Type 2 Diabetes Drugs Research Articles

Benchmarking the medication efficiency and technological progress of diabetes drugs

BackgroundDiabetes poses a serious global challenge, given its increasing prevalence, detrimental effects on public health, and substantial economic burden. Since 1950s, tens of drugs have been approved by the United States (US) Food and Drug Administration (FDA). In the past decade, the medical community and regulatory agencies have moved away from the glucose-centric paradigm and increasingly call for a holistic approach to assess different treatments’ benefits and harms.ObjectiveThis study aimed to assess the medication efficiency and technological progress of Type 2 Diabetes (T2D) drugs, by considering their physiological outcomes, including both benefits (i.e., glucose lowering and weight loss) and adverse effects (mortality), relative to dosing frequency.MethodsTo derive medication efficiency, this study utilized data from the US FDA and prominent meta-analyses. Given that both the benefits and adverse effects of medications are multidimensional, this study employed a nonparametric frontier method, the data envelopment analysis (DEA) model, to integrate these factors into a measure of medication efficiency. Physiological outcomes could assume both positive and negative values. Adverse effects were regarded undesirable outputs. The DEA model was built under the framework of directional distance function and was able to handle negative and undesirable values which naturally arose in the case of T2D medications.ResultsThe paper presented a ranking of 20 T2D drugs in terms of medication efficiency. Three of them were able to attain the highest medication efficiency, all of which were in the GLP-1 class, including oral Semaglutide, subcutaneous Semaglutide and Dulaglutide. However, the other two GLP-1 drugs, Lixisenatide and Liraglutide, were less efficient. The average medication efficiency of drugs approved post-2010 was significantly higher than pre-2010 drugs. High dose frequency, low HbA1c reduction and insignificant weight loss were the main driving factors behind inefficiencies. Overall, medication efficiency provided an alternative perspective on treatment effectiveness other than conventional measures such as cost-effectiveness.

8722 Sodium-Glucose Cotransporter 2 Inhibitors And The Risk Of Kidney Cancer Among Patients With Type 2 Diabetes: A Population-Based Cohort Study

Abstract Disclosure: M. Lee: None. H. Kim: None. R. Kim: None. Y. Yang: None. S. Lee: None. E. Kang: None. There is an important need to develop clinical strategies to reduce the risk of incident kidney cancer, especially in patients with type 2 diabetes (T2D) and concomitant chronic kidney disease. Here, we investigated kidney cancer risk associated with sodium-glucose cotransporter 2 (SGLT2) inhibitor use in patients with T2D, using a nationwide cohort of the Korean National Health Insurance claims and health examination database. After 1:1 propensity score matching, 83,531 SGLT2 inhibitor users and 83,531 non-users on other oral glucose-lowering drugs were selected from 814,685 cancer-free participants, aged 20 to 79 years, who started oral glucose-lowering drugs for T2D from 2014 to 2018. During 559,738 person-years of follow-up, 143 (25.5 per 100,000 person-years) new kidney cancer events occurred. SGLT2 inhibitor use was associated with a 37% reduced risk of kidney cancer compared with other oral glucose-lowering drug use (18.1 vs. 29.9 per 100,000 person-years; hazard ratio [HR], 0.63; 95% CI, 0.43 to 0.92). The reduced kidney cancer risk by SGLT2 inhibitor use was consistent even after additional adjustment for all variables composing the propensity scores (HR, 0.64; 95% CI, 0.43 to 0.93) and regardless of age, sex, BMI, comorbidities, or diabetic complications including nephropathy (all p > 0.1 for interaction). SGLT2 inhibitor use may be a preferable option for patients with T2D at high risk of kidney cancer. Presentation: 6/3/2024

Single-cell Transcriptomics, Web-based Systems Pharmacology and Integrated Transcriptomics Network Analysis Identified Diagnostic Targets and Drug Candidates for Type 2 Diabetes.

To discover new therapeutic targets for Type 2 diabetes (T2D) and develop a new diagnostic model. T2D is a chronic disease that can be controlled by oral hypoglycemic drugs, however, it cannot be fully cured. The continued increase in the prevalence of T2D and the limitations of existing treatments urgently call for the development of new drugs to be able to effectively control the progression of the disease. We aimed to discover new therapeutic targets for T2D and to develop a new diagnostic model. Single-cell transcriptome, web-based systematic pharmacology, and transcriptology were applied to identify T2D diagnostic targets and drug candidates and to analyze the underlying molecular mechanisms. By single-cell clustering analysis, we identified seven subsets between the normal islet β-cell samples and T2D islet β-cell samples. A total of 27 key genes in the intersection of insulin- related genes and diabetes-related genes were selected by protein-protein interaction (PPI) analysis and MolecularComplexDetection (MCODE) analysis. Notably, ESR1, MME, and CCR5 had the area under curves (AUC) values as high as 67.95%, 66.67%, and 66.03% for the diagnosis of T2D, respectively. Since the expression of MME in T2D samples was significantly higher than in normal samples, we screened 155 drug candidates against MME in T2D. Finally, the molecular docking revealed a strong binding strength between MME and DB05490, which was one of the most effective candidate drugs for treating T2D. Our study screens for diagnostic signatures and potential therapeutic agents for T2D, which provides valuable insights into the development of T2D biomarkers and their drug discovery.

Epidemiology of Metabolic Dysfunction-Associated Steatotic Liver Disease

As the rates of obesity and type 2 diabetes (T2D) continue to increase globally, so does the prevalence of metabolic dysfunction associated steatotic liver disease (MASLD). Currently, 38% of all adults and 7-14% of children and adolescents have MASLD. By 2040, the MASLD prevalence rate for adults is projected to increase to over 55%. Although many with MASLD will not develop progressive liver disease, given the vast number of patients with MASLD, it has now become the top indication for liver transplant in the United States for those with hepatocellular carcinoma (HCC) and women. However, the most common cause of mortality among patients with MASLD remains death cardiovascular diseases. In addition to liver outcomes (cirrhosis and HCC), MASLD is associated with increased risk for the developing de-novo T2D, chronic kidney disease, sarcopenia and extrahepatic cancers. Furthermore, MASLD is associated with decreased health related quality of life, decreased work productivity, fatigue and increased healthcare resource utilization and substantial economic burden. Similar to other metabolic disease, lifestyle interventions with heathy diet and increased physical activity remain the cornerstone of managing these patients. Although a number of obesity and T2D drugs are available to treat co-morbid disease, Resmetirom is the only MASH-targeted medication that was recently approved by the Federal Drug Administration for use in the United States for those with stage 2-3 fibrosis. The following review provides an overview of MASLD epidemiology, its related risk factors and outcomes and demonstrates that without further global initiatives, MASLD may continue to increase.

Patient Out-of-Pocket Costs for Type 2 Diabetes Medications When Aging Into Medicare

For people with type 2 diabetes (T2D), out-of-pocket medication costs may influence medication choice, adherence, and overall diabetes management and progression. Little is known about how these costs change as insured people enter Medicare at age 65 years, when coinsurance in the coverage gap and catastrophic phases of Part D coverage can be increased greatly by use of insulin and newer, branded medications (eg, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 agonists, and sodium-glucose cotransporter 2 inhibitors). To identify whether reaching age 65 years is associated with T2D medication out-of-pocket costs and utilization. This retrospective cohort study (2012-2020) featuring 7 years of follow-up used prescription drug claims data from the TriNetX Diamond Network. Participants included people in the US with diagnosed T2D, and claims for T2D medications were observed both before and after age 65 years. Data analysis was performed from October 2022 to September 2023. Reaching age 65 years, according to participants' year of birth. The primary outcome was patient out-of-pocket costs for T2D drugs per quarter (inflation adjusted to 2020 dollars). Utilization, measured as binary utilization of specific classes, and the number of claims for mutually exclusive classes and combinations of classes were also examined. All outcomes were examined using regression discontinuity design. In claims data for 129 997 individuals with T2D diagnosed at ages 58 to 72 years (mean [SD] age, 65.50 [2.95] years; 801 235 female [50.9%]), reaching age 65 years was associated with an increase of $23.04 (95% CI, $19.86-$26.22) in mean quarterly out-of-pocket costs for T2D drugs, and an increase of $56.36 (95% CI, $51.48-$61.23) at the 95th percentile of spending, after utilization adjustment. Utilization decreased by 5.3% at age 65 years, from 3.40 claims per quarter (95% CI, 3.38-3.42 claims per quarter) to 3.22 claims per quarter (95% CI, 3.21-3.24 claims per quarter), but a shift in composition of utilization, including increased insulin use, was associated with additional increases in patient costs. In this cohort study of individuals with T2D, the increase in spending upon reaching age 65 years (when most people enroll in Medicare) was associated with patient coinsurance in the coverage gap and catastrophic coverage phases of Medicare Part D. The increased patient cost burden at age 65 years and a modest reduction in overall T2D drug utilization suggest that as people with T2D age into Medicare, there is potentially an increase in nonadherence and diabetes complications.

Comparative Analysis of Orthosteric and Allosteric GLP-1R Agonists' Effects on Insulin Secretion from Healthy, Diabetic, and Recovered INS-1E Pancreatic Beta Cells.

Despite the availability of different treatments for type 2 diabetes (T2D), post-diagnosis complications remain prevalent; therefore, more effective treatments are desired. Glucagon-like peptide (GLP)-1-based drugs are currently used for T2D treatment. They act as orthosteric agonists for the GLP-1 receptor (GLP-1R). In this study, we analyzed in vitro how the GLP-1R orthosteric and allosteric agonists augment glucose-stimulated insulin secretion (GSIS) and intracellular cAMP production (GSICP) in INS-1E pancreatic beta cells under healthy, diabetic, and recovered states. The findings from this study suggest that allosteric agonists have a longer duration of action than orthosteric agonists. They also suggest that the GLP-1R agonists do not deplete intracellular insulin, indicating they can be a sustainable and safe treatment option for T2D. Importantly, this study demonstrates that the GLP-1R agonists variably augment GSIS through GSICP in healthy, diabetic, and recovered INS-1E cells. Furthermore, we find that INS-1E cells respond differentially to the GLP-1R agonists depending on both glucose concentration during and before treatment and/or whether the cells have been previously exposed to these drugs. In conclusion, the findings described in this manuscript will be useful in determining in vitro how pancreatic beta cells respond to T2D drug treatments in healthy, diabetic, and recovered states.

Comparative analysis of availability and affordability of hypoglycaemic medicines for Ukrainian patients during the war 2022-2023

Purpose: Diabetes care, particularly type 2 diabetes (T2D), is recognised as a growing challenge in emergency situations. During the humanitarian crisis of war in Ukraine, it is important to focus on ensuring that patients have access to essential medicines for T2D. Since 1 April 2017, the Ministry of Health of Ukraine has been implementing the government programme "Affordable medicines". The List of reimbursed medicines necessary for the treatment of hypertension, diabetes and bronchial asthma includes 3 glucose lowering medicines (GLMs) - gliclazide, metformin, glibenclamide. From 01 April 2019, electronic prescribing has been implemented as part of the "Affordable Medicines" programme. It is important to investigate changes in the availability and affordability of GLMs for the treatment of T2D during the war and future directions in 2022-2023 in Ukraine. Methods: Information from the State Register of Medicinal Products of the Ministry of Health of Ukraine from March 2023 and February 2022 (before the start of the war) was the subject of the study. Marketing, analytical, graphical, generalisation analyses were applied. Analysis of the cost of 1 DDD GLM according to the WHO ATC/DDD index and solvency ratio analysis were applied. Results: This study is based on actual data from before the war in Ukraine and now shows that the affordability and availability of GLMs during the war in 2022-2023 has not changed dramatically. The 'Affordable Medicines' program was stably implemented, with €111.9 million allocated in 2023 and within 6 months of 2023. The National Health Service of Ukraine reimbursed €42.8 million to pharmacies for the Reimbursement List. Most Ukrainian manufacturers and foreign GLMs are very affordable due to the reimbursement system. From October 2023, 23 names of test stripes were included in the Reimbursement list of the "Affordable medicines" programme. However, foreign GLMs of innovative groups are moderately affordable for the working population based on the calculated solvency ratio. Conclusions: Our study revealed that despite the challenges of war, the healthcare system in Ukraine remains robust, particularly in ensuring stable access to pharmaceuticals for diabetes treatment. The "Affordable Medicines" programme and the Reimbursement List are updated twice a year, and the introduction of the new drugs for T2D and diabetes insipidus was completed in 2022. Thus, the innovative GLMs, despite being registered on the market in 2022, such as Semaglutide, Semaglutide and Dapagliflozin, are not affordable in 2023. A prospective trend is the inclusion of innovative GLMs for diabetes better care on the reimbursement list.

503 Examination of Labeling for Geriatric Sub-Populations in Recently Approved Type 2 Diabetes Drugs

OBJECTIVES/GOALS: To assess labels of drugs approved for Type 2 Diabetes (T2D) for the inclusion of geriatric sub-population data (ages 65-74, 75-84, ≥85) since January 1, 2013, in accordance with international guidance and US regulations in recognition of an aging populations and global demographics. METHODS/STUDY POPULATION: Utilizing FDA Guidance for Industry: Labeling for Human Prescription and Biological Products - Implementing the Physician’s Labeling Rule (PLR) Content and Format Requirements and the International Council for Harmonization of Technical Requirements (ICH) E7 guidance “Studies in Support of Special Populations: Geriatrics” as reference for assessing labels. The Center for Drug Evaluation and Research (CDER) new drugs/biologic approvals database was filtered for drugs approved between Jan. 1, 2013 and Dec. 31, 2022 with approved T2D indications. Examined original drug labels and supplements from Drugs@FDA for geriatric use efficacy and safety wording in Section 8.5 (Use in Specific Populations, Geriatric Use), for labels. Subpopulation data in labeling for ages 65-74, 75-84, and ≥85 was analyzed. RESULTS/ANTICIPATED RESULTS: Seven T2D drugs (Trulicity, Tresiba, Adlyxin, Ozempic, Steglatro, Kerendia, Mounjaro) approved within the specified time period were analyzed. In the current examination, all labels contain information regarding efficacy differences between ages 65+ and 75+, however, none contain information on efficacy for ≥85 populations. Four of the seven drugs have been updated with increased data from further efficacy trials for older adults conducted after initial approval. The remaining three drugs have only been reworded, or not changed at all, with no further efficacy trials conducted. DISCUSSION/SIGNIFICANCE: This research shows the gap in representation of older adults in clinical trial data and T2D drugs’ labeling. Despite having a higher usage of T2D drugs compared to the general population, older adults and especially the oldest-old (≥85) are underrepresented. Additional demographic requirements ensuring diversity in clinical trials is needed.

Medication persistence and its impact on type 2 diabetes.

Medication persistence in type 2 diabetes (T2D) is a critical factor for preventing adverse clinical events. We assessed persistence among newly treated patients with T2D and documented the impact of persistence on clinical outcomes and costs. Retrospective study of Optum Clinformatics Data Mart commercial and Medicare Advantage enrollees from 2007 to 2020. We identified adult patients who initiated antidiabetic treatments. Patients were required to have at least 1 treatment-free year prior to their first T2D prescription. Persistence was measured as the duration of continuous therapy until a 60-day gap in drug availability appeared in any antidiabetic therapy. Factors associated with duration were documented, focusing on the initial class(es) of T2D drugs. The impact of treatment duration on the risk of hospitalization and on total health care costs was alsoexamined. A total of 673,265 patients were included, with a median follow-up of 7 years. Only 22% of patients maintained continuous treatment, of whom 10% added a second medication. A 1-month increase in duration was associated with reduced risk of hospitalization due to stroke by 0.54% (95% CI, 0.46%-0.60%), acute myocardial infarction by 0.51% (95% CI, 0.44%-0.57%), and all-cause hospitalization by 0.36% (95% CI, 0.34%-0.37%). A 1-month increase in duration was associated with a year-to-year decrease in medical costs of $51 (95% CI, -$54 to -$48) and an increase in year-to-year drug costs of $14 (95% CI, $13-$14). Our findings show low persistence among patients with T2D and emphasize the importance of medication persistence, which is associated with cost savings and lower risk of hospitalizations.

Sociodemographic disparities in GLP-1RA and SGLT2i use among US adults with type 2 diabetes: NHANES 2005-March 2020

Objective Type 2 Diabetes (T2D) is a major cause of morbidity and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) are highly effective but underutilized. Our objective was to assess racial/ethnic and other sociodemographic disparities in GLP-1RA/SGLT2i use among US adults with T2D. Methods We conducted a retrospective analysis using the National Health and Nutrition Examination Survey from 2005–March 2020. Participants were adults with T2D taking ≥1 anti-diabetic medication, excluding pregnant women and adults with probable T1D. We performed univariate analyses to examine the characteristics of patients using GLP-1RA/SGLT2i and multivariable logistic regression to assess disparities in GLP-1RA/SGLT2i use after adjusting for other patient factors. Results Among 4777 people with T2D (representing >18 million US adults) taking ≥1 medication, GLP-1RA/SGLT2i usage increased from 1.4% in 2005–2006 to 13.3% in 2017–2020. In univariate analyses, patients using GLP-1RA/SGLT2i vs. other T2D drugs were more likely to be White than nonwhite (72% vs. 60%, p = .001), but in multivariable analysis there was no significant difference in GLP-1RA/SGLT2i use for nonwhite vs. White patients (aOR = 0.84, 95% CI [0.61, 1.16]). GLP-1RA/SGLT2i use was higher for patients who completed some college (aOR = 1.83, 95% CI [1.06, 3.15]) or above (aOR = 2.06, 95% CI [1.28, 3.32]) vs. high school or less, and for those with an income-poverty ratio ≥4 vs. <2 (aOR = 2.11, 95% CI [1.30, 3.42]). Conclusions The use of GLP-1RA/SGLT2i drugs increased over time but remained low in March 2020. Higher education and income, but not race/ethnicity, were associated with GLP-1RA/SGLT2i use.

Explore the Role and Influence of Bex gliflozin (A Type of SGLT-2 Inhibitors) in Type 2 Diabetes

There are many chronic metabolic diseases in the world, and diabetes is one of them. Blood sugar control and improvement of insulin resistance are the main means of clinical treatment of type 2 diabetes (T2D). A variety of hypoglycemic drugs are now used in the clinic, but due to the different physical conditions of patients, only 50% of the drugs that may play a certain curative effect. Traditional T2D drug treatment relies on the regulation of insulin and has a variety of side effects. Bex gliflozin, as a sodium-glucose co-transporter 2 inhibitor (SGLT2i), the tubules have a reabsorption effect on glucose in the original urine, and the mechanism of action of Bex gliflozin is to inhibit this function of the kidneys, which makes part of the glucose not reabsorbed by the renal tubules and excreted with urine, thereby achieving the purpose of hypoglycemia. As an approved SGLT2i, it has shown good hypoglycemic effect and safety in the treatment of diabetes, combined with others. In addition, Bex gliflozin has a certain protective effect on the heart and kidneys, and some studies have shown that it has no significant effect on blood pressure and weight. This article summarizes the therapeutic progress and mechanism of SGLT2i and Bex gliflozin in T2D, in order to expanse of the indications for Bex gliflozin.

The anti-diabetic effects of metformin are mediated by regulating long non-coding RNA.

Type 2 diabetes (T2D) is a metabolic disease with complex etiology and mechanisms. Long non-coding ribonucleic acid (LncRNA) is a novel class of functional long RNA molecules that regulate multiple biological functions through various mechanisms. Studies in the past decade have shown that lncRNAs may play an important role in regulating insulin resistance and the progression of T2D. As a widely used biguanide drug, metformin has been used for glucose lowering effects in clinical practice for more than 60years. For diabetic therapy, metformin reduces glucose absorption from the intestines, lowers hepatic gluconeogenesis, reduces inflammation, and improves insulin sensitivity. However, despite being widely used as the first-line oral antidiabetic drug, its mechanism of action remains largely elusive. Currently, an increasing number of studies have demonstrated that the anti-diabetic effects of metformin were mediated by the regulation of lncRNAs. Metformin-regulated lncRNAs have been shown to participate in the inhibition of gluconeogenesis, regulation of lipid metabolism, and be anti-inflammatory. Thus, this review focuses on the mechanisms of action of metformin in regulating lncRNAs in diabetes, including pathways altered by metformin via targeting lncRNAs, and the potential targets of metformin through modulation of lncRNAs. Knowledge of the mechanisms of lncRNA modulation by metformin in diabetes will aid the development of new therapeutic drugs for T2D in the future.

1472-P: Polygenic Risk Score for Liver Fat Predicts Earlier Onset of Type 2 Diabetes in an East Asian Population

Liver, pancreas fat deposition and volume have been associated with type 2 diabetes (T2D) risk by Mendelian randomization study. However, it is unknown whether genetic variation in these traits impact on T2D onset, insulin resistance and drug use. We hypothesized that (1) genetic predisposition to smaller pancreas would be associated with earlier onset of T2D and earlier need for insulin; (2) genetic predisposition to higher pancreas and liver fat would be associated with greater insulin resistance, earlier onset of T2D and earlier need for insulin. This study utilized three Chinese cohorts of genotyped T2D patients in Hong Kong: Hong Kong Diabetes Register (HKDR, n=6011), Hong Kong Diabetes Biobank Phase 1 (HKDB-P1, n=6662) and Hong Kong Diabetes Biobank Phase 2 (HKDB-P2, n= 5899). We used lead SNPs (single nucleotide polymorphisms) associated with pancreas volume (13 SNPs), fat (7 SNPs) and liver fat (8 SNPs) from UK Biobank (n&amp;gt;32,000) to construct PRS (Polygenic risk score) in these cohorts. Linear regression models were employed to examine the associations between PRS and age of T2D onset and insulin resistance. Multivariable cox regression models were employed to examine association with time to insulin use. All models included age (except for age of T2D onset), sex and top 4 genetic principal components as covariates. To assess the confounding effects of BMI, we also performed BMI subgroup analysis by stratifying individuals into underweight, normal and overweight groups. Our analyses found that higher PRS for liver fat, but not pancreatic size or fat predicts earlier onset of T2D in HKDB-P1 (p&amp;lt;0.001, t=−3.43). The direction of association in HKDB-P2 was consistent though not significant. When stratified by BMI, higher PRS for liver fat predicts earlier onset of T2D in HKDB-P1 (p= 0.002, t=−3.14) and HKDB-P2 (p=0.029, t=−2.19) among the overweight group. Our results highlighted a PRS of liver fat as a potential biomarker for age of T2D onset, which needs further validation. Disclosure G.Yu: None. C.Huang: None. A.Luk: Research Support; Novo Nordisk, Boehringer-Ingelheim, Bayer Inc., Speaker's Bureau; Eli Lilly and Company. E.S.H.Lau: None. Hong kong diabetes biobank study group: n/a. R.C.Ma: Advisory Panel; AstraZeneca, Merck &amp; Co., Inc., Other Relationship; Bayer Inc., Boehringer-Ingelheim, Research Support; Tricida, Inc., Roche Diagnostics, Novo Nordisk. C.H.Tam: None. M.Shi: None. B.Fan: None. C.K.Lim: Stock/Shareholder; GemVCare Ltd. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer Inc., Celltrion, Boehringer Ingelheim and Eli Lilly Alliance, Sanofi, Research Support; AstraZeneca, Servier Laboratories, Viatris Inc., Hua Medicine, Merck KGaA, Applied Therapeutics Inc., Lee Powder, Pfizer Inc., Speaker's Bureau; Novartis, Stock/Shareholder; GemVCare Ltd. M.N.Weedon: None. R.A.Oram: Consultant; Janssen Research &amp; Development, LLC, Research Support; Randox R &amp; D. Funding Research Grants Council of the Hong Kong Special Administrative Region (CU-R4012-18); Croucher Foundation

Network Pharmacology and Transcriptomics Reveal the Mechanism of GuaLouQuMaiWan in Treatment of Type 2 Diabetes and Its Active Small Molecular Compound.

The main pathophysiological abnormalities in type 2 diabetes (T2D) include pancreatic β-cell dysfunction and insulin resistance. Due to hyperglycemia, patients receive long-term treatment. However, side effects and drug tolerance usually lead to treatment failure. GuaLouQuMaiWan (GLQMW), a common traditional Chinese medicine (TCM) prescription, has positive effects on controlling blood sugar and improving quality of life, but the mechanism is still unclear. To decipher their molecular mechanisms, we used a novel computational systems pharmacology-based approach consisting of bioinformatics analysis, network pharmacology, and drug similarity comparison. We divided the participants into nondisease (ND), impaired glucose tolerance (IGT), and type 2 diabetes groups according to the WHO's recommendations for diabetes. By analyzing the gene expression profile of the ND-IGT-T2D (ND to IGT to T2D) process, we found that the function of downregulated genes in the whole process was mainly related to insulin secretion, while the upregulated genes were related to inflammation. Furthermore, other genes in the ND-IGT (ND to IGT) process are mainly related to inflammation and lipid metabolic disorders. We speculate that 17 genes with a consistent trend may play a key role in the process of ND-IGT-T2D. We further performed target prediction for 50 compounds in GLQMW that met the screening criteria and intersected the differentially expressed genes of the T2D process with the compounds of GLQMW; a total of 18 proteins proved potential targets for GLQMW. Among these, RBP4 is considerably related to insulin resistance. GO/KEGG enrichment analyses of the target genes of GLQMW showed enrichment in inflammation- and T2D therapy-related pathways. Based on the RDKit tool and the DrugBank database, we speculate that (-)-taxifolin, dialoside A_qt, spinasterol, isofucosterol, and 11,14-eicosadienoic acid can be used as potential drugs for T2D via molecular docking and drug similarity comparison.

Roles of long noncoding RNAs and small extracellular vesicle-long noncoding RNAs in type 2 diabetes.

The prevalence of a high-energy diet and a sedentary lifestyle has increased the incidence of type 2 diabetes (T2D). T2D is a chronic disease characterized by high blood glucose levels and insulin resistance in peripheral tissues. The pathological mechanism of this disease is not fully clear. Accumulated evidence has shown that noncoding RNAs have an essential regulatory role in the progression of diabetes and its complications. The roles of small noncoding RNAs, such as miRNAs, in T2D, have been extensively investigated, while the function of long noncoding RNAs (lncRNAs) in T2D has been unstudied. It has been reported that lncRNAs in T2D play roles in the regulation of pancreatic function, peripheral glucose homeostasis and vascular inflammation. In addition, lncRNAs carried by small extracellular vesicles (sEV) were shown to mediate communication between organs and participate in diabetes progression. Some sEV lncRNAs derived from stem cells are being developed as potential therapeutic agents for diabetic complications. In this review, we summarize the current knowledge relating to lncRNA biogenesis, the mechanisms of lncRNA sorting into sEV and the regulatory roles of lncRNAs and sEV lncRNAs in diabetes. Knowledge of lncRNAs and sEV lncRNAs in diabetes will aid in the development of new therapeutic drugs for T2D in the future.

The effects of empagliflozin, dietary energy restriction, or both on appetite-regulatory gut peptides in individuals with type 2 diabetes and overweight or obesity: The SEESAW randomized, double-blind, placebo-controlled trial.

AimTo assess the impact of the sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor empagliflozin (25 mg once‐daily), dietary energy restriction, or both combined, on circulating appetite‐regulatory peptides in people with type 2 diabetes (T2D) and overweight or obesity.Materials and MethodsIn a double‐blind, placebo‐controlled trial, 68 adults (aged 30‐75 years) with T2D (drug naïve or on metformin monotherapy; HbA1c 6.0%‐10.0% [42‐86 mmol/mol]) and body mass index of 25 kg/m2 or higher were randomized to (a) placebo only, (b) placebo plus diet, (c) empagliflozin only or (d) empagliflozin plus diet for 24 weeks. Dietary energy restriction matched the estimated energy deficit elicited by SGLT2 inhibitor therapy through urinary glucose excretion (~360 kcal/day). The primary outcome was change in postprandial circulating total peptide‐YY (PYY) during a 3‐hour mixed‐meal tolerance test from baseline to 24 weeks. Postprandial total glucagon‐like peptide‐1 (GLP‐1), acylated ghrelin and subjective appetite perceptions formed secondary outcomes, along with other key components of energy balance.ResultsThe mean weight loss in each group at 24 weeks was 0.44, 1.91, 2.22 and 5.74 kg, respectively. The change from baseline to 24 weeks in postprandial total PYY was similar between experimental groups and placebo only (mean difference [95% CI]: −8.6 [−28.6 to 11.4], 13.4 [−6.1 to 33.0] and 1.0 [−18.0 to 19.9] pg/ml in placebo‐plus diet, empagliflozin‐only and empagliflozin‐plus‐diet groups, respectively [all P ≥ .18]). Similarly, there was no consistent pattern of difference between groups for postprandial total GLP‐1, acylated ghrelin and subjective appetite perceptions.ConclusionsIn people with T2D and overweight or obesity, changes in postprandial appetite‐regulatory gut peptides may not underpin the less than predicted weight loss observed with empagliflozin therapy.Clinical Trials RegistrationNCT02798744, www.ClinicalTrials.gov; 2015‐001594‐40, www.EudraCT.ema.europa.eu; ISRCTN82062639, www.ISRCTN.org.

Abstract 11459: Mitochondrial Metabolites Predict Cardiovascular Outcomes and Heart Failure in Individuals with Type 2 Diabetes Mellitus: An Exscel Biomarker Substudy

Introduction: Metabolic substrate utilization is central to metabolic disease. Metabolic pathways linking type 2 diabetes (T2D) to major adverse cardiac events (MACE) and heart failure (HF) remain poorly understood and T2D drug effects on metabolite biomarkers could improve biological understanding and support precision medicine approaches. Hypothesis: Circulating metabolites characterizing mitochondrial dysfunction are predictors for MACE and hospitalization for HF (hHF), and are improved with exenatide. Methods: We performed targeted mass-spectrometry profiling of 60 metabolites on baseline and 12-month plasma samples from 978 participants from EXSCEL, a randomized trial of the GLP-1 receptor agonist, exenatide. Principal components analysis (PCA) was used; resultant metabolite factors were analyzed with univariate and multivariable logistic regression (adjusted for history of HF, coronary artery disease, BMI, HbA 1c , eGFR, blood pressure) for association with MACE (CV death, non-fatal MI or stroke) and hHF. Results were validated in participants from TECOS, a randomized trial of the DPP-4 inhibitor sitagliptin. Metabolite changes by treatment arm were tested. Results: Of 12 PCA metabolite factors, two nominally associated with MACE in both univariate and multivariable models and two associated with hHF in univariate, but not multivariable models ( Table ). Individual metabolites remained associated with MACE in multivariable models and with hHF in univariate models. Similar results were seen in the TECOS validation cohort. Individual metabolites decreased to a greater extent in exenatide randomized individuals compared with placebo. Conclusions: Metabolites reporting on dysregulated mitochondrial fatty acid oxidation are increased in individuals with T2D who experience MACE. These biomarkers may improve CV risk prediction models, appear to be beneficially modified by exenatide, and highlight emerging risk mechanisms.

485-P: Insights from Type 2 Diabetes Patients Reveal Education- and Income-Based Disparities in Awareness Surrounding Kidney Disease Risk and Renoprotective Therapies

Objective: Diabetes is a leading cause of chronic kidney disease (CKD), and new drug classes including SGLT-2 inhibitors and GLP-1 receptor agonists have shown renal benefits for those with type 2 diabetes (T2D). This study evaluated T2D patients’ awareness regarding CKD and renoprotective drugs across household income and educational attainment. Method: In an online survey in September 2020, 2,008 adults with T2D not currently being treated for kidney disease rated their level of agreement with statements about CKD risk and renoprotective drugs. Demographic information was collected. Result: The majority (58%) of patients strongly agreed that diabetes increases risk of CKD. Those with an income of &amp;lt;$50k and a high school diploma were less aware of the link between diabetes and CKD than those with the same income and a bachelor’s degree or higher (51%, vs. 62%) and those with an income of &amp;gt;$100k and a bachelor’s degree or higher (65%). Only 30% of patients indicated strong concern about CKD risk, and 25% were aware that some T2D drugs have renal benefits. Among those earning $50k-$100k, patients with a high school diploma were more concerned about their risk (44%) than those with some college (24%) or a bachelor’s degree or higher (29%). Those earning &amp;gt;$100k with a bachelor’s degree or higher were more likely to indicate strong awareness that some T2D drugs are renoprotective (34%) than those earning &amp;lt;$50k (high school diploma: 23%; some college: 24%), those earning $50k-$100k (some college: 24%; bachelor’s degree or higher: 25%), and those earning &amp;gt;$100k with some college (20%). Conclusion: While few T2D patients are aware that some T2D drugs have renoprotective effects, those with higher education and income are more likely to be aware. These findings emphasize the importance of informing patients about renal health and therapeutic options, in efforts to increase accessibility of SGLT-2 and GLP-1 therapies to all who would benefit. Disclosure J. Stevenson: Other Relationship; Self; Abbott, Ascensia Diabetes Care, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, LifeScan, Medtronic, Roche Diabetes Care, Senseonics, Tandem Diabetes Care. E. Ye: Other Relationship; Self; dQ&amp;A. S. Suhl: Other Relationship; Self; dQ&amp;A has several clients (&amp;gt;10) in the diabetes field. R. Gowen: Other Relationship; Self; dQ&amp;A. J. Tait: Other Relationship; Self; dQ&amp;A Market Research Inc. C. Florissi: Other Relationship; Self; Abbott Diabetes, Ascensia Diabetes Care, Dexcom, Inc., Insulet Corporation, LifeScan, Lilly Diabetes, Medtronic, Roche Diabetes Care, Senseonics, Tandem Diabetes Care. R. Wood: Research Support; Self; Abbott Diabetes, American Diabetes Association, Ascensia Diabetes Care, Boehringer Ingelheim International GmbH, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk Inc., Sanofi.

Allosteric MAPKAPK2 inhibitors improve plaque stability in advanced atherosclerosis.

Atherosclerotic vascular disease resulting from unstable plaques is the leading cause of morbidity and mortality in subjects with type 2 diabetes (T2D), and thus a major therapeutic goal is to discover T2D drugs that can also promote atherosclerotic plaque stability. Genetic or pharmacologic inhibition of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2 or MK2) in obese mice improves glucose homeostasis and enhances insulin sensitivity. We developed two novel orally active small-molecule inhibitors of MK2, TBX-1 and TBX-2, and tested their effects on metabolism and atherosclerosis in high-fat Western diet (WD)-fed Ldlr-/- mice. Ldlr-/- mice were first fed the WD to allow atherosclerotic lesions to become established, and the mice were then treated with TBX-1 or TBX-2. Both compounds improved glucose metabolism and lowered plasma cholesterol and triglyceride, without an effect on body weight. Most importantly, the compounds decreased lesion area, lessened plaque necrosis, and increased fibrous cap thickness in the aortic root lesions of the mice. Thus, in a preclinical model of high-fat feeding and established atherosclerosis, MK2 inhibitors improved metabolism and also enhanced atherosclerotic plaque stability, suggesting potential for further clinical development to address the epidemic of T2D associated with atherosclerotic vascular disease.

Friend or foe? ACE2 inhibitors and GLP-1R agonists in COVID-19 treatment.

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a pandemic since WHO made the statement on March 11, 2020. The infection is causing a high mortality in old people, especially those with obesity, type 2 diabetes (T2D) or cardiovascular diseases (CVD). Extra cautions are needed in the treatment of those patients. The CVD drugs ACEIs and ARBs, as well as the T2D drugs GLP-1R agonists, were shown to activate angiotensin-converting enzyme 2 (ACE2) expression in experimental animals. Elevated ACE2 expression may accelerate virus entrance into the host cells during the infection for its replication. However, expression of the soluble ACE2, may neutralize the virus to limit the infection and replication. Given that obese, diabetes and CVD patients often take those medicines in the treatment and prevention of blood pressure and glucose elevation, it remains to be determined whether those medicines represent friend or foe in the treatment of COVID-19. We suggest that retrospective studies should be conducted to determine the exact impact of those medicines in obese, diabetic, or CVD patients who had COVID-19. Results obtained will provide guidance whether those drugs can be utilized in COVID-19 patients with obesity, diabetic, or CVD.