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 Hansen, Louise Lundby-Christiansen, Lise Tarnow, Christian Gluud, Christoffer Hedetoft, Birger Thorsteinsson, Bianca Hemmingsen, Niels Wiinberg, Simone B Sneppen, Søren S Lund, Thure Krarup, Sten Madsbad, Thomas Almdal, Bendix Carstensen, Marit E Jørgensen, CIMT study group, T Almdal, T W Boesgaard, L Breum, B Gade-Rasmussen, E Duun, C Gluud, C Hedetoft, B Hemmingsen, T Jensen, T Krarup, L Lundby-Christensen, S Lund, S Madsbad, E R Mathiesen, O Pedersen, H Perrild, M Røder, S B Sneppen, O Snorgaard, L Tarnow, B Thorsteinsson, H Vestergaard, A Vaag, N Wiinberg, Christian Stevns Hansen, Louise Lundby-Christiansen, Lise Tarnow, Christian Gluud, Christoffer Hedetoft, Birger Thorsteinsson, Bianca Hemmingsen, Niels Wiinberg, Simone B Sneppen, Søren S Lund, Thure Krarup, Sten Madsbad, Thomas Almdal, Bendix Carstensen, Marit E Jørgensen, CIMT study group, T Almdal, T W Boesgaard, L Breum, B Gade-Rasmussen, E Duun, C Gluud, C Hedetoft, B Hemmingsen, T Jensen, T Krarup, L Lundby-Christensen, S Lund, S Madsbad, E R Mathiesen, O Pedersen, H Perrild, M Røder, S B Sneppen, O Snorgaard, L Tarnow, B Thorsteinsson, H Vestergaard, A Vaag, N Wiinberg

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 neuropathy (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 open-labelled 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-2007-112), the Danish Medicines Agency and registered with ClinicalTrials.gov (NCT00657943).

Keywords: Autonomic neuropathy; Cardiovascular autonomic neuropathy; Complications; Metformin; Orthostatic blood pressure recovery; Orthostatic hypotension; Peripheral neuropathy; Type 2 diabetes.

Conflict of interest statement

LLC, TA, LT, SSL owns shares in Novo Nordisk A/S: SSL owns shares in in dynamically traded investment funds, which may own stocks from pharmaceutical companies. SSL has reported former employment at Steno Diabetes Center, which is a diabetes hospital and academic institution previously owned by Novo Nordisk. SSL is now employed at Boehringer Ingelheim International GmbH, Ingelheim, Germany. SSL’s contribution was his alone and does not necessarily reflect the official position of Boehringer Ingelheim.

Figures

Fig. 1
Fig. 1
The effect of metformin on resting blood pressure and drop in blood pressure from resting in a supine position to standing. Estimates are adjusted for baseline values of outcomes, changes during trial in vitamin B12, methylmalonic acid ang HbA1c and in addition pre-trial treatment of metformin. Effects are shown as mmHg and 95% CI. *p = 0.02. **p = 0.045 Only estimates for Model 3 are illustrated

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