with a BG aim between 80 and 180 mg/dl achieved in 54.3% and 55.9%, respectively. 36 In other studies with the basal-bolus scheme, the mean daily BG level after the first day has been reported to range from 145 to 160 mg/ dl with a BG aim <140 mg/dl in a range from 45% to 76%. 15,21,22,25,37

6 710 GRACIA-RAMOS ET AL. FIG. 2. Comparison in the blood glucose registered at different times of the day between the insulin lispro mix 75/25 (LM7525) group and the basal-plus group with glargine (mean standard error). *P < Hypoglycemia is an undesirable side effect in hospitalized patients treated with insulin and has potentially harmful outcomes. 38 Hypoglycemia is also the leading limiting factor in improving glycemic control in patients with diabetes. 39 The incidence of hypoglycemia in noncritical patients treated with insulin has been reported to range from 0.2% to 64.1%. 15,21 25,30,36 In agreement with previous studies, 15,21,22,30 we show that the use of insulin LM75/25 is well tolerated with a low rate of hypoglycemia (BG <70 mg/dl in 16% of patients). There were no patients with severe hypoglycemia (BG <40 mg/dl). However, in the study by Bellido et al., hypoglycemia occurred in 64.1% of patients treated with premixed human insulin regimen during the hospital stay, which resulted in the interruption of the study according to their safety protocol (prespecified stopping rule of >50% of hypoglycemic events). 36 The higher rate of hypoglycemia with the use of premixed human insulin compared with the treatment with premixed insulin analogue in our study is likely the result of a higher dose of insulin ( U/kg for the premixed human insulin vs U/kg for the premixed insulin analogue). Furthermore, the pharmacokinetic profile of premixed insulin analogue has less intraindividual variability with a greater glucoselowering activity and lower risk of hypoglycemia than premixed human insulins Minimizing the rate of hypoglycemic events is of major importance in hospitalized patients because it has been shown to be an independent risk factor of poor clinical outcome. 38 With respect to the insulin dose used in our study, the dose received in the insulin LM75/25 group was similar to the conservative protocol used by Buchs et al. 23 and the insulin glargine dose was calculated according to the proportion of basal insulin received in the insulin LM75/25 group. In both treatment groups, the insulin dose was lower than that used in other studies, but the efficacy and safety in the two schemes was similar to those studies. 21,22,25,30,36,37 The lower insulin glargine dose perhaps also explains the lack of differences between groups and the higher value of glucose before lunch and dinner. However, our findings are similar to those found in the basal-plus trial, in which the basal-plus regimen used half of the insulin dose used in the basal-bolus scheme and both regimens resulted in similar glycemic control with a low rate of hypoglycemia. 30 An important point to consider for the application of insulin in a hospital setting is the changes in oral intake and insulin requirements. In individuals with lack of oral intake or fasting periods, administration of the basal-plus scheme may be preferable. However, if the patient is able to eat without difficulty and does not need fasting, administration of a premixed insulin analogue may be an option. We recognize several limitations to the study, including the relatively small number of patients recruited and the fact that the study was conducted in a single institution with patients only from a single clinical department. The study also excluded patients admitted to or expected to require ICU admission, patients undergoing cardiac surgery, those with

7 PREMIXED INSULIN ANALOGUE IN HOSPITAL SETTING 711 corticosteroid therapy, clinically relevant hepatic disease (Child Pugh score B or C) or impaired renal function (serum creatinine 2.0 mg/dl), and pregnant patients. We also excluded patients with severe hyperglycemia (>400 mg/dl) and patients who were receiving a total dose of insulin >0.4 U/kg/ day before admission. For such patients, higher insulin doses or a standard basal-bolus approach may be the preferred approach in achieving glycemic control. In addition, our study was not powered to determine differences in hospital complications across groups and the estimated sample size was possibly insufficient to measure the impact of secondary outcomes. A large, prospective, randomized multicenter clinical trial of glycemic control is certainly needed to address these important issues. These studies should include additional treatment regimens such as the use of basal-bolus regimen with analogue or human insulin and premixed human insulin. In summary, the results of our pilot study indicate that the inpatient use of a premixed insulin analogue (LM72/25) resulted in a similar improvement in glycemic control and hypoglycemic outcomes compared with the basal-plus regimen. These results indicate that premixed analogue insulin may be an effective alternative in the management of hyperglycemia in hospitalized patients with T2D. However, this result should be interpreted with caution because it included a relatively small number of patients. Further larger controlled studies are needed to validate these findings. Acknowledgments The authors thank the contribution of Dr. Joaquin Vargas Peñafiel, who collaborated in the conduction of this study, and Dr. Alejandro Correa Flores, who contributed with his expertise and knowledge. Also, the authors thank Nutritionist Luz Maria Graciela Cuellar Vazquez, for her close cooperation in the nutritional care of the patients. Author Disclosure Statement No competing financial interests exist. References 1. International Diabetes Federation: Diabetes Atlas, 7th ed. Brussels: International Diabetes Federation, (accessed January 5, 2016). 2. Van den Bergue G, Wilmer A, Milants I, et al.: Intensive insulin therapy in mixed medical/surgical intensive units: benefit versus harm. Diabetes 2006;55: Umpierrez GE, Isaacs SD, Bazargan N, et al.: Hyperglucemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002;87: McAllister FA, Majumdar SR, Blitz S, et al.: The relation between hyperglycemia and outcomes in 2,471 patients admitted to the hospital with community-acquired pneumonia. 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