Metformin Initiation Research Articles

Genetic risk factors for type 2 diabetes mellitus and response to sulfonylurea treatment

BackgroundFollowing the identification of alleles that increase the risk of type 2 diabetes mellitus (T2DM), models have been developed to identify high-risk subjects. The authors hypothesise that these risk alleles...

Quantifying the Impact of Drug Exposure Misclassification due to Restrictive Drug Coverage in Administrative Databases: A Simulation Cohort Study

ObjectiveDrug exposure misclassification may occur in administrative databases when individuals obtain nonreimbursed drugs by paying “out-of-pocket” or via alternative drug coverage plans. We examined the apparent association between oral antidiabetic therapy and mortality by simulating the effects of restrictive drug coverage policies. MethodsPopulation-based cohort study of 12,272 new patients using oral antidiabetic agents were identified using the administrative databases of Saskatchewan Health, 1991 to 1996. We randomly misclassified 0% [base case], 10%, 25%, and 50% of known patients taking metformin according to either overt drug exposure (e.g., metformin users switched to nonusers) or time of metformin initiation (e.g., delayed capture of exposure); thereby simulating the use of a “non-formulary” or “special authorization” policy, respectively. We also simulated an age-dependent coverage policy, mimicking a policy restricted to seniors. ResultsMetformin use was associated with lower mortality compared with sulfonylurea use in the base case (adjusted hazard ratio [aHR] 0.88, 95% confidence interval [CI] 0.78–0.99) and the nonformulary simulations. The special authorization simulations demonstrated, however, an increasing relative mortality hazard of metformin versus sulfonylurea exposure: aHR 0.96, 95% CI 0.96–0.97 and aHR 1.34, 95% CI 1.31–1.37, for 10% and 50% delays in coverage capture respectively when 50% of metformin users were misclassified. Age-dependent drug coverage had a variable impact on mortality risk compared with the base-case cohort; however, a new-user simulation with a 1-year washout revealed consistent results to the base-case analysis. ConclusionRestrictive drug coverage policies may result in substantial drug exposure misclassification, potentially severely biasing the results of drug-outcome relationships using administrative databases.

Metformin restores the correlation between serum-oxidized LDL and leptin levels in type 2 diabetic patients

IntroductionLeptin has lipid peroxidation properties in healthy individuals. Here we aimed to study the correlation between serum-oxidized low-density lipoprotein (ox-LDL) and leptin levels in patients with type 2 diabetes. We also studied the effect of metformin therapy on the correlation between serum ox-LDL and leptin levels in patients with newly diagnosed diabetes.MethodsWe performed a cross-sectional study on two groups of patients with type 2 diabetes stratified according to (1) patients with newly diagnosed diabetes and (2) patients with long-standing diabetes plus healthy controls. Patients with newly diagnosed diabetes were followed for 3 months after the initiation of metformin therapy.ResultsPatients with type 2 diabetes had a higher serum ox-LDL, ox-LDL/LDL ratio, waist circumference, fasting blood sugars (FBSs), hemoglobin A1C (HbA1C), triglyceride, homeostatic model assessment of insulin resistance (HOMA-IR) and a lower serum leptin levels than controls. Serum ox-LDL, ox-LDL/LDL ratio (0.08 (0.08–0.12) vs. 0.06 (0.05–0.08), P < 0.001) and HOMA-IR (3.26 ± 0.23 vs. 2.93 ± 0.32; P < 0.01) were decreased when serum leptin levels (15.9 ± 1.6 vs. 21.4 ± 2.5, P < 0.01) were increased after 3 months of metformin therapy. This remained significant after multiple adjustments for age, body mass index, FBS, HbA1c, and HOMA-IR. Leptin was significantly correlated with ox-LDL/LDL ratio in controls (r = 0.78, P < 0.01), and in patients with newly diagnosed diabetes (r = 0.4, P < 0.05), after metformin therapy. There were not any correlation between leptin and ox-LDL/LDL ratio in patients with long-standing diabetes and patients with newly diagnosed diabetes before treatment.DiscussionMetformin restores the positive correlation between serum ox-LDL and leptin levels in patients with type 2 diabetes.

Effect of concomitant statin, metformin, or aspirin on rituximab treatment for diffuse large B-cell lymphoma

Several pre-clinical studies report that statins interfere with the surface binding of rituximab to CD20. This study investigated the effects of statins in patients with diffuse large B-cell lymphoma (DLBCL) receiving rituximab-based chemoimmunotherapy, and the impact of commonly used drugs, metformin and aspirin, on the clinical outcomes of patients receiving chemoimmunotherapy. We included 213 patients with DLBCL who received rituximab-based chemoimmunotherapy. Details of statin, metformin, and aspirin use and initiation of chemoimmunotherapy were abstracted from medical records. All patients received rituximab, and 47 (22.1%) were taking statins. The median age of patients receiving statins was significantly higher compared to those who did not (p <0.001). Response rates between patients receiving and not receiving statins were not significantly different (85.1% vs. 87.3%; p = 0.688). Event-free survival (EFS) was not significantly different (p = 0.352). Overall survival was lower in patients receiving statins compared to those who did not (p = 0.036). However, it was no longer significant after adjustment for age (p = 0.140). Metformin had no impact on the response rate (p = 0.268), EFS (p = 0.574), and overall survival (p = 0.141). Aspirin had no impact on the response rate (p = 0.784), EFS (p = 0.836), and overall survival (p = 0.779). Statins do not interfere with rituximab, and need not be withheld during rituximab administration. Larger studies are needed to confirm the impact of metformin and aspirin on patients with DLBCL receiving chemoimmunotherapy.

PS1-10: Response to Metformin and Genetic Variants of Organic Cation and Multidrug and Toxin Extrusion Transporters

Background and Aims: Metformin is the most widely-used anti-diabetic drug in the United States. However, medication management fails to achieve therapeutic goals in ~20% of patients. This study attempted to identify genetic polymorphisms associated with metformin treatment failure. We studied the associations between polymorphisms in two liver and kidney organic cation transporter genes (OCT1 & OCT2) and two kidney multidrug and toxin extrusion transporter genes, (MATE1 & MATE2K) and response to metformin monotherapy. Methods: At Kaiser Permanente Southeast and Marshfield Clinic Research Foundation we identified 304 type 2 diabetes (T2DM) patients on metformin monotherapy who: were enrolled for >=6 months prior to initiation; remained on metformin >= 90 days following initiation; and had a HgbA1c measured prior to first metformin prescription and then after initiation. From this group we selected 171 patients who had not received metformin or other anti-diabetics previously, and had baseline HbA1c levels >7.0% prior to metformin initiation. We genotyped 10 SNPs, and assessed response by measuring absolute and relative change in HbA1c after after metformin initiation. Results: Three SNPs were identified that were significantly associated with reduced response to metformin, after adjustment for baseline HbA1c, dose, and ethnicity. In a dominant model, heterozygosity or homozygosity for minor A allele in the MATE1 intronic SNP, rs2289669, resulted in a smaller absolute change in HbA1c (mean of 0.45% less reduction in absolute change in HbA1c; 95% CI 0.17 to 0.74%) compared to individuals homozygous for major G allele. In a recessive model, homozygosity for minor A allele in MATE2K 5′-UTR SNP, rs12943590, resulted in smaller absolute change in HbA1c (mean of 0.43% less reduction in absolute change in HbA1c, 95% CI 0.053 to 0.86%). The reduced function SNPs in OCT1 & OCT2 were not associated with metformin response, except for rs34059508 (G465R). This SNP showed a positive (but not statistically significant) association with smaller absolute change in HbA1c (mean of 0.49%; 95% CI −0.06354 to 1.045%). Conclusions: These three variants of metformin transporter genes may be important for personalizing treatment for patients with T2DM. A replication study in a larger population is currently being planned.

Guideline‐conformity of initiation with oral hypoglycemic treatment for patients with newly therapy‐dependent type 2 diabetes mellitus in Austria

To determine guideline conformity of initiation of oral hypoglycemic (OH) treatment for type 2 diabetes in Austria; to study patient and prescriber correlates of recommended initiation with metformin monotherapy. We used claims from 11 sickness funds that covered 7.5 million individuals, representing >90% of the Austrian population. First-time OH use was defined as a first filled prescription after one year without any OH drug or insulin. Among these incident users, we described the OH drug class used and defined correlates of initiation with metformin monotherapy. From 1/2007 to 6/2008, we identified 42,882 incident users of an OH drug: 70.8% used metformin, 24.7% used a sulfonylurea, and 4.5% initiated treatment with another class. We estimated the incidence of OH-dependent type 2 diabetes at 3.8-4.4 per 1000 patient-years. We conducted multivariate analyses among 39 077 patients with available prescriber information. Independent correlates of initiation with metformin were younger age, female gender, waived co-payment, more recent initiation, fewer hospital days and more therapeutic classes received in the year prior to first OH therapy (all p < 0.001). Prescriber specialty and age (p < 0.001), but not gender, were also associated with metformin initiation. Approximately 20% of metformin initiators had a second OH drug added within <18 months. While we were unable to ascertain specific contraindications to metformin (renal insufficiency, hepatic failure), <10% of the general population are expected to have these conditions. Seventy per cent of new initiators of OH treatment in Austria received metformin as recommended by international guidelines. At least 20% did not, taking into account possible contraindications, which provides an opportunity for intervention.

The effect of incident antidiabetic regimens on lipid profiles in veterans with type 2 diabetes: a retrospective cohort.

Effects of oral antidiabetic drugs (OADs) on lipids may influence cardiovascular outcomes. Our aim was to compare time to initiation of lipid lowering medication (LLM) and 12-month lipid profiles among new OAD users. We identified a retrospective cohort of 17,774 veterans who received care at Veterans Administration (VA) Mid-South Network with a first OAD from 1 January 2000 to 31 December 2007. There were 6917 patients (38.9%) not on a LLM at baseline, and 3871 (56%) had complete covariates. Incident users of sulfonylurea and combination metformin + sulfonylurea were compared to metformin users for time to LLM initiation. Incident users of these OADs and thiazolidendiones were included in comparison of 12-month low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TGs), and total cholesterol. All analyses adjusted for demographics, lipids, HbA1C, healthcare utilization, and cardiovascular disease at baseline. The median time to starting LLM was 2.35 years (interquartile range 0.96, 4.6) following metformin initiation and not statistically different for users of sulfonylureas, or combination OADs. Compared to metformin users, 12-month HDL was 1.35 mg/dl (95%CI: -2.01, -0.72) lower and TGs were 5.7% higher (95%CI: 1.5%, 10.0%) for sulfonylurea users; TGs were 24.8% (95%CI: 0.7%, 54.5%) higher for thiazolidinedione users. Statin users had LDL and total cholesterol 16.7 mg/dl (95%CI: -19.9, -13.5) and 18.6 mg/dl (95%CI: -22.1, -15.1) lower than non-statin users, respectively. Time to LLM initiation was similar between OADs. Metformin use resulted in more favorable lipids at 12 months compared to sulfonylureas or thiazolidinediones.

Hepatotoxicity Associated with Metformin Therapy in Treatment of Type 2 Diabetes Mellitus with Nonalcoholic Fatty Liver Disease

To report a case of idiosyncratic hepatotoxicity associated with metformin in the treatment of type 2 diabetes with nonalcoholic fatty liver disease (NAFLD). A 61-year-old obese man presented with jaundice, nausea, fatigue, and an unintentional weight loss 2 weeks following initiation of metformin. Laboratory findings revealed aminotransferase values 10-15 times the upper limit of normal. Potential causative agents, including metformin, simvastatin, and Niaspan (extended-release niacin), were discontinued. Two months later, the patient's signs and symptoms had resolved and aminotransferase values returned to normal. An objective causality assessment revealed that the adverse reaction was probably associated with metformin. Since numerous medications and disease states can cause abnormalities in liver enzymes, it is important for providers to be able to distinguish the cause(s) and take appropriate actions. This can take a great deal of time and effort in patients with multiple medications and comorbidities. In this patient's case, viral hepatitis, worsening NAFLD, and the concomitant drugs were highly suspected. As hydroxymethylglutaryl coenzyme A reductase inhibitors offer substantial cardiovascular benefits and as metformin is a first-line agent in helping to lower blood glucose concentrations and to normalize the metabolic profile in type 2 diabetes, reintroduction of metformin and simvastatin would likely be beneficial. This is a case report of metformin-induced hepatotoxicity. As the prevalence of type 2 diabetes and subsequent metabolic effects increases in the US, metformin use will likewise increase. As potential for increased idiosyncratic hepatotoxicity associated with metformin use is likely to occur, clinicians should be vigilant.

Adjuvant Metformin Worsens Psychosis in Schizophrenia

To the Editor: Metformin has been reported to be a useful add-on medication in reversing metabolic complications due to antipsychotic treatment in schizophrenia patients.1 However, treatment with metformin can reduce the levels of insulin-like growth factor-1 (IGF-1).2 Since IGF-1 deficiency might be associated with the pathogenesis of schizophrenia,3,4 it is possible that metformin treatment might result in worsening of psychosis.5 In this letter, we provide the first report of a patient with schizophrenia whose psychosis worsened after adjuvant treatment with metformin. Case report. Ms A, a 20-year-old woman with a diagnosis of schizophrenia (ICD-10), had experienced onset of symptoms in November 2007. She was treated with risperidone (4 mg/d) and trihexyphenidyl (2 mg/d). She had near total improvement in her symptoms in March 2008 and started attending her college regularly. Over a period of 5 months, she gained 12 kg. She had developed menstrual disturbances, acne, and hirsutism; her serum prolactin level was elevated (141.5 ng/mL); and ultrasonogram revealed polycystic changes in the ovary. In view of these side effects, her risperidone dose was reduced to 3 mg/d in April 2008, and regular physical exercises were advised. Over the next 1-month period, Ms A maintained clinical improvement but was distressed about her weight gain. Hence, in May 2008, metformin 250 mg/d was added to her treatment. After 2 days, she started experiencing features suggestive of thought broadcast. Metformin treatment was stopped, and her risperidone dose was increased to 3.5 mg/d. Thought broadcast symptoms resolved completely. After 1 week, on repeated request by the patient as well as her family members, metformin was restarted at 250 mg/d and increased to 500 mg/d after a few days, as there was no initial worsening of psychosis. However, after 2 days of treatment with metformin 500 mg, thought broadcast symptoms reemerged, and metformin treatment was stopped. By the next day, these symptoms resolved completely. Over the 6-month follow-up period (ie, up to December 2008), the patient maintained the clinical improvement with optimal functioning. To the best of our knowledge, this is the first report of adjuvant metformin worsening psychotic symptoms in schizophrenia. Although one might argue that the worsening of symptoms could be a part of the illness course, the following factors make this explanation unlikely: (1) on both occasions, the symptoms were time-locked to either metformin initiation or dosage increase in metformin; (2) the symptoms disappeared completely after metformin treatment was stopped—importantly, during the second time, even with no increase in antipsychotic dosage; and (3) after metformin treatment was stopped, no further psychotic symptoms were observed over the follow-up period of 6 months. Metformin can decrease IGF-1 level.2 Recently, antipsychotic-naive schizophrenia patients were demonstrated to have deficient IGF-1 levels, lower than those of healthy controls.4 Moreover, in that study, the lower the IGF-1 levels, the more severe were the positive symptoms.4 Although metformin-induced IGF-1 reduction might have played a role in the worsening of psychotic symptoms in this patient, confirmation of this is needed by concurrent assessment of serum IGF-1 in further studies.

Effectiveness of Medications Used to Attenuate Antipsychotic-Related Weight Gain and Metabolic Abnormalities: A Systematic Review and Meta-Analysis

Antipsychotic-related weight gain and metabolic effects are a critical outcome for patients requiring these medications. A literature search using MEDLINE, Web of Science, PsycNET, and EMBASE for randomized, open and double-blind, placebo-controlled trials of medications targeting antipsychotic-induced weight gain was performed. Primary outcome measures were change and endpoint values in body weight and body mass index (BMI). Secondary outcomes included >or=7% weight gain, all-cause discontinuation, change in waist circumference, glucose and lipid metabolism parameters, and psychiatric symptoms. Sensitivity analyses were conducted to explain heterogeneity of the results. Across 32 studies including 1482 subjects, 15 different medications were tested: amantadine, dextroamphetamine, d-fenfluramine, famotidine, fluoxetine, fluvoxamine, metformin, nizatidine, orlistat, phenylpropanolamine, reboxetine, rosiglitazone, sibutramine, topiramate, and metformin+sibutramine. Compared with placebo, metformin had the greatest weight loss (N=7, n=334, -2.94 kg (confidence interval (CI:-4.89,-0.99)), followed by d-fenfluramine (N=1, n=16, -2.60 kg (CI:-5.14,-0.06)), sibutramine (N=2, n=55, -2.56 kg (CI:-3.91,-1.22)), topiramate (N=2, n=133, -2.52 kg (CI:-4.87,-0.16)), and reboxetine (N=2, n=79, -1.90 kg (CI:-3.07,-0.72)). Weight loss remained significant with metformin initiation after weight gain had occurred, but not when started concomitantly with antipsychotics. Nausea rates were not higher with any treatment compared with placebo. In all, 5 of 15 psychopharmacologic interventions aimed at ameliorating antipsychotic-induced weight gain outperformed placebo. Results were most robust for metformin, although these were modest and heterogeneous. Only one (negative) combination treatment study was available and head-to-head studies are absent. None of the agents were able to entirely reverse weight gain because of antipsychotics. At present, no treatment has sufficient evidence to recommend broad clinical usage. Antipsychotics with no or minimal cardiometabolic liability, as well as interventions that prevent or normalize adverse antipsychotic cardiometabolic effects are needed.

Long-term effect of metformin on blood glucose control in non-obese patients with type 2 diabetes mellitus

BackgroundWe aimed to investigate the long-term effect of metformin on the blood glucose control in non-obese patients with type 2 diabetes mellitus.MethodsA retrospective study was performed in 213 patients with type 2 diabetes mellitus under the administration of metformin for more than one year. The clinical parameters were investigated for 3 years. The obese and non-obese individuals were defined as a body mass index (BMI) of 25 kg/m2 or over (n = 105) and a BMI of less than 25 kg/m2 (n = 108), respectively.ResultsHbA1c levels were significantly decreased compared with those at the baseline time. The course of HbA1c was similar between the non-obese and the obese groups, while the dose of metformin required to control blood glucose was significantly lower in the non-obese group than in the obese group. The reductions in HbA1c were 1.2% and 1.1% at 12 months, 0.9% and 0.9% at 24 months, and 0.8% and 1.0% at 36 months in the non-obese and obese groups, respectively. BMI did not change during the observation periods. Approximately half of all patients required no additional antidiabetic agents or a reduction in other treatments after the initiation of metformin in either of the two groups.ConclusionsThe present study demonstrated the long-term beneficial effect of metformin in non-obese (BMI < 25 kg/m2) diabetic patients. This effect appears to be maintained even after the observation period of this study, because metformin was limited to a relatively low dose in the non-obese group and the observed worsening in glycemic control over time can probably be attenuated by increasing the dose of metformin.

Secondary Failure of Metformin Monotherapy in Clinical Practice

OBJECTIVEWe sought to document the secondary failure rate of metformin monotherapy in a clinical practice setting and to explore factors that predict therapeutic failure.RESEARCH DESIGN AND METHODSWe studied 1,799 type 2 diabetic patients who, between 2004 and 2006, lowered their A1C to <7% after initiating metformin monotherapy as their first-ever anti-hyperglycemic drug. We examined all A1C values recorded through 31 December 2008 (2–5 years of follow-up), defining secondary failure as a subsequent A1C ≥7.5% or the addition or substitution of another anti-hyperglycemic agent. We used logistic regression to identify factors associated with the probability of secondary failure.RESULTSOf the 1,799 patients studied, 42% (n = 748) experienced secondary failure; the mean failure rate was 17% per year. However, patients who initiated metformin within 3 months of diabetes diagnosis failed at an age-and A1C-adjusted rate of 12.2% (10.5–14.4%) per year, and patients who initiated while A1C was <7% failed at an adjusted rate of 12.3% per year. An interaction term between duration of diagnosed diabetes and A1C was not significant. Age, duration, and A1C at initiation were the only factors that predicted secondary failure.CONCLUSIONSAlthough metformin failure may occur more rapidly in clinical practice than in clinical trails, initiating it soon after diabetes diagnosis and while A1C is low might preserve β-cell function, prolong the effectiveness of metformin, reduce lifetime glycemic burden, and prevent diabetes complications. Our findings support the current treatment algorithm for hyperglycemia management that recommends metformin initiation when diabetes is first diagnosed.

Effects of Initiating Insulin and Metformin on Glycemic Control and Inflammatory Biomarkers Among Patients With Type 2 Diabetes

As diabetes is in part an inflammatory condition, the initiation of insulin and/or metformin may beneficially reduce levels of inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP). To determine whether insulin alone or combined with metformin lowers levels of hsCRP, IL-6, and soluble tumor necrosis factor receptor 2 (sTNFr2) in patients with recent-onset type 2 diabetes mellitus. Randomized 2 x 2 factorial trial of open-label insulin glargine and placebo-controlled metformin in 500 adults with type 2 diabetes (median time from diagnosis, 2.0 years), suboptimal glycemic control, and elevated hsCRP levels. Patients were recruited from US office-based practices between October 2006 and December 2008. Random allocation to 1 of 4 treatments (placebo metformin only, placebo metformin and insulin glargine, active metformin only, or active metformin and insulin glargine) with dose titration targeting fasting blood glucose less than 110 mg/dL. Change in hsCRP level (primary end point) and change in IL-6 and sTNFr2 levels (secondary end points) from baseline to 14 weeks. Levels of glucose and glycated hemoglobin (HbA(1c)) were significantly reduced with active treatment vs placebo (all P values <.001). Levels of hsCRP were reduced in all 4 groups. There was no significant difference in hsCRP reduction among those allocated to insulin (-11.8%; 95% CI, -18.7% to -4.4%) or to no insulin (-17.5%; 95% CI, -23.9% to -10.5%) (P for difference = .25), or among those allocated to active metformin (-18.1%; 95% CI, -24.4% to -11.1%) or placebo metformin (-11.2%; 95% CI, -18.1% to -3.7%) (P for difference = .17). In the individual treatment groups, despite a differential impact on glucose control, reductions in hsCRP in the metformin (-16.1%; 95% CI, -25.1% to -6.1%) and metformin plus insulin (-20.1%; 95% CI, -28.8% to -10.4%) groups were no different than reductions with placebo alone (-19.0%; 95% CI, -27.8% to -9.1%; P = .67 and .87 vs placebo, respectively). By contrast, hsCRP reduction was attenuated with insulin alone (-2.9%, 95% CI, -13.2% to 8.6%; P = .03 vs placebo). Similar findings were noted for levels of IL-6 and sTNFr2. In patients with recent-onset type 2 diabetes, treatment with insulin or metformin compared with placebo did not reduce inflammatory biomarker levels despite improving glucose control. clinicaltrials.gov Identifier: NCT00366301.

Safety and Efficacy of Pioglitazone/Metformin Combination Therapy in Treatment of Type 2 Diabetes: A Rationale for Earlier Use

Although multiple new agents for the management of diabetes have become available in the past decade, less than 50% of diabetics in the United States have Hgb A-1-C levels below 7.0% and far fewer at the newer more stringent targets of 6.0% to 6.5%. It has become increasingly clear that the course of Type 2 diabetes is marked by progressive loss of beta-cell function in the setting of relatively fixed insulin resistance. However, treatment algorithms are based on initial monotherapy, usually with metformin, and only move to combination or add-on therapy when treatment has failed and disease has progressed. Few therapeutic agents address both insulin resistance and beta cell function, and no monotherapeutic agent fully addresses any physiologic defect. Metformin, a well-established therapy for diabetes is effective in reducing hepatic and to a lesser extent muscle insulin resistance primarily through AMP-kinase activation, but has only modest effects on long-term beta-cell function. Pioglitazone, an agent in the thiazolidinedione (TZD) class has mechanistically distinct effects on hepatic, muscle and adipocyte insulin resistance, primarily through PPAR-gamma activation, as well as having somewhat greater effects on beta-cell function and durability of glycemic control. The combination of the two agents, either as initial therapy, or as very rapid add-on therapy for the patient who does not achieve target glycemia soon after initiation of metformin is a mechanistically favorable and useful approach to early and durable glycemic control of many new-onset diabetic patients. The efficacy of both metformin and pioglitazone as monotherapy has been well-documented in numerous studies, and combination studies have demonstrated superiority in efficacy of combination therapy over monotherapy with either agent as well as superiority in durability of response over non-TZD based combinations such as sulfonylurea/metformin. Safety issues with metformin remain primarily tolerability based on GI side effects with the rare risk of lactic acidosis in patients with declining renal function. The safety of the TZD class, while well-documented, does carry the risks of volume expansion and resultant CHF, as well as weight gain, which while troublesome, uniquely does not impair glycemic control in these patients. A more recent concern has been raised regarding fracture risk and decreased bone density, and although the relative impact appears small it remains relevant. These risks may be somewhat balanced by more recent studies suggesting a favorable effect of pioglitazone on multiple metabolic risk factors for CVD such as lipids, C-reactive protein, and adipocytokines such as adiponectin. Recent mechanistic and outcome studies such as PROACTIVE and PERISCOPE which suggest there may also be modest benefit on plaque progression and CVD outcomes. Metformin has beneficial effects on metabolic CVD risk factors, such as triglycerides, insulin and PAI-1 and there is a persistent signal of favorable CV outcomes in metformin treated patients. This review will address the safety and efficacy of the agents as monotherapy as well as in combination, and explain the physiologic rationale for earlier or initial use of pioglitazone/metformin combination therapy for newly diagnosed diabetes as well as the long term potential benefit for ongoing management of the treated diabetic.

Evaluation of Adverse Events of Oral Antihyperglycaemic Monotherapy Experienced by a Geriatric Population in a Real-World Setting

To evaluate and compare the risk of adverse events (AEs) associated with the use of metformin, sulfonylureas and thiazolidinediones among geriatric patients in a usual care setting. An electronic medical record database was utilized to identify geriatric patients with type 2 diabetes mellitus aged > or =65 years from 1996 to 2005. Patients naive to oral antihyperglycemic drug (OAD) therapy were followed for 395 days post initiation of metformin, sulfonylurea or thiazolidinedione treatment. AEs related to study drugs were evaluated during the follow-up period, and the risks of developing an AE were evaluated and adjusted for differences in baseline characteristics by OAD treatment. A total of 5438 patients (mean age 73.2 [SD 5.08] years, 56.1% female) were identified. During the follow-up period, 12.5% of patients experienced an AE (8.3% of metformin, 13.9% of sulfonylurea and 19.8% of thiazolidinedione recipients). Sulfonylurea (odds ratio [OR] 1.74; 95% CI 1.41, 2.13) and thiazolidinedione (OR 2.86; 95% CI 2.23, 3.65) recipients were more likely to experience an AE than metformin recipients, after adjustment for baseline demographic and co-morbidity differences. The average time to onset of a metformin AE (175 days) was less than that for sulfonylurea or thiazolidinedione treatment (192 and 201 days, respectively). The most common AEs were abdominal pain with metformin (42.3%) and weight gain >4.5 kg for sulfonylureas (63.2%) and thiazolidinediones (68.2%). Hypoglycaemia occurred in 2.6% and 2.2% of sulfonylurea and thiazolidinedione recipients, respectively. Geriatric patients in a real-world setting experienced AEs with metformin, sulfonylurea and thiazolidinedione therapy, although rates differed from those seen in clinical trials, particularly for weight gain and hypoglycaemia. Lactic acidosis occurred at a higher rate with metformin therapy than has been reported in clinical trials, but our results were in the same range for abdominal pain and lower for diarrhoea, nausea/vomiting and dyspepsia. AEs related to sulfonylurea therapy were in the same range as in clinical trials for weight gain but lower for hypoglycaemia, dizziness and headaches. AEs related to thiazolidinedione therapy were more common in our study than in clinical trials, and within the same range for weight gain and elevated liver enzymes but lower for hypoglycaemia and oedema. While AE reporting is likely to be different in a real-world setting than in clinical trials, the observed variances may also be due to the aetiology of diabetes and the physiological response to hypoglycaemia in an older population.

Metformin reduces thyrotropin levels in obese, diabetic women with primary hypothyroidism on thyroxine replacement therapy

Context It has been reported that metformin might modify thyroid hormone economy. In two retrospective studies, initiation of treatment with metformin caused suppression of TSH to subnormal levels. Objective To prospectively evaluate if administration of metformin to obese, diabetic patients with primary hypothyroidism on stable thyroxine replacement doses modifies TSH levels. Patients and methods Eight obese, diabetic postmenopausal women with primary hypothyroidism participated in the study. They received 1,700 mg of metformin daily for 3 months. Weight, TSH, free T4, and free T3 levels were measured at baseline, 3 months after metformin initiation and 3 months after its withdrawal. Results After 3 months of on metformin, mean TSH was significantly lower than basal TSH (3.11 +/- 0.50 microUI/ml vs. 1.18 +/- 0.36 microUI/ml; P = 0.01). Mean TSH 3 months after metformin withdrawal was 2.21 +/- 0.37 microUI/ml, significantly higher than TSH after metformin (P = 0.05), but not different from basal TSH. Mean fT4 level increased during metformin administration (basal fT4: 1.23 +/- 0.06 ng/dl, fT4 after metformin: 1.32 +/- 0.04 ng/dl; P = ns), and decreased after its withdrawal (fT4 3 months after metformin withdrawal: 1.15 +/- 0.05 ng/dl; vs. 3 months after metformin, P = 0.04; vs. basal; P = ns). Conclusions In obese, diabetic patients with primary hypothyroidism on thyroxine replacement treatment, short-term metformin administration is associated with a significant fall in TSH.

Effect of insulin–metformin combination on hepatic steatosis in patients with type 2 diabetes

Objective Hepatic steatosis occurs in up to 78% of patients with type 2 diabetes. Studies evaluating the effect of metformin on hepatic steatosis are conflicting. Insulin is believed to be detrimental due to its lipogenic effect. Since insulin–metformin combination is commonly used for the treatment of diabetes, it is important to assess the effect of this combined therapy on hepatic steatosis. We evaluated the change in hepatic steatosis following the initiation of insulin and metformin in patients with type 2 diabetes. Methods Newly diagnosed treatment-naïve patients with type 2 diabetes had their hepatic triglyceride (TG) content measured by magnetic resonance spectroscopy at baseline and after 3 months of treatment with BiAsp 30 insulin, in combination with metformin. Insulin was administered twice daily and titrated to achieve normal capillary blood glucose levels. Metformin was titrated during the first month from 500 mg daily to 1000 mg bid. Results The average hepatic TG content in 19 enrolled subjects was 11.83±7.61% (range, 0.93–23.16%) and correlated with body mass index ( r=.567). Three months of treatment reduced hepatic steatosis by 45%, with 75% of the study subjects achieving a normal level. The change in hepatic TG content was partially explained by changes in HbA1c ( P=.006) and cholesterol ( P=.003) levels. Conclusions The combined treatment with insulin and metformin significantly reduced hepatic steatosis in patients with newly diagnosed type 2 diabetes.

Effect of Metformin and Rosiglitazone in a Prepubertal Boy with Alström Syndrome

Alström syndrome (AS) is an autosomal recessive disorder characterized by progressive pigmentary retinopathy, sensorineural hearing loss, fatty liver infiltration, obesity, insulin resistance and early-onset type 2 diabetes mellitus (DM2). Early onset of insulin resistance and DM2 are key components of this syndrome. To study the effect of early initiation of the insulin sensitizer metformin combined with rosiglitazone in a patient with AS with impaired glucose tolerance. An 8 year-old boy with AS presented with acanthosis nigricans and insulin resistance at the age of 6 years. He had progressive excessive weight gain from 9 months of age. By the age of 1 year he developed photosensitivity, blindness and nystagmus. At the age of 5.5 years, his body mass index (BMI) was above the 95th percentile. He developed impaired glucose tolerance at 6 years of age and treatment with metformin was initiated. After 8 months of treatment with metformin he developed DM2. The dose of metformin was increased, and rosiglitazone added. A 2-hour oral glucose tolerance test (OGTT) and a rapid intravenous glucose tolerance test (IVGTT) were performed before treatment was initiated, after treatment with metformin and at the end of 1 year of combination therapy with metformin and rosiglitazone to calculate quantitative insulin sensitivity check index (QUICKI) and acute insulin response (AIR). For mutation analysis, all exons and splice site sequences of the ALMS1 gene were amplified and sequenced. Metformin treatment alone at the stage of impaired glucose tolerance did not prevent progression to DM2. However, metformin at a higher dose and in combination with rosiglitazone resulted in improvement of pancreatic beta-cell function, shown by markedly improved first-phase insulin response to glucose measured by AIR. The patient was found to have two heterozygous nonsense mutations in ALMS1, 8008 C-->T Ter, R2670X, and 11449 C-->T Ter, Q3817X. These alterations cause premature stops and result in a truncated ALMS1 protein. We suggest that early initiation of combined therapy comprising a high dose of metformin plus rosiglitazone may be valuable in managing insulin resistance and DM2 in children with AS.

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

ABSTRACTObjective: 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 HbA1c 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 (AUC0–3h) 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.

Weight changes following the initiation of new anti‐hyperglycaemic therapies

The objective of this study was to quantify 1-year weight gain associated with the initiation of sulphonylurea (SU), metformin, insulin and thiazolidinedione (TZD) therapy in a representative real world population of type 2 diabetic patients. The study population was 9546 members of Kaiser Permanente North-west (KPNW) who initiated an anti-hyperglycaemic drug between 1996 and 2002 and continued use of that drug for at least 12 months without adding other therapies. Change in weight was calculated as the annualized difference between baseline and follow-up weight and was adjusted for demographic and clinical characteristics. We then compared the weight changes observed in patients newly initiating SU, metformin, insulin and TZD therapies. After adjustment for demographic and clinical characteristics that might affect weight change, metformin initiators lost an average of 2.4 kg while all other groups gained weight. SU initiators gained the least (1.8 kg), followed by insulin initiators (3.3 kg) and TZD subjects (5.0 kg). All comparisons were highly statistically significant. In an observational study of 1-year weight changes following the initiation of SUs, metformin, insulin or TZDs, we found similar but somewhat smaller weight changes than those previously reported in clinical trials. Our observed weight changes could not be explained by the many other factors we tested and seemed to apply across the full spectrum of diabetes patients. Our report provides valuable information that will allow the patient and clinician to anticipate, and perhaps address, expected weight changes that accompany the initiation of anti-hyperglycaemic drugs.