Duration Of Metformin Treatment Research Articles

Comparing the effectiveness and cost-effectiveness of sulfonylureas and newer diabetes drugs as second-line therapy for patients with type 2 diabetes

IntroductionWe aimed to compare the effectiveness and cost-effectiveness profiles of glucagon-like peptide-1 receptor agonist (GLP-1-RA), sodium-glucose cotransporter 2 inhibitor (SGLT2i), and dipeptidyl peptidase-4 inhibitor (DPP-4i) compared with sulfonylureas and glinides...

P-665 Timing of metformin treatment in women with polycystic ovarian syndrome and associated pregnancy outcomes: a systematic review and meta-analysis

Abstract Study question Does giving women with polycystic ovarian syndrome (PCOS) preconception metformin and continuing it through at least the first trimester improve pregnancy outcomes? Summary answer Giving women with PCOS preconception metformin and continuing throughout the first trimester significantly reduces the risk of early miscarriage, and can improve pregnancy outcomes. What is known already Metformin, either alone or in combination with other ovulation induction agents, can improve ovulation and clinical pregnancy rates in women with PCOS. Its impact on miscarriage and live birth rate are less well understood. Furthermore the impact of both the timing and duration of metformin treatment on subsequent pregnancy outcomes, in women with PCOS, is unknown. We sought to evaluate the role that preconception metformin, continued until at least the point of positive pregnancy test, may have on pregnancy outcomes in women with PCOS and the effect that stopping metformin once pregnant might have. Study design, size, duration We conducted a systematic review and meta-analysis. A search within MEDLINE, Embase and the Cochrane Central Register of Controlled Trials for studies listed from database inception to 13th October 2022 was conducted. Potentially eligible studies identified through other sources (such as the reference lists of the selected primary studies and review articles) were also screened for inclusion. We adopted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) for determining the quality of the evidence. Participants/materials, setting, methods The full-text of studies identified as being potentially suitable for inclusion were obtained. Those meeting the study selection criteria, outlined, were included in the systematic review and meta-analysis. Studies were included if they were prospective randomised controlled trials, comparing the use of metformin in women with PCOS, which had been started pre-conceptually and continued at least until pregnant (confirmed urinary pregnancy test), to either placebo or no treatment. Main results and the role of chance A total of 12 studies (1517 women) were included in the systematic review and meta-analysis. Women who were given preconception metformin which was continued until at least the end of the first trimester showed a significantly reduced risk of early miscarriage [OR 0.51 95% CI (0.27-0.96), 6 studies, n = 294, I2=0%], compared to either placebo or no treatment. Continuing preconception metformin until at least the end of first trimester also significantly increased clinical pregnancy rates [OR 1.92 95% CI (1.43-2.59), 5 studies, n = 793, I2=67%]. Only 3 studies, looked at live birth outcome which showed an increased odds of live birth in the metformin group, but this was not statistically significant [OR 1.38 95% CI (0.65-2.92), 3 studies, n = 212, I2=0%]. In women who stopped taking metformin following a positive pregnancy test, there was a suggestion of improvement in clinical pregnancy [OR 1.36 95% CI (0.99-1.87), 6 studies, n = 663, I2=45%] and live birth rates [OR 1.15 95% CI (0.57-2.35), 5 studies, n = 244, I2=0%]; but these were not statistically significant. Conversely, there was an increased odds of early miscarriage [OR 1.22 95% CI (0.59-2.52), 6 studies, n = 244, I2=0%], but this was also not statistically significant. Limitations, reasons for caution Whilst a role for commencing metformin pre-conceptually and continuing until at least the end of the first trimester has been demonstrated to be effective in improving clinical pregnancy rates and reducing miscarriage risk, the effectiveness and safety of continuing it throughout the remainder of the pregnancy remains unclear. Wider implications of the findings Continuing metformin treatment until at least the end of first trimester can increase the clinical pregnancy rate and reduce the risk of miscarriage. Stopping metformin once pregnant could be harmful and increase the risk of miscarriage. These findings should be considered when managing women with PCOS wishing to conceive. Trial registration number CRD42017073976

Vitamin B12 deficiency in long-term metformin treated type 2 diabetic patients: Prevalence and risk factors in a Tunisian population.

Objectives: To determine the prevalence of vitamin B12 deficiency in a Tunisian population with type 2 diabetes (T2D) on metformin treatment for more than three years and to identify its risk factors. Methods: This is a cross-sectional study conducted on 257 patients with T2D treated with metformin for at least three years. Patients were divided into two groups according to their vitamin B12 status. Low vitamin B12 was defined as ≤ 203 pg/mL. Results: The mean age of the patients was 59.8 ± 7.9 years. The mean duration of metformin use was 10.2 ± 5.2 years. The mean vitamin B12 level was 294.9 ± 156.4 pg/mL. The prevalence of vitamin B12 deficiency was 28.4%. Male gender, HbA1c < 7% and hyperhomocysteinemia were significantly associated with vitamin B12 deficiency (respectively p = 0.02, p < 0.001, p < 0.001). Homocysteine level was negatively correlated with vitamin B12 level (r = -0.2, p = 0.001). Dose and duration of metformin treatment, peripheral neuropathy and anemia were not associated with vitamin B12 deficiency. On multivariate analysis, HbA1c < 7% and hyperhomocysteinemia were independently associated with vitamin B12 deficiency (respectively OR = 3.2, 95%CI = [1.6-6.3] and OR = 2.3, 95%CI = [1.2-4.2]). Discussion: The prevalence of vitamin B12 deficiency in patients with T2D on metformin treatment was high. Hyperhomocysteinemia is associated with vitamin B12 deficiency suggesting that the deficit occurs at the tissue level.

VITAMIN B12 DEFICIENCY IN CONTINUOUS METFORMIN TREATMENT

As we know type 2 diabetes is a global disease with many complications. The long-term treatment with metformin as a first line of therapy has been proven to cause low levels of cobalamin /vit. B12/. The main purpose of this analysis is to show the frequency of vitamin B12 deficiency among patients treated with biguanides. The RSNC/regional non-profit association/ “Diabetes Care” in Burgas conducted the study. Patients on metformin treatment for 5 to 10 years were included in it. From January to September 2022 was the period when all the data was collected. Information on the duration of metformin treatment was collected through an anamnesis. All patients were tested for vitamin B12 levels and the average value was found to be &lt; 145 pmol/L - according to certified laboratory reference values - from 145 to 569 pmol/l. All participants in this study had laboratory evidence of anemia and were deficient in this vitamin . Vitamin B12 deficiency is preventable and these data show us the need of regular screening in patients on long-term treatment with metformin. This will allow the identification of patients with vitamin deficiency and the addition of treatment with it or/and discontinuation of metformin treatment.

Plasma Amino Acids Metabolomics' Important in Glucose Management in Type 2 Diabetes.

The perturbation in plasma free amino acid metabolome has been observed previously in diabetes mellitus, and is associated with insulin resistance as well as the onset of cardiovascular disease in this population. In this study, we investigated, for the first time, changes in the amino acid profile in a group of people with and without type 2 diabetes (T2D) with normal BMI, from Jordan, who were only managed on metformin. Twenty one amino acids were evaluated in plasma samples from 124 people with T2D and 67 healthy controls, matched for age, gender and BMI, using amino acids analyser. Total amino acids, essential amino acids, non-essential amino acids and semi-essential amino acids were similar in T2D compared to healthy controls. Plasma concentrations of four essential amino acids were increased in the presence of T2D (Leucine, p < 0.01, Lysine, p < 0.001, Phenylalanine, p < 0.01, Tryptophan, p < 0.05). On the other hand, in relation to non-essential amino acids, Alanine and Serine were reduced in T2D (p < 0.01, p < 0.001, respectively), whereas Aspartate and Glutamate were increased in T2D compared to healthy controls (p < 0.001, p < 0.01, respectively). A semi-essential amino acid, Cystine, was also increased in T2D compared to healthy controls (p < 0.01). Citrulline, a metabolic indicator amino acid, demonstrated lower plasma concentration in T2D compared to healthy controls (p < 0.01). These amino acids were also correlated with fasting blood glucose and HbA1c (p < 0.05). Glutamate, glycine and arginine were correlated with the duration of metformin treatment (p < 0.05). No amino acid was correlated with lipid profiles. Disturbances in the metabolism of these amino acids are closely implicated in the pathogenesis of T2D and associated cardiovascular disease. Therefore, these perturbed amino acids could be explored as therapeutic targets to improve T2D management and prevent associated cardiovascular complications.

Metformin and Gastrointestinal Cancer Development in Newly Diagnosed Type 2 Diabetes: A Population-Based Study in Korea.

INTRODUCTION:Clinical studies have produced conflicting results on the effects of metformin on gastrointestinal cancer development. We aimed to investigate the association between metformin use and stomach, colon, liver, and pancreatic cancer development among patients with newly diagnosed, drug-naïve type 2 diabetes.METHODS:This retrospective study evaluated propensity score-matched patients with newly diagnosed type 2 diabetes from the Korean National Health Insurance Service database. Metformin users were categorized into tertiles according to the cumulative dose or duration of metformin treatment, and the risks of gastrointestinal cancers were compared.RESULTS:Metformin users had reduced risks of developing stomach cancer (hazard ratio [HR]: 0.841, 95% confidence interval [CI]: 0.797–0.887), colon cancer (HR: 0.865, 95% CI: 0.822–0.91), and liver cancer (HR: 0.709, 95% CI: 0.675–0.746; P < 0.001). However, metformin users did not have a reduced overall risk of pancreatic cancer (HR: 1.335, 95% CI: 1.209–1.475; P < 0.001). The risks tended to decrease at higher cumulative doses and durations of metformin use, with significantly reduced risks of all 4 cancers at the highest cumulative dose (≥1,200,000 mg) and the longest duration (≥2,000 days) of metformin use.DISCUSSION:This population-based data suggest that metformin could be associated with reductions in the risks of stomach, colon, and liver cancers, as well a reduced risk of pancreatic cancer in some subgroups. Metformin has benefit as a first-line treatment for type 2 diabetes mellitus. A further role in cancer risk reduction could be studied in controlled trials.

Delayed metformin treatment improves functional recovery following traumatic brain injury via central AMPK-dependent brain tissue repair

Accumulating evidence suggests that chronic metformin posttreatment offers potent neuroreparative effects against acute brain injury. However, in previous studies, metformin was not initially administered beyond 24 h postinjury, and the effects of delayed metformin treatment in traumatic brain injury (TBI) and other types of acute brain injury and the related mechanisms are unclear. To test this, male C57BL/6 mice received once daily metformin treatment (20, 50 or 100 mg/kg/d, i.p.) at day 1–14, day 1–2, day 1–10, day 3–10, day 5–12 or day 5–28 after cryogenic TBI (cTBI). The results showed that 100 mg/kg/d metformin administered at day 1–14 postinjury significantly promoted motor functional recovery in the beam walking and gait tests and reduced the infarct volume. Metformin (100 mg/kg/d) administered at day 1–10 or day 3–10 but not day 1–2 or day 5–12 after cTBI significantly improved motor functional outcomes at day 7 and 14, and reduced the infarct volume at day 14. Interestingly, the therapeutic time window was further expanded when the duration of metformin treatment starting at day 5 postinjury was extended to 2 weeks. Furthermore, compared with cTBI, the administration of metformin at day 3–10 or day 5–28 after cTBI significantly elevated the expression of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) and growth associated protein 43 (an axonal regeneration marker) and the number of vascular branch points and decreased the area of glial scar and the number of amoeboid microglia in the peri-infarct area at day 14 or 28 postinjury. The above beneficial effects of metformin were blocked by the intracerebroventricular injection of the AMPK inhibitor compound C (40 μg/mouse/d). Our data provide the first evidence that metformin has a wide therapeutic time window for at least 5 days after cTBI, during which it can improve functional recovery by promoting tissue repair and inhibiting glial scar formation and microglial activation in a central AMPK-dependent manner.

Metformin: current clinical applications in nondiabetic patients with cancer.

Metformin is one of the most commonly used first-line oral medications for type 2 diabetes mellitus. Multiple observational studies, reviewed in numerous systematic reviews, have shown that metformin treatment may not only reduce the risk of cancer but may also improve the efficacy of cancer treatment in diabetic patients. Recent studies have been conducted to determine whether a similar protective effect can be demonstrated in nondiabetic cancer patients. However, the results are controversial. The potential optimal dose, schedule, and duration of metformin treatment and the heterogeneity of histological subtypes and genotypes among cancer patients might contribute to the different clinical benefits. In addition, as the immune property of metformin was investigated, further studies of the immunomodulatory effect of metformin on cancer cells should also be taken into account to optimize its clinical use. In this review, we present and discuss the latest findings regarding the anticancer potential of metformin in nondiabetic patients with cancer.

Relationship between metformin use and vitaminB12 status in patients with type2 diabetes in Japan.

Aims/IntroductionMetformin therapy has been associated with vitamin B12 (VB12) deficiency, but information regarding this adverse effect in Asian populations is limited. We have now examined the relationship between metformin use and VB12 status in individuals with type 2 diabetes mellitus in Japan.Materials and MethodsThis cross‐sectional study was carried out with type 2 diabetes mellitus patients treated (Met group, n = 122) or not treated (control group, n = 63) with metformin. The primary end‐point was the difference in the serum concentration of homocysteine, a marker of VB12 activity, between the two groups. The serum concentrations of VB12, blood hemoglobin level and mean corpuscular volume were also compared between the groups. Subset analysis was carried out with individuals aged ≥70 years. The potential correlation between the daily dose or duration of metformin treatment and the other measured parameters was also examined.ResultsThe level of homocysteine, as well as the VB12 level, hemoglobin concentration and mean corpuscular volume, did not differ significantly between the control and treated with metformin groups. The level of homocysteine was positively and that of VB12 negatively correlated with the daily dose of metformin. Among elderly individuals, the hemoglobin level was significantly lower in the treated with metformin group than in the control group, although the mean corpuscular volume was similar in the two groups.ConclusionsThe risk of VB12 deficiency during metformin treatment appears to be low in Japanese type 2 diabetes mellitus patients. However, high doses of metformin might result in a moderate decrease in the circulating VB12 level, as well as in anemia in elderly individuals.

Metformin and cognition from the perspectives of sex, age, and disease.

Metformin is the safest and the most widely prescribed first-line therapy for managing hyperglycemia due to different underlying causes, primarily type 2 diabetes mellitus. In addition to its euglycemic properties, metformin has stimulated a wave of clinical trials to investigate benefits on aging-related diseases and longevity. Such an impact on the lifespan extension would undoubtedly expand the therapeutic utility of metformin regardless of glycemic status. However, there is a scarcity of studies evaluating whether metformin has differential cognitive effects across age, sex, glycemic status, metformin dose, and duration of metformin treatment and associated pathological conditions. By scrutinizing the available literature on animal and human studies for metformin and brain function, we expect to shed light on the potential impact of metformin on cognition across age, sex, and pathological conditions. This review aims to provide readers with a broader insight of (a) how metformin differentially affects cognition and (b) why there is a need for more translational and clinical studies examining multifactorial interactions. The outcomes of such comprehensive studies will streamline precision medicine practices, avoiding "fit for all" approach, and optimizing metformin use for longevity benefit irrespective of hyperglycemia.

Association between Metformin and a Lower Risk of Age-Related Macular Degeneration in Patients with Type 2 Diabetes.

Purpose This population-based, retrospective cohort study was to investigate whether metformin is associated with a lower risk of subsequent age-related macular degeneration (AMD) in patients with type 2 diabetes. Methods Using the Taiwan National Health Insurance Research Database from 2001 to 2013, 68205 subjects with type 2 diabetes were enrolled in the study cohort. Among them, 45524 were metformin users and 22681 were nonusers. The metformin and nonmetformin groups were followed until the end of 2013. Cox regression analyses were used to estimate hazard ratios (HRs) for AMD development associated with metformin use. Confounders included for adjustment were age, sex, and comorbidities (hypertension, hyperlipidemia, coronary artery disease, obesity, diabetic retinopathy, chronic kidney disease, and insulin treatment). Furthermore, propensity score (PS) matching method was used to choose the matched sample, and PS-adjusted Cox regression was performed. Finally, how HRs changed according to metformin treatment duration and dose was also evaluated in the metformin group. Results After adjusting for confounders, the metformin group had a significantly lower risk of AMD (adjusted HR = 0.54; 95% confidence interval [CI], 0.50–0.58). In the PS-matched sample, the significance remained (adjusted HR = 0.57; 95% CI, 0.52–0.63). In the metformin group, the adjusted HRs for the second (1.5–4 years) and third (≥4 years) tertiles of metformin treatment duration were 0.52 and 0.14, respectively, compared with the first tertile (<1.5 years). We also found significant trends of lower HRs (all p-value for trend <0.05) with increasing total and average doses. Conclusions Among patients with type 2 diabetes, those who use metformin are at a significantly lower risk of developing AMD relative to individuals who do not use metformin. Also, the trend of a significantly lower AMD risk was found with a higher dose of metformin.

Evaluation of the effects of diabetes mellitus and metformin usage on serum vitamin B12 levels in cobalamin deficient subjects

Abstract: Introduction:Although there are studies evaluating vitamin B12 levels in different patient groups, there is none encountered in Turkish adult patients with or without DM reported in the English literature.The aim of the study was to evaluate the possible additional effects of diabetes and metformin usage on serum levels of vitamin B12 in cobalamin deficient Turkish adult patients. Material and Methods:Medical records of subjects ≥18 years of age, having a vitamin B12 level &amp;lt;180 pg/mL were screened, consecutive 98 subjects were included in the study. Results:Among a total of 75 female and 23 male subjects with a mean age of 51.3±15.9 years and vitamin B12 level of 139.3±29.2 pg/mL, 34 had the diagnosis of type 2 diabetes mellitus and 64 had no diabetes diagnosis. Mean ages were 59.0±10.8 years for diabetics and 47.2±16.8 years for nondiabetics. Vitamin B12 levels were found to be insignificantly low in people with the diagnosis of diabetes compared to without diabetes (131.2±30.6 and 143.5±27.7 pg/mL, respectively, p=0.05). Vitamin B12 levels had no correlation with diabetes duration, presence of complications, metformin usage duration. Conclusions:In conclusion, our results demonstrated that people with diabetes had lower levels of vitamin B12 compared to nondiabetics but this fact could not solely be explained by the duration of disease, accompanying complications, metformin treatment duration. All patients with or without the diagnosis of diabetes should be encouraged for sufficient vitamin B12 intake and all possible factors that lead to deficiency should be eliminated.

Vitamin B12 deficiency in diabetic subjects taking metformin: A cross sectional study in a Lebanese cohort

Metformin is the only biguanide derivative used to treat type 2 diabetes mellitus (T2D). Several studies documented that its use contributes to vitamin B12 deficiency in 10–30% of diabetics. The incidence of deficiency varies among populations and studies reported. There has been no reports documenting this incidence in the Middle East and Lebanon.The objectives of this study were to establish the incidence of vitamin B12 in our population, to investigate and characterize any specific associations between taking metformin and vitamin B12 deficiency to establish clear recommendations based on this data.During the first 6 months of 2015, we conducted a cross sectional study on 200 Lebanese individuals. The cohort consisted of subjects with an established diagnosis of T2D and who have been on metformin for at least three months. The patients were subjected to a questionnaire, medical record review, and vitamin B12 level measurement.Thirty three percent of the subjects were found to have borderline values of the serum vitamin B12 (148–220 pg/dl) while 22.5% had a clear, deficiency (levels less than 148 pg/dl). We found a highly significant inverse correlation between the dose and duration of metformin treatment and the serum levels of vitamin B12. Furthermore, both borderline and low levels of vitamin B12 were associated with the presence of different neuropathies and macrocytic anemia in a dose dependent manner.Based on our results, we strongly recommend the routine screening of subjects with T2D on metformin for vitamin B12 deficiency due to its high prevalence and the significant clinical effects it may result in. Furthermore, we recommend, based on our data, to start treating those subjects once a borderline or low level is detected.

Potential of Metformin to Improve Cardiac Risk in Postpartum Women with Gestational Diabetes.

Pregnancy is associated with an increase in total cholesterol, high density lipoproteins (HDL), and low-density lipoproteins (LDL). Postpartum, HDL and LDL decrease over the first 12 weeks postpartum. Oxidized LDL (ox-LDL) is a marker of oxidative stress-related inflammation, which is associated with obesity and also with development of cardiovascular disease. Cardiovascular protection and weight loss are benefits from metformin, especially in women with diabetes. The objective of this study was to compare changes in lipid profiles and biomarkers for obesity during the initial 6 weeks postpartum between women with gestational diabetes mellitus (GDM) treated with metformin versus placebo. This was a planned ancillary study of a randomized controlled trial compares metformin versus placebo in women with GDM for postpartum weight loss. Two 3 mL blood samples were collected within 24 h of delivery and 6 weeks postpartum immediately processed after collection then stored at -20°C until completion of clinical trial prior to analysis. Change in the median plasma concentrations of total cholesterol, HDL, ox-LDL, glucose, insulin, leptin, and unacylated ghrelin were compared between study groups. Of the 77 postpartum women were included, 35 received metformin and 42 received placebo. There was less of a reduction in HDL in the metformin group compared to placebo (-2.3 versus -7.5 mg/dL, p = 0.019). In addition, there was a greater reduction in ox-LDL in those receiving metformin (-12.2 versus -3.8 mg/dL, p = 0.038). No other differences were observed in the selected biomarkers evaluated. Biomarker levels of HDL and ox-LDL were positively affected during the initial 6 weeks postpartum in GDM women treated with metformin. Additional studies with a longer duration of metformin treatment in the postpartum period are warranted to evaluate long-term potential benefits.

Effect of metformin by employing 2-hour postload insulin for measuring insulin resistance in Taiwanese women with polycystic ovary syndrome.

Evidence on clinical effectiveness of metformin in ethnic Chinese women with polycystic ovary syndrome (PCOS) remains scarce. Standard diagnostic approaches to identify insulin resistance (IR) cases in PCOS patients might be invasive, labor intensive, and stressful for patients (i.e., euglycemic clamp), or somewhat complicated for clinicians to calculate and monitor in routine practice [i.e., the homeostatic model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI)]. The aim of this study was to evaluate the clinical effects of metformin in Taiwanese women with PCOS and identify the feasible diagnostic measures of IR for Taiwanese women with PCOS. A total of 114 women from a medical center in Taiwan were studied. All were aged between 18years and 45years, diagnosed with PCOS according to the Rotterdam criteria, and treated with metformin. Outcome end points were body mass index (BMI) and 2-hour postload glucose and insulin levels from a 75-g oral glucose tolerance test. BMI in overweight patients were significantly improved with metformin treatment duration (p<0.001). The 2-hour insulin level statistically improved after treatment (before: 80.7±63.9μIU/mL vs. after: 65.0±60.4μIU/mL; p=0.009). The improved 2-hour insulin level was significantly greater in IR patients than in non-IR patients. Compared with the 2-hour postload insulin level, the fasting insulin level provided 18.15% sensitivity and 94.12% specificity, the HOMA yielded 40% sensitivity and 70.58% specificity, and the QUICKI achieved 63.63% sensitivity and 11.76% specificity. Clinical outcomes in Taiwanese PCOS women were improved with metformin treatment, especially in overweight and IR patients. The 2-hour postload insulin level appears to be a convenient tool for screening IR in Taiwanese patients.

The effect of metformin on neuronal activity in the appetite-regulating brain regions of mice fed a high-fat diet during an anorectic period

Metformin reduces body weight by decreasing food intake in humans and animals. However, the brain regions involved in metformin-induced anorexia remain unclear. Therefore, we investigated c-Fos expression (FOS), a marker of neuronal activity, in the appetite-regulating brain regions after oral administration of metformin (PO, 300mg/kg daily for 1 or 3days) or vehicle.The body weight and food intake decreased in mice treated with metformin for 3days (RM group) and mice that had the same amount of food as the RM group (Pair-fed group; PF) compared to the control group. FOS expression levels increased in the paraventricular nucleus, area postrema, and central amygdala of mice administered an acute single dose of metformin (SM group) compared to the control mice. In the nucleus tractus solitarius, the FOS expression levels increased in both the SM and RM groups compared to the control group. The FOS expression levels also increased in the nucleus accumbens of the RM group compared to other groups. The FOS expression levels decreased in the ventromedial hypothalamic nucleus in the PF group, but not the RM group, compared to the control group, suggesting a potential hypothalamic area involvement for metformin-induced anorexia.These results suggest that both the hypothalamic and extra-hypothalamic regions are associated with metformin-induced anorexia, which is dependent on metformin treatment duration.

Early glycaemic control in metformin users receiving their first add-on therapy: a population-based study of 4,734 people with type 2 diabetes.

The aims of this work were to assess glycaemic control in metformin users receiving their first add-on glucose-lowering therapy and to examine the real-life effectiveness of different add-on drugs. We carried out a population-based cohort study using healthcare databases in northern Denmark during 2000-2012. We included 4,734 persons who initiated metformin monotherapy and added another glucose-lowering drug within 3 years. Attainment of recommended HbA1c goals within 6 months of add-on was investigated, using Poisson regression analysis adjusted for age, sex, baseline HbA(1c), diabetes duration, complications and Charlson Comorbidity Index. Median metformin treatment duration at intensification was 12 months (interquartile range [IQR] 4-23 months) and pre-intensification HbA(1c) was 8.0% (IQR 7.2-9.2%) (64 [IQR 55-77] mmol/mol). Median HbA(1c) dropped 1.2% (13 mmol/mol) with a sulfonylurea (SU) add-on, 0.8% (9 mmol/mol) with a dipeptidyl peptidase-4 (DPP-4) inhibitor, 1.3% (14 mmol/mol) with a glucagon-like peptide-1 (GLP-1) receptor agonist, 0.9% (10 mmol/mol) with other non-insulin drugs and 2.4% (26 mmol/mol) with insulin. Compared with SU add-on, attainment of HbA(1c) <7% (<53 mmol/mol) was higher with GLP-1 receptor agonists (adjusted RR [aRR] 1.10; 95% CI 1.01, 1.19) and lower with DPP-4 inhibitors (aRR 0.94; 95% CI 0.89, 0.99), other drugs (aRR 0.86; 95% CI 0.77, 0.96) and insulin (aRR 0.88; 95% CI 0.77, 0.99). The proportion of metformin add-on users who attained HbA(1c) <7% (<53 mmol/mol) increased from 46% in 2000-2003 to 59% in 2010-2012, whereas attainment of HbA(1c) <6.5% (<48 mmol/mol) remained 30% among patients aged <65 years without comorbidities. Among early type 2 diabetes patients receiving their first metformin add-on treatment, HbA(1c) reduction with different non-insulin drugs is similar to, and comparable with, that observed in randomised trials, yet 41% do not achieve HbA(1c) <7% (<53 mmol/mol) within 6 months.

Evaluation of endocrine changes in women with the polycystic ovary syndrome during metformin treatment

The aim of study was to evaluate endocrine changes in PCOS women during metformin treatment. One hundred women with PCOS, aged 20-40 years were included. A complete hormonal and metabolic pattern was recorded for each subject every 6 months. Metformin treatment after 6 and 12 months significantly reduced weight, BMI, waist circumference, insulin and HOMA-IR (p=0.000) with high differences of variances within repeated measurements. There was significant reduction of PRL, testosterone and estradiol (p=0.000) with small differences within repeated measurements. Metformin did not have effect on TSH. However, results showed important reduction of CRP, LH, LH/FSH, androstendione, DHEA-S and progesterone (p=0.000) with moderate differences within measures. Metformin restored menstrual cyclicity in most participants. At baseline in study group was 69% women with oligomenorrhoea, amenorrhoea or polymenorrhoea. After 12 months of treatment, only 20% PCOS women had irregular menstrual cycle (p=0.000). Hirsutism was also reduced. Intriguingly, during first 6 months of treatment in PCOS women 9 pregnancies occurred (p=0.000), while during last 6 months treatment were 2 pregnancies (p=0.317), in total 11(13%). Multiple regression model revealed that the presence of anovulation in PCOS women was strongly associated with BMI, waist, FSH and age. Insulin resistance was significantly predicted by BMI, cholesterol, progesterone and presence of hirsutism. The metformin therapy significantly improved insulin resistance, imbalance of endocrine hormones, hirsutism and menstrual cyclicity in women with PCOS. The most important predictors for duration of metformin treatment in PCOS women were testosterone, progesterone, FSH, CRP and presence of anovulation.

Metformin Use and All-Cause and Prostate Cancer–Specific Mortality Among Men With Diabetes

To evaluate the association between cumulative duration of metformin use after prostate cancer (PC) diagnosis and all-cause and PC-specific mortality among patients with diabetes. We used a population-based retrospective cohort design. Data were obtained from several Ontario health care administrative databases. Within a cohort of men older than age 66 years with incident diabetes who subsequently developed PC, we examined the effect of duration of antidiabetic medication exposure after PC diagnosis on all-cause and PC-specific mortality. Crude and adjusted hazard ratios (HRs) were calculated by using a time-varying Cox proportional hazard model to estimate effects. The cohort consisted of 3,837 patients. Median age at diagnosis of PC was 75 years (interquartile range [IQR], 72 to 79 years). During a median follow-up of 4.64 years (IQR, 2.7 to 7.1 years), 1,343 (35%) died, and 291 patients (7.6%) died as a result of PC. Cumulative duration of metformin treatment after PC diagnosis was associated with a significant decreased risk of PC-specific and all-cause mortality in a dose-dependent fashion. Adjusted HR for PC-specific mortality was 0.76 (95% CI, 0.64 to 0.89) for each additional 6 months of metformin use. The association with all-cause mortality was also significant but declined over time from an HR of 0.76 in the first 6 months to 0.93 between 24 and 30 months. There was no relationship between cumulative use of other antidiabetic drugs and either outcome. Increased cumulative duration of metformin exposure after PC diagnosis was associated with decreases in both all-cause and PC-specific mortality among diabetic men.

Metformin use and all-cause and prostate-cancer-specific mortality among diabetic men.

5007 Background: To evaluate the association between cumulative duration of metformin use after prostate cancer diagnosis and all-cause and prostate cancer-specific mortality among diabetic patients. Methods: We used a population-based retrospective cohort design. Data were obtained from several Ontario health care administrative databases. Within a cohort of men over the age of 66 with incident diabetes who subsequently developed prostate cancer, we examined the effect of duration of anti-diabetic medication exposure, after prostate cancer diagnosis, on all-cause and prostate cancer-specific mortality. Crude and adjusted hazard ratios were calculated using a time-varying Cox proportional hazard model to estimate effects. Results: The cohort consisted of 3,837 patients. Median age (interquartile range IQR) at diagnosis of prostate cancer was 75 (72-79) years. During a median (IQR) follow up of 4.64 (2.7-7.1) years, 1,343 (35%) died, and 291 patients died of prostate cancer (7.6%). Cumulative duration of metformin treatment, after prostate cancer diagnosis, was associated with a significant decreased risk of prostate cancer-specific and all-cause mortality in a dose-dependent fashion. The adjusted hazard ratio, for prostate cancer-specific mortality was 0.76 (95% confidence interval, 0.64-0.89) for each additional six months of metformin use. The association with all-cause mortality was also significant but declined over-time from a HR of 0.76 in the first 6 months to 0.93 between 24-30 months. There was no relationship between cumulative use of other anti-diabetic drugs and either outcome. Conclusions: Increased cumulative duration of metformin exposure after prostate cancer diagnosis was associated with decreases in both all-cause and prostate-cancer-specific mortality among diabetic men.