Metformin discontinuation in patients beginning second-line glucose-lowering therapy: results from the global observational DISCOVER study programme

Abstract

Objectives: To evaluate the extent to which patients with type 2 diabetes discontinue metformin therapy when initiating second-line treatment and factors associated with metformin discontinuation, using baseline data from the DISCOVER study programme.

Design: DISCOVER is a 3-year, prospective, observational study programme including data from 38 countries across 6 continents from 2014 to 2019.

Setting: Primary and secondary healthcare centres, hospitals and specialist diabetes centres in both urban and rural locations.

Participants: A total of 15 992 patients with type 2 diabetes initiating second-line glucose-lowering therapy.

Primary and secondary outcome measures: The proportion of patients who discontinued metformin as a second-line therapy and the factors associated with this treatment change.

Results: Of the 14 668 patients (from 37 countries) with valid treatment data, 11 837 (80.7%) received metformin as first-line glucose-lowering therapy; 8488 (71.7%) received metformin monotherapy and 3349 (28.3%) received metformin as part of a combination therapy. Overall, treatment with metformin was discontinued in 15.1% (1782) of patients who received first-line metformin (14.1% (1194) and 17.6% (588) in those who received metformin as monotherapy and as part of a combination, respectively); this proportion varied across regions from 6.9% (54) in Africa to 20.6% (628) in South-East Asia. On metformin discontinuation, 73.6% (1311) of patients received a non-insulin monotherapy at second line. Factors associated with an increased odds of metformin discontinuation were older age (≥75 years) and having a history of chronic kidney disease. The probability of metformin monotherapy discontinuation was lower in patients from Africa than in those from Europe.

Conclusions: A substantial number of patients discontinued taking metformin when beginning second-line therapy. Most of these patients subsequently received a non-insulin monotherapy at second line, in contradiction to international guidelines and potentially leaving them at an increased risk of hyperglycaemia and associated adverse outcomes.

Trial registration numbers: NCT02322762 and NCT02226822.

Keywords: diabetes & endocrinology; epidemiology; general diabetes.

Conflict of interest statement

Competing interests: KK, MBG, MK, AN, SP, WR, MVS, IS, HW and LJ are members of the DISCOVER Scientific Committee and received financial support from AstraZeneca to attend DISCOVER planning and update meetings. HC and PF are employees of AstraZeneca. NH is a former employee of AstraZeneca. JC-R is an employee of Evidera. In addition, KK has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, Takeda, Servier and Pfizer, and research support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi and Pfizer, and also acknowledges support from the National Institute for Health Research Collaboration for Applied Research Collaboration—East Midlands (NIHR ARC—EM) and the National Institute of Health Research (NIHR) Leicester Biomedical Research Centre. MBG has received honoraria from Merck Serono. MK has received honoraria from Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Glytec Systems, Intarcia, Janssen, Merck (Diabetes), Novartis, Novo Nordisk, Sanofi and Vifor, and research support from AstraZeneca and Boehringer Ingelheim. AN has received honoraria from AstraZeneca, Eli Lilly, Medtronic and Novo Nordisk, and research support from Artsana, Dexcom, Novo Nordisk and Sanofi. WR has received research support from Novo Nordisk. MVS has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharpe & Dohme, Novo Nordisk, Sanofi and Servier, and research support from Novo Nordisk and Sanofi. IS has received honoraria from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Kowa, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novo Nordisk, Ono Pharmaceutical, Sanwa Kagaku Kenkyusho and Takeda Pharmaceutical, and research support from Astellas Pharma, AstraZeneca, Daiichi Sankyo, Eli Lilly, Japan Foundation for Applied Enzymology, Japan Science and Technology Agency, Kowa, Kyowa Hakko Kirin, Midori Health Management Center, Mitsubishi Tanabe Pharma, Novo Nordisk, Ono Pharmaceutical, Sanofi, Suzuken Memorial Foundation and Takeda Pharmaceutical. HW has received honoraria from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Kissei Pharma, Kowa, Kyowa Hakko Kirin, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novartis, Novo Nordisk, Ono Pharmaceutical, Sanofi, Sanwa Kagaku Kenkyusho and Takeda, and research support from Abbott, Astellas Pharma, AstraZeneca, Bayer, Benefit One Health Care, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Johnson & Johnson, Kissei Pharma, Kowa, Kyowa Hakko Kirin, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nitto Boseki, Novartis, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sanofi, Sanwa Kagaku Kenkyusho, Taisho Toyama Pharmaceutical, Takeda and Terumo Corp. FT is an employee of the Mid America Heart Institute and has received research support from AstraZeneca. LJ has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Takeda, Sanofi and Roche, and research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Roche and Sanofi.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Variables associated with metformin discontinuation in patients receiving metformin (A) as monotherapy and (B) as part of a combination as first-line therapy. ORs were calculated using a hierarchical logistic regression model, with country as a random effect and adjusted for all variables in the figure. BMI, body mass index; HbA1c, glycated haemoglobin.