Effects of saxagliptin added to sub-maximal doses of metformin compared with uptitration of metformin in type 2 diabetes: the PROMPT study

Abstract

Objective:

The PROMPT study compared efficacy and tolerability of two treatment intensification strategies: adding saxagliptin or uptitrating metformin monotherapy, in patients with type 2 diabetes (T2D) and inadequate glycaemic control on a sub-maximal metformin dose.

Research design and methods:

In this double-blind, 24-week study, metformin-tolerant patients with T2D on metformin monotherapy were randomised to receive fixed-dose metformin 1500 mg/day, plus either add-on saxagliptin 5 mg/day (SAXA-MET) or a two-step metformin uptitration (MET-UP) to a maximum dose (2500 mg/day).

Clinical trial registration:

NCT01006590.

Main outcome measures:

Primary: absolute change from baseline in glycated haemoglobin A_1c (HbA_1c) (Week 24). Secondary: proportion of patients achieving a therapeutic glycaemic response (Week 24); change from baseline in fasting plasma glucose (Week 24); safety and tolerability. Exploratory analyses comprised three patient-related questionnaires, including the validated 5-dimension Digestive Health Status Index (DHSI).

Results:

A total of 286 patients were randomised: (SAXA-MET: 147; MET-UP: 139). Baseline mean (SD) HbA_1c: 7.71 (0.85; SAXA-MET); 7.80 (0.82; MET-UP). Adjusted mean reductions from baseline in HbA_1c (Week 24): −0.47% (SAXA-MET); −0.38% (MET-UP); mean (95% CI) difference in treatment effect, −0.10% (−0.26, 0.07); p = 0.260. The proportion of patients (95% CI) achieving a therapeutic glycaemic response (HbA_1c < 7%): 43.8% (34.8, 49.6) (SAXA-MET) vs. 35.0% (29.0, 43.8) (MET-UP). Of the five DHSI domains, mean (95% CI) differences were observed for diarrhoea-predominant score (+0.8 [−2.5, 4.0] vs. +7.9 [4.6, 11.2]) and dysmotility score (−0.5 [−2.0, 1.0] vs. +1.9 [0.3, 3.4]), (SAXA-MET and MET-UP, respectively). The most common adverse event was diarrhoea: 6.1% (SAXA-MET) vs. 12.2% (MET-UP).

Conclusions:

In metformin-tolerant patients with T2D (inadequately controlled on sub-maximal metformin monotherapy), saxagliptin was well tolerated. Although HbA_1c reduction was not significantly different between treatment groups, the lower occurrence of gastrointestinal symptoms in the SAXA-MET group suggests that saxagliptin add-on treatment may be a suitable alternative treatment strategy to metformin uptitration.

Keywords::

• DPP-4 inhibitor
• Hyperglycaemia
• Incretins
• Metformin
• Saxagliptin
• Type 2 diabetes

Transparency

Declaration of funding

The PROMPT study was sponsored by AZ/BMS, who were involved in the design and conduct of the study; data collection, analysis and interpretation; preparation and review of the manuscript; and decision to submit the manuscript for publication. B.C. and P.M. designed the study. LL. and S.J. were the study statisticians. B.C., E.M., L.L., P.M., S.J. and T.D. analysed and interpreted the study data. E.M. and P.M. reviewed the literature. All authors critically reviewed the manuscript and approved the final version for submission. M.P.H., E.M., L.L., P.M.P. and P.M. accept overall responsibility for the accuracy of the data, its analysis, and this report. All authors had full access to the data and had final responsibility for the decision to submit for publication.

Declaration of financial/other relationships

B.C. has received fees for consultancy, speaking, travel and accommodation from: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche, Sanofi, and Takeda. I.F. participated in AZ-sponsored studies and AZ paid for travel to meetings. T.D. has received fees for consultancy, speaking, travel or accommodation from: AstraZeneca, Eli Lilly, Sanofi, Novo Nordisk, Servier, MSD, and Novartis. M.P.H. has served on an advisory panel and/or received speaker’s honoraria or travel grants from Abbott, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Eli Lilly, Menarini, Novartis, Novo Nordisk, Sanofi and Takeda. L.L. and P.M. have disclosed that they are employees of AstraZeneca; E.M. is an employee of Bristol-Myers Squibb. P.M.P. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgements

Statistical work performed by Silke Jörgens of Aptiv Solutions was funded by AstraZeneca. Jennie Frain PhD (QXV Communications, Macclesfield, UK) provided assistance with the manuscript preparation, which was funded by AstraZeneca/Bristol-Myers Squibb.

The authors would also like to thank and acknowledge the PROMPT study investigators: Silvia Acquati, Paul Ainsworth, Olga González Albarrán, Francisco Javier Sierra Alonso, Yalcin Aral, Müyesser Sayki Aslan, Angelo Avogaro, Luc Baeck, Elisabeth Barberan, Jérome Basle, Giancarlo Battello, Deborah Beale, Handan Bekdemir, Paloma Pujol Bengoechea, Michel Bismuth, Marc Bonnefoy, Jack Philippe Bourceau, Odile Bourgeois, Jean-Paul Boyes, Nujen Colak Bozkurt, Nicholas Bradshaw, Evrim Cakir, Guillem Cuatrecasas Camba, Gabriel Cuatrecasas Cambra, Thierry Cantin, Jorge Gómez Cerezo, Alain Chaleon, Guillaume Charpentier, Henri Chaussade, Nieves Martell Claros, Bernard Clarysse, Erwan Colin, Moises De Vicente Collado, Anna Corsi, Francis Coucke, Arturo Fernández Cruz, Cavit Çulha, Susana Rodriguez De Cos, Saula Vigili De Kreutzenberg, Tuncay Delibasi, Karl-Michael Derwahl, Montserrat Martin Diaz, Bernard Dimon, Alessandro Dodesini, Francesca Donadio, Valter Donadon, Francesco Dotta, Pierre Duchene, M Dolores Lopez Eady, Richard Edwards, Canan Ersoy, Emma Evans, Roberto Fabris, Ian Farmer, Margarita De Rivas Fernández, Pierre Andre Ferrand, Gillian French, Gabriele Freyer-Lahres, Horst Frick, Silvia Galasso, Santiago Durán García, Claude Gener, Manuel Ferreiro Gómez, Alfonso Soto González, Trevor Gooding, Pierre-Jean Guillausseau, Ozen Oz Gul, Michael Gumbley, Askin Gungunes, Michel Hermans, Pedro García Hermosa, Nicola Hills, Susanne Höltz, Dan Hubbard, Nigel Hume, André Hutsebaut, Philippe Igigabel, Salvador Tranche Iparaguirre, Manjit Jaspal, Pascal Jelen, Antonius Jonczyk, Nick Jones, Eric Jordan, Josselin Kamga, Basak Karbek, Martina Kleinhardt, Bernard Lefebvre, Philippe Legall, Gilberto Bennet Perez Lopez, Jose Luis Garcia Losa, Pietro Lucotti, Guy Margueritte, Guido Mehuys, Renaud Menard, Sarah Miller, Lucilla Monti, Caroline Monticelli, Marcella Montini, Stephane Moreau, Jaak Mortelmans, Barbara Pagan Muñoz, Alberto Galgo Nafria, Paul Nicholson, Diana Nicula, Maurizio Nizzoli, Italo Nosari, Didier Nourry, Michael Orlowski, Giorgio Pagani, Eduardo José Abad Paniagua, Luis De Teresa Parreño, Javier Güell Peris, Catherine Petit, PierMarco Piatti, Bruno Picard, Chiara Dal Prà, Andreas Preusche, Samir Purell-Mullick, Renate Rennow, Thierry Revol, Valerie Roger Rieux, Iain Rock, Francisco José García Ruiz, Maria Isabel Gonzalez Saavedra, Didier Sacareau, Angel Nieto Sanchez, Amelia Espinosa Santana, Marta Sanz Sanz, Caterina Saponara, Raymond Sarfati, Alessandro Scarda, Carlo Scioldo, Roberto Serra, Emanuela Setola, Jochen Seufert, Ernal Shehaj, Emma Simpson, Kerstin Steinbach, Christopher Strang, Amrit Takhar, Silvia Taroni, Gerard Tatareau, Julia Taylor, Rosa Testa, Scott Thomson, Jérôme Tondut, Vania Torricelli, Roberto Trevisan, Peter Uebel, Ilknur Öztürk Ünsal, Albert Boada Valmaseda, Jos Vanhoof, Marcos Lahera Vargas, Guido Vereecken, Primario Vergara, Roberto Vettor, Christophe Viel, Valentina Villa, Joaquín Aracil Villar, Jürgen Wachter, David Weston, Steven Windmolders, John Mcgregor Winward, Ahmet Yildirim and Giorgio Zanette.

Previous presentation: Hermans et al. Effects of Saxagliptin Added to Sub-maximal Doses of Metformin Compared with Dose Escalation of Metformin in Type 2 Diabetes: Results from the PROMPT study. Poster presented at the 47th EASD meeting, Lisbon, Portugal, 12–16 September 2011.