TY - JOUR

T1 - Metformin may adversely affect orthostatic blood pressure recovery in patients with type 2 diabetes

T2 - Substudy from the placebo-controlled Copenhagen Insulin and Metformin Therapy (CIMT) trial

AU - Hansen, Christian Stevns

AU - Lundby-Christiansen, Louise

AU - Tarnow, Lise

AU - Gluud, Christian

AU - Hedetoft, Christoffer

AU - Thorsteinsson, Birger

AU - Hemmingsen, Bianca

AU - Wiinberg, Niels

AU - Sneppen, Simone B.

AU - Lund, Søren S.

AU - Krarup, Thure

AU - Madsbad, Sten

AU - Almdal, Thomas

AU - Carstensen, Bendix

AU - Jørgensen, Marit E.

PY - 2020

Y1 - 2020

N2 - 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).

AB - 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).

KW - Autonomic neuropathy

KW - Cardiovascular autonomic neuropathy

KW - Complications

KW - Metformin

KW - Orthostatic blood pressure recovery

KW - Orthostatic hypotension

KW - Peripheral neuropathy

KW - Type 2 diabetes

U2 - 10.1186/s12933-020-01131-3

DO - 10.1186/s12933-020-01131-3

M3 - Journal article

C2 - 32979921

AN - SCOPUS:85091811641

VL - 19

JO - Cardiovascular Diabetology

JF - Cardiovascular Diabetology

SN - 1475-2840

IS - 1

M1 - 150

ER -