Oral Antihyperglycemic Medications Research Articles

DEVELOPMENT AND EVALUATION OF METFORMIN TABLETS: EFFECT OF SUPERDISINTEGRANTS

Metformin is an oral antihyperglycemic medication used to treat type 2 diabetes. BCS-III classification of medications includes metformin hydrochloride, which has a high solubility and a low permeability. This study’s objective was to develop wet granulated metformin hydrochloride tablets using various synthetic superdisintegrants. On disintegration and dissolution, the effects of different superdisintegrants have been studied. After evaluation, it were observed that post-compression properties such as weight variability, thickness, hardness, and friability were within the IP ranges. The formulation F4 with Croscarmellose sodium (CCS) in low concentration was chosen as the best formulation. By increasing the quantity of Croscarmellose sodium (CCS), the in vitro dissolution profile increased, and in vitro disintegration time also increased in the formulated tablets using wet granulation method. The statistical significance was determined using one-way ANOVA, and there is no significant difference between formulations.

Efficacy and Safety of Tirzepatide in Patients with Type 2 Diabetes: Analysis of SURPASS-AP-Combo by Different Subgroups.

Tirzepatide is a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist. In the SURPASS-AP-Combo trial, once-weekly tirzepatide was associated with improved glycemic control and weight loss versus insulin glargine and was generally well tolerated in an Asia-Pacific, predominately Chinese, population with type 2 diabetes (T2D). This post hoc subgroup analysis of SURPASS-AP-Combo assessed the potential influence of patient baseline characteristics on the efficacy and safety of tirzepatide. Changes from baseline to week 40 in HbA1c, body weight, fasting serum glucose (FSG), and daily glucose average from self-measured blood glucose profiles were analyzed by potential influential factors including age (< 65, ≥ 65years), sex, baseline HbA1c (≤ 8.5, > 8.5%), body mass index (BMI) (< 25, ≥ 25kg/m2), body weight (< 75, ≥ 75kg), duration of diabetes (< 10, ≥ 10years), and concomitant oral antihyperglycemic medications (metformin, metformin plus sulphonylurea). Gastrointestinal adverse events and hypoglycemia were also evaluated. At week 40, all tirzepatide doses were associated with reduced HbA1c, body weight, FSG, and daily glucose average from baseline in all subgroups. Greater HbA1c reductions were achieved in patients with higher baseline HbA1c across all tirzepatide doses, higher body weight with 10mg and younger age with 15mg tirzepatide. Greater reductions in body weight were observed in patients with higher body weight across all tirzepatide doses, lower baseline HbA1c with 5mg and higher BMI with 5mg tirzepatide. In this post hoc analysis, tirzepatide was associated with reduced blood glucose and body weight in a predominantly Chinese population with T2D across different subgroups, consistent with previous reports for tirzepatide. NCT04093752.

Formulation, Optimization, and Evaluation of Gliclazide loaded Nanosuspension for Dissolution Rate Enhancement

Diabetes mellitus is a prolonged metabolic condition categorized through elevated blood glucose levels. To treat this condition, oral antihyperglycemic medications like gliclazide, a second-generation sulfonylurea insulin secretagogue, are commonly used. Gliclazide comes into the biopharmaceutical classification system (BCS) class-II types, known for its lower solubility. To enhance its solubility, gliclazide was integrated into nanosuspensions. This study focused on formulating these gliclazide nanosuspensions using Kollicoat IR and Soluplus through the anti-solvent-precipitation method, through optimization achieved using the Box Behnken Design. Key parameters assessed included particle size (224 ± 1.23 nm) and entrapment efficiency (95.65 ± 0.12%). The drug release studies conducted on pH 7.4 indicated that over 95% of the drug was released within 30 minutes for the nanosuspension, whereas the pure drug solution released less than 70% in the same time frame, indicating immediate release with the nanosuspension. The morphology was examined using scanning electron microscopy (SEM), while fourier transform infrared (FTIR), X-Ray diffractometers (XRD), and differential scanning calorimeter (DSC) analyses confirmed the presence of the drug within the nanosuspension. In summary, the incorporation of gliclazide into nanosuspensions proved successful, resulting in enhanced release characteristics and ameliorated solubility.

Sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes mellitus and moderate to severe hepatic fibrosis: A retrospective study

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to decrease hepatic transaminases, steatosis, and in some studies, hepatic fibrosis. However, the safety and efficacy of SGLT2i has not been tested in patients who have moderate to severe hepatic fibrosis. In a retrospective study of sixty patients with moderate to severe hepatic fibrosis (kPa estimated by Fibroscan > 10), SGLT2i were prescribed on top of other oral anti-hyperglycemic medications. The safety and efficacy of SGLT2i were evaluated. Using the Fibroscan, CAP scores (decibel/meter), and liver stiffness measurement (LSM) (kPa, kilopascals) were examined before and after treatment. The mean age of the T2DM patients was 54.7±10.3 years, and the mean duration of T2DM was 8.3±7.1 years. SGLT2i were given from 3 to 36 months. After treatment, a decrease in glycated hemoglobin (HbA1c), and hepatic transaminases (SGOT and SGPT) was recorded. Upon follow up, CAP and kPa scores decreased significantly. Importantly, no adverse drug reaction, such as balanoposthitis, vulvovaginitis, urosepsis, and postural drop in blood pressure, were reported in any patient. In this retrospective cohort study, patient with T2DM and moderate to severe hepatic fibrosis, use of SGLT2i is safe with respect to common adverse effects & may have contributed to improved hepatic profile.

The impact of sitagliptin in palmitic acid-induced insulin resistance in human HepG2 cells through the suppressor of cytokine signaling 3/phosphoinositide 3-kinase/protein kinase B pathway.

Patients with type 2 diabetes respond differently to sitagliptin, an oral anti-hyperglycemic medication. Patients whose blood sugar levels were effectively managed while using sitagliptin had significantly lower levels of a protein called suppressor of cytokine signaling 3 (SOCS3), according to our earlier research. In this study, we established an in vitro insulin resistance cell model for human HepG2 cells to investigate the possible mechanism of the effect of sitagliptin on glucose metabolism via the SOCS3/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. Since insulin resistance first develops in the liver, palmitic acid was used to generate an insulin resistance cell model in human HepG2 cells, after which small interfering ribonucleic acid (siRNA)-SOCS3 and sitagliptin were used to intervene. We then examined the changes in cell viability and biochemical indices in the insulin resistance cell model. SOCS3, Akt, and glycogen synthase kinase 3beta (GSK-3β) gene expression levels were quantified using reverse transcription-polymerase chain reaction, and the protein expression levels of SOCS3, Akt, phosphorylated Akt (p-Akt), GSK-3β, and phosphorylated GSK-3β (p-GSK-3β) were quantified using Western blot. In results: the expression of the SOCS3 gene was considerably raised in both the insulin resistance model group and the insulin resistance model + siRNA-negative control group, but decreased following treatment with sitagliptin. After sitagliptin intervention, the protein expression of Akt, p-Akt, and p-GSK-3β were dramatically decreased in the model group, while SOCS3 was significantly decreased. We conclude that sitagliptin can reduce insulin resistance by downregulating SOCS3 and regulating glucose metabolism in a hypoglycemic manner.

DETERMINATION OF METFORMIN AND SITAGLIPTIN IN HEALTHY HUMAN VOLUNTEERS' BLOOD PLASMA AND ITS BIOEQUIVALENCE STUDY UNDER FASTING CONDITION

Objective: Metformin hydrochloride and sitagliptin are the oral anti-hyperglycemic medications used to treat type 2 diabetes and are used in combination to treat patients. In this work, we have developed a bioanalytical method for simultaneous estimation of both the drugs form some formulation and subsequently the validation of the developed method metformin and sitagliptin in human plasma. Methods: The stability studies were done as per USFDA and EMA guidelines. The sample extraction approach presented here was a straightforward liquid extraction. The linearity range of metformin was 11.72 ng/ml to 3000 ng/ml, and sitagliptin was 4.68 ng/ml. to 1200 ng/ml. For metformin, the LOD was 1.0 ng/ml, and LLOQ was 11.72 ng/ml. and for sitagliptin, the LOD was 0.75 ng/ml, and LLOQ was 4.68 ng/ml. LC-ESI-MS/MS was used to develop and validate this method using the Phenomenex Kinetex C18 column. Milli-Q water containing 10 mmol Ammonium Acetate (pH =3.6) and Acetonitrile containing 0.1% Formic Acid (pH =2.4) as solvent systems for the estimation of Sitagliptin in a single dose. Metoprolol is used as an Internal Standard. Results: The total chromatographic run time was only 7.0 min, and the elute time of metformin and sitagliptin was 3.94 min and 3.97 min, respectively. Relative Bioavailability was found at 101.14% for Metformin and 96.96% for Sitagliptin. The overall results show that the Cmax, AUC0-t, and AUC0-∞ for metformin and sitagliptin were within the acceptable limit of 80%-125%. Conclusion: This bioanalytical method was successfully applied in the bioequivalence study. The study design was a randomized, open-label, two treatment, two-period, two sequences, single-dose, crossover bioequivalence study under fasting conditions.

Euglycemic diabetic ketoacidosis: A rare but serious side effect of sodium-glucose co-transporter 2 inhibitors.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an insulin-independent class of oral antihyperglycemic medication and from recently established therapy in chronic heart failure patients. A rare, but potentially life-threatening complication of SGLT2 inhibitor use is euglycemic diabetic ketoacidosis. We described a case of a middle-aged male patient with type 2 diabetes who developed metabolic ketoacidosis after a few days of empagliflozin administration. SGLT2 inhibitor related ketoacidosis presents with euglycemia or only modestly elevated glucose blood concentrations, which causes delayed detection and treatment of ketoacidosis. There are multiple possible risk factors and mechanism that might contribute to the pathogenesis of ketoacidosis. It is implied that SGLT2 inhibitor use and prescription by non-diabetologists (cardiologists, nephrologists, family physicians, etc.) will continue to grow in the future. It is important to inform the general cardiac public about this rare but serious side effect of SGLT2 inhibitors.

Abstract CT518: First-in-human dose-escalation study of the phosphatidylinositol 3-kinase α-selective inhibitor HS-10352 in advanced breast cancer

Abstract Background: PIK3CA mutation is particularly prevalent in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. HS-10352 is a highly potent and selective small molecule inhibitor of phosphoinositide 3-kinase α. Preclinical studies have indicated the favorable safety and antitumor activity of HS-10352 in PIK3CA-mutated tumor models. Methods: A phase 1, open-label, dose-escalation study was conducted to assess the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity, in patients (pts) with advanced HR+HER2- breast cancer for whom standard therapy was ineffective or unavailable. The rolling six dose-escalation scheme was used to determine the maximum tolerated dose (MTD). Tumor tissues were collected for retrospectively central determination of PIK3CA mutation status. Results: Eighteen pts were treated with HS-10352 orally once daily (2 mg n=3; 4 mg n=3; 6 mg n=6; 8 mg n=6). All patients were HR+HER2- female breast cancer with visceral metastases after a median number of 3 prior systemic therapies for advanced disease. The median treatment duration was 111.5 days (range: 13~388). Dose limiting toxicities occurred in 2 pts at 8 mg (2 Grade 3 hyperglycemia). The MTD was established as 6 mg. According to the CTCAE 5.0, the most common (≥ 30%) treatment-related adverse events (TRAEs) were hyperglycemia (88.9%, n=16), weight decreased (61.1%, n=11), insulin C-peptide increased and diarrhea (33.3% each, n=6). Grade 3-4 TRAEs were hyperglycemia (8 mg, n=2), weight decreased (6 mg, n=2), fatigue (8 mg, n=1), vision blurred (8 mg, n=1), hyperkalemia (8 mg, n=1) and hypocalcemia (8 mg, n=1). Hyperglycemia was generally manageable with oral anti-hyperglycemic medications (13/16). Treatment-related rash were mild (22.2%, grade 1: n=2; grade 2: n=2). The overall response rate (ORR) and disease control rate (DCR) for all patients (n=18) were 27.8% and 55.6% respectively. For 6 pts with PIK3CA mutation, ORR was 50.0% (confirmed partial response [PR] in 3 pts at 6 mg) and DCR was 100.0% (6 mg, n=4; 8 mg, n=2), and the 9-month progression-free survival (PFS) rate was 66.7% (95% CI: 28.9%~100.0%). Of 4 pts with PIK3CA mutation at potentially recommended phase 2 dose of 6 mg, three pts (75.0%) achieved confirmed PR and 1 patient (25.0%) had stable disease (PFS ≥ 7.4m). Plasma exposure of HS-10352 increased proportionally following single dose. The mean plasma half-life of HS-10352 was 11~15 hours. Conclusions: HS-10352 showed a manageable safety profile and favorable PK properties. The promising antitumor activity was observed in patients with HR+HER2- advanced breast cancer harboring PIK3CA mutation. Clinical trial information: NCT04631835. Citation Format: Quchang Ouyang, Ying Wang, Jian Zhang, Qiong Wu, Changan Sun, Hongying Wei, Xiaoling Qian, Xichun Hu. First-in-human dose-escalation study of the phosphatidylinositol 3-kinase α-selective inhibitor HS-10352 in advanced breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT518.

92-LB: Higher Adherence and Persistence for Dulaglutide Compared with Oral Semaglutide at Six-Months Follow-Up with U.S. Real-World Data

A retrospective, observational analysis of administrative claims data from the IBM MarketScan Databases assessed adherence and persistence among GLP-1 RA naive adult patients with T2D newly initiating dulaglutide (DU) or oral semaglutide (OS) between Sept 2019 and Nov 2020. Patients had continuous enrollment in the 6-mo pre-index period and 6-mo follow-up periods. The DU patients were propensity-score matched 1:1 to OS patients (6,166 pairs) . The median age was 54 years at index date, and 48% were female. At pre-index, mean aDCSI was 0.6 and 10% of patients had ASCVD. Most patients used oral anti-hyperglycemic medication (87%) ; a smaller proportion used insulin (15%) . The most common prescribing provider was primary care (62%) . More DU patients were adherent (proportion days covered [PDC] ≥80%) (65% vs. 50%, p&amp;lt;0.001) and had higher mean PDC vs. OS (0.78 vs. 0.68, p&amp;lt;0.001) . More DU patients were persistent on therapy compared to OS patients (72% vs. 57% p&amp;lt;0.001) and had longer mean duration of persistence (148 vs. 128, p&amp;lt;0.001) . Among patients with ≥2 fills of their index drug, 73% of DU and 62% of OS patients were adherent. During the 6-mo follow-up period, DU patients had significantly higher adherence and persistence compared to OS patients. Disclosure R. Paczkowski: Employee; Eli Lilly and Company. M. Hoog: Employee; Eli Lilly and Company, Stock/Shareholder; Abbott, Eli Lilly and Company. J. Peleshok: Employee; Eli Lilly and Company, Eli Lilly and Company. M. Yu: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A. Huang: None. B. Limone: None. J. Manjelievskaia: Employee; IBM Watson Health, Other Relationship; Eli Lilly and Company. Funding Eli Lilly and Company

215-OR: Once Weekly (QW) Basal Insulin Fc (BIF) Demonstrated Similar Glycemic Control to Once Daily (QD) Insulin Degludec (DEG) in Insulin-Naïve Patients with Type 2 Diabetes (T2D)

Basal Insulin Fc (BIF; LY3209590) , a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for QW administration. This randomized, parallel, open-label Ph2 study assessed safety and efficacy of BIF vs. DEG in insulin-naïve patients with T2D previously treated with oral antihyperglycemic medication. BIF was injected QW, and DEG was injected QD. Both groups were titrated to fasting blood glucose (FBG) ≤100 mg/dL. The primary endpoint was HbA1c change from baseline (CFBL) to Wk 26 (non-inferiority margin=0.4%) . Patients randomized to BIF (N=129) and DEG (N=135) had a mean age of 58.4 yrs and baseline HbA1c of 8.0%. After 26 wks, BIF showed non-inferiority vs. DEG for HbA1c CFBL with a treatment difference of 0.06% (90% CI = -0.11, 0.24; p = .56) , and both groups had &amp;gt;75% time in range (70-180 mg/dL) on average at Wk 26 (Figure) . BIF and DEG significantly reduced FBG from baseline (treatment difference BIF vs. DEG = 4.7 mg/dL [90% CI = 0.1, 9.3]; p = .09) . Rate of Level 2 hypoglycemia was low and not significantly different (BIF = 0.22; DEG = 0.15 events/pt/yr; p = 0.64) . Occurrence of treatment-emergent adverse events was similar between BIF and DEG. QW BIF achieved excellent glycemic control similar to DEG with no concerning hypoglycemia or other safety findings, supporting continued development of BIF in Ph3. Disclosure J.M. Bue-Valleskey: None. C.M. Kazda: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. C. Ma: None. J. Chien: Employee; Eli Lilly and Company. Q. Zhang: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. E. Chigutsa: Employee; Eli Lilly and Company. W. Landschulz: Employee; Eli Lilly and Company. J. Swan: Employee; Eli Lilly and Company. A. Haupt: Employee; Lilly. Stock/Shareholder; Lilly. J. Frias: Advisory Panel; Altimmune, Becton, Dickinson and Company, Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck &amp; Co., Inc., Sanofi. Consultant; 89bio, Inc., Akero Therapeutics, Inc., Altimmune, Becton, Dickinson and Company, Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk, Pfizer Inc., Sanofi. Research Support; Afimmune Limited, Akero Therapeutics, Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Carmot Therapeutics, Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Ionis Pharmaceuticals, Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi. Speaker's Bureau; Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk, Sanofi. Funding Funded by Eli Lilly and Company.

PREDICTORS OF CHRONIC HEART FAILURE WITH PRESERVED EJECTION FRACTION IN PATIENTS WITH TYPE 2 DIABETES MELLITUS TREATED WITH EMPAGLIFLOZIN

Objective: Currently, it’s not well known what factors influenced the incidence of heart failure with preserved ejection (HFpEF) fraction in patients receiving sodium glucose co-transporter 2 inhibitors (SGLT2i). Objective: To evaluate predictors of HFpEF in patients with type 2 diabetes mellitus (T2DM) receiving SGLT2i Design and method: It was a prospective study in patients with T2DM. Inclusion criteria were: male and female, age 40–65 years, T2DM with duration at least for 1 year, absence of established atherosclerotic cardiovascular disease and HF. Exclusion criteria were: type 1 diabetes mellitus, glycated hemoglobin (HbA1c)&gt; 11% at screening, insulin therapy, atrial fibrillation, clinically significant valvular heart disease, chronic kidney disease, other serious conditions that would make the patient unsuitable for participation in the study. Clinical, laboratory (including biomarkers such as NT-proBNP, sST2, galectin-3, PICP,PIIINP,MMP-9,TIMP-1) and instrumental (echocardiography) data were collected at baseline. Empagliflozin 10 mg daily was prescribed for all patients. After 3 years of follow-up, information about HF events (hospitalization for HF, established HF in outpatient department by cardiologist), other clinically important data were obtained. Results: Seventy-five patients were included in the study. The mean age was 58 (47.9;65.1) years, 45,1% were female. Most patients had T2DM for more than 4 years. Mean HbA1c was 8.6% (7.6;9.5), all patients received oral antihyperglycemic medications. After 3 years of follow-up HFpEF was established in 16 patients. The HF group had higher waist circumference values, higher Nt-proBNP, galectin-3 and P1CP levels at baseline than patients without HF (all p &lt; 0.05). The threshold for galectin-3 level associated with increased risk of HFpEF in this population was 10.3 ng/ml (AUC area = 0.86; sensitivity, 87%; and specificity, 73%; p &lt; 0.001). Multiple logistic regression analysis identified significant risk factors for new onset of HFpEF: age&gt; 60 years, diabetes duration&gt; 10 years and presence of abdominal obesity were independent predictors of HFpEF. Galectin-3 level &gt; 10 ng/ml was associated with increased risk of HF incidence (OR = 2.15; 95% CI, 1.80–5.21; p = 0.01). Conclusions: Predictors for incidence HFpEF in patients with T2DM were age, diabetes duration, presence of abdominal obesity and galectin-3 levels higher than 10 ng/ml.

A Systematic Review of Insulin Management Recommendations to Improve Glycemic Control and Reduce Hypoglycemic Events During Ramadan Fasting in Patients With Insulin-Requiring Type 2 Diabetes

BackgroundMuslims with insulin-requiring type 2 diabetes are at high risk of hypo- and hyperglycemia while fasting during the month of Ramadan. Although a few reviews on diabetic management during Ramadan have been published, surveys reveal knowledge gaps remain among physicians.AimThis systematic review qualitatively analyzes what insulin dosing recommendations are likely to reduce hypoglycemic events and improve glycemic control during the Ramadan fasting for this high-risk group.MethodsA comprehensive search in six databases and gray sources was performed from August 10, 2001, to August 10, 2021, for studies assessing which types of insulin and/or what dosing recommendations reduce hypoglycemic events and improve glycemic control during Ramadan. We excluded studies focusing mainly on oral antihyperglycemic medications, type 1 diabetes, persons with insulin pumps, and studies older than 20 years. Hypoglycemic event rates, pre-, and post-iftar blood glucose levels, overall average blood glucose, and hemoglobin A1c were analyzed, and a narrative synthesis was performed.ResultsOut of 1,101 collected articles, 14 eligible studies including 2,969 participants with an average age of 54.8 years, we found that insulin dose reduction may prevent hypoglycemia without causing subsequent hyperglycemia, and rapid-acting insulin analogs may improve post-iftar and overall blood glucose without incurring hypoglycemia.ConclusionsThough initial findings are promising, more research is needed to confirm the benefits of insulin dose reduction, rapid-acting insulin analogs, and ultra-long-acting insulins.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42021268943.

Association Between Antidepressant Use and Adherence to Antihyperglycemic Medications in Adults With Type 2 Diabetes and Depression: A Retrospective Cohort Study

ObjectivesDepression is a known risk factor for poor medication adherence, but it is unclear whether depression treatment affects adherence rates. In this study, we examined the association between pharmacologic treatment of a new depressive episode and subsequent adherence to oral antihyperglycemic medications. MethodsIn this retrospective cohort study, we used administrative health data to follow adult new metformin users in Alberta, Canada, between 2008 and 2018. Depressive episodes starting ≥1 year after metformin initiation were identified and individuals starting antidepressant treatment within the first 90 days were compared with those who did not. The proportion of days covered (PDC) with oral antihyperglycemic medications in the subsequent year (days 91 to 455) was used to estimate adherence. The association between antidepressant treatment and poor adherence (PDC<0.8) was examined using multivariate logistic regression models. ResultsA new depressive episode occurred in 6,201 people, with a mean age of 56.0 (standard deviation [SD], 15.4) years. Of this cohort, 3,303 (53.2%) were women. Mean PDC was 0.55 (SD, 0.41); 924 (57.0%) of 1,621 people who started antidepressant treatment and 2,709 (59.2%) of 4,580 controls had poor adherence (p=0.13). After adjusting for baseline comorbidities and other characteristics, antidepressant treatment was associated with a lower likelihood of poor adherence (adjusted odds ratio, 0.85; 95% confidence interval, 0.75 to 0.96; p=0.007). ConclusionsAlthough overall adherence to antihyperglycemic medications was low after onset of a depressive episode, antidepressant treatment was associated with a lower likelihood of poor adherence.

The Impact of the FreeStyle Libre&amp;lt;sup&amp;gt;TM&amp;lt;/sup&amp;gt; Flash Glucose Monitoring System on Glycemic Control in Patients with Diabetes; Observational Multicenter 15-Months Study

Objectives: The study was to determine the impact of using the FreeStyle LibreTM flash glucose monitoring system on glycemic control and the rate of events due to diabetes in people with diabetes from different types and age groups. Methods: a retrospective cohort chart review study was carried out at three centers in the Taif region in the Kingdom of Saudi Arabia: The study was approved by an accredited centralized institutional review board. Paper or electronic medical records were included for individuals of any age with diabetes (type 1, type 2, gestational diabetes) managed with diet, insulin therapy, or/and oral antihyperglycemic medication and/or non-insulin injection therapy. The primary outcome measure was the laboratory HbA1c level as well as reduction. Secondary outcome measures were frequency of severe hypoglycemia, admission to hospital or ER visit related to diabetes complications, and severe hyperglycemia (DKA or HHS). Results: Data was analyzed from 1695 patients. The average HbA1c before using the flash glucose monitoring system was 9.60% ± 1.44% and 3 months HbA1c after using the FreeStyle LibreTM flash glucose monitoring system was 8.70% + 1.45% for a difference of -0.90% ([95% CI -0.92: -0.88]; p 65 years, (p-values TM flash glucose monitoring system are self-evident in reducing HbA1c and events due to hyperglycemia or hypoglycemia.

Probiotics Efficacy and Safety as add-on Therapy to Metformin in Type 2 Diabetes Mellitus

Background: Insulin secretion is decreased, and peripheral insulin sensitivity is diminished, resulting in type 2 diabetesmellitus. Diet, oral antihyperglycemic medications, and insulin are all modalities for treatment.Objective: The goal of this study was to compare the efficacy of probiotics as an add-on treatment to metformin inpatients with Type 2 Diabetes Mellitus.Methods: The study participants were randomly allocated to one of two groups, Group A or Group B, using a computergeneratedrandomization chart, with each group consisting of 75 patients. Group A - For 12 weeks, patients in this groupwere administered Tab. Metformin 500 mg twice daily with meals. Group B - For 12 weeks, patients in this group wereadministered Tab. Metformin 500 mg twice daily with meals and Cap. Probiotics 1 capsule twice daily with meals. At theculmination of the second, fourth, eighth, and twelfth weeks, all patients were evaluated. Fasting and postprandial bloodglucose levels were measured at each visit. The HbA1c test was performed at the end of the 12th week.Results: The male predominance was seen with males 57% and females 43% in the group A and the male : female ratiowas 1.34:1. In Group B males were 55% and females were 45%. The male: female ratio was 1.20 : 1. The mean HbA1Cslightly reduced since the start till the end of the study. A total of 37% of the patients experienced minor self-limiting sideeffects in group A as compared to 6.66% of Group – B.Conclusion: In treatment for type 2 diabetes mellitus, probiotics as an add-on therapy with metformin was observedto lower fasting blood glucose, postprandial blood glucose, and HbA1c levels when compared to metformin alone. Interms of effectiveness, probiotics have shown no substantial significant outcomes in combination therapy. However, theprobiotics study group had fewer reported gastrointestinal adverse effects associated with metformin treatment.

Pancreatic Safety of Once-Weekly Dulaglutide in Chinese Patients with Type 2 Diabetes Mellitus: Subgroup Analysis by Potential Influencing Factors.

IntroductionIn the randomized, open-label, parallel-arm, active-controlled phase III AWARD-CHN2 trial, once-weekly dulaglutide plus concomitant oral antihyperglycemic medications (OAMs) improved HbA1c over 26 weeks compared with once-daily insulin glargine in patients with type 2 diabetes mellitus (T2DM). This post-hoc subgroup analysis of AWARD-CHN2 investigated the pancreatic safety of dulaglutide in Chinese patients with T2DM, stratified by potential influencing factors.MethodsChanges in pancreatic enzyme (pancreatic amylase, total amylase, and lipase) levels over 26 weeks were assessed and stratified by patient age (< 60, ≥ 60 years), sex (female, male), duration of diabetes (< 10, ≥ 10 years), baseline weight (< 70, ≥ 70 kg), BMI (< 25, ≥ 25 kg/m2), HbA1c (< 8.5, ≥ 8.5%), triglycerides (< 2.3, ≥ 2.3 mmol/L), and concomitant OAMs (metformin, sulfonylurea, metformin plus sulfonylurea).ResultsA total of 203 Chinese patients with T2DM were included in this post-hoc analysis. Pancreatic enzyme levels increased within the normal range from baseline to Week 26, and no pancreatitis events were confirmed by independent adjudication. Least-squares mean increase in pancreatic amylase (U/L) from baseline to Week 26 was comparable across all subgroups with no statistically (all P-values > 0.05) or clinically significant between-group differences for age (< 60 years: 5.34; ≥ 60 years: 6.71), sex (female: 5.85; male: 5.66), duration of diabetes (< 10 years: 6.15; ≥ 10 years: 4.85), weight (< 70 kg: 6.19; ≥ 70 kg: 5.39), BMI (< 25 kg/m2: 5.92; ≥ 25 kg/m2: 5.61), HbA1c (< 8.5%: 6.82; ≥ 8.5%: 4.08), triglycerides (< 2.3 mmol/L: 4.94; ≥ 2.3 mmol/L: 8.04), and concomitant OAMs (metformin: 5.68; sulfonylurea: 5.44; metformin plus sulfonylurea: 5.87). Similar results were observed for total amylase and lipase.ConclusionIn Chinese patients with T2DM receiving dulaglutide 1.5 mg in AWARD-CHN2, elevations of pancreatic enzymes over 26 weeks were within the normal range and were neither associated with pancreatitis nor baseline factors, which suggests the clinical use of dulaglutide in Chinese patients with T2DM is not associated with pancreatic safety issues.Clinical Trial registrationNCT01648582.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01139-2.

Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial

Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist under development for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of tirzepatide versus titrated insulin degludec in people with type 2 diabetes inadequately controlled by metformin with or without SGLT2 inhibitors. In this open-label, parallel-group, multicentre (122 sites), multinational (13 countries), phase 3 study, eligible participants (aged ≥18 years) had a baseline glycated haemoglobin (HbA1c) of 7·0-10·5%, body-mass index of at least 25 kg/m2, stable weight, and were insulin-naive and treated with metformin alone or in combination with an SGLT2 inhibitor for at least 3 months before screening. Participants were randomly assigned (1:1:1:1), using an interactive web-response system, to once-weekly subcutaneous injection of tirzepatide (5, 10, or 15 mg) or once-daily subcutaneous injection of titrated insulin degludec, and were stratified by country, HbA1c, and concomitant use of oral antihyperglycaemic medications. Tirzepatide was initially given at 2·5 mg and the dose was escalated by 2·5 mg every 4 weeks until the assigned dose was reached. Insulin degludec was initially given at 10 U per day and was titrated once weekly to a fasting self-monitored blood glucose of less than 5·0 mmol/L (<90 mg/dL), following a treat-to-target algorithm, for 52 weeks. The primary efficacy endpoint was non-inferiority of tirzepatide 10 mg or 15 mg, or both, versus insulin degludec in mean change from baseline in HbA1c at week 52. Key secondary efficacy endpoints were non-inferiority of tirzepatide 5 mg versus insulin degludec in mean change from baseline in HbA1c at week 52, superiority of all doses of tirzepatide versus insulin degludec in mean change from baseline in HbA1c and bodyweight, and the proportion of participants achieving HbA1c of less than 7·0% (<53 mmol/mol) at week 52. We used a boundary of 0·3% to establish non-inferiority in HbA1c difference between treatments. Efficacy and safety analyses were assessed in the modified intention-to-treat population (all participants who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, number NCT03882970, and is complete. Between April 1 and Nov 15, 2019, we assessed 1947 participants for eligibility, 1444 of whom were randomly assigned to treatment. The modified intention-to-treat population was 1437 participants from the tirzepatide 5 mg (n=358), tirzepatide 10 mg (n=360), tirzepatide 15 mg (n=359), and insulin degludec (n=360) groups. From a mean baseline HbA1c of 8·17% (SD 0·91), the reductions in HbA1c at week 52 were 1·93% (SE 0·05) for tirzepatide 5 mg, 2·20% (0·05) for tirzepatide 10 mg, and 2·37% (0·05) for tirzepatide 15 mg, and 1·34% (0·05) for insulin degludec. The non-inferiority margin of 0·3% was met. The estimated treatment difference (ETD) versus insulin degludec ranged from -0·59% to -1·04% for tirzepatide (p<0·0001 for all tirzepatide doses). The proportion of participants achieving a HbA1c of less than 7·0% (<53 mmol/mol) at week 52 was greater (p<0·0001) in all three tirzepatide groups (82%-93%) versus insulin degludec (61%). At week 52, from a baseline of 94·3 kg (SD 20·1), all three tirzepatide doses decreased bodyweight (-7·5 kg to -12·9 kg), whereas insulin degludec increased bodyweight by 2·3 kg. The ETD versus insulin degludec ranged from -9·8 kg to -15·2 kg for tirzepatide (p<0·0001 for all tirzepatide doses). The most common adverse events in tirzepatide-treated participants were mild to moderate gastrointestinal events that decreased over time. A higher incidence of nausea (12-24%), diarrhoea (15-17%), decreased appetite (6-12%), and vomiting (6-10%) was reported in participants treated with tirzepatide than in those treated with insulin degludec (2%, 4%, 1%, and 1%, respectively). Hypoglycaemia (<54 mg/dL or severe) was reported in five (1%), four (1%), and eight (2%) participants on tirzepatide 5, 10, and 15 mg, respectively, versus 26 (7%) on insulin degludec. Treatment discontinuation due to an adverse event was more common in the tirzepatide groups than in the insulin degludec group. Five participants died during the study; none of the deaths were considered by the investigators to be related to the study treatment. In patients with type 2 diabetes, tirzepatide (5, 10, and 15 mg) was superior to titrated insulin degludec, with greater reductions in HbA1c and bodyweight at week 52 and a lower risk of hypoglycaemia. Tirzepatide showed a similar safety profile to that of GLP-1 receptor agonists. Eli Lilly and Company.

Evaluation of An Inpatient Pharmacy Consult on Discharge Medications in Bariatric Surgery Patients

Purpose: To evaluate the impact of an inpatient pharmacy consult on discharge medications following bariatric surgery. Methods: A pharmacy consult for discharge medication review for bariatric surgery patients was instituted at an academic medical center. The intervention included conducting a medication history, reviewing home medications for updates post-bariatric surgery, creating and documenting a discharge medication plan, and providing patient education. The impact of the intervention was evaluated by comparing medication classes, doses, and formulations prescribed during the intervention relative to a historical control group. Results: The study included 85 patients who received pharmacist intervention and 167 patients who did not receive pharmacist intervention following bariatric surgery. The prescription of an extended-release medication at discharge in the intervention group was reduced by 19.3% (28.7% vs. 9.4%, p = 0.0005). For patients on hypertension medications, 94.0% had their regimen reduced in the intervention group compared with 37.5% of patients in the control group (p < 0.001). Of patients on insulin at baseline, 87.5% of patients in the intervention group had dose reductions at discharge vs. 66.7% of patients in the control group (p = 0.37). No patients in the intervention group were discharged with oral antihyperglycemic medications or non-insulin injectable medications vs. 33.3% (p = 0.12) and 20.0% (p = 0.47), respectively, in the control group. Readmission rates at 30 days were insignificantly lower in the intervention group (3.5% vs. 4.2%, p = 1). Conclusions: Clinical pharmacist involvement in the discharge medication reconciliation process for bariatric surgery patients reduced prescribing of unadjusted medication classes, doses, and drug formulations.

742-P: Phase 1 Study of Safety, Tolerability, PK, and PD of Once-Weekly Basal Insulin Fc (BIF) in Japanese Patients with T2DM

BIF (LY3209590) is a novel, once weekly, long-acting IgG Fc-fusion protein that is being assessed for the treatment of diabetes mellitus. This phase 1, multiple-site, randomized, single-dose, dose-escalation study of BIF included 3 cohorts. Cohorts 1 and 2 each included 12 Japanese insulin-naïve patients with T2DM who were randomized double-blind to receive a single SC dose (dose 1 in cohort 1; dose 2 in cohort 2) of BIF (N=8) or placebo (N=4). Cohort 3 included 7 Japanese patients with T2DM previously treated with basal insulin, with or without a stable dose of up to 2 prespecified types of oral anti-hyperglycemic medications, who received a single SC dose of open-label BIF at dose 3. The primary objective was to investigate safety and tolerability. Secondary objectives included characterization of the PK and PD. ClinicalTrials.gov identifier: NCT03603704. Four patients (12.9%; 1 patient in each treatment group) reported a treatment-emergent adverse event; all were mild and none were related to study drug. Six patients (19.4%) reported hypoglycemic events (most events were with dose 3 and none were severe); each event was self-treatable and resulted in a prompt recovery. PK analyses showed BIF exposure after administration of each dose increased with dose, and tmax was observed by approximately day 4 at all 3 doses. The geometric mean t1/2 estimates ranged from 11 to 16 days across doses. All 3 doses decreased fasting glucose from baseline to day 15. Fasting glucose decreased from day 2 until approximately day 7 or 8 at all doses followed by a trend of fasting glucose returning to baseline. Compared with placebo, BIF at doses 1 and 2 significantly decreased (p&amp;lt;0.1) fasting glucose levels from baseline at most time points between days 3 and 15. In Japanese patients with T2DM, single SC doses of BIF were well tolerated, and the PK and PD of BIF allows weekly dosing. Disclosure K. Ohwaki: Employee; Self; Eli Lilly Japan K. K., Stock/Shareholder; Self; Eli Lilly and Company. K. Furihata: None. R. Nasu: Employee; Self; Eli Lilly Japan K. K. T. Oura: Employee; Self; Eli Lilly Japan K. K., Stock/Shareholder; Self; Eli Lilly and Company. M. Imori: Employee; Self; Eli Lilly Japan K. K. Funding Eli Lilly and Company

Evaluation of the prognostic significance of leptin, adiponectin and resistin in the development of diabetic retinopathy in type 2 diabetes mellitus patients

Background. There is evidence of the participation of adipose tissue hormones leptin, adiponectin and resistin in the formation of metabolic disorders in the retina, retinal neovascularization, and diabetic microangiopathy. The development of methods for the mathematical evaluation of the prognosis of diabetic retinopathy (DR) formation with the participation of adipokines is a relevant problem in modern diabetology. Aim. Elaboration of a mathematical model for assessing the prognostic significance of serum leptin, adiponectin and resistin to study the likelihood of developing and progressing DR in patients with type 2 diabetes mellitus (DM). Materials and methods. An open observational single-center one-stage selective study was conducted among patients with type 2 DM and DR. The blood serum concentration of leptin, adiponectin and resistin, HbA1с, lipid metabolism findings were determined, the results of an instrumental examination of the fundus were analyzed. The diagnostic predictive value of serum leptin, adiponectin and resistin was assessed using discriminant analysis. Statistical analyses were conducted using Statistica 9.0 (StatSoft, Tulsa, OK, USA) software. The differences were considered statistically significant at p &lt; 0.05. A model with linear combinations of the serum leptin, adiponectin and resistin, triglyceride (TG), HbA1с, type of antihyperglycemic therapy (oral anti-hyperglycemic medication or insulin therapy) were developed, and, subsequently, formulas for classification-relevant discriminant functions were derived. Results. Fifty-nine patients (107 eyes) with type 2 DM and DR (men and women; mean age, 58.20±0.18 years; mean diabetes duration, 9.19±0.46 years; mean HbA1с 9.10±0.17%) were assigned to the basic group and underwent the study. They were divided into three DR groups based on the stage of DR. When performing the ranking of patients for discriminant analysis, the stage 2 DR group was aggregated with the stage 3 DR group for convenience to form the stage 2 + 3 DR group based on the pathognomonic sign (portents of proliferation or actual proliferation). Anti-diabetic therapy (ADT) included metformin, either alone (type 1 ADT) or in combination with oral anti-hyperglycemic medication (metformin + OAHGM, type 2 ADT) or insulin therapy (metformin + IT, type 3 ADT). Inclusion criteria were informed consent, age above 18 years, presence of T2DM and DR. Exclusion criteria were endocrine or body system disorders leading to obesity (Cushing’s syndrome, hypothyroidism, hypogonadism, polycystic ovarian syndrome, or other endocrine disorders, including hereditary disorders, and hypothalamic obesity), type 1 DM, acute infectious disorders, history of or current cancer, decompensation of comorbidities, mental disorders, treatment with neuroleptics or antidepressants, proteinuria, clinically significant maculopathy, glaucoma or cataract. The study followed the ethical standards stated in the Declaration of Helsinki and was approved by the Local Ethics Committee. The formulas for classification-relevant discriminant functions were derived based on the results of physical examination, imaging and laboratory tests, and subsequent assessment of clinical signs of DM (HbA1с), DR stage and serum leptin, adiponectin, resistin, TG concentrations and taking into account the type of antihyperglycemic therapy. The classification functions (CF) computed based on the variables found from the above developed models provided the basis for predicting the development of DR. The formulas for CF from model are as follows: CF1=0.29•TG + 1.55•HbA1С + 1.81•ADT_Type + 0.04•Leptin + 0,34•Adiponectin + 0,91•Resistin– 13,82. CF2= 0.05•TG + 1.36•HbA1С + 3.01•ADT_Type + 0.08•Leptin + 0,35•Adiponectin + 1,01•Resistin – 15.95. Astep-by-step approach to a diagnostic decision should be used. First, blood samples are tested for serum leptin, adiponectin and resistin, TG, blood HbA1c, and the patient is assigned a code for ADT Type (metformin only, 1; metformin + OAHGM, 2; or metformin + IT, 3). Second, CF1 and CF2 values are calculated based on clinical and laboratory data. Finally, the two values are compared to determine which is greater. The predictive decision is made by selecting the classification function with the greater value. Thus, if CF1 &gt; CF2, the process can be stabilized at this stage given adequate glycemic control (through compensation of carbohydrate metabolism) and body mass control as well as patient compliance. If CF1 &lt; CF2, the pathological process may progress to the next stage or even within stage 3, and there is an urgent need to reduce BMI, and to correct the ADT and the blood lipid profile. Conclusions. The informative value and statistical significance of the model were 71.4% and p=0.040, respectively. Using the formulas, one can determine the probability of progression of DR.