ORIGINAL ARTICLE

Glycemic effects of vildagliptin and metformincombination therapy in Indian patients with type 2diabetes: An observational studySanjay CHATTERJEE1 and Sudip CHATTERJEE2

1Apollo Gleneagles Hospital and 2The Park Clinic, Kolkata, India

Correspondence

Sanjay Chatterjee, No. 58, Canal CircularLane, Kolkata 700 054, India.Tel: +91 98 3103 2310Fax: +91 33 2320 5184Email: sanjay_doc@yahoo.co.in

Received 20 March 2013; revised 30 June2013; accepted 22 July 2013.

doi: 10.1111/1753-0407.12078

Abstract

Background: To analyze the glycemic response of Indian patients with type2diabetes mellitus (T2DM) to combination therapy with vildagliptin and met-formin and compare our data with those of clinical trials.Methods: In a retrospective study of the hospital database, the glycemiccontrol of 280 patients with T2DM who were either on a once- or twice-dailyregimen of combination therapy with vildagliptin 50 mg and metformin500 mg was analyzed.Results: The mean duration of follow-up of the patients was 16.8 months.There was a reduction in fasting plasma glucose (FPG) of 1.52 ± 0.79 and1.88 ± 0.87 mmol/L in the once- and twice-daily groups, respectively (bothP < 0.0001) from baseline to last visit. The reduction in postprandial plasmaglucose (PPPG) in the once- and twice-daily groups was 3.98 ± 1.72 and4.33 ± 1.88 mmol/L, respectively (both P < 0.0001), whereas the reduction inHbA1c was 1.41 ± 1.39% and 1.90 ± 1.49%, respectively (both P < 0.0001).The differences in the reductions achieved in FPG and HbA1c with the twodosing regimens were significant.Conclusion: Although the present retrospective study shows a robustresponse to the combination of vildagliptin and metformin in Indian patients,more multicenter studies from India with a greater number patients are nec-essary to confirm this finding.

Keywords: combination therapy, India, metformin, type 2 diabetes mellitus,vildagliptin.

Introduction

The importance of glycemic control in diabetic subjectsin reducing microvascular and macrovascular complica-tions has been established in the Diabetes Control andComplications Trial (DCCT), UK Prospective DiabetesStudy (UKPDS), Steno-2 and several other clinicaltrials.1 However, recent studies like the Action to

Control Cardiovascular Risk in Diabetes (ACCORD)and Veterans Affair Diabetes Trial (VADT), have showna negative impact of hypoglycemia in elderly patientsand those with cardiovascular comorbidities.2 Met-formin is a biguanide derivative and has been used in thetreatment of type 2 diabetes mellitus (T2DM) for morethan four decades. Metformin has been recommended asa first-line therapy for T2DM in guidelines published by

Significant findings of the study: Indian patients show a consistent reduction in fasting and postprandial bloodsugar, as well as HbA1c levels with the combination of vildagliptin and metformin. Twice daily dosing of thecombination may be superior to once daily dosing in the longer term in Indian patients.What this study adds: The long-term response of the Indian population to combination treatment with vildagliptinand metformin may be greater than that of other ethnicities.

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Journal of Diabetes 6 (2014) 237–242

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the American Diabetes Association (ADA), EuropeanAssociation for Study of Diabetes (EASD),3 and Inter-national Diabetes Federation (IDF)4 for being effica-cious, well tolerated, inexpensive and associated with aminimal incidence of hypoglycemia. Vildagliptin belongsto the class of dipeptidyl peptidase (DPP)-4 inhibitors,which block the enzyme DPP-4, which is responsible forthe degradation of the intestinal hormones glucagon-likepeptide-1 (GLP-1) and glucose-dependent insulinotropicpeptide (GIP). The DPP-4 inhibitors prolong the actionof circulating GLP-1, thereby stimulating insulin secre-tion and suppressing glucagon secretion in a glucose-dependent manner.5 Because of their mode of action, theDPP-4 inhibitors cause hypoglycemia at rates no differ-ent from placebo. Vildagliptin is a competitive inhibitorof DPP-4 and dissociates slowly, so that after 24 h itretains 40% DPP-4 inhibition capacity.6 Vildagliptin, likeany other DPP-4 inhibitor, results in lower blood glucosereductions than metformin but, when the two drugs, arecombined, there is a greater reduction in blood glucoselevels.7 In India, vildagliptin and metformin combina-tion tablets are available in 50/500 mg, 50/850 mg and50/1000 mg doses. Vildagliptin has been approved foruse in India for the treatment of T2DM patients asmonotherapy or in combination with metformin, sulfo-nylureas, and thiazolidinediones, as well as with insulin.The advantage of the combination of vildagliptin andmetformin is that it is well tolerated and efficacious withan adverse effect profile similar to that of metforminalone.8 In a recent pooled analysis of vildagliptin asadd-on therapy to metformin, it was shown that theefficacy of vildagliptin was independent of stage ofinsulin resistance, body mass index, disease duration andduration of metformin use.9

The aim of the present study was to analyze the gly-cemic response of Indian patients with T2DM to once-and twice-daily combination of therapy with vildagliptin50 mg and metformin 500 mg. Vildagliptin became avail-able in India from the latter part of 2008. Because expe-rience with this drug in south Asian individuals is fairlylimited, herein we report our results in 280 patients after40 months of use.

Methods

We searched the outpatients database at Apollo Gle-neagles Hospital, Kolkata, from September 2008 to May2012 and found 2330 prescriptions for the combination ofvildagliptin and metformin. Of these, 1285 patients werelost to follow-up, leaving follow-up data for 1045patients. Data for patients who took combination vilda-gliptin and metformin with other antihyperglycemicagents were excluded from analyses, leaving 280 patient

records with at least 6 months follow-up data fit foranalysis. These patients had been started on a once- ortwice-daily regimen on the basis of their presenting fastingplasma glucose (FPG) levels: if FPG was <8.34 mmol/L,patients were put on a once-daily dose; if FPG wasbetween 8.39 and 13.89 mmol/L, they were started on atwice-daily dose. Fasting and postprandial plasmaglucose levels were determined again after 4 weeks and, iftargets had not been reached in patients taking the singledose, they were started on a twice-daily dose. In patientsin whom an inadequate response was recorded, therapywas changed in accordance with published guidelines.

Only data for those patients whose treatmentremained unchanged with either once- or twice-dailyvildagliptin plus metformin combination were analyzed.The last follow-up visit or any further change of dosagewas considered the end of treatment. Plasma glucoselevels were determined by the glucose oxidase method,whereas HbA1c was measured by HPLC (D-10; BioRad,Hercules, CA, USA).

Unless indicated otherwise, data are presented as themean ± SD. Statistical analyses were performed usingSPSS version 16 (SPSS Inc., Chicago, IL, USA). Pairedt-tests were used to compare parameters at baseline andat the end of the study, whereas the Chi-squared test wasused to compare results between the once- and twice-daily groups.

Results

We analyzed changes in fasting and postprandial bloodglucose levels, as well as changes in HbA1c followingtherapy. None of the patients had serum alanine amino-transferase >2.5-fold the upper limit of normal or serumcreatinine levels >0.015 g/L. The duration of treatmentranged from 6 to 30 months, and the mean duration offollow-up was 16.8 months. Hypertension was the pre-dominant comorbidity in the patient population(Table 1).

Of the 280 patients included in the present study, 154(55%) were on a once-daily regimen and 126 (45%)were on a twice-daily regimen (Table 2). In the primaryefficacy analysis, decreases in mean FPG values frombaseline to the end of treatment were significant(P < 0.0001) for patients in both the once-daily (meandifference –1.52 mmol/L; 95% confidence interval [CI]–1.13, –1.93 mmol/L) and twice-daily (mean difference–1.88 mmol/L; 95% CI –1.42, –2.33 mmol/L) groups(Table 3). Similarly, changes in postprandial plasmaglucose (PPPG) values were significant (P < 0.0001)from baseline to the end of treatment in both the once-daily (mean difference –3.98 mmol/L; 95% CI –3.42,–4.53 mmol/L) and twice-daily (mean difference

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–4.33 mmol/L; 95% CI –3.66, –4.99 mmol/L) groups(Table 4).

There was a significant decrease in HbA1c levels frombaseline to the end of treatment in both the once-daily(mean difference –1.41%; 95% CI –0.957%, –1.862%) andtwice-daily (mean difference –1.90%; 95% CI –1.352%,–2.447%) groups (Table 5). Outcomes in terms of FPGand HbA1c were significantly better for patients in thetwice-daily group compared with the once-daily group.However, there were no significant differences whenchanges from baseline to end of treatment PPPG werecompared (Table 6). In addition, the percentage ofpatients achieving a reduction in HbA1c from baseline tobelow 7% did not differ significantly between the twogroups (Table 7).

Discussion

The incretin hormones GIP and GLP-1 were discoveredin the early 1970’s and 1980’s respectively and theirunique effects on glucose-dependent insulin secretionand glucagonostatic action were described.10 As themajor incretin, GLP-1 is responsible for 70% of post-prandial insulin release.11 Glucagon-like peptide-1 has avery short half-life (∼2–3 min) and is degraded byDPP-4. Two groups of incretin-based drugs have beendeveloped for use in T2DM: (i) GLP-1 analogs that resistcleavage by DPP-4; and (ii) DPP-4 inhibitors, which

block the action of the enzyme. The first incretin-basedtherapy for T2DM came about in 2005 when exenatidewas launched. This was a twice-daily injectable drugthat successfully provided glycemic control withoutcausing hypoglycemia.12 In 2006, the first orallyactive DPP-4 inhibitor, sitagliptin, was approved by theFDA (see http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108770.htm, accessed 5August 2013). This was followed by the arrival of vilda-gliptin, another DPP-4 inhibitor, in 2007 in Europe,Asian countries, Australia and New Zealand (see http://www.diabetesincontrol.com/articles/53-diabetes-news/5160, accessed 5 August 2013). Vildagliptin binds tightlyto the active site of DPP-4 by covalent bonds and disso-ciates slowly so that 24 h after ingestion of the drug, 40%DPP-4 inhibition is observed.6 Vildagliptin has been usedin trials and in practice as monotherapy or in combina-tion with metformin, sulfonylurea, pioglitazone andinsulin.13 The usual dose of vildagliptin is 50 mg twicedaily. However, in clinical trials a dose of 50 mg oncedaily reduced HbA1c significantly.14

Although most drug authorities have recommended avildagliptin–metformin combination of 50/500 mg twicedaily, the drug authority of New Zealand has recom-mended a starting dose of 50/1000 mg once daily fordrug-naïve patients.15 A starting dose of 50/500 mgvildagliptin–metformin is recommended in MonthlyIndex of Medical Specialities (MIMS; see https://www.mims.com/Singapore/drug/info/GalvusMet/, accessed 4March 2013), as well as in Singapore16 and in thePhilippines (see www.mims.com/philippines/drug/info/Galvusmet, accessed 4 March 2013) for drug-naïvepatients. Our data show that, at least in some patients,treatment may be initiated using a once-daily regimen andgood control of blood glucose may be maintained oversome time.

In a study from South Korea,17 combination therapywith vildagliptin and metformin resulted in similar bloodglucose control to that seen with glimepiride–metformincombination therapy, but vildagliptin–metformintherapy produced lesser weight gain and was associatedwith a 10-fold lower incidence of hypoglycemia.

The unique feature of vildagliptin is its tight binding tothe active site of DPP-4, which ensures inhibition of the

Table 1 Comorbidities in the 280 patients with type 2 diabetesmellitus evaluated in the present study

Comorbidity No. cases (%)

Obesity/overweight 89 (31.8%)Hypertension 179 (63.9%)Dyslipidemia 56 (20.0%)Hypothyroidism 27 (9.6%)Sensorimotor neuropathy 16 (5.7%)Microalbuminuria 51 (18.2%)Nephropathy 21 (7.5%)Retinopathy 15 (5.4%)Coronary artery disease 28 (10.0%)Osteoarthritis 26 (9.3%)

Table 2 Parameters analysis in patients with various dosage regimens

ParameterTotal no.patients

No. (%) patients with:

Once-daily dosing Twice-daily dosing

Fasting plasma glucose 280 154 (55.0%) 126 (45.0%)Postprandial plasma glucose 269 149 (55.4%) 120 (44.6%)HbA1c 205 115 (56.1%) 90 (43.9%)

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enzyme even when there are no detectable drug levels inplasma. Because metformin enhances the effects of vilda-gliptin to raise plasma levels of intact GLP-1, the twodrugs act synergistically.18

In an analysis of three clinical trials on elderly Euro-pean patients >75 years of age, vildagliptin–metformintwice daily therapy for 24 weeks resulted in a reduction inHbA1c of 1.1%, from a baseline of 8.5%.19 In the present

study, we observed a mean reduction in HbA1c of 1.9%in the twice-daily treatment group from a baseline of8.77%. Another study of the effects of 24 weeks treat-ment with vildagliptin 100 mg once daily plus metformin500 mg twice daily in 456 patients with T2DM reporteda mean reduction in HbA1c of 0.51% from a baseline of7.4%.20

In a study from Milan (Italy),21 a total of 1179treatment-naïve patients were divided equally into tofour groups: (i) vildagliptin + high-dose metformin (50/1000 mg) twice daily; (ii) vildagliptin + low-dose met-formin (50/500 mg twice daily); (iii) vildagliptin 50 mgtwice daily; and (iv) metformin 1000 mg twice daily.After 24 weeks treatment with the vildagliptin–metformin combination (50 mg/500 mg twice daily),HbA1c was reduced by a mean (± SD) of 1.6 ± 0.6%from a baseline of 8.7%.21 In the present study, the mean(± SD) reduction in HbA1c was 1.9 ± 1.5%.

In the present study, we found significant differencesin reductions in FPG and HbA1c between the once- andtwice-daily dosing regimens. However, there were no sig-nificant differences between the two groups in terms ofPPPG. This may be due to the fact that many patients inthe once-daily group took their medicine in the morning.In patients in whom once-daily therapy was successful inachieving glycemic targets, there was definite advantageof this treatment regimen in terms of cost and fewergastrointestinal side effects.22

In a recent study from China,23 vildagliptin 50 mg onceor twice daily was added to patients receiving metformin.After 24 weeks, from a baseline HbA1c of 8.0%, therewas reduction in HbA1c of 1.05 ± 0.08% in the twice-daily group compared with a reduction of 0.92 ± 0.08%in the once-daily group.23

The present study was an observational study and thefrequency of patient visits was not uniform. It is likelythat there was under-reporting of adverse effects in thatsymptoms were forgotten or resolved between visits,hence remaining undocumented. Therefore, we did notattempt to analyze adverse events. However, it is impor-tant to note that there were no reports of severe hypo-glycemia in patients receiving vildagliptin and metforminas the only oral antihyperglycemic drug.

Physicians treating T2DM are especially interested inthe combination of DPP-4 inhibitors and metformin,because data from recent clinical trials have demon-strated the efficacy of this combination, in associationwith minimal episodes of hypoglycemia, compared withplacebo and without any increase in adverse events.8 In arecent review article, it was stated that DPP-4 inhibitors,in addition to lowering blood glucose, preserve pancre-atic β-cells, regulate the immune system, afford cardio-vascular and have an anti-inflammatory effect.24

Table 3 Changes in mean fasting plasma glucose after treatmentaccording to dosing regimen

Dosing regimen

Once daily(n = 154)

Twice daily(n = 126)

Fasting plasma glucose(mmol/L)

At baseline 8.91 ± 2.00 9.02 ± 2.07At end of treatment 7.37 ± 1.56 7.13 ± 1.67Mean change –1.52 ± 0.79† –1.88 ± 0.87‡

Data are the mean ± SD. Analyses using paired t-test revealed:†P < 0.0001 (95% confidence interval [CI] 1.13–1.93; and ‡P < 0.0001(95% CI 1.42–2.33).

Table 4 Changes in mean postprandial plasma glucose after treat-ment according to dosing regimen

Dosing regimen

Once daily(n = 149)

Twice daily(n = 120)

Postprandial plasma glucose(mmol/L)

At baseline 12.05 ± 2.65 12.21 ± 2.87At end of treatment 8.07 ± 2.18 7.87 ± 2.31Mean change –3.98 ± 1.72† –4.33 ± 1.88‡

Data are the mean ± SD. Analyses using paired t-test revealed:†P < 0.0001 (95% confidence interval [CI] 3.42–4.53); and‡P < 0.0001 (95% CI 3.66–4.99).

Table 5 Changes in HbA1c after treatment according to dosingregimen

Dosing regimen

Once daily(n = 115)

Twice daily(n = 90)

HbA1c (%)At baseline 8.65 ± 1.89 8.77 ± 2.02At end of treatment 7.24 ± 1.58 6.87 ± 1.69Mean change –1.41 ± 1.39† –1.90 ± 1.49‡

Data are the mean ± SD. Analyses using paired t-test revealed:†P < 0.0001 (95% confidence interval [CI] 0.957–1.862); and‡P < 0.0001 (95% CI 1.352–2.447).

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The results of the present study show that the combi-nation of vildagliptin and metformin is efficacious in themanagement of hyperglycemia. Furthermore, the dataindicate that the twice-daily regimen of vildagliptin andmetformin results in a greater reduction in blood glucosethan the once-daily regimen. However, once-daily treat-ment with the two drugs was effective in achieving anHbA1c of ≤7% in 47% of patients (vs 53.3% of patients inthe twice-daily group). The present study included a smallnumber of patients. Being observational data, we havenot been able to monitor diet, exercise or drug adherencein our patients. However, we noted a fall in HbA1c thatwas greater than that found in several European studiesand published trials.19,20,21 Our mean follow-up of 16.8months was greater than that in comparable trials. Ourpatients were all Indians and many patients were eitherdrug naïve or inadequately controlled with metformin.Although the present retrospective observational studyshowed a greater response to vildagliptin and metformincombination in Indian patients, more multicenter studiesfrom India with a greater number of patients are neededto confirm this finding.

Disclosure

The authors declare no conflict of interest.

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Table 6 Comparisons of outcomes of once- and twice-daily therapy

Once-daily regimen Twice-daily regimen

Change in FPG (mmol/L) –1.52 ± –0.79 (n = 154) –1.88 ± –0.87 (n = 126)P-value between groups 0.0004

Change in PP PG (mmol/L) –3.98 ± –1.72 (n = 149) –4.33 ± –1.88 (n = 120)P-value between groups 0.1145

Change in HbA1c (%) –1.41 ± –1.39 (n = 115) –1.90 ± –1.49 (n = 90)P-value between groups 0.0161

Data show mean ± SD changes in different parameters (end of treatment – baseline values), with the number of patients given in parentheses.

Table 7 Number of patients achieving HbA1c ≤7.0% according todosing regimen

No.patients

No. (%) achievingHbA1c ≤7%

Once-daily regimen 115 54 (47.0%)Twice-daily regimen 90 48 (53.3%)

Analysis using the Chi-squared test revealed P = 0.37.

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