Clinical Pharmacokinetics of Metformin

Metformin, the only biguanide oral antidiabetic agent available, was first used clinically in the late 1950s. Metformin remains the first-line pharmacologic treatment for type 2 diabetes patients. It can be used as a single agent or in combination therapy with other antidiabetes agents, including insulin. Metformin is absorbed predominately from the small intestine. It is rapidly distributed following absorption and does not bind to plasma proteins. It is excreted unchanged in urine. The elimination half-life of Metformin during multiple dosages in patients with good renal function is approximately 5 hours.

Effect of Metformin on Anthropometric Measurements and Hormonal and Biochemical Profile in Patients with Prediabetes

Objectives. Metformin is the most widely preferred first-line oral antidiabetic agent that results in clear benefits in blood sugar regulation and diabetes-related complications. This study is aimed at assessing the effect of metformin on anthropometric, hormonal, and biochemical parameters in patients with prediabetes or insulin resistance. Methods. A prepoststudy was conducted among 52 patients with prediabetes or insulin resistance who met the inclusion criteria. Weight, body mass index (BMI), and waist circumference were measured before and 12 months after metformin treatment. Serum concentrations of sex steroids, gonadotropins, and lipids were also assessed. Homeostasis model assessment (HOMA) index and quantitative sensitivity check (QUICKI) index scores were calculated before metformin treatment and after 12 months of use. Results. After 12 months of metformin treatment, female patients had significant reduction in weight, BMI, and waist circumference after adjusting for age. Metformin use for 12 months resulted in significant reduction in mean fasting blood glucose and HbA1c in females only. Total cholesterol decreased significantly among men only and serum HDL-C showed a significant rise among females only. Serum LDL-C and triglycerides did not change significantly in females and males. Our study did now significant changes in ACTH and cortisol levels in both females and males after metformin treatment. Metformin use resulted in significant increase in luteinizing hormone (LH) and progesterone levels in males, while it was associated with significant increase in prolactin, follicular stimulating hormone (FSH), and dehydroepiandrostenedione-sulphate (DHEA-S) levels and significant decrease in total testosterone level in females. Conclusion. Metformin treatment in females with prediabetes reduces BMI, waist circumference, fasting blood glucose, and HbA1c. The changes in the studied parameters differed significantly according to sex.

Effect of Metformin on the Kidney Histology of Rats in Gentamicin Induced Toxicity

Acknowledgment: We are indebted to Dr. Rashad Hussain from department of animal sciences, Quaid-i-Azam University, Islamabad for his consistent support and guidance for the write up of this manuscript. Study’s background and aim: Metformin, an oral antidiabetic agent has been studied in the past for its protective effects in aminoglycoside induced renal injuries. We hypothesized that the use of metformin may be protective in the aminoglycoside mediated acute renal failure. We thus tried two doses of metformin (M1; 75mg/kg/day) (M2; 150mg/kg/day) to evaluate this preventive potential on gentamicin induced acute renal failure in rats. Study Design: Randomized controlled trial Place of Study: Animal House of National Institute of Health Islamabad/ Department of Pharmacology, AL Nafees Medical College and Hospital, Islamabad, duration was 1stAugust 2018 to 31stJanuary 2019. Materials and Methods: The rats were divided into three main groups (n=10) kept under similar conditions for food and temperature. Renal failure was induced by injecting gentamicin (80mg/kg/day) intraperitonealy (ip) for eight days with simultaneous administration of oral metformin for 28 days.Slides of rats’ kidneys were prepared for histological comparison at the last day of study. Results: In gentamicin induced renal failure and simultaneous administration of metformin, the histological findings of rat kidneys showed remarkable tissue necrosis in control group and prevention in metformin treated groups. Conclusion: Based on the histological results of our study it was concluded that metformin at a dose of 150mg/kg showed a nephroprotective effect in gentamicin induced renal injuries in Sprague-Dawley rats. Keywords: Metformin, Gentamicin, Nephrotoxicty, Renal injuries, Nephroprotective effect

Metformin Use and Survival in Patients with Advanced Extrahepatic Cholangiocarcinoma: A Single-Center Cohort Study in Fuyang, China

Aims. Metformin is an oral antidiabetic agent that has been widely prescribed for the treatment of type II diabetes. In recent years, anticancer properties of metformin have been revealed for numerous human malignancies. However, there are few indications available regarding the feasibility and safety of these studies in an advanced extrahepatic cholangiocarcinoma (EHCC) population. This study is aimed at evaluating the feasibility, safety, and value of metformin use and survival in patients with advanced EHCC. Methods. All patients with advanced EHCC observed at Fuyang People’s Hospital between January 2015 and November 2020 were included in the study. Case data, clinical information, and imaging results were abstracted from the self-administered questionnaire and electronic medical record. All patients were divided into study subjects and control subjects, and the study subjects were given metformin, 0.5 g, three times a day, while control subjects were without metformin. The metformin use and survival time of the subjects were asked by telephone, out-patient, or door-to-door visit, after they left the hospital. Results. One hundred and thirty-three study cases and 589 controls were included in the analysis. This study showed that metformin use cannot improve the overall survival rate of patients with advanced EHCC ([95% CI]: -17.05-0.375, t = − 1.889 , P value = 0.061), but the survival time of patients with drainage treatment from control group ( n = 496 ) was significantly shorter than that of patients with drainage treatment from the study group ( n = 113 ), and the difference was statistically significant ( z = − 2.230 , P value = 0.026). There were significant differences between metformin used before or after the diagnosis of advanced EHCC (OR[95% CI], 3.432[2.617-4.502]; P value = 0.001) in survival time. And there was significant difference between the duration of metformin use and survival prognosis (OR[95% CI], 2.967[1.383-6.368]; P = 0.005 ). Conclusion. Metformin can improve the survival of advanced EHCC patients who underwent drainage treatment, especially for metformin use after diagnosis of advanced EHCC and long duration of metformin.

Formulation, Development and Evaluation of Colloidosomes of Glipizide

Glipizide is a potent oral antidiabetic agent, a second generation sulphonyl urea used in lowering blood glucose in patients with type II diabetes mellitus. It has a short half life of 2-4 hours. The objective of the present study was development and evaluation of colloidosomes of glipizide for controlled/sustained drug release. An attempt was made to formulate and evaluate colloidosomes of glipizide as a model drug using water in oil emulsion based method by using CaCO3 with a view to deliver drug at controlled/sustained manner in GIT and consequently into systemic circulation. The prepared colloidosomes were evaluated for particle size, shape and surface morphology, FTIR study, % yield, zeta potential, SEM, % drug entrapment efficiency and in-vitro drug release studies. The obtained colloidosomes were found to be discrete and spherical in shape and found to possess mean particle size range of 2228 nm to 3551 nm. The drug entrapment efficiency was found to be 52.13±1.2% to 71.18±1.25%. Amongst the prepared batches, Glipizide colloidosomes of Batch C formulation were stable and exhibited good sustained release of the drug for a period of 12 hours.The release profile was compared with alginate gel spheres. This implied that the developed formulations have a potential to deliver the drug in a sustained manner. This outcome from the release profiling strongly recommends that the developed glipizide loaded colloidosomes may prove to be a useful delivery carrier to deliver the drug in controlled release manner which is a prime requirement for the treatment of type II diabetes mellitus.

Pioglitazone Enhances β-Arrestin2 Signaling and Ameliorates Insulin Resistance in Classical Insulin Target Tissues

<b><i>Introduction:</i></b> Pioglitazone is a thiazolidinedione oral antidiabetic agent. This study aimed to investigate the effects of pioglitazone as insulin sensitizer on β-arrestin2 signaling in classical insulin target tissues. <b><i>Methods:</i></b> Experiments involved three groups of mice; the first one involved mice fed standard chow diet for 16 weeks; the second one involved mice fed high-fructose, high-fat diet (HFrHFD) for 16 weeks; and the third one involved mice fed HFrHFD for 16 weeks and received pioglitazone (30 mg/kg/day, orally) in the last four weeks of feeding HFrHFD. <b><i>Results:</i></b> The results showed significant improvement in the insulin sensitivity of pioglitazone-treated mice as manifested by significant reduction in the insulin resistance index. This improvement in insulin sensitivity was associated with significant increases in the β-arrestin2 levels in the adipose tissue, liver, and skeletal muscle. Moreover, pioglitazone significantly increased β-arrestin2 signaling in all the examined tissues as estimated from significant increases in phosphatidylinositol 4,5 bisphosphate and phosphorylation of Akt at serine 473 and significant decrease in diacylglycerol level. <b><i>Conclusion:</i></b> To the best of our knowledge, our work reports a new mechanism of action for pioglitazone through which it can enhance the insulin sensitivity. Pioglitazone increases β-arrestin2 signaling in the adipose tissue, liver, and skeletal muscle of HFrHFD-fed mice.

A case of unsuspected chronic lithium toxicity presenting with neurological symptoms

Lithium Carbonate is the first line treatment for bipolar depressive disorder. It also has beneficial effects on prophylactic use in Acute manic episodes to prevent recurrence and reduces rate of suicide associated with affective disorder. Low therapeutic index of Lithium (0.8-1.2meq/l) mandates regular and frequent measurement of Serum lithium level in patients taking this drug. Here we present a 59 years Indian male who is a known diabetic, chronic alcoholic and a case of bipolar disorder. He was on Lithium tablet off and on for last 4 years and was also on oral antidiabetic agent. He was admitted in ICU through emergency with complaints of altered level of consciousness for 2 days with H/O recurrent hypoglycemia associated with nausea, reduced food intake, vertigo, tremor of all four limbs with weakness of both lower limbs for approximately last 2 months. Admission serum lithium level was 2.24meq/l. Hemodialysis was started. Neurological symptoms improved and serum Lithium level returned to normal (0.79meq/l) after 2 session of hemodialysis. Bangladesh Crit Care J March 2021; 9(1): 46-48

Efficacy and Safety of Imeglimin Monotherapy Versus Placebo in Japanese Patients With Type 2 Diabetes (TIMES 1): A Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Phase 3 Trial

<b>Objective.</b> The aim of this study was to investigate the efficacy and safety of imeglimin, the first in a new class of oral antidiabetic agent, in Japanese patients with type 2 diabetes. <p><b>Research Design and Methods.</b> This was a double-blind, randomized, parallel-group, placebo-controlled phase 3 trial in 30 sites in Japan. Eligible participants were individuals aged 20 years or older with type 2 diabetes treated with diet and exercise stable for at least 12 weeks prior to screening and an HbA1c of 7.0%-10.0% (53-86mmol/mol). Patients were randomly assigned (1:1) to either oral imeglimin (1000 mg BID), or matched placebo for 24 weeks. Investigators, participants and the sponsor of the study remained blinded throughout the trial. The primary endpoint was the change in mean HbA1c from baseline to week 24, and the key secondary endpoints were the percentage of responders (according to two definitions) at week 24. </p> <p><b>Results.</b> Between 26^th December 2017 and 1^st February 2019, we randomly assigned 106 patients to imeglimin 1000 mg BID and 107 patients to placebo. Compared with placebo, adjusted mean difference in change from baseline HbA1c at week 24 was -0.87% (95% CI -1.04 to -0.69 / -9.5mmol/mol (95%CI -11.4 to -7.5) (p<0.0001). Forty-seven (44.3%) patients reported at least one adverse event in the imeglimin group versus 48 (44.9%) in the placebo group. </p> <p><b>Conclusions.</b> Imeglimin significantly improved HbA1c in Japanese patients with type 2 diabetes compared with placebo, and showed a similar safety profile to placebo, representing a potential new treatment option for this population. </p>

Efficacy and Safety of Imeglimin Monotherapy Versus Placebo in Japanese Patients With Type 2 Diabetes (TIMES 1): A Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Phase 3 Trial

<b>Objective.</b> The aim of this study was to investigate the efficacy and safety of imeglimin, the first in a new class of oral antidiabetic agent, in Japanese patients with type 2 diabetes. <p><b>Research Design and Methods.</b> This was a double-blind, randomized, parallel-group, placebo-controlled phase 3 trial in 30 sites in Japan. Eligible participants were individuals aged 20 years or older with type 2 diabetes treated with diet and exercise stable for at least 12 weeks prior to screening and an HbA1c of 7.0%-10.0% (53-86mmol/mol). Patients were randomly assigned (1:1) to either oral imeglimin (1000 mg BID), or matched placebo for 24 weeks. Investigators, participants and the sponsor of the study remained blinded throughout the trial. The primary endpoint was the change in mean HbA1c from baseline to week 24, and the key secondary endpoints were the percentage of responders (according to two definitions) at week 24. </p> <p><b>Results.</b> Between 26^th December 2017 and 1^st February 2019, we randomly assigned 106 patients to imeglimin 1000 mg BID and 107 patients to placebo. Compared with placebo, adjusted mean difference in change from baseline HbA1c at week 24 was -0.87% (95% CI -1.04 to -0.69 / -9.5mmol/mol (95%CI -11.4 to -7.5) (p<0.0001). Forty-seven (44.3%) patients reported at least one adverse event in the imeglimin group versus 48 (44.9%) in the placebo group. </p> <p><b>Conclusions.</b> Imeglimin significantly improved HbA1c in Japanese patients with type 2 diabetes compared with placebo, and showed a similar safety profile to placebo, representing a potential new treatment option for this population. </p>

Evaluation of PRKAA2 Genetic Variation on Metformin Efficacy as an Initial Therapy Among Drug-Naïve Patients With Type II Diabetes Mellitus

Background: Metformin is the most popular oral antidiabetic agent, which is recommended as initial monotherapy. AMPK is the pivotal target of metformin molecular mechanisms. AMPK subunit a2 (encoded by PRKAA2) is a gene contributable to increase type 2 diabetes mellitus (T2DM) risk. This study aimed to evaluate PRKAA2 rs2796498, rs2746342, and rs980799 genetic variations on metformin efficacy.Methods: This study enrolled 191 newly diagnosed Indonesia T2DM patients in primary health care. Patients who received metformin as monotherapy for at least 3 months were included for genotyping. Genotyping was performed using the Taqman assay.Results: Baseline characteristics showed that BMI was higher among AA than GG+AG (p=0.04). Patients with TT genotype showed a higher FBG and HbA1c than GG+GT (p=0.02 and p=0.02, respectively). There was no significant difference in allele and genotype frequencies between responders and non-responders group in PRKAA2 rs2796498, rs9803799, and rs2746342. However, among PRKAA2 rs2796498, AG carrier had 0.32 times of responding in metformin efficacy after adjusting BMI, WC, blood pressure, lipid profiles, and eGFR. Dominant model of rs2796498 showed a significant association (OR=0.34, 95%CI=0.13 – 0.90) to metformin efficacy. Conclusions: Our findings suggest that PRKAA2 rs2796498 genetic variation may affect metformin efficacy, especially AG carrier, in drug-naïve T2DM patients.