Classes Of Glucose-lowering Drugs Research Articles

Once-weekly insulins: a promising approach to reduce the treatment burden in people with diabetes.

Despite the availability of new classes of glucose-lowering drugs that improve glycaemic levels and minimise long-term complications, at least 20-25% of people with type 2 diabetes require insulin therapy. Moreover, a substantial proportion of these individuals do not achieve adequate metabolic control following insulin initiation. This is due to several factors: therapeutic inertia, fear of hypoglycaemia and/or weight gain, poor communication, complexity of insulin titration, and the number of injections needed, with the associated reduced adherence to insulin therapy. Once-weekly insulins provide a unique opportunity to simplify basal insulin therapy and to allow good glycaemic control with a low risk of hypoglycaemia. Several approaches to developing a stable and effective once-weekly insulin have been proposed, but, to date, insulin icodec and basal insulin Fc (insulin efsitora alfa) are the only two formulations for which clinical studies have been reported. The results of Phase I and II studies emphasise both efficacy (in term of glucose levels) and potential risks and adverse events. Phase III studies involving insulin icodec are reassuring regarding the risk of hypoglycaemia compared with daily basal insulin analogues. Despite some concerns raised in ongoing clinical trials, the available data suggest that weekly insulins may also be an option for individuals with type 1 diabetes, especially when adherence is suboptimal. For the first time there is an opportunity to make an important breakthrough in basal insulin therapy, particularly in people with type 2 diabetes, and to improve not only the quality of life of people with diabetes, but also the practice of diabetologists.

SGLT2 inhibitors and AMPK: The road to cellular housekeeping?

Sodium-glucose co-transporter-2 (SGLT2) inhibitors, known as Gliflozins, are a class of Glucose-lowering drugs in adults with type 2 diabetes (T2D) that induce glucosuria by blocking SGLT2 co-transporters in the proximal tubules. Several lines of evidence suggest that SGLT2 inhibitors regulate multiple mechanisms associated with the regulation of varying cellular pathways. The 5'-adenosine monophosphate-activated protein kinase (AMPK) pathway plays an important role in metabolic homeostasis by influencing cellular processes. Recently, it has been shown that SGLT2 inhibitors can affect the AMPK pathway in differing physiological and pathological ways, resulting in kidney, intestinal, cardiovascular, and liver protective effects. Additionally, they have therapeutic effects on nonalcoholic fatty liver disease and diabetes mellitus-associated complications. In this review, we summarize the results of studies of AMPK-associated therapeutic effects of SGLT2 inhibitors in different organelle functions.

Glyceraldehyde derivatives inspired by empagliflozin as potential anti-heart failure agents independent of glucose-lowering effects

Sodium-glucose cotransporter 2 inhibitors are a class of glucose-lowering drugs known for robust cardiovascular protective properties. However, the side effects induced by Sodium-glucose cotransporter 2 inhibition limit application in cardiovascular medicine. Our prior research showed that thoughtful structural modifications can dissociate the anti-heart failure activity from glucose-lowering effects. Moreover, we showed that the glyceraldehyde derivative, JX22, developed by scaffold hopping from empagliflozin, exhibits a superior cardiomyocyte protective effect, albeit with increased cytotoxicity compared to empagliflozin. In the current study systematic structural modifications of JX22 were performed to enhance anti-heart failure efficacy and safety, while reducing glucose-lowering activity. Twenty glyceraldehyde-based derivatives were synthesized and compound 12 emerged as an optimal candidate by exhibiting an improved cytoprotective effect compared to JX22. Compound 12 significantly inhibited the activity of NHE1 on the myocardial membrane, thereby maintaining intracellular ion homeostasis. In vivo efficacy results demonstrated that compound 12 at 10 mg/kg significantly ameliorated cardiac dysfunction, myocardial fibrosis, and exercise tolerance in isoproterenol-induced heart failure mice without a glucose-lowering effect. Furthermore, compound 12 exhibited favorable safety profiles in single-dose toxicity and hERG inhibition tests, along with promising pharmacokinetic properties in mice. The current study not only underscores the potential of compound 12 for further investigation but also highlights the effectiveness of the scaffold hopping strategy.

#2601 THE MOLECULAR EFFECT OF SGLT2I ON THE AUTOPHAGY PATHWAY IN TYPE II DIABETES MELLITUS AND ITS VASCULAR COMPLICATIONS

Abstract Background and Aims Type II Diabetes mellitus (T2DM) is a severe metabolic disorder characterized by chronic hyperglycemia and its subsequent glucose toxicity that lead to irreversible damages in several organs such as Diabetic Nephropathy (DN) [1]. Autophagy is involved in catabolic processes and plays a key role in the degradation of damaged intracellular proteins in order to maintain intracellular homeostasis and cell integrity. Studies showed that autophagy-related protein 5 (ATG5) and Light chain 3-II (LC3-II) play a critical role in a variety of disease processes, like DN [3]. Empagliflozin (EMPA) is sodium glucose transporter inhibitor (SGLT2i) which represents a new class of glucose lowering drugs and is recommended in T2DM [4]. We hypothesized that EMPA effects renal integrity and function via the autophagy mechanism. The proposed research aim to investigate the molecular effect of SGLT2i on the expression of ATG5 and its downstream collaborator LC3-II in diabetic mice model [5]. Methods 8-week-old male mice: C57BL/6 Wild Type (Con), BTBR ob/ob (DM) and BTBR ob/ob treated with EMPA (1mg/kg/day P.O.) (DM+EMPA) were followed for 12 consecutive weeks for their weight, blood glucose and renal function. After sacrifice lysate from renal cortex were analyzed by Western blot and immunohistochemistry for ATG5, LC3B and fibronectin expression. Results Blood glucose level in DM mice was higher than Con, and lower in DM+EMPA. DM+EMPA mice drunk, urinated more and exerted more glucose than DM mice, yet had less protein in their urine. WB and IHC analyses revealed that renal ATG5 and LC3-II levels were reduced in DM mice compared with Con and DM+EMPA mice. Fibronectin expression was increased in DM compared to Con mice, and DM+EMPA mice. Conclusions EMPA treatment preserved DM mice renal dysfunction. Our data suggest that there is a link between DM and ATG5/LC3-II dysregulation and subsequent DN. EMPA preserves ATG5/LC3-II in DM mice. Our findings may be translated into clinical practice approach and may lead to further studies to address DM and vascular complications by selective modulation of ATG5/LC3-II expression with SGLT2i treatment.

Effects of DPP-4 inhibitors, GLP-1 receptor agonists, SGLT-2 inhibitors and sulphonylureas on mortality, cardiovascular and renal outcomes in type 2 diabetes: A network meta-analyses-driven approach.

The aim of our meta-analyses was to compare the effects of glucose-lowering drugs on mortality, cardiovascular and renal endpoints for a range of type 2 diabetes (T2D) subgroups defined by their specific cardiovascular risk profile. Meta-analyses comparing drugs within the classes of GLP-1RAs and SGLT-2 inhibitors were performed and compared to sulphonylureas and DPP-4 inhibitors with available cardiovascular outcome trials. The comparison between the different classes of glucose-lowering drugs included analyses of T2D populations with low risk and high risk for cardiovascular disease including populations with established cardiovascular disease and/or kidney disease. Outcomes included mortality, major cardiovascular adverse events (MACE), hospitalisation for heart failure (HHF) and a composite renal endpoint as applied in the underlying clinical trials. SGLT-2 inhibitors and GLP-1RAs showed beneficial effects on mortality and MACE compared to the classes of DPP-4 inhibitors and sulphonylureas. SGLT-2 inhibitors were shown to be the most effective treatment in terms of HHF and kidney disease. Metformin was used as background therapy for the vast majority of participants in all included studies. Overall, the absolute effects of SGLT-2 inhibitors and GLP-1RAs on these important outcomes were evident for patients with established or at high risk for cardiovascular disease but limited for the low-risk subgroup. The findings from our analyses substantiate the relevance of treatment with SGLT-2 inhibitors or GLP-1RAs as an add-on to metformin in patients with T2D and a high risk for cardiovascular disease, and furthermore, support the recommendation for SGLT-2 inhibitor treatment in patients with T2D and heart failure or established kidney disease.

Sodium-glucose cotransporter-2 inhibitors and kidney outcomes in real-world type 2 diabetes populations: A systematic review and meta-analysis of observational studies.

To conduct a systematic review of observational studies to explore the real-world kidney benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors in a large and diverse population of adults with type 2 diabetes (T2D). We searched MEDLINE, EMBASE and Web of Science for observational studies that investigated kidney disease progression in adults with T2D treated with SGLT2 inhibitors compared to other glucose-lowering therapies. Studies published from database inception to July 2022 were independently reviewed by two authors and evaluated using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool. A random-effects meta-analysis was performed on studies with comparable outcome data, reported as hazard ratios (HRs) with 95% confidence intervals (CIs). We identified 34 studies performed across 15 countries with a total population of 1 494 373 for inclusion. In the meta-analysis of 20 studies, SGLT2 inhibitors were associated with a 46% lower risk of kidney failure events compared with other glucose-lowering drugs (HR 0.54, 95% CI 0.47-0.63). This finding was consistent across multiple sensitivity analyses and was independent of baseline estimated glomerular filtration rate (eGFR) or albuminuria status. SGLT2 inhibitors were associated with a lower risk of kidney failure when compared with dipeptidyl peptidase-4 inhibitors and a combination of other glucose-lowering drug classes (HR 0.50, 95% CI 0.38-0.67 and HR 0.51, 95% CI 0.44-0.59, respectively). However, when compared to glucagon-like peptide 1 receptor agonists there was no statistically significant difference in the risk of kidney failure (HR 0.93, 95% CI 0.80-1.09). The reno-protective benefits of SGLT2 inhibitors apply to a broad population of adults with T2D treated in routine clinical practice, including those at lower risk of kidney events with normal eGFR and without albuminuria. These findings support the early use of SGLT2 inhibitors in T2D for preservation of kidney health.

Влияние иДПП-4 эвоглиптина на показатели вариабельности уровня глюкозы и времени в целевом диапазоне у пациентов с сахарным диабетом 2 типа в условиях реальной клинической практики по сравнению с препаратами производных сульфонилмочевины (собственный опыт)

An early diagnosis of diabetes to prescribe effective and safe glucose-lowering therapy is important for organizing diabetes care. To analyze the efficacy and safety of modern glucose-lowering drugs, continuous glucose monitoring, or flash glucose monitoring, allowing a more detailed assessment of glycemic fluctuations within a specified period of time is actively introduced into real-world clinical practice. Over the past two decades, significant progress has been made in providing specialized medical care to patients with type 2 diabetes (T2D) due to the introduction of novel classes of glucose-lowering drugs into clinical practice. The mechanism of action of drugs belonging to dipeptidyl peptidase 4 (DPP-4) inhibitors is based on insulin-dependent modulation of insulin and glucagon production. Their use is characterized by a good safety profile, including an extremely low risk of hypoglycemia in T2D. The authors describe their experience with the DPP-4 inhibitor evogliptin in these patients. A strong tendency to a reduction in the total number of hypoglycemia recorded by flash monitoring, overall time below range (<3.9 mmol/l), and time below range (<3.0 mmol/l). The emergence on the Russian market of modern, available, locally produced DPP-4 inhibitors may significantly improve the safety of T2D therapy. KEYWORDS: glucose-lowering drug, continuous glucose monitoring, diabetes, diabetes care, hypoglycemia, evogliptin. FOR CITATION: Kalashnikova M.F., Teplov E.V., Likhodey N.V., Maloletkina E.S., Vavil'chenkova K.S., Glinkina I.V. Effect of dipeptidyl peptidase 4 inhibitor evogliptin on glycemic variability and time in range in patients with type 2 diabetes in real-world clinical practice compared with sulfonylureas (authors experience). Russian Medical Inquiry. 2023;7(9):598–605 (in Russ.). DOI: 10.32364/2587-6821-2023-7-9-7.

SGLT2 Inhibitors in Acute Heart Failure: A Meta-Analysis of Randomized Controlled Trials.

Acute heart failure (AHF) is a major public health concern, affecting 26 million worldwide. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of glucose-lowering drugs, comprising canagliflozin, dapagliflozin, and empagliflozin that are being explored for AHF. We aim to meta-analyze the effectiveness of SGLT2 inhibitors compared to placebo for primary outcomes including all-cause and cardiovascular mortality, heart failure events, symptomatic improvement, and readmissions. Our secondary outcome is the risk of serious adverse events. This meta-analysis has been designed in accordance with the PRISMA Statement 2020. A systematic search across PubMed, Scopus, and Cochrane Library was conducted through August 13, 2022. The following keywords were utilized: sglt2, sodium-glucose transporter 2 inhibitors, sglt2 inhibitors, decompensated heart failure, de-novo heart failure, and/or acute heart failure. Only randomized controlled trials (RCTs) with adult patients (>18 years), hospitalized with de-novo AHF, acutely decompensated chronic heart failure with reduced, borderline, or preserved ejection, and receiving SGLT2 inhibitors were included. A quantitative analytical methodology was applied where the standardized mean difference (SMD) applying 95% confidence intervals (CI) for continuous outcomes and risk ratio (RR) with 95% CI was yielded. All tests were carried out on Review Manager 5.4 (Cochrane). In total, three RCTs were included pooling in a total of 1831 patients where 49.9% received SGLT2 inhibitors. The mean age was 72.9 years in the interventional group compared to 70.6 years in the placebo. Only 33.7% of the sample was female. The follow-up spanned 2-9 months. Heart failure events were reduced by 62% in the interventional group (RR = 0.66, p < 0.0001). readmissions had a reduced risk of 24% with SGLT2 inhibitors (RR = 0.76, p = 0.03). We assessed the efficacy and safety of SGLT2 inhibitors in preventing complications post-AHF. The odds of all-cause mortality, cardiovascular mortality, heart failure events, and re-admissions rates were substantially reduced within the first 1-9 months of hospitalization.

Variations in Use of Diabetes Drugs With Cardiovascular Benefits Among Medicaid Patients

Cardiovascular death remains the leading cause of mortality in patients with type 2 diabetes (T2D). A better understanding of the current use and adoption of glucose-lowering drugs with cardiovascular benefit can inform state policies to ensure their appropriate use in patients with T2D. To characterize the use of glucose-lowering agents with known cardiovascular benefit over time and across states. This cross-sectional pharmacoepidemiological study of Medicaid prescription rates of glucose-lowering agents with known cardiovascular benefit vs those with less well-established cardiovascular benefit was conducted between 2014 and 2019. In 50 states and the District of Columbia, the study focused on nonmetformin, noninsulin glucose-lowering drugs divided into 3 cohorts: (1) sodium-glucose cotransporter 2 (SGLT2) inhibitors, (2) glucagon-like peptide 1 (GLP1) receptor agonists, and (3) all other classes of glucose-lowering drugs. Data were analyzed from January 2014 to December 2019. Number of days supplied of each cohort, use ratios between the aggregated days supplied of glucose-lowering agents with known cardiovascular benefit vs those with less well-established cardiovascular benefit, and the mean change in use ratios per quarter. Across the 50 states and the District of Columbia, the use ratio of glucose-lowering agents with known cardiovascular benefit ranged from 1.58 to 0.14 (mean [SD], 0.48 [0.27]) in 2019. A lower use ratio was seen in states with a higher prevalence of diabetes (β = -0.049; 95% CI, -0.086 to -0.012; P = .01), a larger total population (β = -0.013; 95% CI, -0.023 to -0.003; P = .01), a greater number of Medicaid enrollees (β = -0.054; 95% CI, -0.096 to -0.014; P = .01), a greater proportion of people enrolled in Medicaid (β = -0.018; 95% CI, -0.030 to -0.007; P = .002), and a greater proportion of Medicaid patients enrolled in managed care organizations (β = -0.0032; 95% CI, -0.0051 to -0.0013; P = .002). Higher Medicaid expenditures per enrollee (β = 0.047; 95% CI, 0.007 to 0.089; P = .03) were associated with a higher use ratio of these agents. The relative use of glucose-lowering agents with known cardiovascular benefit by Medicaid enrollees increased 7.4% per year from 2014 to 2019, with wide variations across state Medicaid programs. In this cross-sectional study, glucose-lowering agents with cardiovascular benefit increased in use during the study period, but also demonstrated considerable variation among states in their relative use. Medicaid programs should try to clarify which factors may be contributing to relative underuse of these potentially life-saving drugs.

Diabetes Mellitus and Heart Failure.

The coexistence of diabetes mellitus (DM) and heart failure (HF) is frequent and is associated with a higher risk of hospitalization for HF and all-cause and cardiovascular mortality. It has been estimated that millions of people are affected by HF and DM, and the prevalence of both conditions has increased over time. Concomitant HF and diabetes confer a worse prognosis than each alone; therefore, managing DM care is critical for preventing HF. This article reviews the prevalence of HF and diabetes and the correlated prognosis as well as provides a basic understanding of diabetic cardiomyopathy, including its pathophysiology, focusing on the relationship between DM and HF with a preserved ejection fraction and summarizes the potential aldosterone and the mineralocorticoid receptor antagonists approaches for managing heart failure and DM. Sodium–glucose cotransporter 2 inhibitors (SGLT2Is) are an emerging class of glucose-lowering drugs, and the role of SGLT2Is in DM patients with HF was reviewed to establish updated and comprehensive concepts for improving optimal medical care in clinical practice.

Evaluating the impact of glucokinase activation on risk of cardiovascular disease: a Mendelian randomisation analysis

BackgroundGlucokinase activators (GKAs) are an emerging class of glucose lowering drugs that activate the glucose-sensing enzyme glucokinase (GK). Pending formal cardiovascular outcome trials, we applied two-sample Mendelian randomisation (MR) to investigate the impact of GK activation on risk of cardiovascular diseases.MethodsWe used independent genetic variants in or around the glucokinase gene meanwhile associated with HbA1c at genome-wide significance (P < 5 × 10−8) in the Meta-Analyses of Glucose and Insulin-related traits Consortium study (N = 146,806; European ancestry) as instrumental variables (IVs) to mimic the effects of GK activation. We assessed the association between genetically proxied GK activation and the risk of coronary artery disease (CAD; 122,733 cases and 424,528 controls), peripheral arterial disease (PAD; 7098 cases and 206,541 controls), stroke (40,585 cases and 406,111 controls) and heart failure (HF; 47,309 cases and 930,014 controls), using genome-wide association study summary statistics of these outcomes in Europeans. We compared the effect estimates of genetically proxied GK activation with estimates of genetically proxied lower HbA1c on the same outcomes. We repeated our MR analyses in East Asians as validation.ResultsGenetically proxied GK activation was associated with reduced risk of CAD (OR 0.38 per 1% lower HbA1c, 95% CI 0.29–0.51, P = 8.77 × 10−11) and HF (OR 0.54 per 1% lower HbA1c, 95% CI 0.41–0.73, P = 3.55 × 10−5). The genetically proxied protective effects of GKA on CAD and HF exceeded those due to non-targeted HbA1c lowering. There was no causal relationship between genetically proxied GK activation and risk of PAD or stroke. The estimates in sensitivity analyses and in East Asians were generally consistent.ConclusionsGKAs may protect against CAD and HF which needs confirmation by long-term clinical trials.

SGLT2 inhibitors protect cardiomyocytes from myocardial infarction: a direct mechanism?

SGLT2 inhibitors have been developed as a novel class of glucose-lowering drugs affecting reabsorption of glucose and metabolic processes. They have been recently identified to be remarkably favorable in treating cardiovascular diseases, especially heart failure. Preclinical experiments have shown that SGLT2 inhibitors could hinder the progression of myocardial infarction and alleviate cardiac remodeling by mechanisms of metabolism influence, autophagy induction, inflammation attenuation and fibrosis reduction. Here we summarize the direct mechanism of SGLT2 inhibitors on myocardial infarction and investigate whether it could be applied to the clinic in improving cardiac function and healing after myocardial infarction.

Coronary Microvascular Dysfunction in Diabetes Mellitus: Pathogenetic Mechanisms and Potential Therapeutic Options.

Diabetic patients are frequently affected by coronary microvascular dysfunction (CMD), a condition consisting of a combination of altered vasomotion and long-term structural change to coronary arterioles leading to impaired regulation of blood flow in response to changing cardiomyocyte oxygen requirements. The pathogenesis of this microvascular complication is complex and not completely known, involving several alterations among which hyperglycemia and insulin resistance play particularly central roles leading to oxidative stress, inflammatory activation and altered barrier function of endothelium. CMD significantly contributes to cardiac events such as angina or infarction without obstructive coronary artery disease, as well as heart failure, especially the phenotype associated with preserved ejection fraction, which greatly impact cardiovascular (CV) prognosis. To date, no treatments specifically target this vascular damage, but recent experimental studies and some clinical investigations have produced data in favor of potential beneficial effects on coronary micro vessels caused by two classes of glucose-lowering drugs: glucagon-like peptide 1 (GLP-1)-based therapy and inhibitors of sodium-glucose cotransporter-2 (SGLT2). The purpose of this review is to describe pathophysiological mechanisms, clinical manifestations of CMD with particular reference to diabetes, and to summarize the protective effects of antidiabetic drugs on the myocardial microvascular compartment.

Prevention is still the key to success.

In this issue of the journal, we publish a survey of cardiovascular disease (CVD) risk factors in patients with rheumatoid arthritis (RA) in 14 503 patients from 19 countries during 2014–2019. Dr Semb and co-workers report considerable geographical differences in estimated CVD risk and preventive treatment. Low goal attainment for lipid lowering treatment was observed, and only half of the patients obtained blood pressure goal. The authors conclude that despite a high focus on the increased CVD risk in RA patients over the last decade,1 there is still substantial potential for improvement in CVD preventive measures. In recent years, numerous cardiovascular (CV) outcomes trials have demonstrated not only CV safety but reductions in CV outcomes with two new classes of glucose lowering drugs, namely glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT-2i) in patients with type II DM.2–6 In a Danish study, Dr Nørgaard and co-workers examined CV outcomes associated with the initiation of GLP-1RA vs. SGLT-2i treatment in a real-world setting among patients with type 2 diabetes. They used a Danish nationwide registry-based cohort study included patients with type 2 diabetes with a first-ever prescription of either GLP-1RA or SGLT-2i from 2013 through 2015, with follow-up until the end of 2018. The authors concluded that in this nationwide study of patients with type 2 diabetes, initiating GLP-1RA vs. SGLT-2i was not found to be associated with significant differences in CV risk.

Glucose-lowering drug use, glycemic outcomes, and severe hypoglycemia: 18-Year trends in 0·9 million adults with Diabetes in Hong Kong (2002–2019)

SummaryBackgroundImprovements in glycemic outcomes have stalled since 2010 in several international surveys. We previously reported improvements in glycemic control in 2007-2014 in Hong Kong coinciding with primary care reforms, use of dipeptidyl-peptidase 4 inhibitors (DPP-4is) and metformin. The aim of this study was to estimate more recent trends in drug use and glycemic outcomes following introduction of newer classes of glucose-lowering drugs (GLDs).MethodsUsing population-based data from the Hong Kong Diabetes Surveillance Database, we explored age-specific trends in proportion of patients reaching glycemic targets and incidence rates of severe hypoglycemia (SH) in 963,612 adults with diabetes in 2002-2019. We further assessed patterns of GLDs utilisation by presence of atherosclerotic-cardiovascular disease (ASCVD), heart failure, and estimated-glomerular filtration rate (eGFR).FindingsFollowing rapid decline in HbA1c from 7·7% to 7·2% in 2005-2014 (annual percentage change [APC]= -0·8, 95% CI:-1·0,-0·6), standardized mean HbA1c plateaued since 2014 (HbA1c 7·2% in 2019, APC=0·0, 95% CI:-0·2, 0·2). The incidence rates of SH declined from 3·4 to 0·7 events per 100-person years, but improvements levelled off since 2014. Use of metformin steadily increased (41·1 to 58·7%), sulfonylureas decreased (52·2 to 31·1%) while insulin remained static in 2002-2019. Adoption of DPP-4is slowed following initial rapid uptake in 2007-2011. DPP-4is remained the most widely prescribed newer GLD in all ages (14·3% in 2019). Use of glucagon-like-peptide 1 receptor agonists (GLP1-RAs) and sodium glucose co-transporter-2 inhibitors (SGLT2is) increased rapidly in 2015-2019 with 0·5% and 6% of users respectively in 2019.InterpretationFollowing rapid improvement in 2007-2014, glycemic control and SH rates had plateaued despite changing patterns of newer GLDs use in Hong Kong.FundingDr. Aimin Yang was supported by a CUHK Impact Research Fellowship Scheme.

934-P: Real-World Evidence of Glucose Lowering Drug Use, Glycemic Outcomes, and Severe Hypoglycemia in Hong Kong: Eighteen-Year Trends in 0.9 Million Adults with Diabetes

Introduction: Improvements in glycemic outcomes have stalled since 20in some international surveys. We examined the latest trends in drug use and glycemic outcomes following recent introduction of newer classes of glucose lowering drugs (GLDs) in a territory-wide analysis. Methods: Using data from the Hong Kong Diabetes Surveillance Database, we estimated age-specific trends in the proportion of patients reaching different glycemic targets, and rates of severe hypoglycemia (SH) in 963,612 patients between 2002-2019. We assessed patterns of GLDs use by age, sex, presence of atherosclerotic cardiovascular disease (ASCVD) and estimated glomerular filtration rate (eGFR) . Results: HbA1c improved most markedly between 2007-2014 but plateaued since 2014, with 53.1% patients achieving HbA1c &amp;lt;7% in 2019. The 20-44 age group had the highest proportion with HbA1c ≥9% (22.1% in 2002 and 16.8% in 2019) compared with the ≥75 age-group (14.9% in 2002 and 5.5% in 2019) . SH rates declined between 2002-20 and further in 2010-2014. Between 2002-2019, metformin use increased steadily from 41.1% to 58.7%, sulfonylurea use decreased from 52.2% to 31.1% while insulin use remained static. Use of dipeptidyl-peptidase 4 inhibitors (DPP4i) experienced rapid growth between 2007-20equally in all age groups, with a slower rise between 2011-2019. DPP4i remains the most widely prescribed newer oral GLDs (14.3%) compared with sodium glucose co-transporter 2 inhibitors (SGLT2is) (4.2%) and glucagon like peptide-1 receptor agonists (GLP1-RAs) (0.6%) in 2019. Compared with over 75s, higher proportions of the 20-44 age-group were treated with SGLT2is (6.4% versus 1.7%) and GLP-1RAs (1.5% versus 0.1%) and thiazolidinediones (8.1% versus 3.4%) in 2019, irrespective of ASCVD status. Conclusions: Following rapid improvement in 2007-2014, glycemic control and SH rates had plateaued despite the increasing use of SGLT2is and GLP-1RA in Hong Kong. Disclosure A.Yang: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp &amp; Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. H.Wu: None. E.S.H.Lau: None. X.Zhang: None. M.Shi: None. B.Fan: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc.

898-P: Impact of Switching to a High-Deductible Health Plan on Patients’ Out-of-Pocket Expenditures for Glucose-Lowering Drugs

High deductible health plans (HDHPs) have become increasingly common as a means of increasing access to health insurance while curbing total utilization. However, high out-of-pocket (OOP) expenditures faced by HDHP enrollees may disincentivize high value care, particularly for people with chronic but costly health conditions like diabetes. Glucose-lowering drugs are a large part of direct costs of diabetes management and contribute to cost-related non-adherence, burden of treatment, and poor health outcomes. We examined the changes in OOP expenses for a 30-day supply of each class of glucose-lowering drugs among 43,900 adults with diabetes included in OptumLabs® Data Warehouse between 20 and 2018 who switched from non-HDHPs to HDHPs, compared to 333,803 adults who did not switch. The mean OOP expenses, standardized to 20$US, were higher for HDHP beneficiaries (Table) . Switching to a HDHP significantly increased OOP expenditures for all glucose-lowering classes, ranging from 5% increase (sulfonylurea) to 48% increase (glitazone) . This increased expense for patients may hinder adherence and adversely impact glycemic management and health outcomes among HDHP enrollees. Clinicians should be aware that HDHP enrollees may be more sensitive to OOP costs when choosing medications, and policy makers should exempt evidence-based prescription drugs from high deductibles. Disclosure D.H.Jiang: None. J.Herrin: Consultant; Johnson &amp; Johnson Medical Devices Companies. H.Van houten: None. R.G.Mccoy: Consultant; Emmi. Funding National Institute of Diabetes and Digestive and Kidney Diseases grant number K23DK114497

Canagliflozin Regulates Human Endothelial Cell Function: Role of Heme Oxygenase‐1

Sodium‐glucose cotransporter‐2 (SGLT2) inhibitors are the newest class of glucose lowering drugs that act by inhibiting glucose reabsorption in the proximal tubule of the kidney. Recent clinical trials found that SGLT2 inhibitors reduce cardiovascular disease and mortality in patients with diabetes. The mechanism underlying the salutary actions of these drugs is not completely clear; however, it does not involve differential improvements in glycemic control. Given the critical role that endothelial cells (ECs) play in maintaining vascular homeostasis, the present study investigated the effect of the SGLT2 inhibitor canagliflozin on EC function. It also determined if the vasoprotective protein heme oxygenase‐1 (HO‐1) contributes to the cellular actions of the drug. Treatment of human umbilical vein ECs with clinically relevant concentrations of canagliflozin blocked cell proliferation, and this was associated with a pronounced decline in DNA synthesis. Canagliflozin also inhibited the migration of ECs following scrape injury in a concentration‐dependent manner. Incubation of ECs with a high concentration of glucose (25mM) and oxidized low‐density lipoprotein (oxLDL;50mg/L), which mimics the diabetic milieu, stimulated the adhesion of monocytes to ECs. However, treatment of ECs with canagliflozin markedly reduced the binding of monocytes to these cells. In addition, canagliflozin increased the expression of HO‐1 in a time and concentration‐dependent fashion, leading to a significant rise in endothelial HO‐1 activity. Finally, inhibition of HO‐1 activity or expression increased the adhesion of monocytes to glucose/oxLDL‐challenged ECs exposed to canagliflozin but had no effect on the proliferative or migratory response of canagliflozin‐treated ECs. In conclusion, the present study identifies canagliflozin as a key regulator of EC function. Moreover, it demonstrates that the induction of HO‐1 by canagliflozin contributes to the anti‐inflammatory action the drug. Thus, canagliflozin may exert some of its favorable effects in diabetes by limiting endothelial inflammation via the upregulation of HO‐1.

Old and new classes of glucose-lowering agents as treatments for non-alcoholic fatty liver disease: A narrative review.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease with a global prevalence of about 55% in people with type 2 diabetes mellitus (T2DM). T2DM, obesity and NAFLD are three closely inter-related pathological conditions. In addition, T2DM is one of the strongest clinical risk factors for the faster progression of NAFLD to non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. Increasing evidence suggests that newer classes of glucose-lowering drugs, such as peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors or sodium-glucose cotransporter-2 inhibitors, could reduce the rates of NAFLD progression. This narrative review aims to briefly summarize the recent results from randomized controlled trials testing the efficacy and safety of old and new glucose-lowering drugs for the treatment of NAFLD or NASH in adults both with and without coexisting T2DM.

Utilization Rates of SGLT2 Inhibitors and GLP-1 Receptor Agonists and Their Facility-Level Variation Among Patients With Atherosclerotic Cardiovascular Disease and Type 2 Diabetes: Insights From the Department of Veterans Affairs.

There is mounting evidence regarding the cardiovascular benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) among patients with atherosclerotic cardiovascular disease (ASCVD) and type 2 diabetes mellitus (T2DM). There is paucity of data assessing real-world practice patterns for these drug classes. We aimed to assess utilization rates of these drug classes and facility-level variation in their use. We used the nationwide Veterans Affairs (VA) health care system data set from 1 January 2020 to 31 December 2020 and included patients with established ASCVD and T2DM. Among these patients, we assessed the use of SGLT2i and GLP-1 RA and the facility-level variation in their use. Facility-level variation was computed using median rate ratios (MRR), a measure of likelihood that two random facilities differ in use of SGLT2i and GLP-1 RA in patients with ASCVD and T2DM. Among 537,980 patients with ASCVD and T2DM across 130 VA facilities, 11.2% of patients received an SGLT2i while 8.0% of patients received a GLP-1 RA. Patients receiving these cardioprotective glucose-lowering drug classes were on average younger and had a higher proportion of non-Hispanic Whites. Overall, median (10th-90th percentile) facility-level rates were 14.92% (9.31-22.50) for SGLT2i and 10.88% (4.44-17.07) for GLP-1 RA. There was significant facility-level variation among SGLT2i use-MRRunadjusted: 1.41 (95% CI 1.35-1.47) and MRRadjusted: 1.55 (95% CI 1.46 -1.63). Similar facility-level variation was observed for use of GLP-1 RA-MRRunadjusted: 1.34 (95% CI 1.29-1.38) and MRRadjusted: 1.78 (95% CI 1.65-1.90). Overall utilization rates of SGLT2i and GLP-1 RA among eligible patients are low, with significantly higher residual facility-level variation in the use of these drug classes. Our results suggest opportunities to optimize their use to prevent future adverse cardiovascular events among these patients.