The effects of sitagliptin add-on on insulin resistance, beta cell function in patients with type 2 diabetes who were taking oral hypoglycemic agent – Le Thi Viet Ha

Journal of military pharmaco-medicine n 0 8-2018 142 THE EFFECTS OF SITAGLIPTIN ADD-ON ON INSULIN RESISTANCE, BETA CELL FUNCTION IN PATIENTS WITH TYPE 2 DIABETES WHO WERE TAKING ORAL HYPOGLYCEMIC AGENT Le Thi Viet Ha1; Doan Van De2 SUMMARY Objectives: To evaluate the effects of sitagliptin add-on on insulin resistance and beta cell function in patients with type 2 diabetes who were taking other oral hypoglycemic agent(s). Subjects and method: 101 patients with type 2 diabetes mellitus diagnosed by WHO (1998) criteria, who were taking hypoglycemic agent(s) other than dipeptidyl peptidase-4 inhibitors. The study compared insulin resistance and beta-cell function assessed with HOMA2 before and after sitagliptin to other oral hypoglycemic agent(s) in type 2 diabetic patients for those 2 periods: Received 50 mg of sitagliptin for week 1 to 12, and 100 mg for week 13 to 24. Results: The mean age was 54.13 ± 10.11 years old, the female and male mad up 52.5% and 47.5%, respectively. The mean fasting plasma glucose and HbA1c was 8.62 ± 1.67 mmoL/L and 7.93 ± 0.83%, respectively. After 24 weeks, fasting plasma glucose, HbA1c and fasting plasma C-peptide level decreased by 1.91 ± 1.90 mmoL/L, 1.45 ± 1.0% and 0.34 ± 0.28 nmoL/L, respectively. The HOMA2-IR assessed by C-peptide (HOMA2-IR-Cp) decreased by 1.04 ± 0.81 and HOMA % B assessed by C-peptide (HOMA2- %B-Cp) increased by 14.90 ± 34.55%. All the changes were statistically significant. After 24 weeks, the percentage of patients with increased HOMA2-IR-Cp decreased from 93.1% (baseline) to 78.2%, and the percentage of patients with decreased HOMA2-%B-Cp decreased from 69.0% to 50.6%. The both changes were statistically significant. Conclusion: Sitagliptin addition to other hypoglycemic agent(s) in patients with type 2 diabetes improved beta-cell function and decreased insulin resistance along with improved blood glucose levels. * Keywords: Type 2 diabetes; Sitagliptin; Insulin resistance; Beta cell function. INTRODUCTION Until now, at least 8 pathological mechanisms of type 2 diabetes mellitus (T2DM) have been revealed, including insulin resistance, beta cell function failure, decreased secretion of incretins or decreased response of beta and alpha cells to incretins. Dipeptidyl peptidase-4 (DPP-4) inhibitors are relatively new hypoglycemic agents that prolonge existence of endogenous incretins in blood, which in turn stimulate insulin secretion and supress glucagon one in glucose-dependent manner [5]. Numerous studies around the world have demonstrated that these drugs improve blood glucose control and sitagliptin is an 1. National Hospital of Endocrinology 2. 103 Military Hospital Corresponding author: Le Thi Viet Ha (drvietha72@gmail.com) Date received: 05/08/2018 Date accepted: 27/09/2018 Journal of military pharmaco-medicine n 0 8-2018 143 agent of this class also improve insulin resistance [6]. However, until now, in Vietnam there has been no study evaluating effects of add-on of DDP-4 inhibitors on insulin resistance and beta cell functions in patients with T2DM who were taking other hypoglycemic agents. Therefore, we conducted the present study to: Evaluate the effects of sitagliptin add-on on insulin resistance, beta cell function in patients with type 2 diabetes who were taking oral hypoglycemic agent(s). SUBJECTS AND METHODS 1. Subjects. 101 patients with T2DM diagnosed by WHO (1998) criteria [1] who were taking hypoglycemic agent(s) other than DPP- 4 inhibitors. * Inclusion criteria: The patients with T2DM were recruited in the study if they met all the following: - HbA1c ranged from 7.0% to 10.0%. - Fasting plasma glucose (FPG) < 16 mmoL/L. - Currently use of hypoglycemic agent (s) (other than DPP-4 inhibitors) in stable doses for at least last 3 months before the recruitment. - Giving consent to participate in the study. * Exclusion criteria: Patients were excluded if they had any of the following: - Severe or acute illness such as coma or pre-coma, unstable angina pectoris, acute stroke, acute myocardial infarction, cachexia. - Stage III or higher of chronic kidney disease. - Liver enzyme levels ≥ 3 times of the upper normal limits. - Current use of any of DPP4 inhibitors, GLP-1 receptor agonists or insulin. - Refuse to participate in the study. 2. Methods. * Study design: The study examined changes of insulin resistance and beta cell fuction after adding of sitagliptin for 24 weeks to other hypoglycemic agents in patients with T2DM. The hypoglycemic agent(s) and their doses were remained unchanged for the whole study. Sitagliptin was started with a daily dose of 50 mg or 100 mg that was maintained for the first 12 weeks. For the next 12 weeks, the daily dose increased from 50 mg to 100 mg or decreased from 100 mg to 50 mg if HbA1c in week 12 was above 7% or below 6.5%, respectively. * Sample collection: Any eligible patient was recruited until the sufficient number. * Information collection: Age, sex, BMI, FPG, HbA1c, fasting plasma C-peptide (FPC) at baseline and in week 24. HOMA2 indices were calculated based on FPG (mmoL/L) and FPC (nmoL/L) levels with HOMA2 calculator, version 2.2.3 (2013) by Oxford University (the United Kingdom): HOMA2 for beta cell function Journal of military pharmaco-medicine n 0 8-2018 144 (HOMA2-%B-Cp) and HOMA2 for insulin resistance (HOMA2-IR-Cp) [2]. Insulin resistance state was defined if HOMA2-IR-Cp was above 75th percentiles of HOMA2-IR-Cp of the control (WHO 1999 criteria) [3]. Beta cell function decrease was defined if HOMA2-%B-Cp was below the mean - 1 SD of HOMA2-%B-Cp of the controls. * Data analyses: SPSS 20.0 was used to calculate mean values and rates, compare mean values by t-test and paired t-test. RESULTS 1. Baseline characteristics Table 1: General characters of subjects. Characters Patients (n= 101) Percents Male 48 47.5 Female 53 52.5 General (n) % 101 100.0 Mean ± SD age 54.13 ± 10.11 Mean ± SD year 2.4 ± 3.4 Percents (%) < 5 year 84.1% A total of 101 patients with type 2 diabetes participated were eligible in the study, including 48 men (47.5%) and 53 women (52.5%). Mean age was 54.1 ± 10.1 years. Mean diabetes duration was 2.4 ± 3.4 years. Most patients had diabetes for less than 5 years (84.1%). Table 2: Blood glucose indices, insulin resistance and beta cell function. Indices (n = 101) Value FPG (mmoL/L)* 8.62 ± 1.67 FPG target achievement [% (n)] 81.2 (82) HbA1c (%)* 7.93 ± 0.83 FPC (nmol/l)* 1.16 ± 0.36 Increased FPC [% (n)] 89.1 (90) HOMA2-IR-Cp* 3.03 ± 0.97 Increased HOMA2-IR-Cp [% (n)] 91.1 (92) HOMA2-%B-Cp* 73.51 ± 25.14 Decreased HOMA2-%B-Cp [% (n)] 81.2 (82) (* Mean ± SD) * Use of hypoglycemic agent(s) before the study: Before the study all the patients took oral hypoglycemic agents, as metformin monotherapy or metformin and sulfonylurea in 60.4% (61 patients) and 39.6% (40 patients), respectively. 2. Changes of blood glucose indices, insulin resistance and beta cell function. Table 3: Use of sitagliptin during the study. Sitagliptin use Weeks 1 to 12 n (%) Week 13 to 24 n (%) p Sitagliptin 50 mg/day 24 (23.8) 27 (26.7) > 0.05 Sitagliptin 100 mg/day 77 (76.2) 74 (73.3) > 0.05 Mean ± SD (mg/day) 88.1 ± 21.4 86.6 ± 22.2 > 0.05 Journal of military pharmaco-medicine n 0 8-2018 145 All the patients took daily 50 mg or 100 mg of sitagliptin for the whole study. For the first 12 weeks daily dose of 50 mg and 100 mg was used in 23.8% and 76.2% of the patients, respectively. For the second 12 weeks, the former and the latter dose was used in 26.7% and 73.3%, respectively. The changes were not significant. Table 4: Changes of blood mean values of glucose indices, fasting plasma C-peptide, HOMA2-%B-Cp and HOMA2-IR-Cp after 24 weeks. Index Baseline (n = 87) Week 24 (n = 87) Changes (%) p FPG (mmoL/L) 8.50 ± 1.61 6.59 ± 0.95 -1.91 ± 1.90 < 0.001 HbA1c (%) 7.87 ± 0.82 6.41 ± 0.74 -1.45 ± 1.00 < 0.001 FPC (nmoL/l) 1.18 ± 0.36 0.84 ± 0.19 -0.34 ± 0.28 < 0.001 HOMA2-%B-Cp (%) 76.06 ± 25.16 90.96 ± 27.51 14.90 ± 34.55 < 0.001 HOMA2-IR-Cp 3.07 ± 0.97 2.03 ± 0.49 -1.04 ± 0.81 < 0.001 After 24 weeks, FPG, HbA1c, fasting plasma C-peptide and HOMA2-IR-Cp significantly decreased. In contrary, HOMA2-%B-Cp significantly increased. Table 5: Changes of the rates of increased HOMA2-IR-Cp and decreased HOMA2- %B-Cp after 24 weeks. Index Baseline (n = 87) Week 24 (n = 87) p Increased HOMA2-IR-Cp (> 1,650) 81 (93.1) 68 (78.2) 0.001 Decreased HOMA2-%B-Cp (< 88.48%) 60 (69.0) 44 (50.6) < 0.01 After 24 weeks, the rate of increased HOMA2-IR-Cp significantly diminished. In contrary, the rate decreased HOMA2-%B-Cp significantly declined. DISCUSSION 1. Baseline characteristics of patients. The percentage of men and women was not different in the study. The rate of type 2 diabetes is changed in with research and geographical areas. T2DM in patients was not controlled with oral hypoglycemic monotherapy or combination not including DPP-4 inhibitors, found that FPG and HbA1c did not achieve treatment goals, similar to other studies in the country [2]. This may be due to diabetes over 5 years and FPG control is difficult due to outpatient treatment. The mean HOMA2-IR-Cp was 3.03 ± 0.97 and the rate of increased HOMA2- IR-Cp was 91.1%, that were similar to the above cited others study [1, 2]. The mean HOMA2-%B-Cp was 73.51 ± 25.14% that was higher in comparison to the study by Nguyen Thi Thu Thao and the study by Nguyen Thi Ho Lan reporting the mean Journal of military pharmaco-medicine n 0 8-2018 146 HOM2-%B-Cp of 51.91 ± 37.41 ng/mL and 47.1 ± 36.6 ng/mL, respectively. This suggests that ß-cell function decreased and increased insulin resistance may be due to patients being studied for type 2 diabetes. All the patients used hypoglycemic agent(s) before the start of the study. About two thirds of the patients (60.4%) used metformin alone and the rest (39.6%) combination of metformin and sulfunylurea. All the hypoglycemic agent(s) and their doses that had been used before the stusy remained unchanged for the whole study period. All the patients took daily 50 mg or 100 mg of sitagliptin for the whole study. For the first 12 weeks daily dose of 50 mg and 100 mg was used in 23.8% and 76.2% of the patients, respectively. For the second 12 weeks, the former and the latter daily dose was used in 26.7% and 73.3%, respectively, which resulted in a decrease of mean daily dose from 88.1 mg to 86.6 mg, however, all the changes were not significant. 2. Changes of blood glucose indices, insulin resistance and beta cell function after adding sitagliptin. After 24 weeks of sitagliptin add-on, there were significant improvements in blood glucose control, insulin resistance and beta cell function. Compared to the baseline, after 24 weeks FPG and HbA1c significantly decreased by 1.91 ± 1.90 mmoL/L and 1.45 ± 1.0%, respectively. FPC significantly decreased by 0.34 ± 0.28 nmoL/L. The beta cell function markedly improved as that the mean HOMA-%B-Cp significantly raised by 14.90 ± 34.55% from 76.06 ± 25.16% to 90.96 ± 27.51%, and the rate of decreased HOMA2-%B-Cp significantly declined from 69.0% to 50.6%. In the contrary, the insulin resistance status substantially diminished as that the mean HOMA2-IR- Cp significantly decreased by 1.04 ± 0.81, from 3.07 ± 0.97 to 2.03 ± 0.49, the rate of increased HOMA2-IR-Cp significantly declined from 93.1% to 78.2%. Numerous studies abroad have demonstrated blood glucose, insulin resistance and beta cell function improving effects of sitagliptin when added to other hypoglycemic agents [4, 5]. Charbonnel et al compared addition of daily 100 mg of sitagliptin with placebo in 245 T2DM patients who had a mean HbA1c of 8% and were taking a stable metformin daily dose of 1,500 mg [6]. After 24 weeks, FPG and HbA1c in the sitagliptin group significantly decreased by 0.9 mmoL/L and 0.67% (p < 0.001 for both), respectively; HOMA-%B significantly increased by 19.5% (p < 0,001), insulin sensitivity index QUICKI significantly increased by 0.003 (p < 0,010). Meanwhile FPG in the control group FPG significantly increased by 0.5 mmoL/L, and HbA1c, HOMA-%B and QUICKI did not significantly change. Hermansen et al compared addition of daily 100 mg of sitagliptin with placebo in 441 T2DM patients with baseline HbA1c of 8.34%, who were on glimepiride alone or combination with metformin [7]. After 24 weeks, the sitagliptin group had HbA1c reduction by 0.74% and HOMA-%B increase by 12% relatively to the placebo one. In a meta-analysis from 6 studies of effects of different DPP-4 inhibitors on insulin resistance, only sitagliptin significantly Journal of military pharmaco-medicine n 0 8-2018 147 decreased insulin resistance by a weighted mean reduction of 0.38 (95%CI: -0.69, -0.08) [8]. The favorable effects of DPP-4 inhibitors, including sitagliptin, for improving beta- cell function among patients with T2DM are biologically plausible. DPP-4 inhibitors prolong endogenous incretins existence in blood by suppressing DPP-4. Prolonged blood Incretins stimulate beta cell secret insulin and may restore beta-cell function and survival. In respect to effects on insulin resistance, only sitagliptin, but not the other DPP-4 inhibitors, could significantly improve insulin resistance. This finding needs to be confirmed in future studies. CONCLUSION In patients with T2DM uncontrolled with metformin alone or its combination with other oral hypoglycemic agents, add-on of DPP-4 inhibitor sitagliptin for 24 weeks resulted in significant improvement of beta cell function and insulin resistance in addition to improvement in blood glucose. Suggestions DPP-4 inhibitors should be early added in treatment of patients with T2DM uncontrolled with metformin alone or its combination in order to improve beta cell function and insulin resistance, which result in improvement of blood glucose. REFERENCES 1. Tạ Văn Bình. Những nguyên lý nền tảng bệnh đái tháo đường tăng glucose máu. Nhà xuất bản Y học. Hà Nội. 2007, tr.18-19. 2. Nguyen Thi Ho Lan. Study of blood glucagon like peptide-l levels in patients with type diabetes mellitus in National Hospital of Endocrinology. Thesis of Grade II Specialty Physician. 2015. 3. Nguyen Thi Thu Thao. 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