Pioglitazone and metformin fixed-dose combination in type 2 diabetes mellitus: an evidence-based review of its place in therapy

Introduction:

Type 2 diabetes mellitus, a metabolic disease with increasing incidence, is one of the most important cardiovascular risk factors. Insulin resistance represents the common mechanism that leads to type 2 diabetes in obese subjects. Metformin and the thiazolidinediones, pioglitazone and rosiglitazone, are insulin-sensitizing agents available for treatment of type 2 diabetes. Large clinical trials have demonstrated the effectiveness of both metformin and pioglitazone in reducing cardiovascular morbidity and mortality. The fixed-dose combination of metformin and pioglitazone appears to be a good option for treating diabetes in insulin-resistant patients.

Aims:

The purpose of this article is to review the place in therapy of a fixed-dose combination of pioglitazone and metformin in the management of patients with type 2 diabetes.

Evidence review:

The current evidence suggests that combined therapy may help to achieve the recommended goals in the management of diabetes. A fixed-dose formulation of pioglitazone and metformin may provide advantages in terms of glycemic control and other cardiovascular risk factors frequently associated with diabetes.

Place in therapy:

The current evidence shows that a fixed-dose formulation of pioglitazone and metformin offers an effective option for the management of patients with type 2 diabetes when monotherapy fails in the achievement of the recommended standards of care.     

Protective role of the antidiabetic drug metformin against chronic experimental pulmonary hypertension

Background and purpose:

Pulmonary arterial hypertension (PAH) is associated with increased contraction and proliferation of pulmonary vascular smooth muscle cells. The anti-diabetic drug metformin has been shown to have relaxant and anti-proliferation properties. We thus examined the effect of metformin in PAH.

Experimental approach:

Metformin effects were analysed in hypoxia- and monocrotaline-induced PAH in rats. Ex vivo and in vitro analyses were performed in lungs, pulmonary artery rings and cells.

Key results:

In hypoxia- and monocrotaline-induced PAH, the changes in mean pulmonary arterial pressure and right heart hypertrophy were nearly normalized by metformin treatment (100 mg·kg⁻¹·day⁻¹). Pulmonary arterial remodelling occurring in both experimental models of PAH was also inhibited by metformin treatment. In rats with monocrotaline-induced PAH, treatment with metformin significantly increased survival. Metformin increased endothelial nitric oxide synthase phosphorylation and decreased Rho kinase activity in pulmonary artery from rats with PAH. These effects are associated with an improvement of carbachol-induced relaxation and reduction of phenylephrine-induced contraction of pulmonary artery. In addition, metformin inhibited mitogen-activated protein kinase activation and strongly reduced pulmonary arterial cell proliferation during PAH. In vitro, metformin directly inhibited pulmonary artery smooth muscle cell growth.

Conclusions and implications:

Metformin protected against PAH, regardless of the initiating stimulus. This protective effect may be related to its anti-remodelling property involving improvement of endothelial function, vasodilatory and anti-proliferative actions. As metformin is currently prescribed to treat diabetic patients, assessment of its use as a therapy against PAH in humans should be easier.     

Plasma ghrelin levels are closely associated with severity and morphology of angiographically-detected coronary atherosclerosis in Chineses patients with diabetes mellitus

Aim:

Low plasma ghrelin level was found to be associated with diabetes, and ghrelin was shown to inhibit pro-atherogenic changes in experimental models of atherosclerosis. The aim of this study was to investigate the relationship between plasma ghrelin levels and coronary atherosclerotic lesions in Chinese patients with diabetes.

Methods:

Plasma ghrelin levels were measured using an ELISA kit. The severity of coronary artery disease (CAD) was determined via angiography. Composition of atherosclerotic plaques was detected via coronary CT angiography.

Results:

A total of 178 patients with diabetes were recruited. Among the patients, 70 were diagnosed with acute coronary syndrome (ACS), 82 with stable angina pectoris (SAP) and 26 without coronary angiographic finding (controls). A negative correlation was found between ghrelin levels and the severity of the CAD, as determined via the Gensini score (r=-0.2434; P=0.0217). In diabetic patients with CAD and a complex lesion, the plasma ghrelin levels were significantly lower than in those with a simple lesion (ACS group: 3.81±0.49 ng/mL vs 4.72±0.50 ng/mL, P<0.0001; SAP group: 4.21±0.52 ng/mL vs 4.76±0.59 ng/mL, P=0.0397). Angiographically-detected complex lesion was an independent factor associated with ghrelin levels (adjusted beta coefficient=-0.67, 95% CI -0.97 to -0.37, P<0.0001).

Conclusion:

Low plasma ghrelin level is closely related to angiographically-detected severity and the complex lesion morphology in Chinese diabetic patients with CAD.     

Metformin restores endothelial function in aorta of diabetic rats

BACKGROUND AND PURPOSE

The effects of metformin, an antidiabetic agent that improves insulin sensitivity, on endothelial function have not been fully elucidated. This study was designed to assess the effect of metformin on impaired endothelial function, oxidative stress, inflammation and advanced glycation end products formation in type 2 diabetes mellitus.

EXPERIMENTAL APPROACH

Goto-Kakizaki (GK) rats, an animal model of nonobese type 2 diabetes, fed with normal and high-fat diet during 4 months were treated with metformin for 4 weeks before evaluation. Systemic oxidative stress, endothelial function, insulin resistance, nitric oxide (NO) bioavailability, glycation and vascular oxidative stress were determined in the aortic rings of the different groups. A pro-inflammatory biomarker the chemokine CCL2 (monocyte chemoattractant protein-1) was also evaluated.

KEY RESULTS

High-fat fed GK rats with hyperlipidaemia showed increased vascular and systemic oxidative stress and impaired endothelial-dependent vasodilatation. Metformin treatment significantly improved glycation, oxidative stress, CCL2 levels, NO bioavailability and insulin resistance and normalized endothelial function in aorta.

CONCLUSION AND IMPLICATIONS

Metformin restores endothelial function and significantly improves NO bioavailability, glycation and oxidative stress in normal and high-fat fed GK rats. This supports the concept of the central role of metformin as a first-line therapeutic to treat diabetic patients in order to protect against endothelial dysfunction associated with type 2 diabetes mellitus.     

Population PK/PD analysis of metformin using the signal transduction model

AIMS

To develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model for metformin (500 mg) using the signal transduction model in healthy humans and to predict the PK/PD profile in patients with type 2 diabetes.

METHODS

Following the oral administration of 500 mg metformin to healthy humans, plasma concentrations of metformin were measured using LC-MS/MS. A sequential modelling approach using NONMEM VI was used to facilitate data analysis. Monte Carlo simulation was performed to predict the antihyperglycaemic effect in patients with type 2 diabetes.

RESULTS

Forty-two healthy humans were included in the study. Population mean estimates (relative standard error, RSE) of apparent clearance, apparent volume of distribution and the absorption rate constant were 52.6 l h⁻¹ (4.18%), 113 l (56.6%) and 0.41 h⁻¹, respectively. Covariate analyses revealed that creatinine clearance (CL_CR) significantly influenced metformin: CL/F= 52.6 × (CL_cr/106.5)^0.782. The signal transduction model was applied to describe the antihyperglycaemic effect of metformin. The population means for efficacy, potency, transit time and the Hill coefficient were estimated to be 19.8 (3.17%), 3.68 µg ml⁻¹ (3.89%), 0.5 h (2.89%) and 0.547 (9.05%), respectively. The developed model was used to predict the antihyperglycaemic effect in patients with type 2 diabetes. The predicted plasma glucose concentration value was similar to previous values.

CONCLUSIONS

The population signal transduction model was developed and evaluated for metformin use in healthy volunteers. Model evaluation by non-parametric bootstrap analysis suggested that the proposed model was robust and parameter values were estimated with good precision.     

Pharmacokinetic interaction between itraconazole and metformin in rats: competitive inhibition of metabolism of each drug by each other via hepatic and intestinal CYP3A1/2

BACKGROUND AND PURPOSE

Fungal infection is prevalent in patients with diabetes mellitus. Thus, we investigated whether a pharmacokinetic interaction occurs between the anti-fungal agent itraconazole and the anti-glycaemic drug metformin, as both drugs are commonly administered together to diabetic patients and are metabolized via hepatic CYP3A subfamily in rats.

EXPERIMENTAL APPROACH

Itraconazole (20 mg·kg⁻¹) and metformin (100 mg·kg⁻¹) were simultaneously administered i.v. and p.o. to rats. Concentrations (I) of each drug in the liver and intestine, maximum velocity (V_max), Michaelis–Menten constant (K_m) and intrinsic clearance (CL_int) for the disappearance of each drug, apparent inhibition constant (K_i) and [I]/K_i ratios of each drug in the liver and intestine were determined. Also the metabolism of each drug in rat and human CYPs was measured in vitro.

KEY RESULTS

After simultaneous administration of both drugs, either i.v. or p.o., the total area under the plasma concentration–time curve from time zero to infinity (AUC)s of itraconazole and metformin were significantly greater than that of either drug administered alone. The metabolism of itraconazole and metformin was significantly inhibited by each other via CYP3A1 and 3A2 in rat and 3A4 in human microsomes.

CONCLUSIONS AND IMPLICATIONS

The significantly greater AUCs of itraconazole and metformin after i.v. administration of both drugs are probably due to competitive inhibition of the metabolism of each drug by each other via hepatic CYP3A1/2. Whereas after oral administration of both drugs, the significantly greater AUCs of each drug administered together than that of either drug alone is mainly due to competitive inhibition of intestinal metabolism of each drug by each other via intestinal CYP3A1/2.     

Trimethoprim–metformin interaction and its genetic modulation by OCT2 and MATE1 transporters

Aims

Metformin pharmacokinetics depends on the presence and activity of membrane-bound drug transporters and may be affected by transport inhibitors. The aim of this study was to investigate the effects of trimethoprim on metformin pharmacokinetics and genetic modulation by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1) polymorphisms.

Methods

Twenty-four healthy volunteers received metformin 500 mg three times daily for 10 days and trimethoprim 200 mg twice daily from day 5 to 10. Effects of trimethoprim on steady-state metformin pharmacokinetics were analysed.

Results

In the population as a whole, trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l h⁻¹ and renal metformin clearance from 31 to 21 l h⁻¹, and prolonged half-life from 2.7 to 3.6 h (all P < 0.01). This resulted in an increase in the maximal plasma concentration by 38% and in the area under the plasma concentration–time curve by 37%. In volunteers polymorphic for both OCT2 and MATE1, trimethoprim had no relevant inhibitory effects on metformin kinetics. Trimethoprim was associated with a decrease in creatinine clearance from 133 to 106 ml min⁻¹ (P < 0.01) and an increase in plasma lactate from 0.94 to 1.2 mmol l⁻¹ (P = 0.016).

Conclusions

The extent of inhibition by trimethoprim was moderate, but might be clinically relevant in patients with borderline renal function or high-dose metformin.     

Metformin inhibits HMGB1 release in LPS-treated RAW 264.7 cells and increases survival rate of endotoxaemic mice

BACKGROUND AND PURPOSE

Recently, metformin, a well-known anti-diabetic drug, has been shown to possess anti-inflammatory activities. This study investigated the effect of metformin on the expression of pro-inflammatory cytokines including high mobility group box 1 (HMGB1) in lipopolysaccharide (LPS)-treated animals and cells.

EXPERIMENTAL APPROACH

We investigated whether metformin inhibits the release of HMGB1 in LPS-treated RAW 264.7 cells and increases survival rate in endotoxaemic mice (lethal endotoxaemia was induced by an i.p. injection of LPS). This was achieved by a range of techniques including Western blotting, enzyme-linked immunosorbent assay, specific pharmacological inhibitors, knock out of α₁-subunit of AMP-activated protein kinase (AMPK) and recombinant HMGB1.

KEY RESULTS

Both pre- and post-treatment with metformin significantly improved survival of animals during lethal endotoxaemia (survival rate was monitored up to 2 weeks), decreased serum levels of tumour necrosis factor-alpha (TNF-α), interleukin-1β, HMGB1 expression and myeloperoxidase activity in lungs. However, metformin failed to improve survival in endotoxaemic animals that had additionally been treated with recombinant HMGB1. In an in vitro study, metformin dose-dependently inhibited production of pro-inflammatory cytokines and HMGB1 release. Metformin activated AMPK by its phosphorylation. Compound C (pharmacological inhibitor of AMPK) and siAMPKα1 reversed the anti-inflammatory effect of metformin in LPS-treated cells.

CONCLUSIONS AND IMPLICATIONS

Our data indicate that metformin significantly attenuates the pro-inflammatory response induced by LPS both in vivo and in vitro. Metformin improved survival in a mouse model of lethal endotoxaemia by inhibiting HMGB1 release. AMPK activation was implicated as one of the mechanisms contributing to this inhibition of HMGB1 secretion.     

Vildagliptin: the evidence for its place in the treatment of type 2 diabetes mellitus

Introduction:

Type 2 diabetes is increasing in prevalence worldwide and is a leading cause of morbidity and mortality, mainly due to the development of complications. Vildagliptin is an inhibitor of dipeptidyl peptidase 4 (DPP-4), a new class of oral antidiabetic agents.

Aims:

To evaluate the role of vildagliptin in the management of type 2 diabetes.

Evidence review:

Clear evidence shows that vildagliptin improves glycemic control (measured by glycosylated hemoglobin and blood glucose levels) more than placebo in adults with type 2 diabetes, either as monotherapy or in combination with metformin. Vildagliptin is as effective as pioglitazone and rosiglitazone, and slightly less effective than metformin, although better tolerated. Further glycemic control is achieved when adding vildagliptin to metformin, pioglitazone, or glimepride. There is evidence that vildagliptin improves beta-cell function and insulin sensitivity. Vildagliptin does not appear to be associated with weight gain or with a higher risk of hypoglycemia than placebo or other commonly used oral antidiabetic agents. Economic evidence is currently lacking.

Place in therapy:

Vildagliptin improves glycemic control with little if any weight gain or hypoglycemia in adult patients with type 2 diabetes when given alone or in combination with metformin, thiazolidinediones, or sulfonylureas. Since many diabetic patients require combination therapy, the complementary mechanism of action of vildagliptin and other commonly prescribed antidiabetic drugs represents an important new therapeutic option in diabetes management.     

Metformin and male reproduction: effects on Sertoli cell metabolism

Background and Purpose

Metformin is commonly used to treat type 2 diabetes (T2D). While new clinical applications have been ascribed to metformin, including treatment of anovulatory infertility, its effects on male reproduction have not been investigated. The Sertoli cell (SC) is crucial for germ cell development, exerting metabolic control of spermatogenesis, therefore, we investigated the effects of metformin on SC metabolism.

Experimental Approach

Rat SCs were cultured in the absence and presence of metformin (5, 50 and 500 μM). mRNA and protein levels of glucose transporters (GLUT1 and GLUT3), phosphofructokinase 1 (PFK 1), lactate dehydrogenase (LDH) and monocarboxylate transporter 4 (MCT4) were determined by quantitative PCR and Western blot respectively. LDH activity was assessed and metabolite production/consumption determined by ¹H-NMR.

Key Results

Metformin (50 μM) decreased mRNA and protein levels of GLUT1, GLUT3, MCT4 and PFK 1 but did not affect LDH mRNA or protein levels. However, although glucose consumption was maintained in metformin-treated cells, LDH activity, lactate and alanine production were increased, indicating an enhanced glycolytic flux. No metabolic cytotoxicity was detected in SCs exposed to supra-pharmacological concentration of metformin.

Conclusions and Implications

Our results indicate that metformin: (i) decreases mRNA and protein levels of glycolysis-related transporters in SCs but increases their activity; and (ii) stimulates alanine production, which induces antioxidant activity and maintains the NADH/NAD⁺ equilibrium. The increased lactate in metformin-treated SCs provides nutritional support and has an anti-apoptotic effect in developing germ cells. Thus, metformin can be considered as a suitable antidiabetic drug for male patients of reproductive age with T2D.     

Efficacy and safety of add on therapy of bromocriptine with metformin in Indian patients with type 2 diabetes mellitus: A randomized open labeled phase IV clinical trial

Objective:

To compare the effectiveness and safety of add on therapy of bromocriptine with metformin in type 2 diabetes mellitus (DM) patients.

Material and Methods:

Adult type 2 DM patients fulfilling the inclusion criteria were randomized in three groups. Group A received metformin (1000 mg/ day), while group B patients were treated with metformin (1000 mg/day) plus bromocriptine (0.8 mg/day) and group C received metformin (1000 mg/day) plus bromocriptine (1.6 mg/day) for 12 weeks. Fasting plasma glucose (FPG), postprandial plasma glucose (PPPG), and body weight were measured at week 4, 8, and 12 visits and glycosylated hemoglobin (HbA_1C) at week 12 visit.

Results:

Metformin alone and in combination with bromocriptine in escalating dose (0.8 mg/day and 1.6 mg/day) significantly (P < 0.05) decreased FPG and PPPG levels at weeks 4, 8, and 12 compared with pretreatment values. HbA_1C level in all three treatment groups significantly (P < 0.05) decreased at week 12 as compared with pretreatment baseline value. HbA_1C level in groups B and C significantly (P < 0.05) decreased as compared with group A at week 12. Addition of bromocriptine to metformin also significantly (P < 0.05) decreased FPG and PPPG levels in a dose-dependent manner as compared with metformin alone. Intergroup analysis did not show any statistically significant change in weight of study subjects at different intervals.

Conclusion:

The combination of bromocriptine with metformin significantly decreased FPG, PPPG, and HbA_1C compared with metformin alone in type 2 DM patients in a dose-dependent manner.KEY WORDS: Bromocriptine, diabetes mellitus, metformin     

Verapamil decreases the glucose-lowering effect of metformin in healthy volunteers

Aim

The organic cation transporter 1 (OCT1) plays a key role in the cellular transport of metformin and its subsequent glucose-lowering effect. A recent non-clinical study reported that metformin uptake into hepatocytes is regulated via OCT1, and that uptake was strongly inhibited by verapamil. Therefore, we investigated the effects of verapamil co-administration on the pharmacokinetics and pharmacodynamics of metformin in humans.

Methods

We evaluated the pharmacokinetics and the anti-hyperglycaemic effects of metformin using an oral glucose tolerance test (OGTT) in 12 healthy participants, before (day 1) and after metformin treatment (day 2), and again on days 15 and 16 after co-administration with verapamil.

Results

Verapamil inhibited the ability of metformin to reduce maximum blood glucose concentrations (ΔG_max) by 62.5% (P = 0.008) and decreased the area under the glucose concentration–time curve (ΔAUC_gluc) by 238% (P = 0.015). However, verapamil did not significantly alter the C_max and the AUC of metformin, nor its renal clearance.

Conclusions

Our results suggest that verapamil remarkably decreases the glucose-lowering effect of metformin, possibly by acting as a competitive inhibitor of OCT1.     

The pharmacokinetics of metformin and concentrations of haemoglobin A1C and lactate in Indigenous and non-Indigenous Australians with type 2 diabetes mellitus

AIMS

To compare the pharmacokinetics of metformin between diabetic Indigenous (Aboriginal and Torres Strait Islander) and non-Indigenous patients.

METHODS

An observational, cross-sectional study was conducted on type 2 diabetic Indigenous and non-Indigenous patients treated with metformin. Blood samples were collected to determine metformin, lactate, creatinine and vitamin B₁₂ concentrations and glycosylated haemoglobin levels. A population model was used to determine the pharmacokinetic parameters.

RESULTS

The Indigenous patients (median age 55 years) were younger than the non-Indigenous patients (65 years), with a difference of 10 years (95% confidence interval 6–14 years, P < 0.001). The median glycosylated haemoglobin was higher in the Indigenous patients (8.5%) than in the non-Indigenous patients (7.2%), with a difference of 1.4% (0.8–2.2%, P < 0.001). Indigenous patients had a higher creatinine clearance (4.3 l h⁻¹) than the non-Indigenous patients (4.0 l h⁻¹), with a median difference of 0.3 l h⁻¹ (0.07–1.17 l h⁻¹; P < 0.05). The ratio of the apparent clearance of metformin to the creatinine clearance in Indigenous patients (13.1, 10.2–15.2; median, interquartile range) was comparable to that in non-Indigenous patients (12.6, 9.9–14.9). Median lactate concentrations were also similar [1.55 (1.20–1.88) vs. 1.60 (1.35–2.10) mmol l⁻¹] for Indigenous and non-Indigenous patients, respectively. The median vitamin B₁₂ was 306 pmol l⁻¹ (range 105–920 pmol l⁻¹) for the Indigenous patients.

CONCLUSIONS

There were no significant differences in the pharmacokinetics of metformin or plasma concentrations of lactate between Indigenous and non-Indigenous patients with type 2 diabetes mellitus. Further studies are required in Indigenous patients with creatinine clearance <30 ml min⁻¹.     

Proton pump inhibitors do not impair the effectiveness of metformin in patients with diabetes

Aims

In order to exert its pharmacodynamic effect, the diabetes drug metformin needs to be taken up into hepatocytes by the organic cation transporter (OCT) system. A recent in vitro study found that proton pump inhibitors (PPIs) inhibit OCT1, OCT2 and OCT3, suggesting that PPIs might reduce metformin''s effectiveness. This pharmacoepidemiologic study looked for evidence of a clinical effect of such an interaction.

Methods

This was an observational cohort study examining changes in glycosylated haemoglobin (HbA1c) with exposure to metformin and to PPIs as single agents and in combination. The aim was to assess evidence of a deleterious drug−drug interaction.

Results

PPIs did not reduce the effectiveness of metformin, and indeed were associated with a minimally better glycaemic response by − 0.06 HbA1c percentage points (95% confidence interval, −0.10, −0.01) in metformin initiators.

Conclusions

Despite a mechanistic basis for a potential drug–drug interaction, we found no evidence of a deleterious interaction between PPIs and metformin.     

Sitagliptin, an dipeptidyl peptidase-4 inhibitor, does not alter the pharmacokinetics of the sulphonylurea, glyburide, in healthy subjects

AIMS

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is an incretin enhancer that is approved for the treatment of Type 2 diabetes. Sitagliptin is mainly renally eliminated and not an inhibitor of CYP450 enzymes in vitro. Glyburide, a sulphonylurea, is an insulin sensitizer and mainly metabolized by CYP2C9. Since both agents may potentially be co-administered, the purpose of this study was to examine the effects of sitagliptin on glyburide pharmacokinetics.

METHODS

In this open-label, randomized, two-period crossover study, eight healthy normoglycaemic subjects, 22–44 years old, received single 1.25-mg doses of glyburide alone in one period and co-administered with sitagliptin on day 5 following a multiple-dose regimen for sitagliptin (200-mg q.d. ×6 days) in the other period.

RESULTS

The geometric mean ratios and 90% confidence intervals [(glyburide + sitagliptin)/glyburide] for AUC_0–∞ and C_max were 1.09 (0.96, 1.24) and 1.01 (0.84, 1.23), respectively.

CONCLUSION

Sitagliptin does not alter the pharmacokinetics of glyburide in healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• No data are available on the potential drug interaction of sitagliptin and glyburide.
• Sitagliptin belongs to a new class of drugs called DPP-4 inhibitors recently approved for the treatment of Type 2 diabetes.

WHAT THIS STUDY ADDS

• Glyburide is a commonly used sulphonylurea medication to treat Type 2 diabetes.
• Combination therapy is often required to achieve adequate glucose control in Type 2 diabetes.
• Sitagliptin does not appear to interfere with glyburide pharmacokinetics and therefore may be potentially co-administered with glyburide for the treatment of Type 2 diabetes.

     

Metformin attenuates pressure overload-induced cardiac hypertrophy via AMPK activation

Aim:

To identify the role of metformin in cardiac hypertrophy and investigate the possible mechanism underlying this effect.

Methods:

Wild type and AMPKα2 knockout (AMPKα2^−/−) littermates were subjected to left ventricular pressure overload caused by transverse aortic constriction. After administration of metformin (200 mg·kg⁻¹·d⁻¹) for 6 weeks, the degree of cardiac hypertrophy was evaluated using echocardiography and anatomic and histological methods. The antihypertrophic mechanism of metformin was analyzed using Western blotting.

Results:

Metformin significantly attenuated cardiac hypertrophy induced by pressure overload in wild type mice, but the antihypertrophic actions of metformin were ablated in AMPKα2^−/− mice. Furthermore, metformin suppressed the phosphorylation of Akt/protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in response to pressure overload in wild type mice, but not in AMPKα2^−/− mice.

Conclusion:

Long-term administration of metformin may attenuate cardiac hypertrophy induced by pressure overload in nondiabetic mice, and this attenuation is highly dependent on AMPK activation. These findings may provide a potential therapy for patients at risk of developing pathological cardiac hypertrophy.