Biphasic effect of metformin on human cardiac energetics

Emelyanova, Larisa; Bai, Xiaowen; Yan, Yasheng; Bošnjak, Željko J.; Kress, David C.; Kroboth, Stacie; Rudic, Teodore; Kaushik, Sirisha; Stoeckl, Elizabeth; Ross, Gracious R.; Rizvi, Farhan; Jahangir, Arshad

doi:10.1016/j.trsl.2020.10.002

Cited by 29 publications

(26 citation statements)

References 66 publications

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“…Metformin is only approved for the treatment of type 2 DM; however, a growing number of studies have suggested benefits from its off-label use in other areas, such as dementia [ 19 ], weight loss [ 20 ], glioblastoma [ 21 ], inflammation [ 22 ], hair growth [ 23 ], miscarriage and premature delivery, polycystic ovarian syndrome [ 24 ], breast and colorectal cancer [ 25 ], and cardiovascular protection [ 26 ]. These findings have increased interest in metformin and the development of generic MH-SR drugs.…”

Section: Discussionmentioning

confidence: 99%

Bioequivalence and Safety Assessment of Two Formulations of Metformin Hydrochloride Sustained-Release Tablets (Yuantang® SR and Glucophage® XR) Under Fed Conditions in Healthy Chinese Adult Subjects: An Open-Label, Two-Way Crossover, Sequence Randomized Phase I Clinical Trial

Sun

Liu

Luo³

et al. 2022

Drugs R D

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Objective The purpose of this single-center, randomized, open, two-period, two-sequence crossover, single-dose administration, bioequivalence research was to evaluate the bioequivalence and safety of the generic formulations of metformin hydrochloride sustained-release (MH-SR) 500 mg tablets (test preparation [T]: Yuantang ® SR) and the original formulation (reference preparation [R]: Glucophage ® XR) in 36 healthy Chinese volunteers under postprandial conditions. Methods Subjects received 500 mg T/R in each period, with a 7-day washout period. Venous blood samples of 4 mL each were collected from each subject 19 times spanning predose (0 h) to 36 h postdose. The metformin concentration in deproteinized plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. Bioequivalence (80.00-125.00%) was assessed by adjusted geometric mean ratios (GMRs) and two-sided 90% confidence intervals (CIs) of the area under the curve (AUC) and maximum concentration (C max ) for each component. SAS 9.4 software was used for statistical analysis and Phoenix WinNonlin software v7 was used to analyze the pharmacokinetic parameters. Results Thirty-four volunteers completed the clinical study. The 90% CIs (96.12-105.44% for AUC from time zero to the time of the last measurable concentration [AUC t ], 96.22-105.54% for AUC extrapolated from time zero to infinity [AUC ∞ ], and 98.42-105.00% for C max ) of T/R adjusted GMRs were within the bioequivalence acceptance range of 80.00-125.00%, indicating that they are bioequivalent. No serious adverse events occurred in this study, indicating that the two formulations were effective and well tolerated. Conclusions Yuantang ® SR was confirmed to be a well tolerated and bioequivalent alternative to Glucophage ® XR when taken under postprandial conditions in healthy Chinese volunteers. The Clinical Trials Registry Platform used for this study was http:// www. china drugt rials. org. cn/ clini caltr ials. searc hlist detail. dhtml. The trial registration numbers (TRNs) and dates of registrations were CTR20180476 (19 April 2018) for this clinical trial and CTR20171595 (11 January 2018) for the pilot trial.

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Section: Discussionmentioning

confidence: 99%

Bioequivalence and Safety Assessment of Two Formulations of Metformin Hydrochloride Sustained-Release Tablets (Yuantang® SR and Glucophage® XR) Under Fed Conditions in Healthy Chinese Adult Subjects: An Open-Label, Two-Way Crossover, Sequence Randomized Phase I Clinical Trial

Sun

Liu

Luo³

et al. 2022

Drugs R D

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“…Metformin therapy, a first-line diabetes treatment, is beneficial in a number of cardiovascular disorders(9,10)making it a candidate approach for SCA. Metformin impacts many metabolic processes, including activation of the AMPK signaling pathway, decreased ER stress and ROS, improved autophagy and mitochondrial biogenesis, and inhibition of the mitochondrial permeability transport pore (mPTP) (49–53). Studies of metformin’s effects on cardiac function have largely utilized ischemia-reperfusion injury models with ischemic periods of 25-30 minutes, both in vivo and ex vivo .…”

Section: Discussionmentioning

confidence: 99%

“…Metformin, applied as a therapy, decreases scar size in reversible coronary artery ligation (21,28,53–56) or whole-heart ischemia-reperfusion (21,57), respectively. The long ischemic duration in these models involves substantial cardiomyocyte necrosis, and much of metformin’s beneficial effect has been attributed to reduction of mPTP-mediated cell death in the infarct border zone (49). In contrast, our data demonstrates metformin’s protection of in vivo EF in a SCA model that features 8 minute ischemia period without evidence of cardiac cell death (31).…”

Section: Discussionmentioning

confidence: 99%

“…Metformin therapy, a first-line diabetes treatment, is beneficial in a number of cardiovascular disorders (9,10), making it a candidate approach for SCA. Metformin impacts many metabolic processes, including activation of the AMPK signaling pathway, improvement in autophagy and mitochondrial biogenesis, and inhibition of the mitochondrial permeability transport pore (mPTP) to block apoptosis (52–56). Metformin, applied as a therapy, decreases scar size in both reversible coronary artery ligation (21,28,40,56–58) and ex vivo whole-heart ischemia-reperfusion (21,59).…”

Section: Discussionmentioning

confidence: 99%

“…Studies of metformin’s effects on cardiac function have largely utilized ischemia-reperfusion injury models like these, with ischemic periods of 25-30 minutes. The long ischemic duration in these models involves substantial cardiomyocyte necrosis, and much of metformin’s beneficial effect has been attributed to reduction of mPTP-mediated cell death in the infarct border zone (52). Previous studies have also shown that metformin protects cardiac function acutely through a vasodilatory effect in a rat heart model of cardiac stunning from ex vivo ischemia (39).…”

Section: Discussionmentioning

confidence: 99%

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Metformin preconditioning protects against myocardial stunning and preserves mitochondrial dynamics and protein translation in a mouse model of cardiac arrest

Rutledge

Lagranha

Chiba

et al. 2021

Preprint

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Sudden cardiac arrest (SCA) affects over 600,000 individuals annually in the United States and is associated with substantial mortality. After resuscitation, multi-system organ damage is common and largely attributable to ischemia-reperfusion injury. The anti-diabetic drug metformin improves cardiac outcomes in models of myocardial ischemia and ischemia-reperfusion. In this study, we evaluated the role of metformin pretreatment in a mouse model of SCA. We found that two weeks of metformin pretreatment protects cardiac ejection fraction and reduces acute kidney injury post-SCA in non-diabetic mice. Further, metformin pretreatment prior to SCA activates AMPK signaling and is associated with altered mitochondrial dynamics and markers of autophagy following arrest. Direct AMPK activation and inhibition studies demonstrate that activation is necessary and sufficient for metformin-mediated protection of cardiac and renal tissues in this model. We were unable to demonstrate cardiac protection with a single-dose metformin rescue therapy. Importantly, these findings translate into patients. We retrospectively evaluated the extent of cardiac and kidney damage in diabetic patients resuscitated from SCA. Metformin-treated patients have less evidence of heart and kidney damage after arrest than diabetics who have not received metformin. Together, these data support AMPK activation as a preventive mechanism in ischemia-reperfusion injury.

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Bioequivalence and Safety Assessment of 2 Formulations of Low‐Dose Metformin Hydrochloride under Fasting Conditions in Healthy Chinese Participants: A Randomized Phase 1 Clinical Trial

Sun,

Xu,

Liu

et al. 2024

Clinical Pharm in Drug Dev

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The incidence of type 2 diabetes is high, and the existing metformin hydrochloride (MH) tablets of 250 mg cannot meet the demands of the Chinese drug market. This study aimed to evaluate the bioequivalence and safety of generic formulations of MH tablets (test formulation [T], 250 mg/tablet) and innovative products (reference formulation [R], 250 mg/tablet) under fasting conditions. This was an open‐label, single‐dose, 2‐period, 2‐sequence crossover, single‐center, randomized phase I clinical trial. T and R were considered bioequivalent if the adjusted geometric mean ratios (GMRs) and 90% confidence intervals of the area under the curve (AUC) and maximum concentration (Cmax) were within the range of 0.8‐1.25. Thirty‐five participants completed the trial. The T/R adjusted GMRs (95.7% for Cmax, 98.7% for AUC0→t, 98.8% for AUC0→∞) were within the acceptable bioequivalence range of 80%‐125%. No serious adverse events or suspected or unexpected serious adverse reactions occurred during this trial. The study findings confirmed that generic MH is a well‐tolerated and bioequivalent alternative to innovative products under fasting conditions in healthy Chinese participants. (www.chinadrugtrials.org.cn; registration no. CTR20190356)

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Biphasic effect of metformin on human cardiac energetics

Cited by 29 publications

References 66 publications

Bioequivalence and Safety Assessment of Two Formulations of Metformin Hydrochloride Sustained-Release Tablets (Yuantang® SR and Glucophage® XR) Under Fed Conditions in Healthy Chinese Adult Subjects: An Open-Label, Two-Way Crossover, Sequence Randomized Phase I Clinical Trial

Bioequivalence and Safety Assessment of Two Formulations of Metformin Hydrochloride Sustained-Release Tablets (Yuantang® SR and Glucophage® XR) Under Fed Conditions in Healthy Chinese Adult Subjects: An Open-Label, Two-Way Crossover, Sequence Randomized Phase I Clinical Trial

Metformin preconditioning protects against myocardial stunning and preserves mitochondrial dynamics and protein translation in a mouse model of cardiac arrest

Bioequivalence and Safety Assessment of 2 Formulations of Low‐Dose Metformin Hydrochloride under Fasting Conditions in Healthy Chinese Participants: A Randomized Phase 1 Clinical Trial

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