General Study on Metformin
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Metformin was rediscover during the hunt for an antimalarial drug. The French physician Jean Sterne, who first reported the use of metformin to treat diabetes in 1957. Aim: Over View of Metformin. The commonly used medication metformin has definite advantages in terms of issues related to diabetes and glucose metabolism.Metformin is a widely prescribed antidiabetic BCS Class III drug (low permeability) that depends on active transport for its absorption and disposition. It is recommended by the US Food and Drug Administration as a clinical substrate of organic cation transporter 2/multidrug and toxin extrusion protein for drug–drug interaction studies. Cimetidine is a potent organic cation transporter 2/multidrug and toxin extrusion protein inhibitor. The objective of this study was to provide mechanistic whole-body physiologically based pharmacokinetic models of metformin and cimetidine, built and evaluated to describe the metformin-SLC22A2 808G>T drug–gene interaction, the cimetidine-metformin drug–drug interaction, and the impact of renal impairment on metformin exposure. Physiologically based pharmacokinetic models were developed in PK-Sim® (version 8.0). Thirty-nine clinical studies (dosing range 0.001–2550 mg), providing metformin plasma and urine data, positron emission tomography measurements of tissue concentrations, studies in organic cation transporter 2 polymorphic volunteers, drug–drug interaction studies with cimetidine, and data from patients in different stages of chronic kidney disease, were used to develop the metformin model. Twenty-seven clinical studies (dosing range 100–800 mg), reporting cimetidine plasma and urine concentrations, were used for the cimetidine model development. The established physiologically based pharmacokinetic models adequately describe the available clinical data, including the investigated drug–gene interaction, drug–drug interaction, and drug–drug–gene interaction studies, as well as the metformin exposure during renal impairment. All modeled drug–drug interaction area under the curve and maximum concentration ratios are within 1.5-fold of the observed ratios. The clinical data of renally impaired patients shows the expected increase in metformin exposure with declining kidney function, but also indicates counter-regulatory mechanisms in severe renal disease; these mechanisms were implemented into the model based on findings in preclinical species. Whole-body physiologically based pharmacokinetic models of metformin and cimetidine were built and qualified for the prediction of metformin pharmacokinetics during drug–gene interaction, drug–drug interaction, and different stages of renal disease. The model files will be freely available in the Open Systems Pharmacology model repository. Current guidelines for metformin treatment of renally impaired patients should be reviewed to avoid overdosing in CKD3 and to allow metformin therapy of CKD4 patients.
Cimetidine
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This study was carried out to understand the influence of a selected antiarrhythmic drug on the pharmacodynamics and pharmacokinetics of an antidiabetic drug in animal models. Pharmacodynamic and pharmacokinetic responses were determined by measurements of blood glucose and serum insulin and serum metformin to drug interactions between disopyramide and metformin. Single dose and multi dose studies showed that the maximum blood glucose reductions in normal and diabetic rats were at the 6th hour, and in rabbits at the 3rd hour. Glucose-insulin homeostasis was evaluated to assess the safety and effectiveness of the combination. There was a marginal increase in the pharmacokinetic parameters of metformin with multiple dose treatments of disopyramide but no significant changes in kinetic parameters between single and multiple dose studies, compared to metformine alone. There may be a possibility of disopyramide and metformin interaction at the excretion stage, or an additive pharmacodynamic action. This study validates the drug interaction in two dissimilar species, which indicates more probability of its occurrence in humans.
Disopyramide
Pharmacodynamics
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Objective To investigate the cardiovascular complications of diabetes,especially the hypertension risk factors.Methods The clinical manifestation of 156 cases of diabetic patients in our hospital were summarized,the diabetes and cardiovascular complications,especially the hypertension were analyzed.Results The rate of diabetes in 5 years with hy pertension was 18.75% and it was significantly lower than that of 5 years or more(P 0.05),the occurrence rate of coronary heart disease and angina pectoris in two groups had no statistically significant(P 0.05).Conclusion Diabetic with cardiovascular complications are related to many factors,and the hypertension is the most common complication of diabetes,combi nation of effective auxiliary examination can better early detection and prevention of diabetic cardiovascular complications.
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Effect of metformin on hepatic glucose production in Japanese patients with type 2 diabetes mellitus
We investigated the effect of metformin on hepatic glucose production and peripheral glucose uptake in Asian patients with type 2 diabetes mellitus. We recruited ten Japanese patients whose fasting glucose levels remained poorly controlled under meal-time injection of short-acting insulin. Metformin was added to their insulin therapy, and both hepatic glucose production and peripheral glucose uptake were assessed before and one week after metformin treatment, with the use of stable isotope [6,6-²H₂] glucose. Metformin was titrated to a maximum dose of 500 mg. As a result, fasting glucose levels and hepatic glucose production were significantly improved after the metformin treatment (p < 0.01 and 0.02), whereas their peripheral glucose uptake was not significantly changed (p = 0.63). Furthermore, the change of fasting glucose levels was significantly correlated with that of hepatic glucose production, whose coefficient ρ was 0.76 (p = 0.01). On the other hand, there was no significant correlation between the change of fasting glucose levels and that of peripheral glucose uptake (p = 0.43). In conclusion, low dose of metformin significantly reduced hepatic glucose production in Japanese patients with type 2 diabetes mellitus. The efficacy of metformin on correcting fasting hyperglycemia was strongly associated with reduced hepatic glucose production, rather than ameliorated peripheral glucose uptake.
Fasting glucose
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OBJECTIVE—In the Diabetes Prevention Program (DPP), metformin significantly reduced the risk of diabetes in individuals with impaired glucose tolerance. Diabetes status was assessed by oral glucose tolerance tests (OGTTs) performed while participants were still taking metformin or placebo. To determine whether the observed benefit was a transient pharmacological effect or more sustained, we performed a repeat OGTT after a short “washout” period during which medications (metformin or placebo) were withheld. RESEARCH DESIGN AND METHODS—All participants assigned to medication who had not developed diabetes at the end of the DPP were asked to have a repeat OGTT after discontinuing the study medication for 1–2 weeks. The predesignated outcome was the odds of diabetes in metformin versus placebo comparisons during the trial and washout combined RESULTS—There were 1,274 participants who participated in the washout study and 529 who did not because they had already developed diabetes. Before the washout, the odds of diabetes in the metformin group was lower than that in the placebo group (odds ratio 0.66, 95% CI 0.54–0.82, P < 0.001). After the washout, diabetes was somewhat more frequently diagnosed in the metformin participants (1.49, 0.93–2.38, P = 0.098). Combining diabetes conversions during the DPP and during the washout, diabetes was diagnosed significantly less frequently in the metformin than the placebo group (0.75, 0.62–0.92, P = 0.005). CONCLUSIONS—The primary analysis of the DPP demonstrated that metformin decreased the risk of diabetes by 31%. The washout study shows that 26% of this effect can be accounted for by a pharmacological effect of metformin that did not persist when the drug was stopped. After the washout the incidence of diabetes was still reduced by 25%.
Washout
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Progression-free survival
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Hepatic organic cation transporter 1 (OCT1) can be a determinant of drug clearance and distribution, which can impact drug exposure and response. OCT1 was shown recently to be the rate‐determining step in the clearance of several drugs in humans, and thereby a mechanism of pharmacogenetic variability and drug–drug interactions (DDIs). OCT1 mediates metformin distribution to the liver (key biophase). As OCT1 modulation impacts metformin response, but not pharmacokinetics (PK), metformin DDI studies require pharmacodynamic endpoint(s) to inform rational metformin dose adjustment.
Pharmacodynamics
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Childhood obesity often seems like an intractable problem, with a rising incidence, especially of severe obesity, over the last few decades and few effective treatment options. Lifestyle changes, including dietary modification and exercise, are effective only in a minority of patients, with significant and sustained weight loss most likely to occur in the setting of costly multidisciplinary programs. Thus, clinicians often turn to pharmacotherapy. Currently there is only 1 medication, orlistat, that is approved for childhood obesity, but its effect on weight is modest and its acceptability is limited by side effects related to decreased fat absorption.Metformin is the mainstay of treatment of type 2 diabetes in both children and adults, with effects mainly on improving insulin sensitivity and decreasing hepatic glucose output. Since 2000, there have been a large number of studies that have examined the use of metformin as a weight-loss drug in children with obesity. Although each study has been unique in its size, design, and the patient populations studied, the theme that emerges, as summarized in a systematic review in 2014 based on 14 randomized clinical trials,1 is that “metformin provides a statistically significant, but very modest reduction in BMI when combined with lifestyle interventions over the short term.”The latest addition to this literature, published in this issue of Pediatrics, is a study from Spain, “Metformin for obesity in prepubertal and pubertal children: A Randomized Controlled Trial,”2 which offers some benefit compared with previous clinical trials but leaves more questions unanswered than answered. The main improvement of this study is its large size (160 patients with obesity were randomly assigned) and the inclusion of equal numbers of prepubertal and pubertal subjects. Like most other studies, it lasted only 6 months. However, the authors found an effect of metformin on BMI over 6 months only in the prepubertal subjects, which was both unexpected and disappointing. The effect in drug-treated prepubertal subjects was significant when BMI SD was the outcome (a decrease from 3.4–2.6 versus a decrease from 4.0–3.4 in the placebo group; P = .04), but the decrease in weight from 55.8 kg to 54 kg and in BMI from 28.2 to 26.5 did not reach a statistical significance compared with placebo. No effect on these parameters in the pubertal subjects was found. The authors correctly point out that because they used the same relatively small dose of metformin (500 mg twice daily) in both groups, the failure to see an effect in the pubertal group may have been due to the metformin dose being ∼50% lower on a milligram per kilogram basis. Most other published metformin-obesity studies have used escalating doses up to either 850 mg or 1000 mg twice daily. In addition, several studies have revealed a BMI reduction in teenage subjects as well as in subjects younger than age 12, so there is no evidence that puberty per se mitigates against metformin responsiveness.One study from Colorado briefly cited by the authors3 offers some insight as to why metformin is not more uniformly effective in treating obesity. These authors studied 85 adolescents with obesity aged 12 to 19 with documented insulin resistance, of whom 60 received metformin at doses escalating to 850 mg twice daily by 2 months, whereas 25 got a placebo. Although for the entire group mean BMI did not decrease significantly, the authors of this study found that 23% of subjects on metformin versus 0% on the placebo had a BMI reduction of 5% or more. Moreover, the subjects who lost weight were much more likely to have reported an excellent adherence with metformin as well as a decrease in portion size compared with those who did not reduce their BMI. The current study reported an overall adherence rate of 89%, much higher than the 60% rate in patients taking metformin in the Colorado study. Although dietary information was collected, the authors of the current study only reported on the healthy lifestyle-diet index, which they stated was in the moderate category in both groups, and apparently did not specifically question subjects about portion size. This is important because, in addition to the diarrhea and cramping often seen in patients taking metformin (mostly during the first 2 weeks), decreased appetite with an increased feeling of fullness is one of the medication’s other effects. Studies have documented this effect in both adults and in children,4,5 with the adult study demonstrating the effect to be dose-dependent. Although the exact mechanism is not understood, a study in rats suggests a direct inhibition on neuropeptide Y gene expression in the brain.6 There is no evidence found in any of the metformin trials that weight loss is dependent on improvement in insulin resistance or in other metabolic markers, which have been variable.A common feature of the metformin obesity studies is that nearly all concluded at or before 6 months after commencement, leaving one to wonder if longer treatment would result in further BMI reduction. Although data on this point are limited, the National Institutes of Health study by Yanovski et al7 of 6- to 12-year-old children with obesity did offer open-label metformin at doses of 1000 mg twice daily for an additional 6 months and found no further reduction in BMI. If one considers the public health implications of treating large numbers of children with obesity for extended periods of time, one might conclude that if all or most of the weight benefit is seen in the first 6 months, compliance with long-term therapy would be poor outside of a clinical trial.The just-published Endocrine Society clinical practice guideline on pediatric obesity8 discourages the use of any obesity medication unless the patient has failed a formal program of intensive lifestyle modification. It specifically states that “given its limited weight-loss efficacy, metformin is not considered a weight-loss treatment.” However, metformin does have the advantage of being inexpensive with a low incidence of serious side effects. It has been shown in adults to reduce the progression from elevated fasting glucose and glucose intolerance to type 2 diabetes by 31% over a mean of 2.8 years versus a reduction by 58% with a lifestyle intervention.9 However, it has not been demonstrated to be effective for this purpose in youth, although no large-scale studies to test this possibility have been reported to date.What should be the take-away message from the study of Pastor-Villaescusa et al2 and other similar studies? Although metformin should not be considered standard of care for obesity, it may have a limited role in treating carefully selected patients with prediabetes and a strong family history of type 2 diabetes, or those who have made a major effort at improving their lifestyle and are frustrated by their inability to lose weight. In such situations, it is suggested that clinicians push the dose, if tolerated, to the maximum recommended dose of 1000 mg twice daily to take advantage of the important effect of decreased appetite, which likely is a major factor accounting for its variable and modest effect on BMI.
Orlistat
Pharmacotherapy
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