Dose Of Metformin Research Articles

Metformin antagonizes nickel-refining fumes-induced cell pyroptosis via Nrf2/GOLPH3 pathway in vitro and in vivo

Nickel compounds, an international carcinogen in the industrial environment, increased the risk of lung inflammation even lung cancer in Ni refinery workers. Metformin has displayed the intense anti-inflammation and anti-cancer properties through regulating pyroptosis. This study was designed to explore whether Nickel-refining fumes (NiRF) can induce cell pyroptosis and how AMPK/CREB/Nrf2 mediated the protection afforded by metformin against Ni particles-induced lung impairment. Our results represented that Ni fumes exposure evoked pyroptosis via GOLPH3 and induced oxidative stress, while, metformin treatment alleviated Ni particles-mediated above changes. Moreover, nuclear factor erythroid 2-related factor 2 (Nrf2) involved in the protection of metformin, and the deficiency of Nrf2 attenuated the beneficial protection. We also determined that Nrf2 was a downstream molecule of AMPK/CREB pathway. Furthermore, male C57BL/6 mice were administered with Ni at a dose of 2 mg/kg by non-exposed endotracheal instillation and metformin (100, 200 and 300 mg/kg) via oral gavage for 4 weeks. The results indicated that NiRF promoted GOLPH3 and pyroptosis by stimulating NLRP3, caspase-1, N-GSDMD, IL-18 and IL-1β expression. However, various doses of metformin reduced GOLPH3 and the above protein levels of pyroptosis, also improved AMPK/CREB/Nrf2 expression. In summary, we found that metformin suppressed NiRF-connected GOLPH3-prompted pyroptosis via AMPK/CREB/Nrf2 signaling pathway to confer pulmonary protection.

LBODP083 Pharmacokinetics Of Metformin In Obese Non-diabetic Youth: Drug Clearance Increases With Severity Of Obesity

Abstract Background Severe obesity and obesity-related conditions, such as prediabetes, are increasing in prevalence among pediatric populations. Metformin is an oral biguanide that is often used off label to treat obesity and prediabetes in youth. Despite increased prescribing in youth, there is limited knowledge about pharmacokinetics (PK) of metformin in pediatric populations, and no published data describing the effect of obesity severity on metformin PK. Research Questions What is the variability of pharmacokinetic properties of immediate release metformin in obese, non-diabetic adolescents? Does severity of obesity impact these properties? Methodology Youth 12-17 years of age were included if they were obese with laboratory evidence of insulin resistance (HOMA-IR > 3) or met ADA criteria for prediabetes and had a normal renal function (GFR > 60 mL/min/1.73m2). Obesity classes were defined as class I (BMI > 95th to < 120% of the 95th percentile), class II (> 120% to < 140% of the 95th percentile), and class III (> 140% of the 95th percentile). Youth were treated with immediate release metformin dosed twice daily for at least 6 weeks. Pill diaries and pill counts were conducted to assess adherence. Youth arrived fasting and received their AM dose of metformin with a standardized meal. Blood was drawn pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose and urine collected throughout the visit. Primary outcomes included the mean, standard deviation, and range for steady state area under the plasma drug concentration-time curve adjusted for dose (AUCss_D) and apparent oral clearance at steady state (CLss/F). These outcomes were compared between obesity classes. MAJOR RESULTS There were 11 subjects (10 females), mean (SD) age was 14.3 (1.8) years. Metformin doses included: 1000mg BID (N=8), 500mg qAM 1000mg qPM (N=2), 500mg BID (N=1). Mean (SD) weight was 102.8 (19.2) kg, and mean BMI 37.5 (3.3) kg/m2. Among participants, there were N=4 with class III obesity, N=4 with class II obesity, and N=3 with class I obesity. Across all study participants, mean AUCss _D was 12.5 (SD 2.46; range 8.48-16.9) h*ng/mL/mg and mean CLss/F was 85.7 (SD 16.6; range 59. 0-118) L/h. Mean CLss/F was 76.8, 83.6, and 86.2 L/h in class I, II, and III obesity, respectively. Mean AUCss _D was 13.5, 12.17, 12.14 h*ng/mL/mg in class I, II, and III obesity, respectively. No differences were statistically significant. Conclusions Our pilot data suggest a 2-fold variability in apparent clearance among study participants, with apparent clearance increasing in relation to obesity severity class. Greater clearance, and thus reduced systemic exposure (AUC), may indicate a need for a larger dose of metformin in severely obese youth. Additional data is needed to further evaluate the impact of the severity of obesity on metformin clearance. Presentation: No date and time listed

PSUN124 Weight Loss from Combination Anti-Obesity Medications Including Glucagon-Like Peptide-1 Receptors Agonists can Approach that Achieved from Bariatric Surgery

Abstract Background Obesity is a multifactorial chronic disease for which treatment remains challenging and combination anti-obesity medications including glucagon-like peptide-1 receptor agonists (GLP1-RAs) can be highly effective. Clinical Case We report the case of a 23-year-old male, previously followed in a pediatric weight management clinic, who presented to an adult weight management program with a body mass index (BMI) of 84.3 kg/m2 and impaired glucose tolerance. Factors contributing to his obesity status included a family history, strong hunger and food cravings, and binge eating tendencies. He lost 30% body weight after the addition of semaglutide (a GLP1-RA) 0.5 mg weekly to an anti-obesity medication regimen. At his initial presentation to the adult weight management clinic, with a weight of 643 pounds and hemoglobin A1c 6.4%, he was started on phentermine 15 mg, topiramate 75 mg, and metformin 500 mg daily. Over the next year, he was followed virtually due to the COVID pandemic and, therefore, weight and BMI could not be ascertained. His dose of metformin was increased to 1000 mg, phentermine to 18.75 mg, and topiramate to 100 mg daily during this time. Additionally, extended release bupropion 150 mg daily was added given a history of depression, which was then increased to 300 mg daily. When he was able to return to the clinic in-person, his weight and BMI remained unchanged and, therefore, semaglutide 0.5 mg weekly was added, in addition to monthly virtual registered dietician (RD) visits and a low calorie diet. He reported a significant reduction in hunger after the addition of semaglutide. Eight months later, he had lost 193 pounds, his BMI had decreased to 66.5 kg/m2, and his hemoglobin A1c normalized. The 30% total body weight loss and improved glucose tolerance achieved in less than one year mirrors that typically achieved by metabolic/bariatric surgery. Conclusion This case highlights the potential benefit of combination anti-obesity medication regimens that include GLP1-RAs. Specifically, while some patients may experience suboptimal response to combination anti-obesity therapies, it may be that the addition of GLP1-RAs to such regimens, namely semaglutide, can provide a synergistic effect leading to substantial weight loss approaching that achieved from metabolic/bariatric surgery. This may result from targeting multiple eating behavior pathways simultaneously, including appetite, satiety, and binge eating tendencies. Further studies are needed to evaluate the efficacy of GLp1-RAs as part of combination anti-obesity medication regimens, especially among those who achieve suboptimal response to regimens not including GLP1-RAs. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Quality and Characteristics of 4241 Case Reports of Lactic Acidosis in Metformin Users Reported to a Large Pharmacovigilance Database.

Metformin-associated lactic acidosis (MaLA) occurs rarely and is thus difficult to study. We analysed 4241 individual case safety reports of lactic acidosis (LA) that implicated metformin as a suspected drug reported to the pharmacovigilance database of Merck KGaA, Darmstadt, Germany. The primary objective was to review reports for quality and completeness of data to support diagnoses of MaLA. We also explored the correlations between reported biomarkers, and associations between biomarkers and outcomes. Records were analysed for completeness in supporting diagnoses of LA or metformin-associated LA (MaLA), against commonly used diagnostic criteria. Correlations between indices of exposure to metformin and biomarkers of LA and mortality were investigated. Missing data was common, especially for plasma metformin. Clinical/biomarker evidence supported a diagnosis of LA in only 33% of cases (LA subpopulation) and of MaLA in only 9% (MaLA subpopulation). The metformin plasma level correlated weakly with plasma lactate (positive) and pH (negative). About one-fifth (21.9%) of cases reported a fatal outcome. Metformin exposure (plasma level or dose) was not associated with increased mortality risk (there was a suggestion of decreased risk at higher levels of exposure to metformin). Plasma lactate was the only variable associated with increased risk of mortality. Examination of concomitant risk factors for MaLA identified renal dysfunction (including of iatrogenic origin) as a potential driver of mortality in this population. Despite the high frequency of missing data, this is the largest analysis of cases of MaLA supported by measurements of circulating metformin, and lactate, and pH, to date. Plasma lactate, and not metformin dose or plasma level, appeared to be the main driver of mortality in the setting of LA or MaLA. Further research with more complete case reports is required.

ODP173 Control of Alpelisib-Induced Hyperglycemia With DPP4- Inhibitors as add on to Metformin and Insulin

Abstract Context Alpelisib is an oral phosphatidylinositol-3-kinase alpha (PI3Ka) inhibitor approved in 2019 for treatment of ER/PR+, HER2-negative advanced breast cancer. The main side effect of PI3Ka inhibition is hyperglycemia. Case A 38 year-old woman was started on alpelisib and fulvestrant therapy for Stage IV bilateral breast carcinoma (ER+, PR+, HER2-negative) with multiple distant metastases. She had previously received multiple courses of systemic therapy with palbociclib, letrozole, and everolimus, in combination with fulvestrant. She was lean (BMI 20.6 kg/m 2), had a prior history of GDM only requiring diet control, and pre-existing pre-diabetes, with a baseline FPG of 5.6 mmol/L and HbA1c of 5.9%. She developed hyperglycemia after 2 months of Alpelisib 200 mg OD (FPG 138.6 mg/dL; HbA1c 5.8%) and was started on metformin 500 mg BD. Glucose levels remained under control (fasting BG of 108-126 mg/dL) until alpelisib dose was increased to 300 mg OD. Within 6 weeks of dose increment, her fasting BG markedly increased to 324 mg/dL and HbA1c to 10%. Metformin dose was increased to 1000 mg BD, linagliptin 5 mg OD and isophane insulin at 8 units once daily, was introduced in addition to lifestyle modifications. Due to the side effects resulting in diarrhea, alpelisib was discontinued temporarily for 3 weeks before subsequent reintroduction and titration to a maximum tolerable dose of 200 mg OD. Glycemic control subsequently improved with metformin, linagliptin and titration of insulin to 14units daily, with HbA1c reduction to 6. 0% and fasting BG of 84.6 mg/dL, without any hypoglycemia. Oncological assessment showed disease response, with smaller primary tumour and stable metastatic lesions. Discussion The PI3K/AKT pathway plays a central role in cellular growth and glucose metabolism. This pathway is a potent target of anticancer therapy. In physiological glucose homeostasis, postprandial insulin secretion activates the PI3Ka pathway, subsequently upregulating glucose transporters for cellular uptake and utilization of glucose. In the phase III clinical trial (SOLAR-1), the incidence of alpelisib-induced hyperglycemia was 63.7%, and was treated with insulin sensitizers such as metformin and pioglitazone. Subsequent case series have reported effective glycemic control using very low calorie diet (VLCD), SGLT2-inhibitors and insulin therapy 1 . In our patient, linagliptin, was chosen as an adjunct therapy in addition to metformin due to its mechanism of action that address insulin resistance and favourable safety profile. We also note that the severity of alpelisib side effects appeared to be dose-dependent, as seen in the clinical trial. Conclusion We demonstrated effective control of alpelisib-induced hyperglycemia using DPP4-inhibitors as an option, in combination with metformin and insulin.

PSUN173 Factors determining insulin dose while transitioning from intravenous insulin infusion to subcutaneous insulin in patients with type 2 diabetes following cardiac bypass surgery.

Abstract Introduction In patients with type 2 diabetes undergoing cardiac bypass surgery, data regarding the factors predicting insulin dose while transitioning from intravenous insulin infusion to subcutaneous insulin are scarce. This study was therefore planned to determine the factors that predict postoperative subcutaneous insulin dose, basal-to-bolus insulin ratio and the factors determining this ratio. Methods This is a single centre prospective observational study in 280 consecutive cardiac bypass surgery patients with type 2 diabetes at a tertiary care facility in India. Results In linear regression analysis, the subcutaneous insulin dose following cardiac surgery was determined by glycated hemoglobin (HbA1c) at admission (beta 0.34, p <0.0001), insulin dose before surgery (beta 0.33, p <0.0001), sulphonylurea (beta 0.19, p = 0.002), and metformin doses (beta 0.14, p = 0.017) before surgery, and intravenous insulin dose (beta 0.11, p =0.041) after surgery. The basal-to-bolus ratio of insulin after surgery was 0.9, and was negatively predicated by serum creatinine levels and age, and positively by body weight of the patients. Conclusions In our study, post-surgery subcutaneous insulin dose after transitioning from intravenous insulin infusion depends on several factors, such as HbA1c and insulin dose before surgery, metformin and sulfonylurea use before surgery and intravenous insulin infusion dose during surgery. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

LBODP038 Metformin-Associated Severe Lactic Acidosis: A Case Study Of The Perfect Storm

Abstract Background Metformin carries a rare risk of lactic acidosis. Medications that can increase the concentration of metformin in the serum can increase the risk of lactic acidosis. Similarly, kidney dysfunction leads to decreased clearance of the drug, hence potentiating its adverse effects. Clinical Case A 62-year-old male with HIV (undetectable viral load) on dolutegravir, atazanavir/cobicistat, rilpivrine, type 2 DM (A1C 7.2%) on metformin and dulaglutide presented with 1 day history of dyspnea. He had a respiratory rate of 28 and heart rate of 131. Blood glucose was 43 mg/dL (nl 74-99 mg/dL). Labs were also notable for lactate 23.6 mmol/L (nl 0.4-2 mmol/L), severe anion gap metabolic acidosis with pH <6.8, bicarbonate 5 mmol/L (nl 21-32 mmol/L). Creatinine was 2.29 mg/dL (nl 0.5-1.3 mg/dL) with a normal baseline kidney function. Beta-hydroxybutyrate was elevated at 0.73 mmol/L (nl 0. 02-0.27 mmol/L). Osmolar gap was 17.3 mOsm, ethanol level was 22 mg/dL (nl <10 mg/dL), ethylene glycol was not detected. Patient reported drinking four beers daily but endorsed binge drinking the previous night with associated emesis. Review of records showed that the patient was started on dulaglutide recently and he endorsed nausea and diarrhea with initiation of the medication. He otherwise had no changes in his metformin dose or antiretroviral regimen. He was admitted to the ICU for further management of his severe lactic acidosis. Patient's antiretroviral regimen, dulaglutide, and metformin were held on admission. Medical toxicology was consulted, and metformin associated lactic acidosis was suspected. He was initiated on dialysis and his lactic acidosis resolved within 24 hours. His antiretroviral regimen was resumed prior to discharge when his creatinine improved to 1.38 mg/dL. Metformin was discontinued and he was discharged on dulaglutide with endocrinology follow up. Conclusion This case demonstrates how multiple factors such as alcohol use, kidney injury, and other medications can increase the, otherwise rare, risk of lactic acidosis in patients taking metformin. The patient had experienced GI losses due to emesis from his increased alcohol intake as well as diarrhea with the initiation of dulaglutide leading to dehydration and acute kidney injury. The latter can give rise to decreased metformin clearance. In addition, dolutegravir increases metformin plasma exposure. Together, the constellation of factors had likely led to increased metformin plasma levels and associated severe lactic acidosis. Patients should be counseled on the use of alcohol while taking metformin. Additionally, drug interactions should be monitored, and dose reductions of metformin should be considered in patients taking dolutegravir. Presentation: No date and time listed

Effects of Hydroxychloroquine on Progression of Diabetic Retinopathy in Subjects with Rheumatoid Arthritis and Type 2 Diabetes Mellitus.

The study was conducted to investigate the effects of hydroxychloroquine, an anti-inflammatory drug, which was recently approved and used as an add on oral antidiabetic drug for uncontrolled Type 2 Diabetes Mellitus (DM) on an adequate dose of sulfonylurea and metformin on the progression of diabetic retinopathy (DR) in subjects with Rheumatoid Arthritis and Type 2 Diabetes Mellitus. The primary objective was to evaluate the effect of hydroxychloroquine on the onset of Diabetic Retinopathy (DR) and progression of the disease. Best-corrected visual acuity (BCVA) charts with 3 or more lines worsening of visual acuity and the development of clinically significant macular edema (CSME) were added as secondary objectives as described in the Early Treatment Diabetic Retinopathy Study (ETDRS). This retrospective analysis was done from medical records of all Rheumatoid Arthritis (RA) patients who also had T2DM and were treated with hydroxychloroquine (HCQ) 400 mg OD or 200 mg BID (N=65) and received ophthalmologic care at an endocrinology clinic in India up to a mean follow-up of 3.5±0.5 years and matched subjects taking any other disease-modifying antirheumatic drugs (DMARD) and pioglitazone (N=34). Baseline characteristics were similar in both the groups, with matched glycated haemoglobin (9.1 % and 9.2 % respectively, p=0.127). In both groups, over 3.5 years, HbA1c was reduced significantly. No new cases of DR were detected in the HCQ group, whereas 2 patients had developed DR in the pioglitazone group. At the base line visit, mild non-proliferative Diabetic Retinopathy (NPDR) was present in 18 eyes and 14 eyes in the HCQ and pioglitazone groups, respectively. Progression to moderate NPDR over 3.5 years occurred in 2 out of 18 (11 %) eyes in the HCQ group and 8 out of 14 (57 %) eyes in the pioglitazone group, respectively, representing a significant relative risk reduction (p=.001). No patients had progressed from mild NPDR to severe NPDR in the HCQ group, whereas 2 eyes had progressed from mild NPDR to severe NPDR in the pioglitazone group. None of the patients in either arm developed diabetic macular oedema. Progression of DR from mild to moderate NPDR or severe NPDR may be delayed by HCQ. Large scale randomised prospective clinical trial is required to establish the risk-benefit profiles of HCQ in T2DM.ct.

PSUN265 Metformin-Induced Severe Lactic Acidosis Requiring Urgent Dialysis Associated With Influenza A Infection in a Patient With Previous Preserved Renal Function: Case Report

Abstract Background Although rare, metformin-induced lactic acidosis it's a severe acute condition, that requires immediate recognition and management due to its high lethality. Clinical case Female, 70-years-old, presents to the E.R. with generalized malaise, weakness and myalgia for 4 days associated with diarrhea and vomits for 2 days. Denies fever or flu-like symptoms. History of hypertension and T2DM using metoprolol 100mg/day, perindopril 10mg/day, indapamide 2.5mg/day, amlodipine 5mg/day, linagliptin 5mg/day, rosuvastatin 10mg/day, gliclazide 120mg/day, aspirin 100mg/day, clonidine 0.3mg/day and metformin XR 1g/day. On clinical exam she was dehydrated and tachypneic with no other important findings. Laboratory showed glucose 31mg/dL, severe metabolic acidosis - pH 6,0; HCO3 5,4mmol/L; lactate 11.6mmol/L (n<1.6mmoL/L), acute renal failure KDIGO 3, creatinine 8.08mg/dL eGFR 5mL/min/1.73m2 (patient's baseline 0.9mg/dL), BUN 213mg/dL (n<50mg/dL), potassium 6.8mEq/L (3.5>n<5.1mEq/L), phosphor 14.9mg/dL (2.7>n<4.5mg/dL), chlorine 92mEq/L (98>n<107mEq/L), magnesium 1.7mg/dL (1.6>n<2.6mg/dL), calcium 0.95mmol/L (1.16>n<1.32mmol/L), and normal blood count. She was admitted to the ICU, hemodynamically stable with no need for vasoactive amine, breathing under nasal cannula and proceed with emergency hemodialysis. Acidosis was corrected after 6h of hemodialysis. Patient turned eupneic in room air and presented renal function improvement (BUN 44mg/dL; Creatinine 2.66mg/dL). She continued under intensive care and daily hemodialysis for another 4 days. The etiological investigation excluded glomerulopathies of rheumatological cause, blood cultures, serology for hepatitis, HIV and Dengue were all negative. However, respiratory viral panel was positive for influenza A. Although metformin serum dosage was not performed, renal function stability without the need for hemodialysis was only achieved after discontinuation of metformin. The main diagnostic hypothesis was metformin-induced severe metabolic acidosis. Finally, the patient was discharged on day 10, with stable renal function without hemodialysis (creatinine 2.19mg/dL eGFR 22mL/min/1.73m2) and no neurological deficits. The patient was referred to the endocrinologist and nephrologist to follow-up. Conclusion Metformin is affordable, safe and widely prescribed since the 50's. Although rare, metformin-induced lactic acidosis is a lethal toxicity, with identifiable risk factors that must be considered by prescribers. References Lazarus, Benjamin et al. "Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function: A Community-Based Cohort Study." JAMA internal medicine vol. 178,7 (2018): 903-910. doi: 10.1001/jamainternmed.2018.0292 Salpeter, Shelley R et al. "Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus." The Cochrane database of systematic reviews vol. 2010,4 CD002967. 14 Apr. 2010, doi: 10.1002/14651858.CD002967.pub4 Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

ODP169 Challenges with use of HbA1C for Evaluation of Blood Glucose Control

Abstract Background Glycated hemoglobin (A1C) is widely used to diagnose diabetes mellitus and monitor glucose control. It represents a measurement of a proportion of glycated hemoglobin which reflects average glycemia over the lifespan of a red blood cell. Genetic factors that affect A1C values have been extensively studied and there is a growing knowledge of some variants that lead to abnormal fasting glucose-A1C ratio. Still, in some patients, delayed diagnosis or suboptimal treatment of diabetes mellitus remains an existing problem when glycated hemoglobin is underestimating blood glucose levels. Case 69-year-old man was seen in endocrine clinic following a hospital admission for newly diagnosed type 2 DM with hyperglycemic hyperosmolar state and a complicated urinary infection. Prior to admission the patient presented to primary care physician with symptoms of urinary infection and was found to have glucose >500mg/dL on point-of-care test and A1C of 9.5% without known history of diabetes mellitus. After a short hospital course the patient was discharged to home on low dose basal insulin and metformin. His morning glucose in the week after hospital stay was ranging between 140-182mg/dL. At the time of first visit in endocrinology he endorsed symptoms suggestive of peripheral neuropathy and had long standing polyuria, normal BMI and no other medical history or complaints. He was educated about the new diagnosis, diabetic diet, treatment and monitoring and no medication change was made at that time. On the next follow up he reported home glucose readings of 134-191mg/dL and repeated A1C was 5.1%. Urine test was remarkable for microalbuminuria and blood test showed low Hb of 8.7g/dL. Work up for anemia revealed alpha talassemia minor, hemoglobin SC disease and G6PD deficiency. During the following year regular clinic follow up visits were conducted, insulin was discontinued and the patient remained on metformin and empagliflozin over the next 4 years to date. When goal glucose control was achieved with fasting glucose of 90-130mg/dL A1C was 3.8% without any hypoglycemia. Hemoglobin at that time was 9.1g/dL. Over the next 4 years and to date his A1C was still checked 1-2 times a year and remained between 4-4.6%. On review of this patient's chart prior to hospital admission his HbA1C was 5.7% so diabetes mellitus was not suspected before the patient developed diabetic emergency that carries high mortality Discussion: There are known genetic and non-genetic factors that affect HbA1C value. It is very likely that this patient as well as many others have significant delay in diagnosis of diabetes mellitus if only HbA1C is used as screening test. A possibility of genetic variant that affects A1C values, especially in patients of African descent should always be considered when there is a discrepancy between fasting glucose and glycated hemoglobin value. Presentation: No date and time listed

Add-on imeglimin versus metformin dose escalation regarding glycemic control in patients with type 2 diabetes treated with a dipeptidyl peptidase-4 inhibitor plus low-dose metformin: study protocol for a multicenter, prospective, randomized, open-label, parallel-group comparison study (MEGMI study)

IntroductionImeglimin is a novel anti-hyperglycemic drug that improves both insulin resistance and insulin secretion. The effects of imeglimin on glycemic control were confirmed in phase III clinical trials, but little...

PSUN250 Empagliflozin Induced Bladder Cancer in an Adult Patient With Latent Autoimmune Diabetes

Abstract Sodium glucose cotransporter type 2 (SGLT2) inhibitor is a novel class of antidiabetic agent. The association of SGLT2 inhibitors and incidence of bladder cancer has not been well established due to few numbers of cases and not enough length of exposure. Here we describe a case of bladder cancer developed one year after empagliflozin exposure in a patient with latent autoimmune diabetes. Case description A 51-year-old man presented to our endocrine clinic with a one-year diagnosis of type 2 diabetes mellitus. His glycosylated hemoglobin (HbA1c) was 8% on maximum dose metformin and well adherence to diet. The patient had no significant past medical history and his body mass index was 23.6 kg/m2. Empagliflozin 25 mg daily was added to his regimen, in addition to sulfonylurea and dipeptidyl peptidase-4 (DPP-4) inhibitor drugs. The patient continued to have persistent hyperglycemia despite medical therapy with HbA1c ranged between 7.5-7.9%. After one year, he presented with fatigue, unintentional 7-kg weight loss and perianal pain. A transrectal ultrasound of the pelvis showed a 10-mm solid lesion in the urinary bladder. He underwent transurethral resection of bladder tumor; pathology showed a low grade papillary urothelial carcinoma with focal areas of high grade. Empagliflozin was discontinued and due to persistent hyperglycemia, further labs were requested. Fasting blood glucose of 265 mg/dl, HA1c of 7.9%, anti-GAD antibody was positive 37.52 u/ml (<10.0), C-peptide of 0.51 ng/ml (0.37-1.47), insulin of 2.0 mu/ml (2.6-24.9). These findings suggested latent autoimmune diabetes with mild pancreatic reserve. Patient was then started on insulin therapy of Glargine and Aspart. Conclusion The use of SGLT2 inhibitors in patients with autoimmune diabetes may have a higher risk of bladder cancer as compared to patients with type 2 diabetes. An individualized selection of antidiabetic agent with consideration of proper diagnosis is recommended to prevent a serious consequence. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Effect of Oral Antidiabetic Drugs on Tuberculosis Risk and Treatment Outcomes: Systematic Review and Meta-Analysis.

Tuberculosis and diabetes mellitus are two global pandemics and rising public health problems. Recent studies suggest that oral antidiabetic drugs (OADs) could reduce the risk of tuberculosis and improve clinical outcomes. However, the evidence is controversial. Therefore, we aimed to assess the effect of OADs on the risk of tuberculosis and treatment outcomes. We systematically searched for six databases from inception to 31 August 2022. We followed a predefined PICO/PECO strategy and included two randomized controlled trials and sixteen observational studies. This study collects 1,109,660 participants, 908,211 diabetic patients, and at least 13,841 tuberculosis cases. Our results show that metformin decreases the risk of active tuberculosis by 40% (RR 0.60; 95% CI 0.47-0.77) in diabetic patients. In addition, metformin exhibits a dose-response gradient (medium doses reduce the risk of active tuberculosis by 45%, while high doses reduce this risk by 52%). On the other hand, DPP IV inhibitors increase the risk of active tuberculosis by 43% (RR 1.43; 95% CI 1.02-2.02). Subgroup analysis showed that study design and metformin dose accounted for the heterogeneity. We conclude that metformin significantly protects against active tuberculosis among diabetic patients. On the contrary, DPP IV inhibitors could increase the risk of developing active tuberculosis.

The present status of metformin in fertility-preserving treatment in atypical endometrial hyperplasia and endometrioid endometrial cancer.

Progestin therapy is the main fertility-sparing treatment for women with endometrial cancer (EC) and atypical endometrial hyperplasia (AEH). However, still 15-25% of these women failed to achieve complete response (CR) and then lost their fertility after definitive surgery. Metformin has been demonstrated to play an anti-cancer role in multiple cancers including EC. Several studies also suggested metformin had potential benefit in improving the therapeutic outcome of fertility-preserving treatment alongside with progestin. This review has discussed existed evidence regarding the effect of metformin combined with progestin for women with AEH and EC who desire childbearing. Nevertheless, the therapeutic effect of metformin varied in different studies due to the high heterogeneity in the patient's characteristics, the inconsistency in dose and treatment duration of metformin, the combined use of hysteroscopy, the insufficient sample size and underpowered study-design. Therefore, care should be taken when interpreting the current results on this issue. Till now, there is still no strong evidence supporting the use of metformin in fertility-preserving treatment in AEH and EEC patients. Further research is needed to provide high-quality data to validate the role of metformin as adjunctive therapy alongside with progestin to preserve fertility for AEH and EEC patients.

Examining the relationship between metformin dose and cancer survival: A SEER-Medicare analysis.

Cancer is a major health problem in the U.S and type 2 diabetes mellitus (T2DM) is known to increase the risk for the development of many cancers. Metformin, a first-line therapy for treating T2DM, is increasingly being used for its anticancer effects; however, the literature is limited on the effect of metformin dose on overall survival in patients with stage IV cancer. Overall survival was defined as the time interval from the date of diagnosis to the last known follow-up or death from any cause. Subjects who were alive on December 31, 2016 were censored. In this cohort study we examined the relationship between metformin dose and overall survival in persons with both T2DM and stage IV lung, breast, colorectal, prostate, or pancreas cancers. We used a retrospective study design with Cox proportional hazards regression analysis of the 2007–2016 of the Surveillance Epidemiology and End Results-Medicare (SEER) dataset. Of the 7,725 patients, 2,981(38.5%) had been prescribed metformin. Patients who used metformin had significantly better overall survival in both unadjusted (Unadjusted HR, 0.73; 95% CI, 0.69–0.76; p < 0.001) and adjusted models (adjusted HR, 0.77; 95% CI, 0.73–0.81; p < 0.001). The overall survival between patients who took metformin with average daily dose ≥ 1000mg or < 1000mg were not statistically significant (aHR, 1.00; 95% CI, 0.93–1.08; p = 0.90). Metformin use regardless of dose is associated with increased overall survival in older adults with stage IV cancer.

Factors influencing prolactin levels in chronic long-term hospitalized schizophrenic patients with co-morbid type 2 diabetes mellitus.

For long-term hospitalized patients suffering from schizophrenia, metabolic disease and hyperprolactinemia (HPRL) are common comorbidities. This article is aimed at analyzing the factors influencing comorbid type 2 diabetes mellitus (T2DM) on prolactin (PRL) levels in long-term hospitalized patients suffering from schizophrenia. This study included 378 long-term hospitalized patients with schizophrenia. Common metabolic markers and PRL levels of included samples were collected, and the severity of psychopathology was assessed using the Positive and Negative Symptoms Scale (PANSS). Based on the patients with or without T2DM, the samples were divided into two groups. The differences in clinical parameters between the two groups were compared, and the effects of the parameters on the PRL levels were analyzed. Compared with non-DM patients, the patients in the DM subgroup had lower PRL levels (P < 0.0001) and rather severe psychiatric symptoms (P = 0.016). Female, treated by risperidone, and high levels of triglyceride (TG) were faced with risk for HPRL (B = 26.31, t = 5.39, P < 0.0001; B = 19.52, t = 4.00, P < 0.0001; B = 2.71, t = 2.31, P = 0.022, respectively). Meanwhile, co-morbid DM and aripiprazole treatment were protective factors (B = 15.47, t = 3.05, P = 0.002; B = -23.77, t = -2.47, P = 0.014; respectively). Ultimately, in the DM subgroup, the dose of metformin was found to be a protective factor for HPRL (B = -0.01, t = -1.46, P = 0.047), while female and aripiprazole were risk factors (B = 16.06, t = 3.26, P = 0.001; B = 20.13, t = 2.57, P = 0.011; respectively). Aripiprazole is a protective factor for HPRL in long-term hospitalized patients, whereas the female is a risk factor. Metformin is beneficial in reducing PRL levels in patients with co-morbid DM. More aggressive and effective interventions are required for preventing adverse drug reactions in women and patients with co-DM.

Adherence to metformin in adults with type 2 diabetes: a combined method approach

BackgroundMedication adherence, one of the most important aspects in the process of optimal medicines use, is unfortunately still a major challenge in modern healthcare, and further research is required into how adherence can be assessed and optimised. The aim of this study was to use a combined method approach of self-report and dried blood spot (DBS) sampling coupled with population pharmacokinetic (PopPK) modelling, to assess adherence to metformin in adult patients with type 2 diabetes. Further aims were to assess metformin exposure levels in patients, determine factors associated with non-adherence with prescribed metformin, and to explore the relationship between adherence and therapeutic outcomes.MethodsA combined method approach was used to evaluate metformin adherence in patients with type 2 diabetes who had been prescribed metformin for a minimum period of 6 months. Patients were recruited from consultant-led diabetic outpatient clinics at three hospitals in Northern Ireland, UK. Data collection involved self-reported questionnaires [Medication Adherence Report Scale (MARS), Beliefs about Medicines Questionnaire and Centre for Epidemiologic Studies Depression Scale], direct measurement of metformin concentration in DBS samples, and researcher-led patient interviews. The DBS sampling approach was coupled with population pharmacokinetic (PopPK) modelling, which took account of patient characteristics, metformin dosage and type of formulation prescribed (immediate or sustained release).ResultsThe proportion of patients considered to be adherent to their prescribed metformin, derived from self-reported MARS scores and metformin concentration in DBS samples, was 61.2% (74 out of 121 patients). The majority (n = 103, 85.1%) of recruited patients had metformin exposure levels that fell within the therapeutic range. However, 17 patients (14.1%) had low exposure to metformin and one patient (0.8%) had undetectable metformin level in their blood sample (non-exposure). Metformin self-administration and use of a purchased adherence pill box significantly increased the probability of a patient being classified as adherent based on logistic regression analysis. Both HbA1c and random glucose levels (representing poor glycaemic control) in the present research were, however, not statistically linked to non-adherence to metformin (P > 0.05).ConclusionsA significant proportion of participating patients were not fully adherent with their therapy. DBS sampling together with the use of a published PopPK model was a useful, novel, direct, objective approach to estimate levels of adherence in adult patients with type 2 diabetes (61.2%).

Tumour, whole-blood, plasma and tissue concentrations of metformin in lung cancer patients.

Metformin is used for the management of type 2 diabetes mellitus (T2DM) and is being tested clinically as an anticancer agent. Metformin concentrations safely achievable in human solid tissues including tumours are unknown. This study was designed to determine metformin concentration in tissue compartments as a function of dose to inform rational dosing in preclinical models and interpretation of clinical results." Subjects with solid tumours to be treated by resection and either (A) willingness to take metformin for 7-10 days before surgery or (B) taking metformin for T2DM were eligible. Whole blood, plasma, tumour, tumour-adjacent uninvolved tissue and subcutaneous adipose tissue were obtained for liquid chromatography with tandem mass spectrometry to measure metformin concentrations. All subjects had primary lung tumours. Metformin dose was significantly correlated with drug concentrations in all tissues analysed. Intersubject metformin concentrations varied by over two orders of magnitude. Metformin concentrations were significantly higher in tumour tissues and lower in adipose tissues compared to other tissues. Concentrations in blood and plasma were significantly correlated with concentrations in solid tissues. Metformin accumulates in cellular compartments. Concentrations observed in plasma, blood, lung and tumour tissues in subjects treated with US Food and Drug Administration-approved doses for T2DM are lower than those typically used in tissue culture studies. However, such tissue concentrations are in line with those found within cultured cells treated with supra-pharmacological doses of metformin. Given the large intersubject variability in metformin concentrations, it is imperative to determine whether there is an association between tissue metformin concentration and anticancer activity in humans.

Metformin and risk of gingival/periodontal diseases in diabetes patients: A retrospective cohort study.

AimTo compare the risk of gingival and periodontal diseases (GPD) between ever users and never users of metformin in patients with type 2 diabetes mellitus.MethodsThe Taiwan’s National Health Insurance database was used to enroll 423,949 patients with new onset diabetes mellitus from 1999 to 2005. After excluding ineligible patients, 60,309 ever users and 5578 never users were followed up for the incidence of GPD from January 1, 2006 until December 31, 2011. Propensity score-weighted hazard ratios were estimated by Cox regression.ResultsGPD was newly diagnosed in 18,528 ever users (incidence: 7746.51 per 100,000 person-years) and 2283 never users (incidence: 12158.59 per 100,000 person-years). The hazard ratio that compared ever users to never users was 0.627 (95% confidence interval: 0.600-0.655). When metformin use was categorized by tertiles of cumulative duration and cumulative dose, the risk significantly reduced in a dose-response pattern when the cumulative duration reached approximately 2 years or the cumulative dose reached 670 grams. Analyses on the tertiles of defined daily dose of metformin showed that the reduction of GPD risk could be seen in all three subgroups but the benefit would be greater when the daily dose increased.ConclusionLong-term use of metformin is associated with a significantly reduced risk of GPD.

Positive effect of vitamin D supplementation on weight loss in obese patients treated with glucagon-like peptide 1 and lifestyle interventions

Background. Obesity, prediabetes and type 2 diabetes mellitus (T2DM) are global diseases affecting the population of Ukraine, with an annual increase in morbidity. Insulin resistance occurs in up to 90% of obese patients, contributing to the accumulation of white adipose tissue, and has a risk for the further development of prediabetes and T2DM. However, other factors also play a negative role in the development of obesity, particularly cholecalciferol (vitamin D) deficiency. Vitamin D is a steroid hormone the main function of which is to regulate calcium and phosphorus metabolism, but this molecule also exhibits various properties, including the effects on carbohydrate metabolism. The purpose of this study was to identify and evaluate the role of vitaminD elevation in patients receiving glucagon-like peptide-1 agonists (GLP-1a) in combination with lifestyle interventions for the treatment of obesity and to compare its effectiveness with that in patients treating with metformin and sodium-glucose cotransporter 2 inhibitors (SGLT2i). Materials and methods. A prospective study included 155 obese patients, and follow-up data were available for 49 of them. The study group consisted of 30 patients receiving combination therapy with GLP-1a liraglutide at a dose of 1.2 to 3.0 mg per day. The control group included 19 patients receiving combination therapy with metformin in daily doses of 500 to 2,000 mg, and SGLT2i in daily doses of 10 to 12.5 mg. Treatment of vitamin D deficiency was performed with cholecalciferol at a dose of 4,000 IU/day. Results. In study group GLP-1a, 25 (83.3%) patients had vitamin D insufficiency, which is statistically similar to control group (p&gt;0.05)— 17 (89.5%) cases. All patients with vitamin D insufficiency received 4,000 IU of cholecalciferol daily during the follow-up period. In study group GLP-1a, the mean body mass before the treatment was 104.6 kg, after treatment— 96.36 kg (p=0.000007), the mean weight lost was 7.8% (range is 1–23.71%) of the initial level. Mean body mass index (BMI) before treatment was 37.1 kg/m2, after treatment— 34.11 kg/m2 (p=0.000006). In the control group, the mean weight before the treatment was 99.4 kg, after treatment— 91.74 kg (p=0.000196), the mean weight lost was 7.73% (range is 0–16.9%) of the initial level. BMI before treatment averaged 35.6 kg/m2, after treatment— 34.11 kg/m2 (p=0.000196). The analysis of carbohydrate metabolism parameters showed a significantly lower blood glucose level— 5.75 mmol/l in the study group GLP-1a compared to 8.42 mmol/l in the control group (p=0.00024). It should be noted that a similar clinical picture was also observed after treatment, despite the compensation of T2DM in all patients: a significantly lower blood glucose level— 5.03 mmol/l in the study group GLP-1a compared to 5.99 mmol/l in controls (p=0.002453). However, significantly higher levels of insulin were detected in the study group GLP-1a before treatment— 27.02 mU/L compared to 18.59mU/L in control patients (p=0.003286). After treatment, a similar situation was observed in terms of significantly higher levels of insulin: 19.41 mU/l in patients of the study group GLP-1a compared to 14.42mU/l in controls (p=0.0024). Corresponding changes were also observed for the HOMA index. Conclusions. Our results suggest high effectiveness of increasing the level of vitamin D in case of its insufficiency as a part of measures for the treatment of obese patients with liraglutide, metformin or SGLT2i.