Metformin: not only per os

Berstein, Lev M.

doi:10.1080/17446651.2018.1431123

Cited by 9 publications

(7 citation statements)

References 20 publications

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“…Because the METTEN trial failed to identify also a large difference, i.e., a 25% increase over an expected pCR of 60% with chemotherapy plus trastuzumab before a phase 3 trial could be justified, it might be tempting to suggest that testing against high bars of clinical outcome endpoints instead of using a priori non-inferiority trial designs should be cautiously considered before concluding that studies using metformin for treating cancer should be abandoned. Moreover, negative results of first-generation cancer trials using metformin at the same dose and route of administration that in diabetic patients would not rule out the clinical utility of biguanides other than metformin (e.g., phenformin) or non-conventional routes for administering biguanides if previously optimized for oncology indications [ 68 – 71 ]. However, as we did not achieve the target number of patients to power the study, we cannot be certain whether the lack of significant difference between the two arms of the METTEN trial is a type II error or reflects a true lack of efficacy for the metformin-based neoadjuvant strategy in early HER2-positive BC.…”

Section: Discussionmentioning

confidence: 99%

A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study

et al. 2018

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The METTEN study assessed the efficacy, tolerability, and safety of adding metformin to neoadjuvant chemotherapy plus trastuzumab in early HER2-positive breast cancer (BC). Women with primary, non-metastatic HER2-positive BC were randomized (1:1) to receive metformin (850 mg twice-daily) for 24 weeks concurrently with 12 cycles of weekly paclitaxel plus trastuzumab, followed by four cycles of 3-weekly FE75C plus trastuzumab (arm A), or equivalent regimen without metformin (arm B), followed by surgery. Primary endpoint was the rate of pathological complete response (pCR) in the per-protocol efficacy population. pCR rate was numerically higher in the metformin-containing arm A (19 of 29 patients [65.5%, 95% CI: 47.3–80.1]) than in arm B (17 of 29 patients [58.6%, 95% CI: 40.7–74.5]; OR 1.34 [95% CI: 0.46–3.89], P = 0.589). The rate of breast-conserving surgery was 79.3% and 58.6% in arm A and B (P = 0.089), respectively. Blood metformin concentrations (6.2 μmol/L, 95% CI: 3.6–8.8) were within the therapeutic range. Seventy-six percent of patients completed the metformin-containing regimen; 13% of patients in arm A dropped out because of metformin-related gastrointestinal symptoms. The most common adverse events (AEs) of grade ≥3 were neutropenia in both arms and diarrhea in arm A. None of the serious AEs was deemed to be metformin-related. Addition of anti-diabetic doses of metformin to a complex neoadjuvant regimen was well tolerated and safe. Because the study was underpowered relative to its primary endpoint, the efficacy data should be interpreted with caution.

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Section: Discussionmentioning

confidence: 99%

A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study

et al. 2018

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“…The long history and much clinical experience with metformin has also encouraged the repurposing of this drug for further therapeutic applications (BOX 3), from cancer to the modulation of age-related diseases, highlighting the vast range of different possible actions of metformin. In addition, moving from the traditional oral use of metformin to different route of administration 213 or drug delivery systems (for example microparticles or nanoparticles) 214,215 might help to accelerate the development of novel therapeutic applications for this multifaceted drug.…”

Section: Metformin and T1dmmentioning

confidence: 99%

Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

2019

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Despite its position as the first-line treatment for type 2 diabetes mellitus, the mechanisms underlying the plasma glucose level-lowering effects of metformin (1,1dimethylbiguanide) still remain incompletely understood. Metformin is thought to exert its primary antidiabetic action through the suppression of hepatic glucose production. Furthermore, the discovery that metformin inhibits the mitochondrial respiratory-chain complex 1 has placed energy metabolism and activation of AMP-activated protein kinase (AMPK) at the center of its mechanism of action. However, the role of AMPK has been challenged and might only account for indirect changes in hepatic insulin sensitivity. Various mechanisms involving alterations of cellular energy charge, AMP-mediated inhibition of adenylate cyclase or fructose-1,6-bisphosphatase-1 (FBP1) and modulation of the cellular redox state through direct inhibition of mitochondrial glycerol-3phosphate dehydrogenase (mG3PDH) are proposed for the acute inhibition of gluconeogenesis by metformin. Emerging evidence suggests that metformin could improve obesity-induced meta-inflammation via direct and indirect effects on tissueresident immune cells in metabolic organs (that is, adipose tissue, the gastrointestinal tract and the liver). Furthermore, the gastrointestinal tract also has a major role in metformin action through modulation of glucose-lowering hormone glucagon-like peptide-1 (GLP-1) and intestinal bile acid pool and alterations in gut microbiota composition. 3 Key points • Metformin is the first-line drug for treatment of type 2 diabetes mellitus, with an excellent safety profile, high efficacy on glycaemic control and clear but incompletely understood cardioprotective benefits. • The pleiotropic properties of metformin suggest that the drug acts on multiple tissues through various underlying mechanisms rather than on a single organ via an unifying mode of action. • The mitochondrial respiratory-chain complex 1 is a key cellular target of metformin and its mild and transient inhibition is involved in the AMPK-independent regulation of hepatic gluconeogenesis by triggering alterations in the cellular energy charge and redox state. • Metformin might contribute to improvements in obesity-associated metainflammation and tissue-specific insulin sensitivity through direct and indirect effects on various resident immune cells in metabolic organs. • The gastrointestinal tract has an important role in the action of metformin, which modulates bile acid recirculation and enhances the secretion of the glucose-lowering gut incretin hormone glucagon-like peptide-1 (GLP1). • The gut microbiota represents a novel target in the mechanisms of metformin action and is involved in both the therapeutic and adverse effects of the drug.

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“…37 In contrast, we show that topical metformin alone was associated with significant improvement in AV lesions among patients, and this may be attributed to the suggested variability of metformin effect according to the route of administration. 14 The fact that AV lesions increased after stopping active treatment in our study suggests that the improvement observed was induced by metformin, especially when stopping treatment on the placebo side did not induce similar change. This is consistent with the results of a previous study of systemic metformin in experimental rabbits where lesions reappeared following metformin withdrawal, 29 however, in the current study despite the increase in comedonal and papular lesions counts after withdrawal of topical metformin, there was still a significant difference in lesions counts between both treated sides.…”

Section: Discussionmentioning

confidence: 54%

“…12 In their systematic review, Yen et al conclude that metformin either alone or as an adjuvant improves AV in women with polycystic ovary syndrome (PCO). 13 Hypothetically, metformin cellular effects might vary when used via different routes, 14 therefore, several indications have been studied using variable routes of administration and formulations of metformin. [15][16][17][18][19][20][21][22][23][24] Topical metformin treatment showed promising results in patients suffering from melasma 21,25 and recalcitrant central centrifugal cicatricial alopecia.…”

mentioning

confidence: 99%

Topical metformin 30% gel in the treatment of acne vulgaris in women, a split face, placebo‐controlled study

El-Komy

Abdo²,

Shamma

et al. 2023

Experimental Dermatology

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Acne vulgaris (AV), a widely common disorder, that negatively affects the quality of life. Metformin is a relatively safe, cheap and well tolerated drug that is widely used in the treatment of Diabetes. Systemic metformin has demonstrated promising results in treating acne, while topically it was studied for melasma and recalcitrant central centrifugal cicatricial alopecia. To study the safety and efficacy of topical metformin 30% in the treatment of AV. Twenty‐seven female AV patients were asked to blindly apply metformin and placebo gels to either side of the face for 12 weeks. AV lesion count was performed at baseline, at each visit and 4 weeks after end of treatment. At the end of the treatment period, the treated side showed significant improvement of comedones, papules and nodules but not pustules. Although, lesions count increased 1 month after stopping treatment, comedones and papules numbers were still significantly less on the metformin side compared to placebo. No side effects were reported. The limited number of patients studied and the limited follow‐up period. The metformin effect was not studied on cellular and molecular levels. Topical metformin nanoemulsion gel can be a promising safe and effective treatment of AV.

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Metformin: not only per os

Cited by 9 publications

References 20 publications

A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study

A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study

Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

Topical metformin 30% gel in the treatment of acne vulgaris in women, a split face, placebo‐controlled study

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