TITLE: 
Comparative evaluation of efficacy and safety of combination of metformin-vidagliptin versus metfromin-glimepiride in most frequently used doses in patients of type 2 diabetes mellitus with inadequately controlled metformin monotherapy-A randomised open label study



ABSTRACT.AIM AND OBJECTIVE:
The aim was to evaluate and compare the efficacy and safety of combinations of metformin-vidagliptin (MF-VG) and metfromin-glimepiride (MF-GP) in type 2 diabetes mellitus (T2DM) patients.

ABSTRACT.MATERIALS AND METHODS:
A comparative randomized open-label trial was conducted on patients with uncomplicated T2DM, on treatment with MF for 4 months out of which on maximum tolerated dose of MF (1000-2500 mg/day) for 4 weeks, glycosylated Haemoglobin [HbA1c]) ≥6.5%, fasting blood glucose (FBG) ≥126 mg/dl and post prandial glucose (PPG) ≥200 mg/dl were included in the study. Patients were randomized to receive MF (500 mg BD) + VG (50 mg BD) or MF (500 mg BD) + GP (2 mg BD).

ABSTRACT.RESULTS:
Both the groups caused significant decline in blood glucose levels both FBG as well as PPG levels (P < 0.01). HbA1c was also reduced significantly in both groups at 12 weeks (P < 0.01). Total serum cholesterol, triglycerides, low-density lipoprotein and very low-density lipoprotein decreased significantly, whereas high-density lipoprotein levels increased significantly from baseline levels in both the groups (P < 0.01). Intergroup comparison failed to demonstrate any statistical difference on all of above parameters. Both weight and body mass index did not alter statistically from baseline in either of the groups as well as demonstrated no difference statistically on comparison (P > 0.05). At the end of the study, both liver functions tests and renal functions tests remained unaltered statistically and within normal clinical range in both the groups (P > 0.05). However, hypoglycemia and other adverse events were numerically more in MF + GP group.

ABSTRACT.CONCLUSION:
Both the regimens on comparison revealed similar efficacy and safety thereby failing to prove superiority over each other.

BODY.INTRODUCTION:
Diabetes is one of the most prevalent non-communicable diseases globally demanding continuous research. Approximately one-half or more of patients with type 2 diabetes do not obtain an glycosylated hemoglobin (HbA1c) level lower than 7%[1] and failure rate of 4% with metformin (MF) monotherapy has been recorded.[2] Hence, the patients on MF monotherapy with inadequate response require combination therapy. The combination of MF and sulfonylureas is most commonly used in India because of its low cost and can attain a greater reduction in HbA1c than either drug alone.[3] However, this combination therapy is prone to weight gain and severe hypoglycemia. VG is an oral and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, which lacks these adverse event reports.[4]
There is a scarcity of research comparing the commonly used combinations of MF-glimepiride (MF-GP) and MF-vidagliptin (MF-VG) in clinical practice for management of type 2 diabetes mellitus (T2DM). However, whatever data is available originates from the developed countries. Furthermore, a recent ban in some part of world regulatory and flip flops policy adopted by Indian Drug regulating authorities on pioglitazone is expected to increase the use of gliptins.
Therefore, the current study was undertaken to evaluate and compare the efficacy and safety of combinations of MF-VG and MF-GP in T2DM patients.

BODY.MATERIALS AND METHODS:
A comparative randomized open-label trial was conducted for a period of 1 year commencing from November, 2012. A total of 110 patients from medical outpatient department diagnosed with T2DM were screened for this study. Ninety patients were included after evaluating for inclusion and exclusion criteria, and finally, 84 completed the study as six patients were lost to follow-up. A written informed consent was obtained. The study was approved by Institutional Ethical Committee Vide ref. no. Pharma/2012/2753 dated 07-11-2012.
Patients with uncomplicated T2DM with or without stable co-morbid conditions, on treatment with MF for 4 months out of which on maximum tolerated dose of MF (1000-2500 mg/day) for 4 weeks, HbA1c ≥ 6.5%, Blood glucose: Fasting ≥ 126 mg/dl and post prandial (PP) ≥200 mg/dl were included in the study.[5]
Pregnancy/lactation, allergy, intolerance, any acute or chronic complication of diabetes mellitus, acute left ventricular failure and myocardial infarction, unstable angina, bypass surgery, liver disease, renal disease, abnormal micral test and patients on drug grossly affecting blood glucose level were excluded from the current study.
Patients were randomized to receive either of two drugs combinations:

Group 1: MF (500 mg BD) + VG (50 mg BD)
Group 2: MF (500 mg BD) + GP (2 mg BD).


Primary end points - At 6 weeks - Blood sugar (Fasting and PP): At 12 weeks - Blood sugar (Fasting and PP) and HbA1c. Number and Percent of patients achieving primary target end points were noted.
Target end points: Fasting blood glucose (FBG) ≤126 mg/dl.[5] PP Blood Glucose ≤ 180 mg/dl.[5] HbA1c ≤ 6.5%.[5]
Secondary end points - At 6 weeks - Weight, any adverse drug reaction. At 12 weeks - Weight, body mass index (BMI), lipid profile, liver functions tests (LFTs), renal functions tests (RFTs) and any adverse drug reaction.
BODY.STATISTICAL ANALYSIS:
Data was analysed using computer Statistical Package for Social Sciences version 17.0 for windows. Mean ± standard error of the mean were calculated for quantitative variables for both the groups. Statistical significance between both groups was assessed by use of independent-t test for equality of means. Intra-group comparison from baseline to 6 and 12 weeks was done using Paired sample t-test. P < 0.05 was considered as statistical significant. Chi-square test was used to evaluate statistical significance in the occurrence of adverse events. All analysis were carried out by employing intention to treat principle.


BODY.RESULTS:
Both the groups caused a significant decline in blood glucose levels both fasting as well as PP blood glucose levels (P < 0.01). On the comparison both the groups demonstrated no difference statistically. HbA1c was also reduced significantly in both the groups at 12 weeks (P < 0.01). Intergroup comparison failed to demonstrate any statistical difference [Figures 1-3].
Figure 1Intra and Inter group comparison of fasting blood glucose levels **Significant: P < 0.01 versus baseline (using Paired t-test), †Non significant: P > 0.05 versus other group (using Unpaired t-test)
Figure 2Intra and Inter group comparison of post prandial blood glucose levels **Significant: P < 0.01 versus baseline (using Paired t-test), †Non significant: P > 0.05 versus other group (using Unpaired t-test)
Figure 3Mean glycosylated Haemoglobin (%) levels in Group 1 and Group 2 **Significant: P < 0.01 versus baseline (using Paired t-test) †Non significant: P > 0.05 versus other group (using Unpaired t-test)
Total serum cholesterol, triglycerides, low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) decreased significantly whereas high-density lipoprotein (HDL) levels increased significantly from baseline levels in both the groups (P < 0.01). On the comparison, both the groups failed to elucidate any statistical significant difference in lipid profile [Figure 4].
Figure 4Comparative evaluation of plasma lipids at 12 weeks in Group 1 and Group 2 †Non significant: P > 0.05 versus other group (using Unpaired t-test)
Both weight and BMI did not alter statistically from baseline in either of the groups as well as demonstrated no difference statistically on comparison (P > 0.05) [Table 1].
Table 1Comparative evaluation of mean body weight and mean BMI at 6 and 12 weeks in Group 1 (MF+VG) and Group 2 (MF+GP)
At the end of the study, both LFTs and RFTs remained unaltered statistically and within normal clinical range in both the groups (P > 0.05) [Tables 2 and 3].
Table 2LFTs in Group 1 (MF+VG) and Group 2 (MF+GP)
Table 3RFTs in Group 1 (MF+VG) and Group 2 (MF+GP)
Adverse events were observed in 19 (22.6%) patients out of 84. In Group 1 adverse events were observed in 8 (20%) out of 40 patients, whereas in Group 2, adverse events were reported in 11 (25%) out of 44 patients. The incidence of hypoglycemia was slightly more in Group 2 (three patients) when compared to one patient in Group 1. Intergroup comparison demonstrated no statistical difference in term of all the adverse events in both groups (P = 0.690) [Table 4].
Table 4Adverse drug reactions in Group 1 (MF+VG) and Group 2 (MF+GP)

BODY.DISCUSSION:
In the current study, the patients on MF and VG combination showed significant decline in mean FBG and PP blood glucose to the maximum tone of 75 mg/dl and 98 mg/dl at 12 weeks, respectively (P < 0.01). Our results are consistent with Bosi et al., 2007[6] who demonstrated significant dose-related decrease in FBG and 2 h post prandial glucose (PPG) levels. Ved and Shah, 2012[7] showed similar results in which combination of MF and VG was evaluated against VG monotherapy in patients on Insulin. Similarly, Pan et al., 2012[8] like our study showed MF-VG combination to significantly reduce FBG levels (P < 0.001) at 24 weeks when compared with MF-Placebo. Chatterjee and Chatterjee, 2013[9] in accordance with the results of present study showed significant reduction in FBG in both once daily and twice daily regime of MF and VG from baseline (P < 0.0001). The reduction in PPG level was also highly significant in both groups (P < 0.0001). Thus, the results underscores that DPP-4 inhibitor VG when added to MF monotherapy result in significant decrease in FBG and PPG.
Whereas patients on MF and GP combination also showed significant reduction in FBG and PP Glucose to the maximum tone of 62 mg/dl and 91 mg/dl at 12 weeks, respectively (P < 0.01). These results are similar to Charpentier et al., 2001[10] who showed a significant reduction in FBG and PP blood glucose (P < 0.001) from baseline than either GP or MF alone.
Shimpi et al., 2009[11] also recorded similar results. MF and GP combination showed a significant reduction in both FBG and PPG (P < 0.0001) as compared to MF and Glibenclamide combination.
Our results are in concurrence with Wang et al., 2011[12] where FBG and PPG decreased significantly (P < 0.01) from baseline and Pareek et al., 2013[13] as their results demonstrated a significant reduction in both FBG and PPG at 12 weeks (P < 0.001).
In controlling FBG and PP glucose on comparison both the groups demonstrated no difference (P > 0.05) which is similar to Ferrannini et al., 2009[14] in which efficacy and safety of VG or GP as add on to MF inadequately controlled with MF alone was evaluated. FPG showed a similar reduction in both the groups and statistically there was no difference.
Our results are in concurrence with Jeon and Oh, 2011[15] who conducted a comparative trial of MF-VG and MF-GP combination. A similar reduction in 2 h-PPG and FPG was demonstrated in both the groups.
In our study both the groups showed a significant reduction in mean HbA1c from baseline to the end of the study at 12 weeks (P < 0.01). Our results are in concurrence with Bosi et al., 2007,[6] Pan et al., 2012[8] and Ved and Shah, 2012.[7]
In the current study, MF-GP combination also demonstrated a significant reduction in HbA1c at 12 weeks (P < 0.01). Similar results are shown in numerous studies by Charpentier et al., 2001,[10] Ingle and Talele, 2012.[16]
However, on comparison both the groups demonstrated no difference statistically. These results are consistent with Ferrannini et al., 2009,[14] Jeon and Oh, 2011.[15]
In the present study, patients on MF and VG combination demonstrated significant reduction in serum cholesterol, triglycerides, LDL and VLDL at 12 weeks (P < 0.01) while there was significant increase in HDL at 12 weeks (P < 0.01).
Our results are consistent with Bolli et al., 2008[17] in which MF-VG combination demonstrated a significant reduction in total cholesterol, LDL and VLDL (P < 0.001) than MF-Pioglitazone Triglycerides decreased slightly with MF-VG when compared to MF-Pioglitazone (P = 0.004), while HDL increased with both the combinations (P < 0.001).
Similar results are shown by Bosi et al., 2007[6] who demonstrated significant reduction in total cholesterol, LDL, VLDL and increase in HDL from baseline to 24 weeks with MF and VG compared with MF and placebo but triglycerides showed minimal increase with VG and MF (P = 0.014 and P = 0.052).
Patients on MF and GP also demonstrated a significant decrease in total cholesterol, triglycerides, LDL and VLDL (P < 0.001), while there was an increase in HDL at the end of the study (P < 0.01).
Similar results are shown by Shimpi et al., 2009[11] in which significant reduction in the total cholesterol, triglycerides, LDL and VLDL was found in the MF and GP (P < 0.0001) as compared to MF and Glibenclamide group. The HDL concentration was increased significantly (P: 0.0190) in the MF-GP group. However there was no change found in the values of HDL cholesterol in MF-Glibenclamide group. Ingle and Talele, 2012[16] demonstrated results concurrent to our study. There was a significant reduction in total cholesterol, triglycerides and LDL from to 26 weeks. HDL increased from baseline to 26 weeks in MF-GP combination when compared with MF and Glibenclamide.
In the present study, patients on MF and VG combination showed no significant change in weight (P > 0.05) at both 6 and 12 weeks and in BMI (P > 0.05) at 12 weeks.
Our results concur with Bosi et al., 2007[6] who demonstrated that the body weight did not change significantly after 24 weeks of treatment with 50 mg or 100 mg VG daily along with MF. While in patients receiving placebo and continuing MF monotherapy, body weight decreased by 1.0 ± 0.3 kg (P < 0.001 vs. baseline).
Similar results are observed in the study by Bolli et al., 2008[17] where body weight remained stable throughout the 24-week treatment with a combination of MF and VG. In patients receiving MF and Pioglitazone, body weight increased progressively from 4 to 24 weeks (P < 0.001).
The results of the present study are in contrast with Ved and Shah, 2012[7] where significant reduction in mean weight by VG and MF from baseline to end of treatment at 3 months was shown (P < 0.001). Filozof et al., 2010[18] also demonstrated a significant reduction in body weight in both MF-VG combination and MF alone (P < 0.001). However, reduction in MF group was more compared with the combination group (P < 0.001). This difference from our study could be due to shorter duration and smaller sample size of our study.
Patients on MF and GP also demonstrated no change in body weight at the end of 6 weeks as well as 12 weeks (P > 0.05) and BMI at 12 weeks (P > 0.05) similar to Charpentier et al., 2001[10] in which combination treatment with MF and GP resulted in no change in BMI than either GP or MF alone (P < 0.001).
Concurrent results are shown by Ingle and Talele, 2012[16] where combination of MF and GP demonstrated no significant reduction in BMI from the baseline value to the end of 6 months of study.
Scan of literature revealed three similar studies to our study. Ferrannini et al., 2009[14] documented that VG when added to MF provided efficacy comparable to that of GP when added to MF after 52 weeks and displayed a favorable adverse event profile with no weight gain and a significant reduction in hypoglycemia compared with MF + GP.
Matthews et al., 2010[19] also compared MF and VG with MF and GP. Their results showed that VG add-on to MF has similar efficacy to GP add-on after 2 years of treatment but with markedly reduced hypoglycemic risk and no weight gain.
Jeon and Oh, 2011[15] demonstrated MF-VG combination provided glucose control efficacy comparable to MF GP combination and resulted in better adverse event profile with low risk of hypoglycemia and weight gain.
In the present study, LFTs and RFTs were also evaluated at baseline and at 12 weeks. They demonstrated no statistical difference and remained within normal clinical range thereby indicating both the groups to be safe as per Liver and Renal functions is concerned. Moreover, we failed to cite any study looking into these important safety aspects. The combination of MF and VG showed little better adverse event profile than MF and GP though it did not reach statistical significance.
BODY.LIMITATIONS:
It was a short duration study of 12 weeks only with less sample size. Patients were not given maximum dose of MF. Insulin levels, pancreatic beta cell functions and C-peptides were not a part of the study that might have otherwise collaborated the observations. No causality assessment was done for adverse events.


BODY.CONCLUSION:
Current study demonstrated the effectiveness of both the combinations (MF + VG and MF + GP) in T2DM patients who were inadequately controlled with MF monotherapy. Both the regimens on comparison revealed similar efficacy thereby failing to prove the superiority over each other. However, the incidence of hypoglycemia and other adverse events were numerically more in MF + GP group. This suggests that combination of MF and VG to be a promising option in patients inadequately controlled with MF monotherapy. But further studies are required to establish superiority of VG over most commonly used sulfonylurea, that is, GP as anadd on therapy to MF.

Question: Compared to MF (500 mg BD) + GP (2 mg BD) metfromin-glimepiride (MF-GP) what was the result of MF (500 mg BD) + VG (50 mg BD) metformin-vidagliptin  on HbA1c?
Evidence: HbA1c was also reduced significantly in both groups at 12 weeks (P < 0.01).
Answer: no significant difference