Effects of an EE/CA compared with EE/CA-metformin on serum ADMA levels in women with polycystic ovary syndrome

To determine the effects of EE/CA (Ethinylestradiol/ Cyproterone Acetate) and EE/CA-metformin treatments on the asymmetric dimethylarginine (ADMA) levels in women with PCOS (Polycystic Ovary Syndrome). Among 43 patients diagnosed with PCOS, one study arm (n=22) was administered (35 μg EE, 2mg CA) and the other (n=21) was administered (35 μg EE, 2mg CA plus 1700mg metformin). Serum ADMA, lipid profile, androgens, insulin, and HOMA-IR (Homeostatic Model Assessment of Insulin Resistance ) values were assessed prior to treatment and after 3 months of therapy. A significant reduction in ADMA levels relative to pre-treatment in the EE/CA+metformin group (1.2±0.4 vs 0.95±0.4, p=0.016) compared to the EE/CA group (1.0±0.5 vs 1.03±0.4, p >0.05). Andogens, insulin and HOMA-IR levels decreased in both treatment groups. All lipid profiles significantly improved in-group EE/CA+metformin while no significant decrease was observed in TG and HDL-cholesterol levels in EE/CA group. Post-treatment levels of HDL-C levels correlated significantly with the reducing ADMA levels in the EE/CA+metformin group (P=0.005, r= 0.602). Adding metformin to EE/CA therapy in PCOS may beneficial endothelium effects associated with reduction of ADMA levels.     

Effect of high uric acid on the disposition of metformin: in vivo and in vitro studies

Metformin is always used as the baseline antidiabetic therapy for patients with type 2 diabetes mellitus (T2DM) and hyperuricemia. Metformin is excreted into urine through active secretion mediated by rOCTs and rMATE1.The aim of this study was to identify the effects of high uric acid on the disposition and its mechanism. For the in vivo study, a hyperuricemic animal model was induced by intraperitoneal injection of potassium oxonate (250 mg/kg) in rats. Metformin (100 mg/kg) was administered orally to investigate the pharmacokinetics in control and hyperuricemic rats, respectively. For the in vitro study, HEK293 and HepaRG cells were used to investigate the effect of uric acid (15 mg/dl) on the expression of OCT1, OCT2 and MATE1 and the disposition of metformin, respectively. The in vivo study showed that the AUC_0 → 600 of metformin was significantly decreased by 33.3%, whereas the cumulative urinary excretion of metformin was increased by 25.4% in hyperuricemic rats compared with that in control rats. The renal rOCT1, rOCT2 and rMATE1 and hepatic rMATE1 levels were increased in hyperuricemic rats compared with those in control rats, respectively. The in vitro study showed that uric acid could upregulate the expression of OCT2 and MATE1 in HEK293 cells and MATE1 in HepaRG cells and increase the intracellular metformin concentration in these two cell lines. These results demonstrated that a high uric acid level promoted urinary metformin excretion and decreased the plasma metformin concentration; the in vivo and in vitro studies provided a possible explanation being that high uric acid could upregulate the expression of renal metformin transporters OCTs and MATE1.     

Using a semi‐mechanistic model to identify the main sources of variability of metformin pharmacokinetics

Metformin pharmacokinetics (PK) is highly variable, and researchers have for years tried to shed light on determinants of inter‐individual (IIV) and inter‐occasion variability (IOV) of metformin PK. We set out to identify the main sources of PK variability using a semi‐mechanistic model. We assessed the influence of subject characteristics, including seven genetic variants. Data from three studies of healthy individuals with PK measurements of plasma and urine after single dose or at steady‐state were used in this study. In total, 87 subjects were included (16 crossover subjects). Single nucleotide polymorphisms in ATM, OCT1, OCT2, MATE1 and MATE2‐K were investigated as dominant, recessive or additive. A three‐compartment model with transit absorption and renal elimination with a proportional error was fitted to the data using NONMEM 7.3. Oral parameters were separated from disposition parameters as dose‐dependent absolute bioavailability was determined with support from urine data. Clearance was expressed as net renal secretion and filtration, assuming full fraction unbound and fraction excreted. Mean transit time and peripheral volume of distribution were identified as the main sources of variability according to estimates, with 94% IOV and 95% IIV, respectively. Clearance contributed only with 16% IIV. Glomerular filtration rate and body‐weight were the only covariates found to affect metformin net secretion, reducing IIV to 14%. None of the genetic variants were found to affect metformin PK. Based on our analysis, finding covariates explaining absorption of metformin is much more valuable in understanding variability and avoiding toxicity than elimination.     

No significant influence of OCT1 genotypes on the pharmacokinetics of morphine in adult surgical patients

We investigated the impact of genetic variants in OCT1 (SLC22A1) on morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) pharmacokinetics in adult patients scheduled for major surgery. Blood samples were taken before and 5, 10, 15, 30, 45, 60 and 90 min after a bolus of morphine (0.15 mg/kg). Patients were genotyped for the genetic variants (rs12208357, rs34059508, rs72552763 and rs34130495) in OCT1. Eighty-six patients completed the trial. The mean difference (95% confidence interval) for dose adjusted morphine, M3G and M6G AUC was 0.9 (?0.7–2.4), ?5.9 (?11.8 to ?0.03) and ?1.1 (?2.5–0.4) h/L*10^?6, respectively, in patients with two reduced function alleles compared to patients with no reduced function alleles in OCT1. Accordingly, the (AUC_M3G/Dose)/(AUC_{morphine/Dose}) and (AUC_M6G/Dose)/(AUC_{morphine/Dose}) ratio was reduced, ?1.8 (?3.2 to ?0.4) and ?0.4 (?0.7 to ?0.03), respectively, when comparing the same groups. OCT1 variants had no influence on the experience of pain, adverse events or the number of PCA doses used. In conclusion, genetic variants in OCT1 had a small and clinically unimportant impact on the exposure of morphine after intravenous administration. Our results do not support pre-emptive genotyping for OCT1 prior to morphine administration in patients scheduled for major surgery.     

Polycystic ovary syndrome: treatment strategies and management

Background: The polycystic ovary syndrome (PCOS) is possibly the most common endocrine disorder in premenopausal women, with prevalences in the 6 – 7% range reported worldwide. Although PCOS is primarily a disorder of androgen excess, affected women frequently present with abdominal adiposity and insulin resistance, explaining the association of PCOS with metabolic comorbidities and an increased cardiovascular risk. Abdominal adiposity, and very especially the compensatory hyperinsulinism resulting from insulin resistance, further contribute to hyperandrogenism. These pathophysiological mechanisms must be considered when deciding the optimal therapy for PCOS patients. Objective: To review the impact of the current approaches to the treatment of PCOS on the metabolic associations and the cardiovascular risk of these women. Methods: Review of published studies addressing the effects of different treatment strategies of PCOS. Results: The resolution of PCOS after the marked and sustained weight loss attained after bariatric surgery makes this therapeutic option a first-line strategy in women presenting with severe obesity. In patients with lesser grades of obesity who desire fertility, a short trial of metformin, followed by classic ovulation induction and/or assisted reproductive techniques in case pregnancy is not achieved in a few months, is a reasonable approach. If fertility is not an immediate concern, third generation oral contraceptive pills containing a neutral or antiandrogenic progestin remains the drug of choice, considering their efficacy, their excellent tolerability, and their overall metabolic safety. Conclusion: Strategies targeting obesity and abdominal adiposity, insulin resistance and hyperandrogenism, alone or in combination, are effective in ameliorating the signs and symptoms of hyperandrogenism while improving the metabolic comorbidities and the cardiovascular risk of these patients in most cases.     

KCNJ11 rs5219基因多态性对新发2型糖尿病患者二甲双胍及格列齐特联用疗效的研究

目的 探讨ATM(rs11212617)、KCNJ11(rs5219)、CYP2C9(rs1799853、rs1057910)、TCF7L2(rs12255372、rs290487)及IRS1(rs1801278)位点对二甲双胍及格列齐特联用治疗新诊断2型糖尿病患者疗效的影响。方法 在浙江中医药大学附属嘉兴中医院内分泌科标准化代谢性疾病管理中心门诊就诊,并使用盐酸二甲双胍片和格列齐特缓释片联合治疗的81例新诊断2型糖尿病患者被纳为研究对象,使用MassARRAY技术对上述位点进行分型,并进行为期3个月的随访,对比治疗前后空腹血糖、糖化血红蛋白及空腹胰岛素的变化。结果 上述单核苷酸多态性位点的基因频率符合Hardy-Weinberg遗传平衡,样本代表性良好。rs1799853、rs1057910、rs12255372与rs1801278位点突变频率较低,临床意义欠佳。rs5219C等位基因纯合患者在治疗后的空腹血糖达标率、空腹胰岛素上升量及糖化血红蛋白下降量上的获益均强于T等位基因携带患者(P<0.05)。而rs11212617和rs290487位点各基因型间并未显示出治疗效果的差...     

The influence of telmisartan on metformin pharmacokinetics and pharmacodynamics

Metformin is the most widely used drug among type 2 diabetes mellitus patients. However, drug interaction on metformin will influence its glucose-lowering effect or increase its side effect of lactic acidosis. In this study, a randomized, two-stage, crossover study was conducted to unveil the potential drug interaction between metformin and the anti-hypertension drug, telmisartan. Totally, 16 healthy Chinese male volunteers were enrolled. Blood samples from various time-points after drug adminstration were analyzed for metformin quantification. Oral glucose tolerance test (OGTT) was conducted 2 h after metformin administration. The AUC_0-12 and Cmax of metformin in subjects co-administrated with telmisartan were significantly lower than with placebo. The geometric mean ratios (value of metformin plus telmisartan phase/value of metformin plus placebo phase) for Cmax and AUC_0-12 is 0.7972 (90%CI: 0.7202–0.8824) and 0.8336 (90%CI: 0.7696–0.9028), respectively. Moreover, telmisartan co-administration significantly increased the plasma concentrations of both glucose and insulin at 0.5 h since OGTT (7.64 ± 1.86 mmol/l·min vs 6.77 ± 0.83 mmol/l·min, P = 0.040; 72.91 ± 31.98 μIU/ml·min vs 60.20 ± 24.20 μIU/ml·min, P = 0.037), though the AUC of glucose and insulin after OGTT showed no significant difference. These findings suggested that telmisartan had a significant influence on the Pharmacokinetics of metformin in healthy groups, though the influence on glucose-lowering effect was moderate.     

Phosphatidylinositide 3-kinase inhibition: A new potential target for the treatment of polycystic ovarian syndrome

Context: Quercetin, a flavonoid, has been tried in traditional medicine for treating many disorders and reported to have inhibitory action on PI3 kinase.

Objective: This study investigates the effect of quercetin on testosterone propionate induced polycystic ovary syndrome (PCOS) model, which shows both metabolic and endocrine features of PCOS.

Materials and methods: Female pre-pubertal Sprague–Dawley rats were randomly divided into four groups: normal control, PCOS control, quercetin, and metformin treated. PCOS was induced by testosterone propionate (10?mg/kg, s.c.) and treatments were carried out orally at the dose of 150?mg/kg from the 6th week. At the 6th and 10th week, blood was collected to investigate metabolic indices, and reproductive biochemical parameters including morphology of ovary, uterus, and estrous cyclicity were assessed. The ovaries were processed to determine CYP17A1 gene expression.

Results: The treatment with quercetin did not modify body weight gain but uterine (296.7?±?5.11 versus 263.0?±?8.60?mg) and ovary weights (49.5?±?1.93 versus 37.8?±?3.43?mg) were found to be decreased significantly (p <0.05) as compared with the PCOS control group. The PCOS control group showed hyperinsulinemia, hyperandrogenemia, and dyslipidemia. Treatment with quercetin showed statistically significant (p?<0.01) improvement in insulin (12.46?±?0.3 versus 10.0?±?0.28 μU/ml), testosterone (0.65?±?0.02 versus 0.29?±?0.02 μU/ml), luteinising hormone (20.6?±?0.28 versus 15.1?±?0.36 U/ml), and lipid profile. Histological examination of ovary and uterus confirmed the disease occurrence and remission state in the diseased and treated groups, respectively. Quercetin also demonstrated PI3 kinase inhibition in a docking study and decreased CYP17A1 gene expression.

Discussion and conclusion: Thus, we can conclude that quercetin may have beneficial effect in PCOS by virtue of inhibition of PI3K which attributes to a decrease in the expression of CYP17A1 gene, having a key role in steroidogenesis.     

Insulin resistance, polycystic ovary syndrome and metformin

Polycystic ovary syndrome (PCOS) is the most common disorder of ovarian function in premenopausal women. PCOS is characterised by chronic anovulation and androgen excess with clinical manifestation of irregular menstrual cycles, hirsutism and/or acne. Insulin resistance with resultant hyperinsulinaemia, irrespective of excess weight or frank obesity, has been reported in patients with PCOS, and, as insulin has a direct effect on ovarian androgen production in vitro, insulin resistance may play a crucial role in the physiopathology of PCOS. Although the molecular mechanism(s) of insulin resistance in PCOS is unclear, excessive insulin-independent serine phosphorylation of the beta subunit of the insulin receptor, as reported in some patients with PCOS, has been put forward as a new mechanism for insulin resistance. Insulin-sensitising agents have recently been investigated for their role in the short term treatment of insulin resistance in PCOS. Controlled studies have shown that metformin administration, by promoting bodyweight loss, can decrease fasting and stimulated plasma insulin levels. However, other studies have shown metformin 500 mg 3 times daily to decrease insulin secretion and to reduce ovarian production of 17alpha-hydroxyprogesterone with recovery of spontaneous or clomifene-induced ovulation, independently of weight loss. These findings suggest a new indication for metformin and present insulin-sensitising agents as a novel approach in the treatment of ovarian hyperandrogenism and abnormal ovulation in PCOS. They also suggest that long term administration of metformin might be helpful in treating insulin resistance, thus reducing risks of type 2 (non-insulin-dependent) diabetes and cardiovascular disease in these patients.     

A study of the pharmacokinetic interactions of the direct renin inhibitor aliskiren with metformin,pioglitazone and fenofibrate in healthy subjects*

ABSTRACT

Objective: Hypertension and type 2 diabetes are common comorbidities, thus many patients receiving antihypertensive medication require concomitant therapy with hypoglycemic or lipid-lowering drugs. The aim of these three studies was to investigate the pharmacokinetics, safety and tolerability of aliskiren, a direct renin inhibitor for the treatment of hypertension, co-administered with the glucose-lowering agents metformin or pioglitazone or the lipid-lowering agent fenofibrate in healthy volunteers.

Methods: In three open-label, multiple-dose studies, healthy volunteers (ages 18 to 45 years) received once-daily treatment with either metformin 1000?mg (n?=?22), pioglitazone 45?mg (n?=?30) or fenofibrate 200?mg (n?=?21) and aliskiren 300?mg, administered alone or co-administered in a two-period study design. Blood samples were taken frequently on the last day of each treatment period to determine plasma drug concentrations.

Results: Co-administration of aliskiren with metformin decreased aliskiren area under the plasma concentration–time curve during the dose interval (AUC_τ) by 27% (geometric mean ratio [GMR] 0.73; 90% confidence interval [CI] 0.64, 0.84) and maximum observed plasma concentration (C_max) by 29% (GMR 0.71; 90% CI 0.56, 0.89) but these changes were not considered clinically relevant. Co-administration of aliskiren with fenofibrate had no effect on aliskiren AUC_τ (GMR 1.05; 90% CI 0.96, 1.16) or C_max (GMR 1.05; 90% CI 0.80, 1.38); similarly, co-administration of aliskiren with pioglitazone had no effect on aliskiren AUC_τ (GMR 1.05; 90% CI 0.98, 1.13) or C_max (GMR 1.01; 90% CI 0.84, 1.20). All other AUC_τ and C_max GMRs for aliskiren, metformin, pioglitazone, ketopioglitazone, hydroxypioglitazone and fenofibrate were close to unity and the 90% CI were contained within the bioequivalence range of 0.80 to 1.25.

Conclusion: Co-administration of aliskiren with metformin, pioglitazone or fenofibrate had no significant effect on the pharmacokinetics of these drugs in healthy volunteers. These findings indicate that aliskiren can be co-administered with metformin, pioglitazone or fenofibrate without the need for dose adjustment.     

Influences of Organic Cation Transporter Polymorphisms on the Population Pharmacokinetics of Metformin in Healthy Subjects

This study investigated the effects of genetic polymorphisms in organic cation transporter (OCT) genes, such as OCT1-3, OCTN1, MATE1, and MATE2-K, on metformin pharmacokinetics. Of particular interest was the influence of genetic polymorphisms as covariates on the variability in the population pharmacokinetics (PPK) of metformin using nonlinear mixed effects modeling (NONMEM). In a retrospective data analysis, data on subjects from five independent metformin bioequivalence studies that used the same protocol were assembled and compared with 96 healthy control subjects who were administered a single oral 500 mg dose of metformin. Genetic polymorphisms of OCT2-808 G > T and OCTN1-917C > T had a significant (P < 0.05) effect on metformin pharmacokinetics, yielding a higher peak concentration with a larger area under the serum time–concentration curve. The values obtained were 102 ± 34.5 L/h for apparent oral clearance (CL/F), 447 ± 214 L for volume of distribution (V_d/F), and 3.1 ± 0.9 h for terminal half-life (mean ± SD) by non-compartmental analysis. The NONMEM method gives similar results. The metformin serum levels were obtained by setting the one-compartment model to a first-order absorption and lag time. In the PPK model, the effects of OCT2-808 G > T and OCTN1-917C > T variants on the CL/F were significant (P < 0.001 and P < 0.05, respectively). Thus, genetic variants of OCTN1-917C > T, along with OCT2-808 G > T genetic polymorphisms, could be useful in titrating the optimal metformin dose.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-013-9460-z) contains supplementary material, which is available to authorized users.KEY WORDS: genetic polymorphism, metformin, OCTs, population pharmacokinetics     

Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin-induced lactic acidosis

BACKGROUNDS AND PURPOSE

Lactic acidosis is a fatal adverse effect of metformin, but the risk factor remains unclear. Multidrug and toxin extrusion 1 (MATE1) is expressed in the luminal membrane of the kidney and liver. MATE1 was revealed to be responsible for the tubular and biliary secretion of metformin. Therefore, some MATE polymorphisms, that cause it to function abnormally, are hypothesized to induce lactic acidosis. The purpose of this study is to clarify the association between MATE dysfunction and metformin-induced lactic acidosis.

EXPERIMENTAL APPROACH

Blood lactate, pH and bicarbonate ion (HCO₃^-) levels were evaluated during continuous administration of 3 mg·mL⁻¹ metformin in drinking water using Mate1 knockout (−/−), heterozygous (+/−) and wild-type (+/+) mice. To determine the tissue accumulation of metformin, mice were given 400 mg·kg⁻¹ metformin orally. Furthermore, blood lactate data were obtained from diabetic patients given metformin.

KEY RESULTS

Seven days after metformin administration in drinking water, significantly higher blood lactate, lower pH and HCO₃^- levels were observed in Mate1^−/− mice, but not in Mate1^+/− mice. The blood lactate levels were not affected in patients with the heterozygous MATE variant (MATE1-L125F, MATE1-G64D, MATE2-K-G211V). Sixty minutes after metformin administration (400 mg·kg⁻¹, p.o.) the hepatic concentration of metformin was markedly higher in Mate1^−/− mice than in Mate1^+/+ mice.

CONCLUSION AND IMPLICATIONS

MATE1 dysfunction caused a marked elevation in the metformin concentration in the liver and led to lactic acidosis, suggesting that the homozygous MATE1 variant could be one of the risk factors for metformin-induced lactic acidosis.     

胰高血糖素样肽1受体激动剂治疗多囊卵巢综合症的效果分析

目的 探讨胰高血糖素样肽1受体激动剂对多囊卵巢综合症的临床疗效.方法 收集2015年3月至2016年3月入院的72例多囊卵巢综合症患者,随机分为对照组与实验组.对照组二甲双胍+达英35联合治疗,实验组二甲双胍+胰高血糖素样肽1受体激动剂治疗,比较两组治疗前后相关临床指标与临床事件发生率.结果 治疗后,实验组空腹胰岛素[(9.55±1.47)μU/ml]、餐后2h胰岛素[(56.83±9.54)μU/ml]、总胆固醇[(1.17±0.34) mmol/L]、低密度脂蛋白[(2.24±0.21) mmol/L]、促黄体生成素[(6.61±0.37) mmol/L]、垂体分泌卵泡刺激素[(1.39±0.44) mmol/L]、睾丸酮[(0.13±0.06)mmol/L]与垂体泌乳素水平[(52.04±13.58 mmol/L)]均显著低于对照组[(12.33±2.03)μU/ml、(80.64±10.78)μU/ml、(1.43±0.31)mmol/L、(2.55±0.26) mmol/L、(7.09±0.43) mmol/L、(3.05±0.71)mmol/L、(0.39±0.16) mmol/L、(80.16±11.48) mmol/L],差异有统计学意义(均P＜0.01);实验组排卵率(75.00％)与妊娠率(44.44％)明显高于对照组(50.00％、19.44％),差异有统计学意义(均P＜0.05).结论 胰高血糖素样肽l受体激动剂治疗多囊卵巢综合症临床效果显著,具有借鉴意义.     

温肾调经汤对多囊卵巢综合征内分泌及脂代谢的影响

目的 探讨温肾调经汤对多囊卵巢综合征(PCOS)患者内分泌及脂代谢的影响。方法 将符合纳入标准的90例患者采用随机数字表法分为2组,每组各45例,观察组选用温肾调经汤治疗,对照组选用二甲双胍治疗,2组用药时间均为2个月,比较2组治疗前后体质量指数(BMI)、空腹血糖、餐后2 h血糖、空腹胰岛素、餐后2 h胰岛素、瘦素、脂联素、稳态胰岛素评价指数(HOMA-IR)、血脂及性激素的变化,并进行中医证候评分。结果 通过2个月的治疗,温肾调经汤比二甲双胍能更好地降低肥胖型PCOS患者的平均BMI,调节性激素和大部分脂代谢(除高密度脂蛋白胆固醇、载脂蛋白A外),降低中医症候评分,差异有统计学意义(P<0.05)。2组患者降低血糖、胰岛素抵抗疗效相仿。结论 温肾调经汤可降低肥胖患者BMI,改善胰岛素抵抗,调整PCOS患者性激素水平,改善脂代谢异常,降低中医证候评分。     

MCP-1 and fetuin A levels in patients with PCOS and/or obesity before and after metformin treatment

Background/Aims

The aim of the study was to investigate MCP-1 and fetuin A levels in women with PCOS and/or obesity before and after metformin treatment.

Materials/Methods

In the study consisted of 59 patients. Anthropometric measurements and biochemical tests, including MCP-1 and fetuin A measurement, were performed. For patients that were diagnosed with insulin resistance and started metformin treatment all the laboratory tests and anthropometric measurements were repeated after 6 months.

Results

MCP-1 and fetuin A levels did not differ between patients with obesity with and without PCOS, between patients with PCOS with and without obesity, insulin resistance, arterial hypertension, dyslipidemia or menstrual disturbances. MCP-1 levels were significantly higher in patients with hyperandrogenemia than in patients without (456.3±141.1pmol/L vs. 372.5±108.5 pmol/L), while fetuin A levels were significantly higher in patients with metabolic syndrome (MetS) than in patients without MetS (278.5±41.1 mcg/ml vs. 240.0±42.0 mcg/ml). There was no significant change in MCP-1 and fetuin A levels after of metformin treatment.

Conclusions

MCP- 1 levels are higher in patients with hyperandrogenemia and fetiun A levels are higher in patients with metabolic syndrome. MCP-1 and fetuin A levels do not change significantly after metformin treatment.     

青春期多囊卵巢综合征30例的干预与治疗

目的　探讨青春期多囊卵巢综合征 (PCOS)的干预与治疗。方法　选择 30例青春期多囊卵巢综合征患者口服妈富隆 ,或妈富隆联合二甲双胍治疗 3个周期 ,对比治疗前后女性激素及胰岛素的改变。结果　 30例患者完成 3个周期治疗后观察 2个月 ,2 1例月经不规则患者中 86 %月经周期正常 ;与服药前比较黄体生成素(L H)、睾酮 (T)、雄酮 (A)均有显著降低。肥胖及空腹胰岛素 (INS) >16 m mol/L 两种药物 +饮食限制 +运动联合治疗 3个周期后 6 0 %体重指数 (BMI)下降 ,99.5 %空腹 INS<9m mol/L。结论　妈富隆或妈富隆联合二甲双胍对纠正青春期 PCOS患者的异常血激素相及卵巢状态有良好的效果。     

Multidrug and toxin extrusion protein 1-mediated interaction of metformin and Scutellariae radix in rats

1.?The metformin and Scutellariae radix extract (SB) combination has been previously reported to enhance anti-diabetic activity. Considering that organic cation transporters (OCTs) and multi-drug and toxin extrusion proteins (MATEs) in the liver and kidney are determinant factors on hepatic distribution and renal clearance of metformin, the effects of SB on OCT or MATE-mediated systemic exposure of metformin as well as on glucose tolerance and hypoglycemia were examined.

2.?Although SB inhibited metformin uptake through human transporters OCT1 and MATE1 in vitro, the systemic exposures of metformin in vivo rats were not altered after metformin treatment with and without SB due to unchanged renal excretion of metformin.

3.?However, 28-day metformin treatment with SB decreased the mRNA level of hepatic MATE1 in rats, resulting in reduced biliary excretion of metformin and thereby higher concentration of metformin in the liver. In addition, in rats with 28-day metformin treatment with SB, glucose tolerance and plasma lactate level were enhanced, while hypoglycemia was not detected.

4.?Thus in rats, intervention of SB on transporter-mediated metformin transportation partially improves glucose tolerance without hypoglycemia and increases hepatic distribution of metformin. Also the further investigations in humans are required to clarify the relevance of these findings to the clinical significance.     

Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase-4 inhibitor sitagliptin when co-administered in patients with type 2 diabetes

ABSTRACT

Objective: As part of the clinical development of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of type 2 diabetes, the potential for pharmacokinetic interactions with other antihyperglycemic agents used in managing patients with type 2 diabetes are being carefully evaluated. The purposes of this study were to evaluate the tolerability of co-administered sitagliptin and metformin and effects of sitagliptin on metformin pharmacokinetics as well as metformin on sitagliptin pharmacokinetics under steady-state conditions.

Methods: This placebo-controlled, multiple-dose, crossover study in patients with type 2 diabetes assessed the tolerability of co-administered sitagliptin (50?mg b.i.d.) with metformin (1000?mg b.i.d.). Patients received, in a randomized crossover manner, three treatments (each of 7 days duration): 50?mg sitagliptin twice daily and placebo to metformin twice daily; 1000?mg of metformin twice daily and placebo to sitagliptin twice daily; concomitant administration of 50?mg of sitagliptin twice daily and 1000?mg of metformin twice daily. Following dosing on Day 7 of each treatment period, these pharmacokinetic parameters were determined for plasma sitagliptin and metformin: area under the plasma concentrations–time curve over the dosing interval (AUC_{0–12 h}), maximum observed plasma concentrations (C_max), and time of occurrence of maximum observed plasma concentrations (T_max). Renal clearance was also determined for sitagliptin.

Results: In this study, no adverse experiences were reported by 11 of 13 patients. Two patients had adverse experiences, which were not related to study drugs as determined by the investigators. The mean metformin plasma concentration–time profiles were nearly identical with or without sitagliptin co-administration [metformin AUC_{0–12 h} geometric mean ratio (GMR; [metformin + sitagliptin]/metformin)] was 1.02 (90% CI 0.95, 1.09). Similarly metformin administration did not alter the plasma sitagliptin pharmacokinetics [sitagliptin AUC_{0–12 h} GMR ([sitagliptin + metformin]/sitagliptin)] was 1.02 (90% CI 0.97, 1.08) or renal clearance of sitagliptin. No efficacy measurements (glycosylated hemoglobin or fasting plasma glucose) were obtained during this study. Urinary pharmacokinetics for metformin were not determined due to the lack of effect of sitagliptin on plasma metformin pharmacokinetics.

Conclusions: In this study, co-administration of sitagliptin and metformin was generally well tolerated in patients with type 2 diabetes and did not meaningfully alter the steady-state pharmacokinetics of either agent.     

Efficacy and safety of therapy with metformin plus pioglitazone in the treatment of patients with type 2 diabetes: a double-blind,placebo-controlled,clinical trial

ABSTRACT

Objective: To assess the efficacy and safety of combination therapy with pioglitazone and metformin in Japanese patients with type 2 diabetes.

Research design and methods: During a 12-week observation period 236 patients were treated with metformin 500 or 750?mg/day. 169 patients with a confirmed HbA_1c level ≥ 6.5% were randomized (stratified according to metformin dosage) to receive pioglitazone 15?mg/day for 12 weeks then increased to 30?mg/day for a further 16 weeks (n?=?83), or placebo (n?=?86). Outcome measures included HbA_1c, fasting blood glucose (FBG), percentage of patients achieving HbA_1c?<?6.5%, lipid profile, and other metabolic parameters.

Results: Mean HbA_1c was reduced by 0.67% in patients receiving pioglitazone plus metformin versus an increase of 0.25% in those receiving metformin alone (p?<?0.0001). After 8 weeks’ treatment and until the end of the study, HbA_1c was significantly lower with pioglitazone plus metformin and more patients in this group achieved an HbA_1c?<?6.5% (38.6% vs. 8.1%; p?<?0.0001). FBG was also reduced by a significantly greater amount in patients receiving pioglitazone plus metformin compared with metformin monotherapy (?20.5 vs. 1.9?mg/dl; p?<?0.0001). Combination therapy was associated with significantly increased HDL-cholesterol, total cholesterol, and adiponectin, and significantly decreased levels of fasting insulin, free fatty acids, and homeostasis model assessment insulin resistance (HOMA-R) compared with metformin monotherapy. Overall, combination therapy and monotherapy were equally well tolerated and the incidence of adverse effects ‘possibly’ related to therapy was 15.7% and 11.6% (p?=?0.505), respectively. Edema occurred slightly more often in the combination group (6.0 vs. 1.2%).

Conclusion: Pioglitazone plus metformin significantly improved glycemic control (HbA_1c and FBG), and markers associated with increased insulin resistance and cardiovascular risk compared with metformin monotherapy.

Clinical trial registration number: UMIN 000001110.     

Reductions in biomarkers of cardiovascular risk in type 2 diabetes with rosiglitazone added to metformin compared with dose escalation of metformin: an EMPIRE trial sub-study*

ABSTRACT

Objective: To compare the effects of rosiglitazone added to metformin with dose escalation of metformin on cardiovascular risk biomarkers in type 2 diabetes mellitus.

Research design and methods: Cardiovascular biomarkers were assessed in a sub-population of 122 subjects with type 2 diabetes mellitus (mean age 54.6 and 56.0 years, BMI 34.7 and 32.1?kg/m² for the rosiglitazone plus metformin and metformin groups, respectively) from the multicenter (63 centers in the USA), double-blind, randomized parallel-group Escalation of Metformin theraPy vs. Initiation of Rosiglitazone Early (EMPIRE) study. Treatment group sizes were slightly imbalanced owing to central, rather than local, randomization. Subjects receiving metformin 1000?mg/day at baseline were randomized to rosiglitazone 4?mg/day plus metformin 1000?mg/day (RSG + MET) or metformin 1500?mg/day (up-titrated MET) for 24 weeks. At 8‐weeks, rosiglitazone was increased to 8?mg/day in RSG + MET recipients and metformin to 2000?mg/day in up-titrated MET recipients.

Results: Reductions from baseline in HbA_1c at week 24 (mean ± SD) occurred in both groups (RSG + MET: –0.61% ± 1.16%; up-titrated MET: –0.65% ± 1.18%). Post-prandial glucose levels (AUC_0–3h) decreased with RSG + MET (–3.5?mmol/L.h; 95% confidence interval [CI]: –5.2 to –1.8) and up-titrated MET (–1.3?mmol/L.h; 95% CI: –3.8 to 1.1). Homeostasis Model Assessment (HOMA)-estimated insulin sensitivity increased by 37.7% (95% CI: 22.8 to 54.5) in RSG + MET and 6.9% (95% CI: –6.2 to 21.9) in up-titrated MET recipients. RSG + MET reduced C‐reactive protein (CRP; –23.9%; 95% CI: –40.4 to –2.8), plasminogen activator inhibitor‐1 (PAI‐1) activity (–30.1%; 95% CI: –44.5 to –11.9), PAI‐1 antigen (–15.5%; 95% CI: –28.3 to –0.3) and matrix metalloproteinase‐9 (MMP‐9; –13.8%; 95% CI: –25.1 to –0.9), but increased tumor necrosis factor‐α (TNF‐α; 27.0%; 95% CI: 6.8 to 50.9). Corresponding values for up-titrated MET were CRP –9.3% (95% CI: –36.9 to 30.2), PAI‐1 activity –7.2% (95% CI: –28.2 to 20.0), PAI‐1 antigen –1.5% (95% CI: –17.4 to 17.5), MMP‐9 29.0% (95% CI: –1.3 to 68.6) and TNF‐α –6.0% (95% CI: –22.0 to 13.2).

Conclusions: These results suggest that rosiglitazone plus metformin has positive cardiovascular effects against a background of similar glycemic improvements.