Sulfonylurea Group Research Articles

Effects of Sulfonylureas and Dipeptidyl Peptidase 4 Inhibitors on Percentage Body Fat Change in Type 2 Diabetes Mellitus Patients on Metformin at 4 and 12 Weeks.

Introduction Anti-diabetic drugs used for the treatment of type 2 diabetes mellitus (T2DM) have a unique effect on the body weight and fat distribution of a patient. This study aimed to find out the change inpercentage body fat and body composition with the addition of sulfonylureas or dipeptidyl peptidase 4 (DPP-4) inhibitors to metformin monotherapy. Methods An observational 12-week follow-up study was conducted with a sample size of 52 patients. All patients enrolled in the study were evaluated forbaseline percentage body fat and body composition parameters including total body weight, total body water, and skeletal muscle mass using the ACCUNIQ BC300, added on to either sulfonylureas or DPP-4 inhibitors over a stable dose of metformin; repeat assessment performed at 4 weeks and 12 weeks, and change in values was noted. Results Of the 52 patients, 28 patients were on sulfonylureas and 24 were on DPP-4 inhibitors. In the sulfonylurea group, there was an increase in percentage body fat from 31.97 ± 8.77% at baseline to 32.65 ± 8.94% at 12 weeks (p = 0.041), while in the DPP-4 inhibitor group, there was a decrease in percentage body fat from 31.87 ± 7.41% at baseline to 31.24 ± 8.5% at 12 weeks (p = 0.102). In the sulfonylurea group, there was a decrease in body weight from 67.25 ± 14.79 kilograms (kg) at baseline to 66.97 ± 14.62 kg at 12 weeks (p = 0.429). In the DPP-4 inhibitor group, there was a decrease in body weight from 66.56 ± 10.82 kg at baseline to 65.76 ± 12.56 kg at 12 weeks (p = 0.079). In the sulfonylureagroup, total body water decreased from32.54 ±6.65 L at baseline to 32.06 ±6.51 L at 12 weeks (p = 0.084), while in the DPP-4 inhibitor group, the total body water decreased from 32.46 ±5.39 L at baseline to 32.18 ±5.48 L at 12 weeks (p = 0.741).Skeletal muscle mass decreased from 24.78 ±5.12 kgto 24.4 ±5.04 kg (p = 0.041) in the sulfonylurea group and from 24.74 ±4.2 kgto 24.53 ±4.25 kg(p = 0.666) in the DPP-4 inhibitor group. Conclusion Our study shows that sulfonylureas are associated with an increase in percentage body fat, while there were no significant changes associated with DPP-4 inhibitors when given in addition to metformin. There are no significant changes in body weight associated with sulfonylureas or DPP-4 inhibitors in addition to metformin. Also, sulfonylureas are associated with a decrease in skeletal muscle mass after 12 weeks.

Assessment of cardiovascular risk with sulfonylurea use in type 2 diabetes mellitus: A retrospective cohort study

AimsThe utilization of sulfonylurea (SU) for the management of Type 2 Diabetes Mellitus (T2DM) has witnessed a decline, attributed to the rising popularity of alternative medications and uncertainties surrounding the cardiovascular risk profile of SUs. This study aimed to investigate the potential association between SU intake and the incidence of cardiovascular events in patients with T2DM. MethodsA retrospective cohort study, based on a general practice (GP) registry, was designed, encompassing patients diagnosed with T2DM between 2005 and 2014.Follow-up persisted until the occurrence of a cardiovascular event, loss to follow-up, or until December 31, 2022. Comparative analyses were conducted between patients, receiving SU treatment and those without ResultsData from a cohort comprising 5589 patients revealed that 13 % and 13.1 % of individuals in the comparator group and the SU group, respectively, experienced a cardiovascular event. However, no statistically significant elevation in the risk of cardiovascular events was observed after SU usage. Furthermore, the glycated haemoglobin (HbA1c) levels were significantly higher in the SU group (7.0 % vs. 6.4 %,p < 0.001). ConclusionsThe findings from this study indicate that the use of sulfonylureas SUs is not associated with a statistically significant increase in the risk of cardiovascular events among patients with type T2DM. These results contribute to the ongoing discourse on the safety and efficacy of SU therapy in diabetes management.

Heterogeneous treatment effects of sodium-glucose cotransporter 2 inhibitors on risk of dementia in people with type 2 diabetes: A population-based cohort study.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors exhibit potential benefits in reducing dementia risk, yet the optimal beneficiary subgroups remain uncertain. Individuals with type 2 diabetes (T2D) initiating either SGLT2 inhibitor or sulfonylurea were identified from OneFlorida+ Clinical Research Network (2016-2022). A doubly robust learning was deployed to estimate risk difference (RD) and 95% confidence interval (CI) of all-cause dementia. Among 35,458 individuals with T2D, 1.8% in the SGLT2 inhibitor group and 4.7% in the sulfonylurea group developed all-cause dementia over a 3.2-year follow-up, yielding a lower risk for SGLT2 inhibitors (RD, -2.5%; 95% CI, -3.0% to -2.1%). Hispanic ethnicity and chronic kidney disease were identified as the two important variables to define four subgroups in which RD ranged from -4.3% (-5.5 to -3.2) to -0.9% (-1.9 to 0.2). Compared to sulfonylureas, SGLT2 inhibitors were associated with a reduced risk of all-cause dementia, but the association varied among different subgroups. New users of sodium-glucose cotransporter 2 (SGLT2) inhibitors were significantly associated with a lower risk of all-cause dementia as compared to those of sulfonylureas. The association varied among different subgroups defined by Hispanic ethnicity and chronic kidney disease. A significantly lower risk of Alzheimer's disease and vascular dementia was observed among new users of SGLT2 inhibitors compared to those of sulfonylureas.

Novel phenylpiperazine derivatives as potent transient receptor potential vanilloid 1 antagonists.

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, which is considered a highly validated target for pain perception. Repeated activation with agonists to desensitize receptors or use the antagonists can both exert analgesic effects. In this work, two series of novel phenylpiperazine derivatives were designed, synthesized, and evaluated for the invitro receptor inhibitory activity and invivo analgesic activity. Among them, L-21 containing sulfonylurea group was identified with potent TRPV1 antagonistic activity and analgesic activity in various pain models. At the same time, L-21 exhibited low risk of hyperthermia side effect. These results indicated that L-21 is a promising candidate for further development of novel TRPV1 antagonist to treat pain.

POLA PERESEPAN OBAT ANTIDIABETIK PADA PASIEN DIABETES MELLITUS TIPE II DI PUSKESMAS PANDAK 1 BANTUL

Diabetes mellitus in Indonesia is in the top five countries with the most DM sufferers, namely 19.5 million people and this number will increase to 28.6 million people in 2045. If diabetes is not treated properly loss of vision, kidney failure, nerves, limb amputation, and can cause premature death. This study aims to determine the pattern of prescribing for type II diabetes mellitus medication at the Pandak I Bantul Community Health Center for the period 2022. The research methodology used is descriptive observational with retrospective collection of medical record data with a sample of 90 medical records. The results of research on the prescribing pattern for type II diabetes mellitus drugs at the Pandak I Community Health Center consisted of the use of single diabetes mellitus drugs, namely 73.33% of metformin 500 mg, 24.45% of glimepirid 2 mg and 2.22% of glibenclamide 5 mg. The percentages are based on drug class, namely the biguanide group 73.33% and the sulfonylurea group 26.67%. So the pattern of prescribing medication for type II diabetes mellitus at the Pandak I Community Health Center with the single treatment mostly using metformin 500 mg with the biguanide group is 73.33%.

Environmental Fate and Dietary Risk Assessment Associated with Triafamone, Ethoxysulfuron and Their Metabolites in Rice Ecosystem

ABSTRACT Triafamone and ethoxysulfuron are ALS inhibitor herbicides belonging to sulfonamide and sulfonylurea group of herbicides used for control of weeds in rice ecosystem. Considering the environmental risk of these herbicides, the fate of triafamone and ethoxysulfuron was assessed to understand the best use of these herbicides. Degradation studies were carried out under field conditions in direct seeded rice (DSR) and transplanted rice (TPR) at an application rate of 67.5 and 135 g ha−1 and adsorption-desorption studies were carried out using batch equilibration technique. Residues of triafamone, ethoxysulfuron and their metabolites were extracted by ultrasonic assisted extraction method from soil and rice grain samples and liquid liquid extraction from straw samples and quantified using HPLC. Degradation half-life (DT50) of triafamone varied from 13.02–20.93 and 12.09–14.67 days under DSR and TPR conditions, respectively while for ethoxysulfuron DT50 ranged from 11.71–15.64 and 9.90–12.19 days. Among both the herbicides, triafamone was more persistent in the soil and at harvest, concentrations of triafamone and ethoxysulfuron in soil and rice were below the acceptable limit (<0.01 mg kg−1) imposed by principal regulatory agencies. Appearance and persistence of studied metabolites corroborated the degradation of parent molecule. Hazard quotient (HQ) of triafamone and ethoxysulfuron was 0.0013 and 0.000657 suggesting that application of these herbicides was safe for use in rice. Triafamone and ethoxysulfuron had a transient effect on soil biochemical and microbiological parameters depending on herbicide dose and moisture conditions. Freundlich adsorption coefficient (Kf) was 1.81 and 1.06 µg1–1/ng−1ml1/n for triafamone and ethoxysulfuron, respectively. GUS index for triafamone and ethoxysulfuron were 1.4 and 2.0 indicating low and moderate mobility, respectively. Principal component analysis (PCA) indicated that ethoxysulfuron has higher leachability than triafamone. Low to moderate persistence, adsorption and leaching of triafamone and ethoxysulfuron and transient ecological impacts on soil microorganisms may pave the way for safe and efficient weed control in rice cultivation.

Dipeptidyl peptidase-4 inhibitors versus sulfonylureas on the top of metformin in patients with diabetes and acute myocardial infarction.

Recent trials have shown that both the extent of glycated hemoglobin reduction and the duration of enhanced glycemic control are major factors that may affect cardiovascular outcome results. We aimed to investigate the impact of metformin (MET) combined with dipeptidyl peptidase-4 (DPP4) inhibitors or sulfonylureas (SU) on long-term clinical outcomes in patients with acute myocardial infarction (AMI) and type 2 diabetes mellitus (DM). This study was a prospective cohort trial. From November 2011 to December 2015, a total of 13,104 AMI patients were consecutively enrolled from the Korea AMI registry-National Institutes of Health. The patients were divided into the MET + DPP4 inhibitors group and the MET + SU group. The primary endpoint, major adverse cardiac events (MACE), was defined as the composite of all-cause death, recurrent myocardial infarction (MI), and any repeat revascularization up to 3-year follow-up. To adjust baseline potential confounders, an inverse probability weighting (IPTW) analysis was performed. Baseline well-matched two groups were generated (the MET + DPP4 inhibitors group, n=468 and the MET + SU group, n=468). During 3-year clinical follow-up, the cumulative incidence of MACE between the two groups was not significantly different after adjustment (16.8% for MET + DPP4 inhibitors group vs. 19.4% for MET + SU group, P=0.302). However, the MET + DPP4 inhibitors group was associated with reduced risk of MI [1.3% vs. 4.9%; hazard ratio (HR): 0.228, 95% confidence interval (CI): 0.090-0.580, P=0.001] than the MET + SU group. In patients with AMI and type 2 DM, the use of MET combined with DPP4 inhibitors was associated with reduced incidence of recurrent MI than MET combined with SU during 3-year follow-up.

Effect of Sulfonylureas Residues on the Lupine and Vigna Seedlings Development during Biotesting Research on Sod-Podzolic Soil

In a series of consecutive vegetation experiments on biotesting on samples of sod-podzolic cultivated soil after its treatment with herbicides from the class of sulfonylureas: Magnum, VDG, metsulfuron-methyl 600 g/kg, manufactured by August and Alistair Grand, MD, diflufenican 180 g/l + mesosulfuronmethyl 6.0 g/l, iodosulfuron-methyl-sodium 4.5 g/l + mephenpyrdiethyl 27 g/l (antidote), manufactured by Bayer. The residual phytotoxicity of these preparations for seedlings of sensitive cultures of white lupin (Lupinus albus) and masha (Vigna radiata) was studied. The initial soil samples were taken in the field on the 5th day after herbicides were applied in the field in winter wheat crops using 2 different tillage technologies: traditional on the basis of dump plowing and zero tillage. According to the results of biotesting samples at a temperature of 20°C and humidity at the level of 60% soil moisture capacity, it was shown that the half-life of herbicides (DT50) was reached after 40 ± 3 days of incubation, and detoxification to the level of 70–80% occurred 200–240 days after the introduction of herbicides into the soil. Regardless of the method of tillage and the applied herbicide, 2 years after the application of herbicides, the suppression of test crops at the level of 10% of the control was detected. White lupin and mash are highly sensitive to the effects of micro-quantities of herbicides of the sulfonylurea group, therefore it is recommended to use these test cultures to determine the residual phytotoxicity of the soil. The manifestation of the aftereffect of sulfonylureas on legumes is shown, which is important even in specialized crop rotations designed for zero tillage.

Relationship between HbA1c with Hypoglycaemic Attack and Diabetic Complications of Patients Admitted in a Tertiary Hospital

Background: Hypoglycemia is a major complication of diabetes mellitus and common causes of admission in hospital. Those who have long duration of diabetes having poor glycemic control, frequently experienced such events were self treated at home. The present study pointed to identify whether hemoglobin A1c (HbA1c) a marker of average plasma glucose, relates with severe hypoglycemia and diabetic complications or not.&#x0D; Materials and methods: A retrospective observational study was conducted in the Department of Medicine, Maa-Shishu-O-General Hospital, Agrabad, Chattogram from April 2019 to September 2021. Total 36 patients were selected, as presenting in Medicine Department with documented hypoglycaemia. All data was taken meeting exclusion criteria and analysed.&#x0D; Results: Hypoglycaemic episodes mostly occurred in elder cases (&gt;61 year of ages) n=16, 44% and HbA1c mostly belongs to between 7.6 to 8 groups. Confusion is the most common presentation, N=63, 63.9%. Neuropathy was found as common complication, (30.6% , n=11) cases and most of the neuropathy found in HbA1c 7.6 to 8.5 groups 54.54% , n=6 . Most of the patients were taking sulfonylurea group of drugs 47.2% , n=17, and mixed acting insulin n=21 ,58.3%.&#x0D; Conclusion: Hypoglycemic admission is not related to extensive Diabetic control rather with related to elder patients , various Diabetic complications and injudicious use of ant diabetic agents.&#x0D; Chatt Maa Shi Hosp Med Coll J; Vol.22 (1); January 2023; Page 44-47

A Placebo-Controlled, Double-Blind Clinical Investigation to Evaluate the Efficacy of a Patented Trigonella foenum-graecum Seed Extract “Fenfuro®” in Type 2 Diabetics

Background Trigonella foenum-graecum (Fenugreek) is an extensively researched phytotherapeutic for the management of Type 2 diabetes without any associated side effects. The major anti-diabetic bioactive constituents present in the plant are furostanolic saponins, which are more abundantly available in the seed of the plant. However, the bioavailability of these components depends on the method of extraction and hence formulation of the phytotherapeutic constitutes a critical step for its success. Objective The present study reports the efficacy of a novel, patented fenugreek seed extract, Fenfuro®, containing significant amount of furostanolic saponins, in an open-labelled, two-armed, single centric study on a group of 204 patients with Type 2 diabetes mellitus over a period of twelve consecutive weeks. Results Administration of Fenfuro® in the dosage of 500 mg twice daily along with metformin and/or sulfonylurea-based prescribed antidiabetic drug resulted in a reduction of post-prandial glucose by more than 33% along with significant reduction in fasting glucose, both of which were greater than what resulted for the patient group receiving only Metformin and/or Sulfonylurea therapy. Fenfuro® also resulted in reduction in mean baseline HOMA index from 4.27 to 3.765, indicating restoration of insulin sensitivity which was also supported by a significant decrease in serum insulin levels by >10% as well as slight reduction in the levels of C-peptide. However, in the case of the Metformin and/or Sulfonylurea group, insulin levels were found to increase by more than 14%, which clearly indicated that drug-induced suppression of glucose levels instead of restoration of glucose homeostasis. Administration of the formulation was also found to be free from any adverse side effects as there were no changes in hematological profile, liver function and renal function. Conclusion The study demonstrated the promising potential of this novel phytotherapeutic, Fenfuro®, in long-term holistic management of type-2 diabetes.

894-P: Sodium–Glucose Cotransporter 2 Inhibitors and Risk of Dementia in People with Type 2 Diabetes—A Population-Based Cohort Study

Background: SGLT2 inhibitors show promising associations with decreased dementia risk. However, it is unclear which population subgroups would benefit the most. Methods: Using electronic health records data from the OneFlorida+ Clinical Research Network, we identified individuals with T2D (aged ≥ 50 years) who initiated SGLT2 inhibitors or sulfonylureas from Jan 1, 2016 - Jan 31, 2022. The study outcome was incident dementia. We applied a causal machine learning approach - doubly robust learning - to estimate the conditional average treatment effects (CATE) in the overall cohort and heterogeneous treatment effect subgroups using a summary decision tree model. Results: Among 36,756 individuals with T2D, 3.2% in the SGLT2 inhibitor group and 6.4% in the sulfonylureas group developed dementia over a 3.4-year follow-up. In the overall cohort, SGLT2 inhibitors were associated with a lower risk of dementia (Risk Difference [RD], -10.3%; 95% confidence interval [CI], -12.0% to -8.6%) compared to sulfonylureas. We identified four subgroups with varying risks for dementia, determined by traumatic brain injury, ever-smoking, and epilepsy (Figure). Conclusion: SGLT2 inhibitors were associated with a lower risk of dementia in people with T2D compared to sulfonylureas, with significant variability across subgroups. Disclosure H.Tang: None. C.Shaaban: None. Y.Wu: None. T.Magoc: None. W.T.Donahoo: None. S.T.Dekosky: Advisory Panel; Acumen Pharmaceuticals, Cognition Therapeutics, Other Relationship; Biogen, Prevail Pharmaceuticals, UpToDate, Up-To-Date. J.Bian: None. J.Guo: Consultant; Pfizer Inc., Research Support; PhRMA Foundation, NIH - National Institutes of Health. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK133465)

Abstract WP171: Impact Of Pre-stroke Sulfonylurea Use On Functional Outcomes In The SHINE Trial

Background: Pharmacological and clinical evidence suggest that sulfonylurea (SU) medications may improve acute ischemic stroke (AIS) outcomes. The SHINE trial studied intensive vs standard blood sugar management in patients presenting with AIS and hyperglycemia. We investigated whether pre-existing SU use impacted functional outcomes in SHINE. Methods: SHINE data collection forms were reviewed to identify AIS patients taking SUs at the time of study enrollment. Our primary outcome compared the adjusted 90-day utility weighted modified Rankin Scale (UW-mRS) score in the SU and non-SU cohorts. The UW-mRS score was adjusted for age, baseline NIHSS, baseline glucose, and reperfusion therapy. Pre-specified analyses of the 90-day UW-mRS scores assessed for heterogeneity of SU effect across the following subgroups: age, stroke severity, reperfusion therapy, type of SU, and SHINE study arm. Results: In total, 1066 SHINE subjects with a final diagnosis of AIS were included (SU=248 [23.3%], non-SU=818 [76.7%]). Baseline demographics were generally similar (Table 1). Calculated 90-day mean UW-mRS score were higher in the non-SU group compared to the SU group: mean 0.617 ± 0.012 versus mean 0.566 ± 0.022 (Diff 0.051, 95% CI 0.001-0.1) without heterogeneity of treatment effect (Figure 1). Conclusion: Contrary to our hypothesis and published literature, our retrospective analysis of the SHINE trial demonstrated better functional outcomes in the non-SU cohort. This may be due to selection bias with inadequate controlling for baseline risk factors present in the SU cohort. Definitive prospective studies are required.

Comparison of Mitochondrial Adenosine Triphosphate–Sensitive Potassium Channel High- vs Low-Affinity Sulfonylureas and Cardiovascular Outcomes in Patients With Type 2 Diabetes Treated With Metformin

Sulfonylureas are frequently used as add-on to metformin in type 2 diabetes (T2D), and individual sulfonylurea agents carry different risks of cardiovascular disease. Sulfonylureas' different affinities to cardiac mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channels have been speculated to account for the intraclass difference in cardiovascular risk from in vitro and ex vivo studies; however, this hypothesis has not been assessed in a general population with diabetes receiving sulfonylureas added to metformin. To compare the risk of myocardial infarction (MI), ischemic stroke, or cardiovascular death in patients with T2D treated with mitoKATP channel high-affinity sulfonylureas and low-affinity sulfonylureas as add-on to metformin. This is a new-user, active-comparator, and propensity score-matched cohort study with analysis of the Taiwanese Diabetes Mellitus Health Database from 2006, to 2017. Data analysis was performed from August 2020 to July 2021. Cardiac mitoKATP channel high-affinity (glyburide and glipizide) and low-affinity (gliclazide and glimepiride) sulfonylureas combined with metformin. Primary outcome was major adverse cardiovascular events (MACEs), a composite of cardiovascular death or hospitalization for either MI or ischemic stroke. Secondary outcomes included individual MACE components, heart failure, arrhythmia, all-cause mortality, and severe hypoglycemia. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs). Each sulfonylurea group comprised 53 714 patients (mean [SD] age, 54.7 [12.1] years; 31 962 men [59.5%]). MitoKATP channel high-affinity sulfonylureas vs low-affinity sulfonylureas when combined with metformin were associated with an increased risk of MACE (aHR, 1.18; 95% CI, 1.03-1.34), MI (aHR, 1.34; 95% CI, 1.04-1.73), all-cause mortality (aHR, 1.27; 95% CI, 1.03-1.57), and severe hypoglycemia (aHR, 1.82; 95% CI, 1.58-2.10), but not with increased risks of ischemic stroke, cardiovascular death, arrhythmia, and heart failure. The duration analyses revealed the highest MACE risk during 1 to 90 days after initiation of mitoKATP channel high-affinity sulfonylureas (aHR, 6.06; 95% CI, 4.86-7.55). Use of mitoKATP channel high-affinity sulfonylureas vs low-affinity sulfonylureas was associated with an increased MACE risk in patients with T2D concomitantly receiving metformin, suggesting that high-affinity blockage of the mitoKATP channels could account for sulfonylurea-associated MACEs.

Effects of second-line antihyperglycemic drugs on the risk of chronic kidney disease: applying a target trial approach to a hospital-based cohort of Thai patients with type 2 diabetes

BackgroundThe reno-protective effect of second-line treatments in type 2 diabetes has been assessed by clinical trials but generalizability to routine clinical practice is still uncertain. We aimed to assess the effectiveness of these treatments, when added to metformin, on the risk of chronic kidney disease (CKD).MethodsA real-world, hospital-based, type 2 diabetes cohort was retrospectively assembled at Ramathibodi Hospital from 2010 to 2019. Patients who received sulfonylureas (SU), thiazolidinediones (TZD), dipeptidyl peptidase-4 inhibitors (DPP4i), or sodium-glucose cotransporter-2 inhibitors (SGLT2i), as second-line antihyperglycemic treatment were included. Treatment effect models with inverse probability weighting and regression adjustment were used to estimate CKD risk according to treatment.ResultsCKD was identified in 4,132 of the 24,777 patients with type 2 diabetes (16.7%). The CKD incidence (95% CI) was 4.1% (2.2%, 6.9%), 13.5% (12.5%, 14.6%), 14.8% (13.5%, 16.1%), and 18.0% (17.4%, 18.5%) for patients receiving SGLT2i, DPP4i, TZD, and SU treatment, respectively. The average treatment effects (i.e., the difference in CKD risk) for SGLT2i, DPP4i, and TZD compared to SU were − 0.142 (− 0.167, − 0.116), − 0.046 (− 0.059, − 0.034), and − 0.004 (− 0.023, 0.014), respectively, indicating a significant reduction in CKD risk of 14.2% and 4.6% in the SGLT2i and DPP4i groups, respectively, compared to the SU group. Furthermore, SGLT2i significantly reduced CKD risk by 13.7% (10.6%, 16.8%) and 9.5% (6.8%, 12.2%) when compared to TZD and DPP4i, respectively.ConclusionsOur study identified 14.2%, 13.7%, and 9.5% reduced CKD risk in Thai patients with type 2 diabetes who were treated with SGLT2i compared to those treated with SU, TZD, and DPP4i, respectively, in real-world clinical data. Previous evidence of a reno-protective effect of SGLT2i reported in other populations is consistent with our observations in this Southeast Asian cohort.

Metformin Use and Incidence of Cancer: A Large Retrospective Cohort Study of U.S. Veterans

Introduction: Metformin may have anti-cancer properties through multiple mechanisms yet data are limited. In this study, we sought to examine the association between metformin use and the risk of incident hematologic and non-hematologic cancers. Methods: We conducted a large retrospective cohort study among regular users of Veteran Administration (VA) care identified from the National Veteran Administration's clinical and administrative databases and Medicare. We included veterans aged ≥55 years with diabetes (DM) started on metformin or sulfonylurea (SU) between 2001-2012. We excluded patients with any prior cancer history (by ICD-9 code) or with missing data on kidney function, weight, race, and/or hemoglobin A1c. Drug exposure was assessed by extraction of medication lists from pharmacy databases (Clinical Data Warehouse and Central Management Server). Regular medication use was defined as filling ≥2 outpatient prescriptions per year. After initial prescriptions, a 2-year washout period was observed during which eligible patients continued regular use of initially prescribed DM drug, free of cancer, and had no exposure to other DM medications. Follow-up began at the end of the washout period and ended at first cancer diagnosis, death, oral DM medication change (metformin users started on/switched to SU and vice versa), or end of follow-up (July 10, 2016), whichever came first. The primary outcome was any newly diagnosed cancer (≥2 ICD-9 diagnosis codes for the same cancer, ≥1 week apart, within 6 months). We further sub-categorized new cancer diagnoses as hematologic (leukemia, lymphoma, or multiple myeloma) and non-hematologic (solid tumors). We used a new user design to mitigate risk of prevalent user bias and an active-comparator cohort of new users of SU to isolate metformin's effect beyond glycemic control. To minimize confounding by indication, we developed a propensity score and used inverse probability treatment weighting (IPTW). Baseline characteristics between metformin and SU groups were then compared to ensure similarity between groups. Cox proportional hazards models, using age as the time scale, were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the association between metformin (vs. SU) and incident cancer. Results: The study sample included 88,714 Veterans; mean age 68.6 ± 7.8 years; 98% male; 84% white, 13% black, and 3% other race. After IPTW, baseline characteristics were balanced between groups (Table 1). We identified 60,477 metformin new users and 28,237 of SU new users. Over a mean follow-up of 4.2 ± 3.0 years, there were 7,383 incident cancer diagnoses, or 19.8 per 1,000 person-years (p-y); 17.5 per 1,000 p-y were in metformin users and 24.5 per 1,000 p-y were in SU users. Given the substantial effect modification of the association between medication use and cancer by age, a piecewise analysis was performed, stratifying the models by age group (55-64, 65-74, ≥75 years). In patients 55-64 years, incidence of any cancer was 14.2 per 1000 p-y in metformin users and 18.4 per 1000 p-y in SU users. The association between metformin or SU and incident cancer had a crude HR 0.69 (95% CI 0.64-0.75) and an IPTW-adjusted HR 0.81 (95% CI 0.73-0.88). A similar trend was observed in patients 65-74 years: users of metformin had fewer incident cancers, with an IPTW-adjusted HR 0.87 (95% CI 0.81-0.94). However, in patients ≥75 years, cancer incidence did not differ between metformin and SU users, IPTW-adjusted HR 0.91 (95% CI 0.82-1.01). Associations between metformin and incident hematologic cancers were similar to those observed for all incident cancers: in patients 55-64 years, IPTW-adjusted HR 0.68 (95% CI 0.54-0.87) and in patients 65-74 years, IPTW-adjusted HR 0.79 (95% CI 0.63-0.98). Incidence rates of hematologic malignancies in older adults (≥75 years) did not differ between metformin and SU groups (IPTW-adjusted HR 0.93 (95% CI 0.69-1.25). Conclusions: Among U.S. Veterans with diabetes, new metformin users aged 55-75 years had lower incidence of hematologic and non-hematologic malignancies compared to SU users. Metformin use was not associated with cancer incidence among patients ≥75 years. Our findings make more urgent the need for randomized controlled trials to determine the potential of metformin in primary prevention of cancer in both solid and liquid tumors, as well as further studies into the mechanism of metformin's anti-cancer effects. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CHARACTERIZATION AND DISSOLUTION RATE STUDIES OF INCLUSION COMPLEX OF GLIBENCLAMIDE AND HYDROXYPROPYL-Β-CYCLODEXTRIN USING CO-GRINDING METHOD

Objective: Glibenclamide belongs to the 2nd generation sulfonylurea group as an oral antidiabetic with low solubility in water and high bioavailability in systemic circulation (Biopharmaceutical Classification System class II). This study aimed to increase the solubility and dissolution rate of glibenclamide by preparing an inclusion complex of Glibenclamide and Hydroxypropyl-β-cyclodextrin. Methods: Inclusion complexes were prepared by the co-grinding method in two ratios 1:1 and 1:2 mol. Characterizations of inclusion complex were carried out by Scanning Electron Microscopy (SEM), Fourier Transform Infrared (FT-IR) spectroscopy, Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD) analysis. Solubility test was carried out in CO2-free distilled water and dissolution rate was carried out in phosphate buffer pH 7.4. Results: The results of the SEM analysis showed changes in particle morphology. FT-IR spectroscopy shows a shift in wavenumber. DSC analysis showed a decrease in the melting point of the inclusion complex. XRD characterization results showed a decrease in the intensity of the inclusion complex. Solubility of inclusion complex of glibenclamide increased nine times 1:1 mol inclusion complex, twelve times 1:2 mol inclusion complex compared to intact glibenclamide. The dissolution of glibenclamide, inclusion complex 1:1, and inclusion complex 1:2 in phosphate buffer pH 7.4 medium at 60 min was 17.19%, 34.15% and 52.83% respectively. Conclusion: Based on the results of the study, it can be said that the glibenclamide inclusion complex with Hydroxypropyl-β-cyclodextrin successfully increases the solubility and dissolution rate of glibenclamide significantly.

Concurrent Use of Oral Anticoagulants and Sulfonylureas in Individuals With Type 2 Diabetes and Risk of Hypoglycemia: A UK Population-Based Cohort Study.

ObjectiveTo investigate the association of concurrent use of oral anticoagulants (OACs) and sulfonylureas and the risk of hypoglycemia in individuals with type 2 diabetes mellitus (T2DM).Research Design and MethodsA retrospective cohort study was conducted between 2001 and 2017 using electronic primary healthcare data from the IQVIA Medical Research Data (IMRD) that incorporates data supplied by The Health Improvement Network (THIN), a propriety database of Cegedim SA. Individuals with T2DM who received OAC prescription and sulfonylureas were included. We compared the risk of hypoglycemia with sulfonylureas and OACs using propensity score matching and Cox regression.Results109,040 individuals using warfarin and sulfonylureas and 77,296 using direct oral anticoagulants (DOACs) and sulfonylureas were identified and included. There were 285 hypoglycemia events in the warfarin with sulfonylureas group (incidence rate = 17.8 per 1,000 person-years), while in the sulfonylureas only, 304 hypoglycemia events were observed (incidence rate = 14.4 per 1,000 person-years). There were 14 hypoglycemic events in the DOACs with sulfonylureas group (incidence rates = 14.8 per 1,000 person-years), while in the sulfonylureas alone group, 60 hypoglycemia events were observed (incidence rate =23.7 per 1,000 person-years). Concurrent use of warfarin and sulfonylureas was associated with increased risk of hypoglycemia compared with sulfonylureas alone (HR 1.38; 95% CI 1.10–1.75). However, we found no evidence of an association between concurrent use of DOACs and sulfonylureas and risk of hypoglycemia (HR 0.54; 95% CI, 0.27–1.10) when compared with sulfonylureas only.ConclusionsWe provide real-world evidence of possible drug-drug interactions between warfarin and sulfonylureas. The decision to prescribe warfarin with coexistent sulfonylureas to individuals with T2DM should be carefully evaluated in the context of other risk factors of hypoglycemia, and availability of alternative medications.

Implementation of factorial experimental design in chitosan - tripolyphosphate nanoparticles development by ionotropic gelation

Glimepiride (GM) is third generation sulfonylurea group and preferably used for the treatment of type -II diabetes mellitus. It belongs to BCS class II drugs according to biopharmaceutical classification system which shows low aqueous solubility. The purpose of this work was to develop and optimize glimepiride loaded chitosan- tripolyphosphate nanoparticles by ionotropic gelation method using 32 full factorial experimental designs. The developed chitosan nanoparticles were evaluated for particle size, zeta potential, entrapment efficiency, %yield and in vitro drug release etc. Factorial experimental design was implemented to optimize the independent variables like drug: polymer ratio (X1) and concentration of cross linking agent (X2) on dependent variables like particle size (Y1) and entrapment efficiency (Y2). A statistical analysis was performed using minitab 16 software with respect to ANOVA, regression analysis. The surface plots and contour plots represent the relationship between the experimental responses and the set of independent variables. The factorial experimental design was validated by checkpoint analysis and desirability function approach was applied for optimization of chitosan nanoparticle formulation. Drug entrapment efficiency and mean particle size of optimized formulation was found to be 61.25% and 222 nm respectively. Nanoparticles revealed initial burst release followed by slow drug release.

NARRATIVE REVIEW: COST-EFFECTIVENESS ANALYSIS OF THE USE OF ORAL ANTIDIABETIC DRUGS BIGUANIDE AND SULFONYLUREA GROUP IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Diabetes Mellitus requires long-term management at a considerable cost. Therefore, a cost-Effectiveness analysis was used to assess several health interventions. Biguanide and Sulfonylurea provided the best results at the cheapest cost in this study. This study aims to gain a supporting theoretical foundation regarding the cost-effectiveness of using oral antidiabetic drugs biguanide and sulfonylureas in patients with type 2 diabetes mellitus. The method used in this study is a Narrative Review using literature that discusses the cost-effectiveness of oral antidiabetic drugs biguanide and sulfonylureas in patients with type 2 diabetes mellitus. Based on the results of this study, the age range of the occurrence of Type 2 Diabetes Mellitus is 45-65 years, with more percentage of male patients than women and a common complication is hypertension. In this study, the use of the biguanide drug (Metformin) was shown to provide a significant reduction in blood sugar levels at a reasonably low cost. The ICER results showed that combination drugs increased additional costs, but their use was more effective in healing and improving patients' quality of life. In conclusion to this study, the use of biguanide and sulfonylurea groups proved cost-effective compared to other antidiabetic drugs.

High incidence of undetected low sensor glucose events among elderly patients with type 2 diabetes more than a decade on after the ACCORD study

Objective Hypoglycaemia leads to significant morbidity and impacts negatively on quality-of-life, especially in elderly people with increased frailty. The aims of this study were to determine the prevalence of low interstitial fluid glucose (IFG) in patients with tightly controlled type 2 diabetes (T2D), and to evaluate whether there were differences in burden of low IFG between sulphonylurea and insulin treated groups. Methods A Freestyle Libre-Pro sensor was used for sampling of the IFG continuously. Patients were blinded to the IFG levels. The sensor was returned to the investigators after a 2-week period and the data were downloaded for analysis. Results There was a total of 69 patients (median age 72 years (IQR = 69–74)) − 40 were sulfonylurea-treated and 29 insulin-treated. In total, 781 low sensor glucose events (<4.0 mmol/L) were detected, of which 254 were very low sensor glucose events (<2.8 mmol/L). Twenty-six out of 29 insulin-treated (89.6%) and 36 out of 40 sulphonylurea-treated patients (90%) contributed to the 781 events of low sensor glucose. Twenty out of 29 insulin-treated (69%) and 26 out of 40 sulphonylurea-treated patients (65.0%) contributed to the 254 very low sensor glucose events. Only 9% of all events were identified by patients. Nocturnal events represented 55.8% of low sensor glucose events and 61.0% of very low sensor glucose events. At a cut-off of <2.8 mmol/L, it was found that the insulin group had a significantly greater number of such events as compared to the sulfonylurea group. Conclusions This study demonstrates that elderly patients with tightly-controlled T2D have a significant number of low sensor glucose events which go by undetected.