Metformin may adversely affect orthostatic blood pressure recovery in patients with type 2 diabetes: substudy from the p
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ORIGINAL INVESTIGATION
Cardiovascular Diabetology Open Access
Metformin may adversely affect orthostatic blood pressure recovery in patients with type 2 diabetes: substudy from the placebo‑controlled Copenhagen Insulin and Metformin Therapy (CIMT) trial Christian Stevns Hansen1* , Louise Lundby‑Christiansen1,2, Lise Tarnow3,4, Christian Gluud5, Christoffer Hedetoft6, Birger Thorsteinsson7, Bianca Hemmingsen7, Niels Wiinberg8, Simone B. Sneppen9, Søren S. Lund1, Thure Krarup10, Sten Madsbad11, Thomas Almdal12,13, Bendix Carstensen1, Marit E. Jørgensen1,14 and the CIMT study group
Abstract Background: Metformin has been shown to have both neuroprotective and neurodegenerative effects. The aim of this study was to investigate the effect of metformin in combination with insulin on cardiovascular autonomic neu‑ ropathy (CAN) and distal peripheral neuropathy (DPN) in individuals with type 2 diabetes (T2DM). Methods: The study is a sub-study of the CIMT trial, a randomized placebo-controlled trial with a 2 × 3 factorial design, where 412 patients with T2DM were randomized to 18 months of metformin or placebo in addition to openlabelled insulin. Outcomes were measures of CAN: Changes in heart rate response to deep breathing (beat-to-beat), orthostatic blood pressure (OBP) and heart rate and vibration detection threshold (VDT) as a marker DPN. Serum levels of vitamin B12 and methyl malonic acid (MMA) were analysed. Results: After 18 months early drop in OBP (30 s after standing) was increased in the metformin group compared to placebo: systolic blood pressure drop increased by 3.4 mmHg (95% CI 0.6; 6.2, p = 0.02) and diastolic blood pressure drop increased by 1.3 mmHg (95% CI 0.3; 2.6, p = 0.045) compared to placebo. Beat-to-beat variation decreased in the metformin group by 1.1 beats per minute (95% CI − 2.4; 0.2, p = 0.10). Metformin treatment did not affect VDT group difference − 0.33 V (95% CI − 1.99; 1.33, p = 0.39) or other outcomes. Changes in B12, MMA and HbA1c did not confound the associations. Conclusions: Eighteen months of metformin treatment in combination with insulin compared with insulin alone increased early drop in OBP indicating an adverse effect of metformin on CAN independent of vitamin B12, MMA HbA1c. Trial registration The protocol was approved by the Regional Committee on Biomedical Research Ethics (H–D-2007112), the Danish Medicines Agency and registered with ClinicalTrials.gov (NCT00657943).
*Correspondence: [email protected] 1 Steno Diabetes Center Copenhagen, A/S, Niels Steensens Vej 2‑4, 2820 Gentofte, Denmark Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material
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