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

Cardiovasc Diabetol. 2020 Sep 26;19(1):150. doi: 10.1186/s12933-020-01131-3.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Autonomic Nervous System Diseases / etiology
  • Autonomic Nervous System Diseases / physiopathology*
  • Blood Pressure / physiology*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology
  • Diabetic Neuropathies / etiology
  • Diabetic Neuropathies / physiopathology*
  • Female
  • Glycated Hemoglobin / metabolism
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Hypotension, Orthostatic / epidemiology*
  • Insulin / therapeutic use*
  • Male
  • Metformin / therapeutic use*
  • Middle Aged
  • Peripheral Nervous System Diseases / etiology
  • Peripheral Nervous System Diseases / physiopathology*
  • Risk Factors
  • Standing Position*
  • Vitamin B 12 / metabolism

Substances

  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Insulin
  • hemoglobin A1c protein, human
  • Metformin
  • Vitamin B 12

Associated data

  • ClinicalTrials.gov/NCT00657943