Effects Of Sitagliptin As Add-On Blood Glucagon Level In Patients With Type 2 Diabetes - Le Thi Viet Ha

Journal of military pharmaco-medicine n o 3-2019 112 EFFECTS OF SITAGLIPTIN AS ADD-ON BLOOD GLUCAGON LEVEL IN PATIENTS WITH TYPE 2 DIABETES Le Thi Viet Ha1; Doan Van De2 SUMMARY Objectives: To evaluate the effects of dipeptidyl peptidase-4 inbibitors sitagliptin as add-on blood glucagon in patients with type 2 diabetes inadequately controlled with oral antidiabetic drug monotherapy or combination. Subjects and methods: An intervention study was conducted on 101 adult patients with type 2 diabetes inadequately controlled with oral antidiabetic drug monotherapy or combination other than dipeptidyl peptidase-4 inhibitors with HbA1c from 7 to 10%. The outcome measures were fasting plasma glucose, 2 hour postprandial glucose and HbA1c that were assessed at the baseline after 12 weeks. A dipeptidyl peptidase-4 inhibitor was started with a half or full dose for the first 12 weeks and could increase to full dose for the last 12 weeks if started as half dose. The other oral antidiabetic drug and their doses were kept unchainged during the whole study. Results: The mean age and diabetes duration was 54.1 ± 10.1 and 2.4 ± 3.4 years, respectively. Before the study start, metformin monotherapy was used by 60.4% of patients, and the most used combination was metformin plus sulfonylurea (39.6% of all the patients). Sitagliptin was the only used dipeptidyl peptidase-4 inhibitor with mean dose of 88.1 mg/day and 86.6 mg/day for the first and second 12 weeks. After 12 weeks, compared to the baseline, the mean fasting plasma glucagon decreased by 13.63 pg/ml, respectively (p < 0.001) and the proportion of patients achieving American Diabetes Association 2015 fasting plasma glucose, 2 hour postprandial glucose and HbA1c targets significantly increased from 18.8%, 11.9% and 0% to 69.3%, 78.2% và 69.3%, respectively (p < 0.001), the duration of the intervention was 12 weeks. Conclusions: The add-on of the dipeptidyl peptidase-4 inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled with metformin alone or oral antidiabetic drug combinations resulted in improvements of glycemic control for a period of 12 weeks. * Keywords: Type 2 diabetes; Dipeptidyl peptidase inhibitor; Blood glucagon plasma. INTRODUCTION The number of type 2 diabetes is increasing all over the world, especially in the developing countries. It causes numerous severe complications in almost all body organs and systems, in particular eyes, kidneys, nerves, heart and blood vessels. Type 2 diabetes has multiple pathophysiologic defects. Besides the long well known defects such as insulin resistance, beta cell failure and increased hepatic glucose production, relatively new defects have been discovered. Some of them are incretin defects and inappropriately 1. National Hospital of Endocrinology 2. 103 Military Hospital Corresponding author: Le Thi Viet Ha (drvietha72@gmial.com) Date received: 07/12/2018 Date accepted: 18/02/2019 Journal of military pharmaco-medicine n o 3-2019 113 increased glucagon secretion. Multiple pathophysiologic defects and progressive beta cell failure results in failure of multiple old oral antidiabetic drug (OAD) combinations in the long run. It is necessary to develop new antidiabetic drug classes that aim at these new defects and complement the old OADs effects. One of the new OAD classes is dipeptidyl peptidase (DPP)-4 inhibitors that prolong endogenous incretins and are rapidly inactivated by that enzyme. Incretins are gut hormones secreted in response to nutrients (mainly carohydrate). There are two incretins: glucagon like peptide (GLP) - 1 and glucose-dependent insulinotropic peptide (GIP). They simulate insulin release and supress glucagon release in response to a meal in a glucose-dependent manner as well as slow gastric emptying and enhance satiety. Add-on of DPP-4 inhibitors to ongoing different OAD monotherapy or combinations have been shown to improve blood glucose control in numerous studies abroad, but it has not been studied in Vietnam. The present study aims at: Evaluating the effects of DPP-4 inhibitors sitagliptin as add-on therapy on glucose level in patients with type 2 diabetes inadequately controlled with oral antidiabetic drug (OAD) monotherapy or combination in National Hospital of Endocrinology. SUBJECTS AND METHODS 1. Subjects. Patients with type 2 diabetes diagnosed by American Diabetes Association (ADA) 2015 criteria and inadequately controlled with OAD(s). - Inclusion criteria: + Type 2 diabetic patients who were treated by oral hypoglycaemic drugs or combination non-DPP-4 combination therapy were given stable doses over 3 months and failed to achieve glycemic control. + The standard has not met the target based on GM from 7 mmol/L to ≤ 16 mmol/L and has HbA1c from 7.0% to ≤ 10%. + No anemia; age of 30 years or above; agreed to participate in research. - Exclusion criteria: + Over 30 years old. + Currently identified as healthy people based on medical history, physical examination and basic biochemical tests. + No risk factors; FPG, HbA1c normal. + Agree to participate in research. 2. Methods. - Study design: This was an uncontrolled trial evaluating effects on blood glucose of DDP-4 inhibitors added to other oral antidiabetic drug monotherapy or combination in patients with type 2 diabetes who did not reach HbA1c target of below 7.0%. Oral antidiabetic drugs and their dosage remained unchanged throughout the follow-up period. Sitagliptin, a DPP-4 inhibitor, is supplemented with a starting dose of 50 or 100 mg once a day. In cases where the dose is increased to 100 mg per day at week 12 if HbA1c remains above 7.0%, if HbA1c is less than 7.0%, the dose should be reduced to 50 mg. Intervention time is 12 weeks. Journal of military pharmaco-medicine n o 3-2019 114 - Sample collection: All the patients who met the inclusion and exclusion criteria were recruited into the study. - Outcomes measures: The patients’ baseline characteristics that were assessed included age, sex, BMI, diabetes duration, use of oral diabetic drugs, and blood glucose control indices (FPG, 2hPPG and HbA1c). The last three measurements were reassessed at weeks 12 and 24. The ADA 2015 targets of blood glucose control were as follows: FPG: 4.4 - 7.2 mmol/L; 2hPPG: < 10 mmol/L; HbA1c < 7.0%. - Statistical analysis: SPSS version 20.0 was used for data analysis. The effects of adding DPP-4 inhibitors on blood glucagon were evaluated by comparing the blood glucagon control indices in weeks 12 at baseline by using fraired t-test, and the rates of achieving blood glucose control targets at those points of time. RESULTS 1. Patients baseline characteristics. A total of 101 eligible patients with type 2 diabetes participated in the study, including 48 men (47.5%) and 53 women (52.5%). The mean age was 54.1 ± 10.1 years, which ranged from above 30 to 79 years, age group 50 - 59 years old accounted for 40.6%. The mean diabetes duration (defined as time period elapsed since diabetes was diagnosed) was 2.4 ± 3.4 years. Most patients had diabetes for less than 5 years (84.1%). Before the invention at baseline, all the patients were on oral antidiabetic drug(s) only (no patients was on insulin). Metformin monotherapy was used by 60.4% and metformin and sulfonylurea combination by 39.6% of the patient. The mean FPG, 2hPPG and HbA1c was 8.62 ± 1.67 mmol/L, 12.36 ± 2.36 mmol/L and 7.93 ± 0.83%, respectively. 2. Baseline plasma glucagon indices. Table 1: Mean indices of plasma in glucagon control and diabetes group. Blood glucagon indices (n = 30) Control (n = 30) Diabetis (n = 30) p ( X ± SD) 34.29 ± 4.41 70.86 ± 12.73 < 0.001 Upper limit ( X ± SD 29.88 Decreased (< 29.88) 4 (13.3%) 0 (0.0%) Nomal (29.88 - 38.70) 22 (73.3%) 0 (0.0%) Glucagon (pg/mL) Increased (> 38.70) 4 (13.3%) 30 (10.0%) < 0.001 The mean plasma glucagon was 70.86 ± 12.73 pmol/mL, increased to 100.0%. Journal of military pharmaco-medicine n o 3-2019 115 3. Correlation between FPG, 2hPPG, HbA1c with plasma glucagon. Table 2: Correlation between FPG, 2hPPG, HbA1c with plasma glucagon indices baseline. Indices (Y) Correlate r p FPG (mmol/L) Y = 4.982X + 26.818 0.682 < 0.001 2hPPG (mmol/L) Y = 2.564X + 36.969 0.498 < 0.01 HbA1c (%) Y = 10.1X - 6.316 0.568 < 0.01 Fasting plasma glucagon correlated with FPG, 2hPPG, HbA1c at the beginning with statistical significance. 4. The effects of adding DPP-4 inhibitors on blood glucose weeks 12 compared with baseline. Patients using oral hypoglycemic agents did not change during the study period. All patients use sitagliptin 50 mg or 100 mg per daily. Table 3: Changes of blood glucose indices and fasting plasma glucagol at week 12 compared with baseline. Blood glucose indices Baseline Week 12 Changes p FPG (mmol/L) (n = 101) 8.62 ± 1.67 6.92 ± 1.69 -1.70 ± 2,06 < 0.001 2hPPG (mmol/L) (n = 101) 12.36 ± 2.36 9,56 ± 1.19 -2.80 ± 2.26 < 0.001 HbA1c (%) (n = 101) 7.93 ± 0.83 6.72 ± 0.86 -1.21 ± 0.86 < 0.001 Glucagon (pg/mL) (n = 30) 70.86 ± 12.73 57.23 ± 14.76 -13.63 ± 9.60 < 0.001 (Values are mean ± SD) Compared with the baseline values, the mean FPG, 2hPPG and HbA1c at week 12 decreased by 1.70 ± 2.06 mmol/L, 2.80 ± 2.26 mmol/L and 1.21 ± 0.86 mmol/L. Compared with the baseline values, the mean plasma glucagon at week 12 decreased by 13.63 ± 9.60 pg/mL, significant statistically with p < 0.001. 5. Correlation between FPG, 2hPPG, HbA1c with plasma glucagon at 12 week. Bảng 4: Indices (Y) Correlation r p FPG (mmol/L) Y = 5.513X + 19.062 0.763 < 0.001 2hPPG (mmol/L) Y = 4.577X + 12.573 0.496 < 0.01 HbA1c (%) Y = 8.708X + 1.181 0.454 < 0.05 Fasting plasma glucagon correlated with FPG, 2hPPG, HbA1c at 12 week, which was statistically significant. Journal of military pharmaco-medicine n o 3-2019 116 Table 5: Correlation between the variation of plasma glucagon at the change with FPG, 2hPPG, HbA1c after 12 weeks. Indices (Y) Correlation r p* FPG (mmol/L) Y = 3.47X + 7.681 0.729 < 0.001 2hPPG (mmol/L) Y = 0.766X + 11.681 0.215 > 0.05 HbA1c (%) Y = 3.555X + 10.078 0.345 > 0.05 The variation of the plasma glucagon levels correlated with the change of with FPG, respectively, but did not correlate with the changes of 2hPPG, HbA1c after 12 weeks. DISCUSSIONS 1. Baseline patients’ characteristics. The increased overweight or obese prevalence in patients with type 2 diabetes may reflect the tendency in our general population over time. 84.1% of patients had short duration of diabetes less than 5 years. Only small proportion of patients had diabetes for more than 10% (5%). The baseline mean FPG, 2hPPG, HbA1c was 8.62 mmol/L, 12.36 mmol/L, 7.93%, respectively. Most patients did not achieve ADA 2015 PFG and 2hPPG targets that were 81.2% and 88.1%, respectively. All the patients had baseline HbA1c > 7%. Most patients in our study were outpatients so their blood glucose control was better than inpatients’ one in other domestic studies. In a study by Nguyen Thi Ho Lan, in type 2 diabetes patients treated at National Hospital of Endocrinology (NHoE), the baseline mean FPG and HbA1c was 12.1 mmol/L and 9.8%; in Nguyen Thi Duyen’s study, they were 10.32 mmol/L and 9.29%, respectively [1, 2 ]. 2. Use of OAD during the study. Before the intervention, all the patients were on oral antidiabetic drug(s) only (no patient was on insulin). 60.4% of patients used metformin monotherapy and 39.6% of patients used metformin and sulfonylurea combination. 3. Correlation between FPG, 2hPPG, HbA1c with fasting plasma glucagon baseline. We found that the correlation between fasting plasma glucagon and fasting plasma glucose and HbA1c in the initial group of patients, the initial fasting plasma glucagon correlated well with the severity, which was statistically significant with blood glucose at fasting. This result suggests that fasting blood glucagon may be one of the factors that contribute to hyperglycaemia. This finding is not similar to other authors’: In the control group, study by Nguyen Thi Duyen, serum glucagon concentration was moderately correlated with glucose concentration, r = 0.336, p < 0.05, in the diabetic group, there was no statistically significant correlation between Journal of military pharmaco-medicine n o 3-2019 117 fasting serum glucose concentrations and glucose concentrations (p > 0.05). Taborsky GJ et al (2010) studied the physiologic effect of glucagon and showed that when endogenous glucagon levels increased glucose production from the liver, primarily by the glucose- degrading pathway, eg (10 pg/mL) endogenous glucagon will increase glucose production from the liver by about 25%. Thus, glucagon excretion within the physiological limits is responsible for controlling glucose production within the physiological limits of the body. Because the blood glucose of the study group was higher than that of the control group, which may indicate elevated glucagon secretion, not only in fasting but also after meals. This may explain the association between fasting glucagon and postprandial glucose as well as HbA1c. 4. Effects of add-on of DPP-4 inhibitors on blood glucose. In our study, effects of the add-on of sitagliptin on the patients who were already on other OAD monotherapy or combinations, their blood glucose control substantially improved with significant reductions of the mean FPG, 2hPPG and HbA1c, and high proportion of the patients achieved blood glucose indices targets. After 12 weeks, compared with the baseline, FPG, 2hPPG and HbA1c significantly decreased by 1.7 ± 2.06 mmol/L, 2.8 ± 2.26 mmol/L and 1.21 ± 0.86%, respectively. Compared with the baseline values, the mean glucagon after 12 weeks decreased by -13.63 ± 9.60 pg/mL, significant with p < 0.001. Concerning the blood glucose targets achievement, at week 12, about two thirds of the patients achieved ADA 2015 targets of FPG, 2hPPG and HbA1c. At week 12, 69.3%, 70.3% and 61.4% of the patients achieved the targets of FPG, 2hPPG and HbA1c, respectively, which substantially increases compared with the baseline when the proportion of the patients achieving the targets were only 18.8%, 11.9% and 0%, respectively. Numerous randomized control trials have proved that effects of sitagliptin add- on on other OAD monotherapy (mainly metformin) or combinations improved glycemic control compared with placebo in type 2 diabetes patients not achieving blood glucose targets. Charbonnel et al studied effects of sitagliptin add-on (100 mg/day) on ongoing metformin monotherapy (≥ 1,500 mg/day) in type 2 diabetes patients with mean HbA1c of 8% compared with continued metformin monotherapy alone [3]. After 24 weeks, FPG and HbA1c in the sitagliptin add-on group significantly decreased by 1.4 mmol/L and 0.65% (both p values < 0.001), respectively, compared with those indices in the metformin monotherapy group. A significantly greater proportion of patients achieved an A1C < 7% with sitagliptin (47.0%) than with placebo (18.3%). In a study by Chien et al [7], Taiwanese type 2 diabetes patients (n = 97) were randomized to receive the existing OAD combinations or add-on with sitagliptin (100 mg daily) for 24 weeks. Compared with the change of 0.0% (95% confidence interval: -0.6% to 0.5%) from a baseline of 10.0% in the controlled arm, Journal of military pharmaco-medicine n o 3-2019 118 HbA1c change from a mean baseline of 9.5% was -1.14% ± 1.18 after add-on sitagliptin (p < 0.0001). In randomized controlled trials that combination of sitagliptin and metformin compared with metformin or sitagliptin monotherapy as initial OAD therapy, the former resulted in clearly better glycemic control than the latter. Williams-Herman et al [8] compared different sitagliptin and metformin combinations with sitagliptin or metformin monotherapy in type 2 diabetes drug- naùve patients in a 54 week multinational study. At week 54, the HbA1c reduction was the highest in the combination with high metformin dose (S100/M2000 mg/day), -1.8%, followed by the combination with low metformin dose (S100 mg/M1000 mg/day), -1.4%, monotherapy with higher metformin dose (M2000 mg/day), -1.3%, monotherapy with low metformin dose (M1000 mg/day), -1.0% and monotherapy with sitagliptin (100 mg/day), -0,8%. Similarly, the proportion of patients with an HbA1c < 7% at week 54 were 67%, 48% (S100/M1000), 44%, 25% and 23%, respectively. The extents of effects of adding sitagliptin on existing OAD(s) therapy or those of combinations of sitagliptin and metformin compared to metformin or sitaglitin monotherapy are different from study to study, because patients’ characteristics varied. However, the improvement of glycemic control after adding sitagliptin to existing OAD(s) or better glycemic control of sitagliptin combinations compared with metformin or sitagliptin monotherapy has been proved. The mechanisms of action of DPP-4 inhibitors are different from those of other OAD classes such as biguanide, sulfonylureas and alpha-glucosidase inhibitors. This explains additional effects of adding DPP-4 inhibitors on the other OADs on glycemic control. 5. Correlation between FPG, PPG, HbA1c with fasting plasma glucagon at 12 weeks. In our study, fasting plasma glucagon concentrations were strongly correlated with fasting plasma glucose, postprandial and HbA1c levels prior to treatment with DPP-4 inhibitor. After 12 weeks of supplementation with DPP-4 inhibitors, these correlations were also noted: fasting serum glucagon concentrations were statistically significantly correlated with fasting plasma glucose, postprandial blood glucose and HbA1c. Increased levels of fasting blood glucagon also reflect elevated glucagon secretion, both at the time of fasting and after meals in patients with type 2 diabetes. This suggests that glucagon secretion contributes to hyperglycemia, both after fasting and mean blood glucose levels through HbA1c. Moreover, after 12 weeks of treatment with DPP-4 inhibitor, there was a positive correlation between changes of fasting plasma glucagon and fasting plasma glucose. This adds to the evidence that a decrease in glucagon concentration by inhibiting DPP-4 enzymes may be a contributing factor to fasting plasma glucose. However, after 12 weeks, there was no statistically significant correlation between fasting plasma glucagon changes with postprandial glucose change and HbA1c change. This may be due to Journal of military pharmaco-medicine n o 3-2019 119 increased insulin secretion and the effects of DPP-4 inhibitor which plays a key role in postprandial and postprandial hypoglycemia. CONCLUSIONS The add-on of the DPP-4 inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled with metformin alone or OAD combinations resulted in substantial improvements of glycemic control for a period of 12 weeks. After 12 weeks, compared with the baseline, the mean FPG, 2hPPG and HbA1c significantly decreased by 1.70 mmol/L, 2.80 mmol/L and 1.21%. Compared with the baseline values, the mean glucagon at week 12 decreased by -13.63 ± 9.60 pg/mL, respectively (p < 0.001 for all), the proportions of patients achieving ADA 2015 FPG, 2hPPG and HbA1c targets significantly increased from 18.8%, 11.9% and 0% to 69.3%, 70.3% and 61.4%, respectively, with p < 0.001. REFFERENCES 1. Nguyễn Thi Duyờn. Khảo sỏt nồng độ glucagon huyết tương và mối liờn quan với một số biểu hiện lõm sàng, cận lõm sàng ở bệnh nhõn đỏi thỏo đường týp 2. Luận văn Tốt nghiệp Bỏc sĩ Nội trỳ. 2016. 2. Nguyễn Thị Hồ Lan. Nghiờn cứu nồng độ glucagon like peptide-1 ở bệnh nhõn đỏi thỏo đường týp 2 tại Bệnh viện Nội tiết TW. Luận văn Chuyờn khoa Cấp 2. 2015. 3. Charbonnel B, Karasik A, Liu J et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006, 29 (12), pp.2638-2643. 4. Reasner C, Olansky L, Seck T.L et al. The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2011, 13 (7), pp.644-652. 6. Brazg R, Xu L, Dalla Man C et al. Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes. Diabetes Obes Metab. 2007, 9 (2), pp.186-193. 7. Ming-Nan Chien, Chun-Chuan Lee, Wei-Che Chen et al. Effect of sitagliptin as add-on therapy in elderly type 2 diabetes patients with inadequate glycemic control in Taiwany. International Journal of Gerontology. 2011, 5, pp.103-106. 8. Williams-Herman D, Khatami, Raz I. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Sitagliptin Study 023. Diabetologia. 2006, 49, pp.2564-2571.