Abstract
BackgroundMetformin 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).MethodsThe 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.ResultsAfter 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.ConclusionsEighteen 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).
Highlights
Patients with diabetes are at risk of neurological complications which can be manifested as cardiovascular autonomic neuropathy (CAN) and distal peripheral neuropathy (DPN)
Metformin may potentially increase the risk of diabetic neurological complications, as metformin has been shown to impair absorption of vitamin B12 [14] leading to reduced levels of serum B12, which has been associated with both cardiovascular autonomic neu‐ ropathy (CAN) [15] and DPN [16]
Symptoms of autonomic neuropathy and distal peripheral neuropathy were present in 16% and 38% of all participants, respectively
Summary
Patients with diabetes are at risk of neurological complications which can be manifested as cardiovascular autonomic neuropathy (CAN) and distal peripheral neuropathy (DPN). Metformin has been shown to have neuroprotective effects and has been demonstrated to reduce pain sensation in patients with lumbar radicular pain [17] and in diabetic animal pain models [18], to protect against chemotherapy induced peripheral neuropathy [19], and to reduce apoptotic cell death in cortical neurons [20]. These beneficial effects have been suggested to be mediated by a metformin-induced reduction in oxidative stress [20]. 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)
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