SUPPLEMENTARY MATERIAL
Supplement 1 Search strategy
MEDLINE (via PubMed)
#1 vildagliptin [Text Word]
#2 LAF-237 [Text Word]
#3 LAF237 [Text Word]
#4 vildagliptin [Supplementary Concept]
#5 lipoyl vildagliptin [Supplementary Concept]
#6 #1 OR #2 OR #3 OR #4 OR #5
EMBASE (via OVID)
#1 vildagliptin.mp.
#2 LAF-237.mp.
#3 LAF237.mp
#4 exp vildagliptin/
#5 exp vildagliptin plus metformin/
#6 exp vildagliptin plus metformin hydrochloride/
#7 #1 OR #2 OR #3 OR #4 OR #5 OR #6
THE COCHRANE LIBRARY
#1 vildagliptin
#2 LAF NEXT 237
#3 #1 OR #2
Supplement 2 Articles excluded after full-text screening (n=137), including reason for
exclusion)
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Trials with less than 12 weeks duration of follow-up (n=22) [Refs 1-22]
Narrative or systematic reviews/meta-analyses (n=84) [Refs 23-106]
Non-randomized trials (n=6) [Refs 107-112]
Pooled analyses (n=7) [Refs 113-119]
Post-hoc analyses or studies of subgroups/special populations (n=7) [Refs
120-126]
Trials in patients with impaired glucose tolerance (n=3) [Refs 127-129]
Trials in obese patients (n=1) [Ref 130]
Commentaries (n=1) [Ref 131]
Non-eligible comparisons (n=6) [Refs 132-137]
Ahren, B., Farngren, J., Persson, M., Schweizer, A., Foley, J.: Improved glucagon
dynamics during hypoglycaemia and foodrechallenge by DPP-4 inhibition by
vildagliptin in insulin-treated patients with type 2 diabetes. Diabetologia 56, S51-S52
(2013).
Baranov, O., Deacon, C.F., Holst, J.J., Buss, U., Nauck, M.A.: Feed-back suppression
of meal-induced GLP-1 secretion: A randomised, prospective comparison of the
DPP-4 inhibitors sitagliptin and vildagliptin. Diabetologia 1), S378 (2014).
CLAF237A2347:
In.
http://www.novctrd.com/CtrdWeb/displaypdf.nov?trialresultid=3044,
CLAF237A2387:
In.
http://www.novctrd.com/CtrdWeb/displaypdf.nov?trialresultid=2563,
Derosa, G., D'Angelo, A., Bonaventura, A., Bianchi, L., Romano, D., Maffioli, P.:
Glucose-lowering effect and glycemic variability of acarbose added to a
metformin/vildagliptin combination in type 2 diabetic patients. Diabetes Technology
and Therapeutics 16, A155 (2014).
Farngren, J., Persson, M., Schweizer, A., Foley, J.E., Ahren, B.: Glucagon dynamics
during hypoglycaemia and food-re-challenge following treatment with vildagliptin in
insulin-treated patients with type 2 diabetes. Diabetes, obesity & metabolism (2014).
doi:http://dx.doi.org/10.1111/dom.12284
Fujimoto, K., Hamamoto, Y., Honjo, S., Yamaguchi, E., Shibayama, Y., Tokumoto,
S., Koshiyama, H.: Adding the combination drug of mitiglinide and voglibose to
vildagliptin results in less glucose excursions than adding glimepiride in patients with
type 2 diabetes. Diabetes 63, A284 (2014).
Goke, R., Dutting, E.D.: Efficacy of vildagliptin and sitagliptin in reducing fasting
plasma glucose in type 2 diabetes mellitus: Results from a randomised controlled
trial. Diabetologia (2014). doi:http://dx.doi.org/10.1007/s00125-014-3355-0
Gonzalez-Ortiz, M., Sanchez-Pena, M.J., Gonzalez-Ortiz, L.J., Robles-Cervantes,
J.A., Garcia-Ortega, Y.E., Gomez-Gaitan, E.A., Perez-Rubio, K.G., MartinezAbundis, E.: Effect of vildagliptin on glucose and insulin concentrations during a 24hour period in type 2 diabetes patients with different ranges of baseline hemoglobin
A1c levels. Diabetes technology & therapeutics (2013). doi:10.1089/dia.2013.0020
Guerci, B., Monnier, L., Serusclat, P., Petit, C., Valensi, P., Huet, D., Raccah, D.,
Colette, C., Quéré, S., Dejager, S.: Continuous glucose profiles with vildagliptin
versus sitagliptin in add-on to metformin: results from the randomized Optima study.
Diabetes & metabolism (2012). doi:10.1016/j.diabet.2012.06.001
He, Y.L., Ito, H., Yamaguchi, M., Terao, S., Shimada, S., Irie, S., Sekiguchi, K.:
Effects of meal timing relative to dosing on the pharmacokinetics and
pharmacodynamics of vildagliptin in Japanese patients with Type 2 diabetes.
International Journal of Clinical Pharmacology and Therapeutics 50(4), 237-247
(2012).
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He, Y.L., Sabo, R., Picard, F., Wang, Y., Herron, J., Ligueros-Saylan, M., Dole,
W.P.: Study of the pharmacokinetic interaction of vildagliptin and metformin in
patients with type 2 diabetes. Current medical research and opinion (2009).
doi:10.1185/03007990902869102
He, Y.L., Serra, D., Wang, Y., Campestrini, J., Riviere, G.J., Deacon, C.F., Holst, J.J.,
Schwartz, S., Nielsen, J.C., Ligueros-Saylan, M.: Pharmacokinetics and
pharmacodynamics of vildagliptin in patients with type 2 diabetes mellitus. Clinical
Pharmacokinetics 46(7), 577-588 (2007).
He, Y.L., Yamaguchi, M., Ito, H., Terao, S., Sekiguchi, K.: Pharmacokinetics and
pharmacodynamics of vildagliptin in Japanese patients with type 2 diabetes.
International journal of clinical pharmacology and therapeutics (2010).
Katzeff, H.L., Tatosian, D.A., Guo, Y., Schaeffer, A.K., Gaibu, N., Popa, S.,
Langdon, R.B., Kauh, E.: Comparison of trough dipeptidyl peptidase-4 inhibition in
patients with type 2 diabetes treated with saxagliptin, sitagliptin, and vildagliptin.
Diabetologia 56, S53 (2013).
Malha, L.P., Taan, G., Zantout, M.S., Azar, S.T.: Glycemic effects of vildagliptin in
patients with type 2 diabetes before, during and after the period of fasting in
Ramadan. Therapeutic advances in endocrinology and metabolism (2014).
doi:http://dx.doi.org/10.1177/2042018814529062
Rahmi, R.M., Uchida, A.H., Rezende, P.C., Lima, E.G., Garzillo, C.L., Favarato, D.,
Strunz, C.M.C., Takiuti, M., Girardi, P., Hueb, W., Kalil Filho, R., Ramires, J.A.F.:
Effect of hypoglycemic agents on ischemic preconditioning in patients with type 2
diabetes and symptomatic coronary artery disease. Diabetes care (2013).
doi:10.2337/dc12-1495
Serra, D., He, Y.L., Bullock, J., Riviere, G.J., Balez, S., Schwartz, S., Wang, Y.,
Ligueros-Saylan, M., Jarugula, V., Dole, W.P.: Evaluation of pharmacokinetic and
pharmacodynamic interaction between the dipeptidyl peptidase IV inhibitor
vildagliptin, glyburide and pioglitazone in patients with Type 2 diabetes. International
journal of clinical pharmacology and therapeutics (2008).
Strojek, K., Gorska, J., Rokicka, D., Szymborska-Kajanek, A., Wrobel, M., Sedek, L.,
Szczepanski, T.: Is there an impact of treatment with DPP-4 inhibitors on lymphocyte
subpopulations in type 2 diabetic patients? Endokrynologia Polska 65(2), 78-82
(2014).
Tatosian, D.A., Guo, Y., Schaeffer, A.K., Gaibu, N., Popa, S., Stoch, A.: Dipeptidyl
peptidase-4 inhibition in patients with type 2 diabetes treated with saxagliptin,
sitagliptin, or vildagliptin. Diabetes Therapy Research, Treatment and Education of
Diabetes and Related Disorders (2013). doi:http://dx.doi.org/10.1007/s13300-0130045-8
Van Poppel, P.C.M., Gresnigt, M.S., Smits, P., Netea, M.G., Tack, C.J.: The
dipeptidyl peptidase-4 inhibitor vildagliptin does not affect ex vivo cytokine response
and lymphocyte function in patients with type 2 diabetes mellitus. Diabetes Research
and Clinical Practice 103(3), 395-401 (2014).
Vardarli, I., Nauck, M.A., Köthe, L.D., Deacon, C.F., Holst, J.J., Schweizer, A.,
Foley, J.E.: Inhibition of DPP-4 with vildagliptin improved insulin secretion in
response to oral as well as "isoglycemic" intravenous glucose without numerically
changing the incretin effect in patients with type 2 diabetes. The Journal of clinical
endocrinology and metabolism (2011).
LAF237 for type 2 diabetes - horizon scanning review (Structured abstract). Health
Technology Assessment Database (2005).
Vildagliptin (Structured abstract). Health Technology Assessment Database (2006).
Vildagliptin (Galvus®) 50 mg tablets (Structured abstract). Health Technology
Assessment Database (2012).
Vildagliptin (Galvus®) 50 mg tablets (Structured abstract). Health Technology
Assessment Database (2013).
Diabetes: Vildagliptin-a novel treatment option for NODAT. Nat Rev Nephrol
(2013).
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Agarwal, S., Parashar, A., Menon, V.: Meta-analysis of the cardiovascular outcomes
with dipeptidyl peptidase 4 inhibitors: Validation of the current FDA mandate.
American Journal of Cardiovascular Drugs 14(3), 191-207 (2014).
Aroda, V.R., Henry, R.R., Han, J., Huang, W., DeYoung, M.B., Darsow, T.,
Hoogwerf, B.J.: Efficacy of GLP-1 receptor agonists and DPP-4 inhibitors: metaanalysis and systematic review. Clin Ther 34(6), 1247-1258.e1222 (2012).
Aroda, V.R., Henry, R.R., Han, J., Huang, W., Peters, Y., Darsow, T., Hoogwerf,
B.J.: Meta-analysis of the efficacy of GLP-1R agonists and DPP-4 inhibitors for
treatment of type 2 diabetes mellitus. Diabetologia 53, S333 (2010).
Babai, S., Robin, P., Hillaire-Buys, D., Jean-Pastor, M.J., Le Louet, H.: Dipeptidyl
peptidase-IV inhibitors and bullous pemphigoid in France: Analysis of spontaneous
reports from French Regional Pharmacovigilance Centres and manufacturers.
Fundamental and Clinical Pharmacology 28, 49 (2014).
Biryukova, E.V.: Clinical implementetion of vildagliptin: Data from recent studies
comparing incretin-based medications. [Russian]. Diabetes Mellitus(1), 81-84 (2014).
Cai, L., Cai, Y., Lu, Z.J., Zhang, Y., Liu, P.: The efficacy and safety of vildagliptin in
patients with type 2 diabetes: a meta-analysis of randomized clinical trials. J Clin
Pharm Ther 37(4), 386-398 (2012).
Craddy, P., Palin, H.J., Johnson, K.I.: Comparative effectiveness of
dipeptidylpeptidase-4 inhibitors in type 2 diabetes: a systematic review and mixed
treatment comparison. Diabetes Ther 5(1), 1-41 (2014).
Davis, T.M.E.: Dipeptidyl peptidase-4 inhibitors and cardiovascular safety. Medical
Journal of Australia 200(8), 450-451 (2014).
Deacon, C.F., Mannucci, E., Ahren, B.: Glycaemic efficacy of glucagon-like peptide1 receptor agonists and dipeptidyl peptidase-4 inhibitors as add-on therapy to
metformin in subjects with type 2 diabetes-a review and meta analysis. Diabetes,
Obesity and Metabolism 14(8), 762-767 (2012).
Esposito, K., Chiodini, P., Capuano, A., Maiorino, M.I., Bellastella, G., Giugliano,
D.: Baseline glycemic parameters predict the hemoglobin A response to DPP-4
inhibitors : Meta-regression analysis of 78 randomized controlled trials with 20,053
patients. Endocrine (2013).
Esposito, K., Chiodini, P., Maiorino, M.I., Bellastella, G., Capuano, A., Giugliano,
D.: Glycaemic durability with dipeptidyl peptidase-4 inhibitors in type 2 diabetes: A
systematic review and meta-analysis of long-term randomised controlled trials. BMJ
Open 4(6) (2014).
Esposito, K., Cozzolino, D., Bellastella, G., Maiorino, M.I., Chiodini, P., Ceriello, A.,
Giugliano, D.: Dipeptidyl peptidase-4 inhibitors and HbA1c target of <7% in type 2
diabetes: meta-analysis of randomized controlled trials. Diabetes Obes Metab
13(7), 594-603 (2011).
Evans, M., McInnes, G., Stumvoll, M., Del Prato, S., Schweizer, A., Shao, Q.,
Lukashevich, V., Kothny, W.: Assessment of heart failure risk with vildagliptin in
diabetic patients: Pooled analysis of safety data from approximately 17,000 patients.
Diabetologia 1), S361 (2014).
Fakhoury, W.K., Lereun, C., Wright, D.: A meta-analysis of placebo-controlled
clinical trials assessing the efficacy and safety of incretin-based medications in
patients with type 2 diabetes. Pharmacology 86(1), 44-57 (2010).
Fass, A.D., Gershman, J.A.: Efficacy and safety of dipeptidyl peptidase-4 inhibitors
in combination with metformin. Adv Ther 30(4), 337-353 (2013).
Forst, T., Bramlage, P.: Vildagliptin, a DPP-4 inhibitor for the twice-daily treatment
of type 2 diabetes mellitus with or without metformin. Expert Opinion on
Pharmacotherapy 15(9), 1299-1313 (2014).
Gao, W., Dong, J., Liu, J., Li, Y., Liu, F., Yang, L., Zhou, X., Liao, L.: Efficacy and
safety of initial combination of DPP-IV inhibitors and metformin versus metformin
monotherapy in type 2 diabetes: A systematic review of randomized controlled trials.
Diabetes, Obesity and Metabolism 16(2), 179-185 (2014).
Gibbs, J., Fredrickson, J., Barbee, T., Correa, I., Smith, B., Lin, S., Gibbs, M.:
Quantitative model of the relationship between DPP-4 inhibition and response: Meta-
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analysis of alogliptin, saxagliptin, sitagliptin, and vildagliptin efficacy results.
Clinical Pharmacology and Therapeutics 87, S30-S31 (2010).
Giorda, C.B., Nada, E., Tartaglino, B.: Pharmacokinetics, safety, and efficacy of
DPP-4 inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes
mellitus and renal or hepatic impairment. A systematic review of the literature.
Endocrine 46(3), 406-419 (2014).
Goossen, K., Graber, S.: Longer term safety of dipeptidyl peptidase-4 inhibitors in
patients with type 2 diabetes mellitus: systematic review and meta-analysis. Diabetes
Obes Metab (2012).
Halimi, S., Levy, M.: Management of type 2 diabetic patients during Ramadan: What
place for DPP-4 inhibitors?. [French] Prise en charge des patients diabetiques de type
2 durant le Ramadan: Quelle place pour les inhibiteurs de la DPP-4? Medecine des
Maladies Metaboliques 8(3), 299-305 (2014).
Heinzl, S.: [Dipeptidylpeptidase IV inhibitors and dual action PPAR-agonists]. Med
Monatsschr Pharm 29(3), 93-96 (2006).
Karagiannis, T., Boura, P., Tsapas, A.: Safety of dipeptidyl peptidase 4 inhibitors: A
perspective review. Therapeutic Advances in Drug Safety 5(3), 138-146 (2014).
Karagiannis, T., Paschos, P., Paletas, K., Matthews, D.R., Tsapas, A.: Dipeptidyl
peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting:
Systematic review and meta-analysis. BMJ (Online) 344(7850), 17 (2012).
Karagiannis, T., Paschos, P., Paletas, K., Matthews, D.R., Tsapas, A.: Dipeptidyl
peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting:
systematic review and meta-analysis (Structured abstract). Bmj (2012).
Keating, G.M.: Vildagliptin: A review of its Use in type 2 diabetes mellitus. Drugs
74(5), 587-610 (2014).
Kim, J., Samson, S.L.: Cardiovascular effects of incretin therapy in diabetes care.
Metabolic Syndrome and Related Disorders 12(6), 303-310 (2014).
Kim, Y.G., Hahn, S., Oh, T.J., Kwak, S.H., Park, K.S., Cho, Y.M.: Differences in the
glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and
non-Asians: A systematic review and meta-analysis. Diabetologia 56(4), 696-708
(2013).
Kleppinger, E.L., Helms, K.: The role of vildagliptin in the management of type 2
diabetes mellitus. Ann Pharmacother 41(5), 824-832 (2007).
Kothny, W., Schweizer, A., Dickinson, S., Ligueros-Saylan, M.: Hepatic safety
profile of vildagliptin, a new DPP-4 inhibitor for the treatment of type 2 diabetes.
Diabetologia 52 (S1), S301 (2009).
Koznarova, R.: [Use of vildagliptin from an internal disease specialists point of
view]. Vnitr Lek 59(4), 322-324 (2013).
Krum, H., Skiba, M., Wu, S., Hopper, I.: Heart failure and dipeptidyl peptidase-4
inhibitors. European Journal of Heart Failure 16(6), 603-607 (2014).
Kruyt, N.: Glucose regulation by continuous tube feeding and Vildagliptin in addition
to insulin in hyperglycemic acute stroke patients. Nederlands Trial Register
(http://wwwtrialregisternl) (2009).
Kwok, A.J., Mashar, M., Khavandi, K., Sabir, I.: DPP-IV inhibitors: Beyond
glycaemic control? Trends in Cardiovascular Medicine 24(4), 157-164 (2014).
Ligueros-Saylan, M., Foley, J.E., Schweizer, A., Couturier, A., Kothny, W.: An
assessment of adverse effects of vildagliptin versus comparators on the liver, the
pancreas, the immune system, the skin and in patients with impaired renal function
from a large pooled database of Phase II and III clinical trials. Diabetes Obes Metab
12(6), 495-509 (2010).
Ligueros-Saylan, M., Schweizer, A., Dickinson, S., Kothny, W.: Vildagliptin therapy
is not associated with an increased risk of pancreatitis. Diabetologia 52 (S1), S303
(2009).
Liu, S.C., Tu, Y.K., Chien, M.N., Chien, K.L.: Effect of antidiabetic agents added to
metformin on glycaemic control, hypoglycaemia and weight change in patients with
type 2 diabetes: A network meta-analysis. Diabetes, Obesity and Metabolism 14(9),
810-820 (2012).
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Liu, Y., Hu, Y.: Novel DPP-4 inhibitors against diabetes. Future Medicinal Chemistry
6(7), 793-808 (2014).
McInnes, G., Del Prato, S., Evans, M., Stumvoll, M., Schweizer, A., Lukashevich, V.,
Shao, Q., Kothny, W.: Cardiovascular safety of vildagliptin: An adjudicated metaanalysis of 40 studies. Diabetologia 1), S362-S363 (2014).
Monami, M., Ahren, B., Dicembrini, I., Mannucci, E.: Dipeptidyl peptidase-4
inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials
(Structured abstract). Diabetes Obesity and Metabolism (2013).
Monami, M., Ahren, B., Dicembrini, I., Mannucci, E.: Dipeptidyl peptidase-4
inhibitors and cardiovascular risk: Ameta-analysis of randomized clinical trials.
Diabetes, Obesity and Metabolism 15(2), 112-120 (2013).
Monami, M., Cremasco, F., Lamanna, C., Marchionni, N., Mannucci, E.: Predictors
of response to dipeptidyl peptidase-4 inhibitors: Evidence from randomized clinical
trials. Diabetes/Metabolism Research and Reviews 27(4), 362-372 (2011).
Monami, M., Dicembrini, I., Antenore, A., Mannucci, E.: Dipeptidyl peptidase-4
inhibitors and bone fractures: a meta-analysis of randomized clinical trials (Structured
abstract). Diabetes Care (2011).
Monami, M., Dicembrini, I., Mannucci, E.: Review: In type 2 diabetes, dipeptidyl
peptidase-4 inhibitors do not increase pancreatitis. Annals of Internal Medicine
160(2), JC8-JC9 (2014).
Monami, M., Dicembrini, I., Mannucci, E.: Dipeptidyl peptidase-4 inhibitors and
heart failure: A meta-analysis of randomized clinical trials. Nutrition, Metabolism and
Cardiovascular Diseases 24(7), 689-697 (2014).
Monami, M., Dicembrini, I., Mannucci, E.: Dipeptidyl peptidase-4 inhibitors and
pancreatitis risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab
16(1), 48-56 (2014).
Monami, M., Dicembrini, I., Martelli, D., Mannucci, E.: Safety of dipeptidyl
peptidase-4 inhibitors: a meta-analysis of randomized clinical trials. Curr Med Res
Opin 27 Suppl 3, 57-64 (2011).
Monami, M., Iacomelli, I., Marchionni, N., Mannucci, E.: Dipeptydil [dipeptidyl]
peptidase-4 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials
(Structured abstract). Nutrition, Metabolism and Cardiovascular Diseases (2010).
Monami, M., Lamanna, C., Desideri, C.M., Mannucci, E.: DPP-4 inhibitors and
lipids: systematic review and meta-analysis (Structured abstract). Advances in
Therapy (2012).
Monami, M., Lamanna, C., Desideri, C.M., Mannucci, E.: DPP-4 inhibitors and
lipids: systematic review and meta-analysis. Adv Ther 29(1), 14-25 (2012).
Monami, M., Vitale, V., Ambrosio, M.L., Bartoli, N., Toffanello, G., Ragghianti, B.,
Monami, F., Marchionni, N., Mannucci, E.: Effects on lipid profile of dipeptidyl
peptidase 4 inhibitors, pioglitazone, acarbose, and sulfonylureas: Meta-analysis of
placebo-controlled trials. Advances in Therapy 29(9), 736-746 (2012).
Monami, M., Vitale, V., Ambrosio, M.L., Bartoli, N., Toffanello, G., Ragghianti, B.,
Monami, F., Marchionni, N., Mannucci, E.: Effects on lipid profile of dipeptidyl
peptidase 4 inhibitors, pioglitazone, acarbose, and sulfonylureas: meta-analysis of
placebo-controlled trials (Structured abstract). Database of Abstracts of Reviews of
Effects (2012).
Neumiller, J.J.: Pharmacology, efficacy, and safety of linagliptin for the treatment of
type 2 diabetes mellitus. Ann Pharmacother 46(3), 358-367 (2012).
Park, F.L., Kim, Y., Rascati, K.: Efficacy and safety of dipeptidyl peptidase-4 [DPP4] inhibitors in type 2 diabetes: Meta-analysis. Journal of the American Pharmacists
Association 51 (2), 225 (2011).
Park, H., Kim, Y.A., Rascati, K.L.: Efficacy and safety of dipeptidyl-peptidase 4
[DPP 4] inhibitors in type 2 diabetes: Meta-analysis. Value in Health 13 (7), A283
(2010).
Park, H., Park, C., Kim, Y., Rascati, K.L.: Efficacy and safety of dipeptidyl
peptidase-4 inhibitors in type 2 diabetes: meta-analysis (Structured abstract). Annals
of Pharmacotherapy (2012).
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Park, H., Park, C., Kim, Y., Rascati, K.L.: Efficacy and safety of dipeptidyl
peptidase-4 inhibitors in type 2 diabetes: meta-analysis. Ann Pharmacother 46(11),
1453-1469 (2012).
Park, H., Park, C., Kim, Y., Rascati, K.L.: A meta-analysis of efficacy and safety of
dipeptidyl peptidase-4 [DPP-4] inhibitors in type 2 diabetes. Value in Health 15 (4),
A172 (2012).
Patil, H.R., Al Badarin, F.J., Al Shami, H.A., Bhatti, S.K., Lavie, C.J., Bell, D.S.H.,
O'Keefe, J.H.: Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on
cardiovascular risk in type 2 diabetes mellitus. American Journal of Cardiology
110(6), 826-833 (2012).
Pratley, R.E., Rosenstock, J., Pi-Sunyer, F.X., Banerji, M.A., Schweizer, A.,
Couturier, A., Dejager, S.: Management of type 2 diabetes in treatment-naive elderly
patients: benefits and risks of vildagliptin monotherapy. Diabetes Care 30(12), 30173022 (2007).
Pratley, R.E., Schweizer, A., Rosenstock, J., Foley, J.E., Banerji, M.A., Pi-Sunyer,
F.X., Mills, D., Dejager, S.: Robust improvements in fasting and prandial measures of
beta-cell function with vildagliptin in drug-naive patients: analysis of pooled
vildagliptin monotherapy database. Diabetes Obes Metab 10(10), 931-938 (2008).
Richard, K.R., Shelburne, J.S., Kirk, J.K.: Tolerability of dipeptidyl peptidase-4
inhibitors: a review. Clin Ther 33(11), 1609-1629 (2011).
Richter, B., Bandeira-Echtler, E., Bergerhoff, K., Lerch, C.: Emerging role of
dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes. Vasc Health
Risk Manag 4(4), 753-768 (2008).
Richter, B., Bandeira-Echtler, E., Bergerhoff, K., Lerch, C.L.: Dipeptidyl peptidase-4
(DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev(2),
Cd006739 (2008).
Rizos, E.C., Ntzani, E.E., Papanas, N., Tsimihodimos, V., Mitrogianni, Z., Maltezos,
E., Elisaf, M.S.: Combination Therapies of DPP4 Inhibitors and GLP1 Analogues
with Insulin in Type 2 Diabetic Patients: A Systematic Review. Curr Vasc Pharmacol
(2012).
Rizos, E.C., Ntzani, E.E., Papanas, N., Tsimihodimos, V., Mitrogianni, Z., Maltezos,
E., Elisaf, M.S.: Combination therapies of DPP4 inhibitors and GLP1 analogues with
insulin in type 2 diabetic patients: A systematic review. Current Vascular
Pharmacology 11(6), 992-1000 (2013).
Rosenstock, J., Fitchet, M.: Vildagliptin: clinical trials programme in monotherapy
and combination therapy for type 2 diabetes. Int J Clin Pract Suppl(159), 15-23
(2008).
Scheen, A.J., Paquot, N.: [Vildagliptin (Galvus) and fixed combination vildagliptinemetformin (Eucreas) in the treatment of type 2 diabetes]. Rev Med Liege 64(3), 161167 (2009).
Schweizer, A., Dejager, S., Foley, J.E., Couturier, A., Ligueros-Saylan, M., Kothny,
W.: Assessing the cardio-cerebrovascular safety of vildagliptin: meta-analysis of
adjudicated events from a large Phase III type 2 diabetes population. Diabetes Obes
Metab 12(6), 485-494 (2010).
Schweizer, A., Dejager, S., Shao, Q., Ligueros-Saylan, M., Kothny, W.: Assessing
the cardiovascular safety of vildagliptin: A meta-analysis of adjudicated
cardiovascular and cerebrovascular events from a large phase 3 population.
Diabetologia 52 (S1), S300 (2009).
Signorovitch, J.E., Wu, E.Q., Swallow, E., Kantor, E., Fan, L., Gruenberger, J.B.:
Comparative efficacy of vildagliptin and sitagliptin in Japanese patients with type 2
diabetes mellitus: a matching-adjusted indirect comparison of randomized trials
(Provisional abstract). Clinical Drug Investigation (2011).
Standl, E., Erbach, M., Schnell, O.: Dipeptidyl-peptidase-4 Inhibitors and Heart
Failure: Class Effect, Substance-Specific Effect, or Chance Effect? Curr Treat
Options Cardiovasc Med 16(12), 353 (2014).
Walczak, J., Nogas, G., Organa, M., Przada, P., Potoczny, R.: Systematic review of
the efficacy and safety of vildagliptin for type 2 diabetes mellitus. Value in Health 12
(7), A402 (2009).
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
Wani, J.H., John-Kalarickal, J., Fonseca, V.A.: Dipeptidyl peptidase-4 as a new target
of action for type 2 diabetes mellitus: a systematic review. Cardiol Clin 26(4), 639648 (2008).
Wong, M.C.S., Wang, H.H.X., Kwan, M.W.M., Zhang, D.D.X., Liu, K.Q.L., Chan,
S.W.M., Fan, C.K.M., Fong, B.C.Y., Li, S.T.S., Griffiths, S.M.: Comparative
effectiveness of dipeptidyl peptidase-4 (DPP-4) inhibitors and human glucagon-like
peptide-1 (GLP-1) analogue as add-on therapies to sulphonylurea among diabetes
patients in the asia-pacific region: A systematic review. PLoS ONE 9(3) (2014).
Wu, D., Li, L., Liu, C.: Efficacy and safety of dipeptidyl peptidase-4 inhibitors and
metformin as initial combination therapy and as monotherapy in patients with type 2
diabetes mellitus: a meta-analysis. Diabetes Obes Metab 16(1), 30-37 (2014).
Wu, S., Hopper, I., Skiba, M., Krum, H.: Dipeptidyl peptidase-4 inhibitors and
cardiovascular outcomes: Meta-analysis of randomized clinical trials with 55,141
participants. Cardiovascular Therapeutics 32(4), 147-158 (2014).
Zhan, M., Wu, F.B., Huang, J., Tang, Y.: Vildagliptin versus placebo in treatment of
type 2 diabetes: a meta-analysis (Provisional abstract). Chinese Journal of EvidenceBased Medicine (2011).
Zhang, Y., Hong, J., Chi, J., Gu, W., Ning, G., Wang, W.: Head-to-head comparison
of dipeptidyl peptidase-IV inhibitors and sulfonylureas - a meta-analysis from
randomized clinical trials. Diabetes/Metabolism Research and Reviews 30(3), 241256 (2014).
Abdulwahid, N.A., Al-Zakwani, I.: Addition of sitagliptin or vildagliptin to
uncontrolled type II DM with oral hypoglycemic medications. Diabetes 61, A616
(2012).
Cakirca, M., Karatoprak, C., Zorlu, M., Kiskac, M., Kanat, M., Cikrikcioglu, M.A.,
Soysal, P., Hursitoglu, M., Camli, A.A., Erkoc, R., Abdul-Ghani, M.: Effect of
vildagliptin add-on treatment to metformin on plasma asymmetric dimethylarginine
in type 2 diabetes mellitus patients. Drug Design, Development and Therapy 8, 239243 (2014).
Choe, E.Y., Cho, Y., Choi, Y., Yun, Y., Wang, H.J., Kwon, O., Lee, B.W., Ahn,
C.W., Cha, B.S., Lee, H.C., Kang, E.S.: The effect of DPP-4 inhibitors on metabolic
parameters in patients with type 2 diabetes. Diabetes and Metabolism Journal 38(3),
211-219 (2014).
Kuribayashi, N.: Compare clinical efficacy between vildagliptin 100 mg and
sitagliptin 100 mg in inadequate patients with sitagliptin 50 mg. [Japanese].
Therapeutic Research 33(5), 703-710 (2012).
Shestakova, M.V., Suhareva, O., Chernova, T.O., Shmushkovich, I.A., Aleksandrov,
A.A., Il'in, A.V., Dedov, II: [A combination of dipeptidyl peptidase-4 inhibitor and
metformin in the treatment of patients with type 2 diabetes mellitus: effective control
of glycemia, weight, and quantitative body composition]. Ter Arkh 85(8), 49-55
(2013).
Zhang, X., Brooks, B., Molyneaux, L., Landy, E., Banatwalla, R., Wu, T., Wong, J.,
Su, B., Yue, D.K.: Dipeptidyl peptidase-4 inhibitors as a third-line oral
antihyperglycaemic agent in patients with type 2 diabetes mellitus: The impact of
ethnicity. International Journal of Endocrinology 2014(354040) (2014).
Bader, G., Schweizer, A.: Vildagliptin more effectively achieves a composite
endpoint of HbA1c <7% without hypoglycaemia or weight gain compared with SUs:
A pooled analysis of clinical trials. Diabetologia 55, S356 (2012).
Bader, G., Schweizer, A.: Vildagliptin more effectively achieves a composite
endpoint of reaching HbA1c target without hypoglycemia or weight gain compared
with sUS: A pooled analysis of clinical trials. Diabetes 61, A595 (2012).
Lukashevich, V., Foley, J., Schweizer, A., Rendell, M.S., Kothny, W.: Safety profile
of the DPP-4 inhibitors vildagliptin and sitagliptin in patients with type 2 diabetes and
severe renal impairment. Diabetologia 1), S362 (2014).
Monnier, L., Colette, C., Comenducci, A., Vallee, D., Dejager, S.: Add-on therapies
to metformin in type 2 diabetes: what modulates the respective decrements in
postprandial and basal glucose? Diabetes Technol Ther 14(10), 943-950 (2012).
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
Schweizer, A., Dejager, S., Foley, J.E.: Impact of insulin resistance, body mass index,
disease duration, and duration of metformin use on the efficacy of vildagliptin.
Diabetes Ther 3(1), 8 (2012).
Schweizer, A., Dejager, S., Foley, J.E., Kothny, W.: Assessing the general safety and
tolerability of vildagliptin: value of pooled analyses from a large safety database
versus evaluation of individual studies. Vasc Health Risk Manag 7, 49-57 (2011).
Schweizer, A., Dejager, S., Foley, J.E., Shao, Q., Kothny, W.: Clinical experience
with vildagliptin in the management of type 2 diabetes in a patient population >/=75
years: a pooled analysis from a database of clinical trials. Diabetes Obes Metab 13(1),
55-64 (2011).
Bader, G., Geransar, P., Schweizer, A.: Vildagliptin more effectively achieves a
composite endpoint of HbA?c < 7.0% without hypoglycaemia and weight gain
compared with glimepiride after 2 years of treatment. Diabetes research and clinical
practice (2013). doi:10.1016/j.diabres.2013.03.011
Kim, S.W., Baik, S.H., Yoon, K.H., Lee, H.W., Filozof, C.: Efficacy and safety of
vildagliptin/pioglitazone combination therapy in Korean patients with diabetes.
World J Diabetes 1(5), 153-160 (2010).
Kozlovski, P., Foley, J., Shao, Q., Lukashevich, V., Kothny, W.: Vildagliptin-insulin
combination improves glycemic control in Asians with type 2 diabetes. World J
Diabetes 4(4), 151-156 (2013).
Krum, H., Lukashevich, V., Bolli, G.B., Kozlovski, P., Kothny, W., Ponikowski, P.:
No significant difference in risk of heart failure hospitalization with vildagliptin in
diabetic patients with systolic chronic heart failure: VIVIDD study. Diabetes 63,
A265 (2014).
Lukashevich, V., Araga, M., Kothny, W.: Efficacy and safety of vildagliptin in triple
combination with metformin plus sulfonylurea in subgroup of patients with T2DM
and baseline HbA1c <8%. Diabetes 62, A294 (2013).
Lukashevich, V., Schweizer, A., Foley, J.E., Dickinson, S., Groop, P.H., Kothny, W.:
Efficacy of vildagliptin in combination with insulin in patients with type 2 diabetes
and severe renal impairment. Vasc Health Risk Manag 9, 21-28 (2013).
Schweizer, A., Dejager, S.: Experience with vildagliptin in patients >/=75 years with
type 2 diabetes and moderate or severe renal impairment. Diabetes Ther 4(2), 257267 (2013).
Rosenstock, J., Foley, J.E., Rendell, M., Landin-Olsson, M., Holst, J.J., Deacon, C.F.,
Rochotte, E., Baron, M.A.: Effects of the dipeptidyl peptidase-IV inhibitor
vildagliptin on incretin hormones, islet function, and postprandial glycemia in
subjects with impaired glucose tolerance. Diabetes Care 31(1), 30-35 (2008).
Werzowa, J., Hecking, M., Haidinger, M., Lechner, F., Doller, D., Pacini, G., Stemer,
G., Pleiner, J., Frantal, S., Saemann, M.D.: Vildagliptin and pioglitazone in patients
with impaired glucose tolerance after kidney transplantation: a randomized, placebocontrolled clinical trial. Transplantation 95(3), 456-462 (2013).
Werzowa, J., Hecking, M., Lechner, F., Haidinger, M., Saemann, M.D., Pleiner, J.,
Pacini, G.: Vildagliptin and pioglitazone in impaired glucose tolerance after renal
transplantation: Results from the Glucose Control in Pre-diabetic Renal Transplant
Patients (GCPD) study. European Surgery - Acta Chirurgica Austriaca 43, 15-16
(2011).
Gooding, K.M., Shore, A.C., Mawson, D., Ball, C.I., Pitt, A., Aizawa, K., Strain,
W.D.: A pilot study investigating whether dipeptidyl peptidase-IV inhibition alters
vascular function in obese men. Diabetic Medicine 30, E8-E9 (2013).
Rizzo, M.R., Barbieri, M., Marfella, R., Paolisso, G.: Response to comment on: Rizzo
et al. Reduction of oxidative stress and inflammation by blunting daily acute glucose
fluctuations in patients with type 2 diabetes: Role of dipeptidyl peptidase-IV
inhibition. Diabetes Care 2012;35:2076-2082. Diabetes Care 36(1), e31 (2013).
CLAF237A2301E1:
In.
http://www.novctrd.com/CtrdWeb/displaypdf.nov?trialresultid=2311,
Karpova, E., Ametov, A.: DPP-IV inhibitors improved glycemic control in type 2
diabetes patients. Diabetes Technology and Therapeutics 13 (2), 236 (2011).
134.
135.
136.
137.
Kudo-Fujimaki, K., Hirose, T., Yoshihara, T., Sato, F., Someya, Y., Ohmura, C.,
Kanazawa, A., Fujitani, Y., Watada, H.: Efficacy and safety of nateglinide plus
vildagliptin combination therapy compared with switching to vildagliptin in type 2
diabetes patients inadequately controlled with nateglinide. Journal of Diabetes
Investigation (2014). doi:http://dx.doi.org/10.1111/jdi.12160
Xu, L., Lin, K., Deng, H.O., Li, Y.L., Zhi, X.M., Zhang, W.J., Wu, W.: [Therapeutic
effect of vildagliptin and insulin aspart injection in elderly patients with type 2
diabetes]. Nan Fang Yi Ke Da Xue Xue Bao 34(10), 1511-1518 (2014).
Yamaguchi, M., Saji, T., Mita, S., Kulmatycki, K., He, Y.L., Furihata, K., Sekiguchi,
K.: Pharmacokinetic and pharmacodynamic interaction of vildagliptin and voglibose
in Japanese patients with Type 2 diabetes. International journal of clinical
pharmacology and therapeutics (2013). doi:10.5414/CP201902
Yoshiki, M., Odawara, M., Sano, M., Hamada, I., Lukashevich, V., Kothny, W.:
Efficacy and safety of a fixed-dose combination of vildagliptin and metformin
(LMF237) in Japanese patients with type 2 diabetes. Diabetologia 1), S367 (2014).
Risk of Bias in Included Studies
We used the “Cochrane’s Collaboration tool for assessment of risk of bias of included studies.
Presented below are the rules by which we determined overall risk of bias in every study.
Key domains for the primary outcome were the following: “sequence generation”, “allocation
concealment”, “incomplete outcome data” and “selective outcome reporting”. The overall risk
of bias was assessed in compliance with the following rules:
 If a study was considered “in high risk” for any of the aforementioned domains, then that
study was characterized at “high risk of bias”
 If a study was considered “in low risk” for every of the aforementioned domains, then that
study was characterized at “low risk of bias”
 In any other case the study was considered at “unclear risk of bias”
Supplementary Fig 1 Risk of bias graph.
Supplementary Fig 2 Risk of bias summary
Supplementary Fig 3 Weighted mean difference in change from baseline in HbA1c (%): Vildagliptin in
monotherapy, dual therapy or triple therapy regimens, versus placebo or active comparators. Results are from
inverse variance random-effects meta-analysis. IV: inverse variance.
Supplementary Fig 4 Odds ratio for incidence of any hypoglycemia: Vildagliptin vs placebo, grouped as
monotherapy or add-on treatment. Results are from Mantel-Haenszel fixed-effects meta-analysis with a treatment
arm continuity correction, including total zero events trials.
Supplementary Fig 5 Odds ratio for incidence of any hypoglycemia: Vildagliptin vs active comparators, grouped
as monotherapy or add-on treatment. Results are from Mantel-Haenszel fixed-effects meta-analysis with a
treatment arm continuity correction, including total zero events trials.
Supplementary Table 1 Odds ratios for safety outcomes
Outcome
Incidence of serious adverse events
Incidence of nasopharyngitis
Incidence of urinary tract infections
Incidence of elevation of hepatic enzymes
Incidence of skin reactions
Number of studies
52
22
8
11
4
Odds ratio (95%CI); I2
0.98 (0.88 to 1.09); 0%
1.06 (0.93 to 1.21); 0%
0.94 (0.57 to 1.56); 8%
0.61 (0.28 to 1.36); 0%
2.07 (0.67 to 6.36); 0%
Supplementary Table 2 Odds ratio for the incidence of death and pancreatitis. Peto, inverse variance and MantelHaenszel fixed effect meta-analysis with constant and treatment arm continuity correction.
Meta-analytic method
Fixed, Peto
Number of studies
19
Death
Odds ratio (95% CI); I2
1.15 (0.72 to 1.84); 0%
Fixed, IV (CC+)
48
0.93 (0.63 to 1.39); 0%
Fixed, IV (CC)
19
1.02 (0.63 to 1.64); 0%
Fixed, IV (TAC+)
48
1.04 (0.69 to 1.56); 0%
Fixed, IV (TAC)
19
1.05 (0.65 to 1.70); 0%
Fixed, MH (CC+)
48
0.98 (0.67 to 1.43); 0%
Fixed, MH (CC)
19
1.07 (0.69 to 1.67); 0%
Fixed, MH (TAC+)
48
1.10 (0.75 to 1.61); 0%
Pancreatitis
Number of studies
Odds ratio (95% CI); I2
3
0.95 (0.29 to 3.06); 0%
8
3
8
3
8
3
0.93 (0.34 to 2.52); 0%
0.96 (0.28 to 3.22); 0%
0.97 (0.36 to 2.64); 0%
0.96 (0.28 to 3.22); 0%
0.93 (0.35 to 2.42); 0%
0.95 (0.30 to 2.99); 0%
0.97 (0.37 to 2.53); 0%
8
Fixed, MH (TAC)
19
1.13 (0.72 to 1.77); 0%
3
0.95 (0.30 to 2.99); 0%
CC = constant correction for continuity; CC+ = constant correction for continuity that includes all zero total event studies; CI =
confidence interval; IV = inverse variance; MH = Mantel–Haenszel; TAC = treatment arm correction for continuity; TAC+ =
treatment arm correction for continuity that includes all total zero event studies.