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Concept: Metformin

192

Since the first ADA working group report on the recommendations for management of diabetes during Ramadan in 2005 and our update in 2010, we received many inquiries asking for regular updates on information regarding education, nutritional habits and new oral and injectable agents that may be useful for the management of patients with diabetes during Ramadan. Patients can be stratified into their risk of hypoglycemia and/or complications prior to the start of the fasting period of Ramadan. Those at high risk of hypoglycemia and with multiple diabetic complications should be advised against prolonged fasting. Even in the lower hypoglycemia risk group, adverse effects may still occur. In order to minimize adverse side effects during fasting in patients with diabetes and improve or maintain glucose control, education and discussion of glucose monitoring and treatment regimens should occur several weeks prior to Ramadan. Agents such as metformin, thiazolidinediones and dipeptidyl peptidase-4 inhibitors appear to be safe and do not need dose adjustment. Most sulfonylureas may not be used safely during Ramadan except with extreme caution; besides, older agents, such as chlorpropamide or glyburide, should not be used. Reduction of the dosage of sulfonylurea is needed depending on the degree of control prior to fasting. Misconceptions and local habits should be addressed and dealt with in any educational intervention and therapeutic planning with patients with diabetes. In this regard, efforts are still needed for controlled prospective studies in the field of efficacy and safety of the different interventions during the Ramadan Fast.

Concepts: Therapeutic effect, Nutrition, Diabetes mellitus, Hypoglycemia, Sulfonylurea, Metformin, Adverse drug reaction, Fasting

184

Human embryonic stem cell (hESC)-derived pancreatic progenitor cells effectively reverse hyperglycemia in rodent models of type 1 diabetes, but their capacity to treat type 2 diabetes has not been reported. An immunodeficient model of type 2 diabetes was generated by high-fat diet (HFD) feeding in SCID-beige mice. Exposure to HFDs did not impact the maturation of macroencapsulated pancreatic progenitor cells into glucose-responsive insulin-secreting cells following transplantation, and the cell therapy improved glucose tolerance in HFD-fed transplant recipients after 24 weeks. However, since diet-induced hyperglycemia and obesity were not fully ameliorated by transplantation alone, a second cohort of HFD-fed mice was treated with pancreatic progenitor cells combined with one of three antidiabetic drugs. All combination therapies rapidly improved body weight and co-treatment with either sitagliptin or metformin improved hyperglycemia after only 12 weeks. Therefore, a stem cell-based therapy may be effective for treating type 2 diabetes, particularly in combination with antidiabetic drugs.

Concepts: Insulin, Diabetes mellitus type 2, Diabetes mellitus, Stem cell, Obesity, Embryonic stem cell, Sulfonylurea, Metformin

171

BACKGROUND: Although oral hypoglycemic agents (OHAs) are an essential element of therapy for the management of type 2 diabetes, OHA adherence is often suboptimal. Pharmacists are increasingly being integrated into primary care as part of the move towards a patient-centered medical home and may have a positive influence on medication use. We examined whether the presence of pharmacists in primary care clinics was associated with higher OHA adherence. METHODS: This retrospective cohort study analyzed 280,603 diabetes patients in 196 primary care clinics within the Veterans Affairs healthcare system. Pharmacists presence, number of pharmacist full-time equivalents (FTEs), and the degree to which pharmacy services are perceived as a bottleneck in each clinic were obtained from the 2007 VA Clinical Practice Organizational Survey—Primary Care Director Module. Patient-level adherence to OHAs using medication possession ratios (MPRs) were constructed using refill data from administrative pharmacy databases after adjusting for patient characteristics. Clinic-level OHA adherence was measured as the proportion of patients with MPR >= 80%. We analyzed associations between pharmacy measures and clinic-level adherence using linear regression. RESULTS: We found no significant association between pharmacist presence and clinic-level OHA adherence. However, adherence was lower in clinics where pharmacy services were perceived as a bottleneck. CONCLUSIONS: Pharmacist presence, regardless of the amount of FTE, was not associated with OHA medication adherence in primary care clinics. The exact role of pharmacists in clinics needs closer examination in order to determine how to most effectively use these resources to improve patient-centered outcomes including medication adherence.

Concepts: Cohort study, Diabetes mellitus, Anti-diabetic drug, Metformin

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Objectives To derive and validate updated QDiabetes-2018 prediction algorithms to estimate the 10 year risk of type 2 diabetes in men and women, taking account of potential new risk factors, and to compare their performance with current approaches.Design Prospective open cohort study.Setting Routinely collected data from 1457 general practices in England contributing to the QResearch database: 1094 were used to develop the scores and a separate set of 363 were used to validate the scores.Participants 11.5 million people aged 25-84 and free of diabetes at baseline: 8.87 million in the derivation cohort and 2.63 million in the validation cohort.Methods Cox proportional hazards models were used in the derivation cohort to derive separate risk equations in men and women for evaluation at 10 years. Risk factors considered included those already in QDiabetes (age, ethnicity, deprivation, body mass index, smoking, family history of diabetes in a first degree relative, cardiovascular disease, treated hypertension, and regular use of corticosteroids) and new risk factors: atypical antipsychotics, statins, schizophrenia or bipolar affective disorder, learning disability, gestational diabetes, and polycystic ovary syndrome. Additional models included fasting blood glucose and glycated haemoglobin (HBA1c). Measures of calibration and discrimination were determined in the validation cohort for men and women separately and for individual subgroups by age group, ethnicity, and baseline disease status.Main outcome measure Incident type 2 diabetes recorded on the general practice record.Results In the derivation cohort, 178 314 incident cases of type 2 diabetes were identified during follow-up arising from 42.72 million person years of observation. In the validation cohort, 62 326 incident cases of type 2 diabetes were identified from 14.32 million person years of observation. All new risk factors considered met our model inclusion criteria. Model A included age, ethnicity, deprivation, body mass index, smoking, family history of diabetes in a first degree relative, cardiovascular disease, treated hypertension, and regular use of corticosteroids, and new risk factors: atypical antipsychotics, statins, schizophrenia or bipolar affective disorder, learning disability, and gestational diabetes and polycystic ovary syndrome in women. Model B included the same variables as model A plus fasting blood glucose. Model C included HBA1c instead of fasting blood glucose. All three models had good calibration and high levels of explained variation and discrimination. In women, model B explained 63.3% of the variation in time to diagnosis of type 2 diabetes (R(2)), the D statistic was 2.69 and the Harrell’s C statistic value was 0.89. The corresponding values for men were 58.4%, 2.42, and 0.87. Model B also had the highest sensitivity compared with current recommended practice in the National Health Service based on bands of either fasting blood glucose or HBA1c. However, only 16% of patients had complete data for blood glucose measurements, smoking, and body mass index.Conclusions Three updated QDiabetes risk models to quantify the absolute risk of type 2 diabetes were developed and validated: model A does not require a blood test and can be used to identify patients for fasting blood glucose (model B) or HBA1c (model C) testing. Model B had the best performance for predicting 10 year risk of type 2 diabetes to identify those who need interventions and more intensive follow-up, improving on current approaches. Additional external validation of models B and C in datasets with more completely collected data on blood glucose would be valuable before the models are used in clinical practice.

Concepts: Epidemiology, Diabetes mellitus, Obesity, Diabetes, Relative risk, Blood sugar, Metformin, Schizophrenia

114

 To determine whether pioglitazone compared with other antidiabetic drugs is associated with an increased risk of bladder cancer in people with type 2 diabetes.

Concepts: Diabetes mellitus type 2, Diabetes mellitus, Obesity, Anti-diabetic drug, Sulfonylurea, Metformin, Pioglitazone, Thiazolidinedione

100

We report that the anticancer activity of the widely used diabetic drug metformin is strongly potentiated by syrosingopine. Synthetic lethality elicited by combining the two drugs is synergistic and specific to transformed cells. This effect is unrelated to syrosingopine’s known role as an inhibitor of the vesicular monoamine transporters. Syrosingopine binds to the glycolytic enzyme α-enolase in vitro, and the expression of the γ-enolase isoform correlates with nonresponsiveness to the drug combination. Syrosingopine sensitized cancer cells to metformin and its more potent derivative phenformin far below the individual toxic threshold of each compound. Thus, combining syrosingopine and codrugs is a promising therapeutic strategy for clinical application for the treatment of cancer.

Concepts: DNA, Gene expression, Cancer, Oncology, Glucose, The Canon of Medicine, Obesity, Metformin

72

Although many studies indicate the interplay of genetic and environmental factors in the etiology of autism spectrum disorder (ASD), our limited understanding of the underlying mechanisms hampers the development of effective ways of detecting and preventing the disorder. Recent studies support the hypothesis that prenatal androgen exposure contributes to the development of ASD. This would suggest that maternal polycystic ovary syndrome (PCOS), a condition associated with excess androgens, would increase the risk of ASD in the offspring. We conducted a matched case-control study nested within the total population of Sweden (children aged 4-17 who were born in Sweden from 1984 to 2007). The sample consisted of 23 748 ASD cases and 208 796 controls, matched by birth month and year, sex and region of birth. PCOS and ASD were defined from ICD codes through linkage to health-care registers. Maternal PCOS increased the odds of ASD in the offspring by 59%, after adjustment for confounders (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.34-1.88). The odds of offspring ASD were further increased among mothers with both PCOS and obesity, a condition common to PCOS that is related to more severe hyperandrogenemia (OR 2.13, 95% CI 1.46-3.10). Risk estimates did not differ between sexes. In conclusion, children of women with PCOS appear to have a higher risk of developing ASD. This finding awaits confirmation, and exploration of potentially underlying mechanisms, including the role of sex steroids in the etiology of ASD.Molecular Psychiatry advance online publication, 8 December 2015; doi:10.1038/mp.2015.183.

Concepts: Luteinizing hormone, Autism, Pervasive developmental disorder, Metformin, Asperger syndrome, Autism spectrum, PDD-NOS, Polycystic ovary syndrome

30

Inflammation and oxidative stress are known risk factors for preterm birth (PTB); however, the mechanisms and pathways that influence this condition are not fully described. Previously, we showed that mTORC1 signaling is increased in mice harboring a uterine-specific deletion of transformation-related protein 53 (p53d/d mice), which exhibit premature decidual senescence that triggers spontaneous and inflammation-induced PTB. Treatment with the mTORC1 inhibitor rapamycin reduced the incidence of PTB in the p53d/d mice. Decidual senescence with heightened mTORC1 signaling is also a signature of human PTB. Here, we have identified an underlying mechanism for PTB and a potential therapeutic strategy for treating the condition. Treatment of pregnant p53d/d mice with either the antidiabetic drug metformin or the antioxidant resveratrol activated AMPK signaling and inhibited mTORC1 signaling in decidual cells. Both metformin and resveratrol protected against spontaneous and inflammation-induced PTB in p53d/d females. Using multiple approaches, we determined that p53 interacts with sestrins to coordinate an inverse relationship between AMPK and mTORC1 signaling that determines parturition timing. This signature was also observed in human decidual cells. Together, these results reveal that p53-dependent coordination of AMPK and mTORC1 signaling controls parturition timing and suggest that metformin and resveratrol have therapeutic potential to prevent PTB.

Concepts: Pregnancy, Childbirth, Antioxidant, Oxidative stress, Radical, Anti-diabetic drug, Metformin, Cervix

30

The objectives of this study were to evaluate the efficacy and tolerability of glimepiride plus extended release metformin (MET) on glycemic control in patients with type-2 diabetes mellitus uncontrolled on monotherapy with sulfonylurea or MET. This was a prospective, open-labeled, multicentric study over 12 weeks. Patients who were diagnosed with type-2 diabetes and were uncontrolled on monotherapy with single oral hypoglycemic agents such as glimepiride or MET and characterized by glycosylated hemoglobin (HbA1c) ≥7% and ≤10% and fasting plasma glucose (FPG) ≥ 140 mg/dL were enrolled in this study. Treatment regimen was started at 1 mg of glimepiride plus 500 mg of MET once a day and was titrated to next dose level depending on the clinician’s judgment, not exceeding a total daily dose of 8 mg of glimepiride and 2000 mg of MET. After 12-weektreatment, glimepiride plus MET combination showed improvement in metabolic control as assessed by changes in HbA1c, FPG, and post prandial glucose (PPG). Primary efficacy parameter, HbA1c, was significantly reduced to (7.65 ± 1.70) at the end of the treatment from the baseline value (8.35 ± 0.93) (P < 0.001). Of the patients, 65.79% showed ≥0.5% reduction in HbA1c and or HbA1c <7% at the end of the therapy. FPG and PPG were significantly reduced at the end of the therapy as compared with baseline values (P < 0.001). Moreover, the lipid profile was also improved during the treatment period. The addition of glimepiride to MET is an effective treatment for patients inadequately controlled on sulfonylurea or Met alone. A combination of glimepiride with MET achieves good glycemic control with better tolerability profile.

Concepts: Insulin, Diabetes mellitus type 2, Diabetes mellitus, Obesity, Diabetes, Anti-diabetic drug, Sulfonylurea, Metformin

29

This review updates the pharmacology, efficacy, safety, and tolerability of liraglutide, a glucagon-like peptide 1 (GLP-1) analog approved for the treatment of type 2 diabetes (T2DM) in January 2010. MEDLINE was searched (May 2009-January 1, 2011) for articles in English, using the terms liraglutide, NN2211, incretin mimetic, glucagon-like peptide (GLP)-1, and GLP-1 receptor agonist. Abstracts from key meetings (ADA 2009 and 2010, AACE 2010, EASD 2009, and EASD 2010) were also searched for relevant data. A GLP-1 analog with pharmacokinetic properties allowing once-daily administration via subcutaneous injection, liraglutide has shown clinical benefits when used as monotherapy or in combination. Liraglutide monotherapy has demonstrated efficacy in reducing hemoglobin A1c (A1C) and body weight, with low risk for hypoglycemic events. Liraglutide has also been studied in combination with metformin, glimepiride, and rosiglitazone for the treatment of T2DM. Extension studies within the Liraglutide Effects and Action in Diabetes clinical program have demonstrated the efficacy of liraglutide over 2 years of treatment. Overall, liraglutide has been shown to be well tolerated, with dose-dependent nausea, vomiting, and diarrhea being the most commonly reported adverse events in clinical trials. Extended dosing periods have demonstrated the durability of response of liraglutide with respect to glycemic control, lack of weight gain, and blood pressure benefits. Compared with exenatide and sitagliptin, liraglutide seems to offer greater improvements in A1C, fasting plasma glucose, and body weight. Adverse events commonly associated with liraglutide in clinical trials included nausea and hypoglycemia. Emerging data suggest that liraglutide may be a useful option for patients with T2DM.

Concepts: Pharmacology, Diabetes mellitus type 2, Diabetes mellitus, Diabetes, Sulfonylurea, Metformin, Glucagon-like peptide-1, Exenatide