Classes Of Antidiabetic Medications Research Articles

Empagliflozin: primum inter pares among sodium-glucose cotransporter-2 inhibitors?

Sodium/glucose cotransporter 2 (SGLT2) inhibitors are a novel class of anti-diabetic medications which have proved capable of providing breakthrough cardiovascular benefits in a variety of clinical scenarios, including patients with heart failure or obesity, irrespective of diabetic status. Several SGLT2 inhibitors are available, but the most prominent ones are canagliflozin, dapagliflozin, and empagliflozin. Several studies have focused on empagliflozin, and its effects on the risk of heart failure incidence and recurrences. Most recently, empagliflozin has been recently tested in patients with recent myocardial infarction in the EMPAgliflozin on Hospitalization for Heart Failure and Mortality in Patients With aCuTe Myocardial Infarction (EMPACT-MI) randomized trial, with apparently ambiguous findings. The present viewpoint succinctly illustrates the main features of SGLT2 inhibitors as a pharmacologic class, their ever expanding role as a cardiovascular medication, and the comparative effectiveness of different individual SGLT2 inhibitors, explicitly commenting on the recent data on empagliflozin in patients with acute myocardial infarction. The reader will find in this article a poignant perspective on this novel avenue for cardiovascular prevention and treatment, which greatly expands the management armamentarium of cardiovascular practitioners. Indeed, we make the case that SGLT2 inhibitors have a clearly favorable class effect, with differences between individual agents mainly suitable for personalization of care and minimization of side effects.

CO2 Association Between Classes of Antidiabetic Medications and Their Potential Risk or Protective Effects on Cancer: A Systematic Review and Network Meta-Analysis

CO2 Association Between Classes of Antidiabetic Medications and Their Potential Risk or Protective Effects on Cancer: A Systematic Review and Network Meta-Analysis

Incretin-based drugs decrease the incidence of prostate cancer in type 2 diabetics: A pooling-up analysis.

Incretin-based drugs, a class of Antidiabetic medications (ADMs) used in the treatment of type 2 diabetes, may affect the incidence of prostate cancer (PCa). But real-world evidence for this possible effect is lacking. Therefore, the aim of this study is to assess the effect of incretin-based drugs on the incidence of PCa, including glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. We searched PubMed, Embase, and Cochrane Library databases for eligible studies through September 2023. Two independent reviewers performed screening and data extraction. We used the Cochrane Handbook for Systematic Reviews and the Newcastle-Ottawa Scale (NOS) to assess the quality of included randomized controlled trials (RCTs) and cohort studies. We did a meta-analysis of available trial data to calculate overall risk ratios (RRs) for PCa. A total of 1238 articles were identified in our search. After screening for eligibility, 7 high-quality studies met the criteria for meta-analysis, including 2 RCTs and 5 cohort studies, with a total of 1165,738 patients. Compared with the control group, we found that incretin-based drugs reduced the relative risk of PCa by 35% (95% confidence interval (CI), 0.17-0.49; P = .0006). In subgroup analysis, the RR values for GLP-1 receptor agonists and DPP-4 inhibitors were 62% (95% CI, 0.45-0.85; P = .003) and 72% (95% CI, 0.46-1.12; P = .14), respectively. Incretin-based drugs are associated with lower incidence of prostate cancer and may have a preventive effect on prostate cancer in patients with type 2 diabetes.

The IDEAL (Insulin therapy DE-intensificAtion with iglarLixi) Randomised Controlled Trial-Study Design and Protocol.

Multiple daily injection insulin regimen (MDI) represents the most intensive insulin regimen used in the management of people with type 2 diabetes (PwT2D). Its efficacy regarding glycaemic control is counterbalanced by the increased risk of hypoglycaemia, frequently observed tendency to weight gain and necessity for frequent glucose monitoring. Recent introduction of novel antidiabetic medications with pleiotropic effects reaching far beyond the reduction of glycaemia (HbA1c), such as the glucagon-like peptide 1 receptor agonist (GLP-1 RA), has significantly widened the therapeutic options available for management of T2D. Consequently, there is currently asubstantial number of PwT2D for whom the MDI regimen was initiated at a time when no other options were available. Yet, in present times, these individuals could benefit from simplified insulin regimens ideally taking advantage of the beneficial effects of the novel classes of antidiabetic medications. iGlarLixi (Suliqua®) is a once-daily fixed-ratio combination of basal insulin analogue glargine 100U/ml and a GLP-1 RA lixisenatide. Insulin therapy DE-intensificAtion with iglarLixi (IDEAL) is a six-centre, open-label, parallel-group, active comparator, phase IV randomised controlled trial with a 24-week active treatment period examining the efficacy and safety of MDI regimen de-intensification with once-daily administration of iGlarLixi versus MDI regimen continuation in PwT2D on a backgroud therapy with metformin ± sodium-glucose cotransporter 2 inhibitor. The primary objective is to compare the effects of MDI therapy de-intensification with iGlarLixi versus MDI regimen continuation regarding glycaemic control (HbA1c). Secondary objectives include detailed evaluation of the effects of MDI regimen de-intensification with iGlarLixi on glycaemic control using standardised continuous glucose monitoring (CGM) metrics and self-monitoring of plasma glucose. Furthermore, body weight and body composition analysis, quality of life and safety profile are evaluated. ClinicalTrials.gov, identifier NCT04945070.

Long-term results of transferring the patient from therapy with glucagon-like peptide-1 receptor agonists in combination with metformin to a dipeptidyl peptidase-4 inhibitor in combination with pioglitazone and inhibitor of type 2 sodium-glucose cotransporter in type 2 diabetes

The pioglitazone belongs to the class of antidiabetic medications and has various pleiotropic effects. The evidence base for this medication, based on the results of randomized clinical trials, demonstrates convincing cardio- and cerebroprotective efficacy of pioglitazone, comparable to innovative glucose-lowering drugs from the classes of GLP-1 agonists and SGLT-2 inhibitors. Currently, in Russia, a fixed combination of pioglitazone and alogliptin is available. However, it should be noted that there has been a recent lack of GLP-1 agonists on the domestic pharmaceutical market, which raises questions about the choice of further tactics for patients who have been taking them until recently.This clinical case presents an example of the transformation of glucose-lowering therapy from a combined treatment regimen with semaglutide and metformin to the combined use of a fixed combination of alogliptin and pioglitazone with empagliflozin. Against the background of therapy change, a stable and pronounced glucose-lowering effect was obtained and confirmed after six months, comparable to GLP-1 receptor agonists without the effect of escape and hypoglycemia. No edema or weight gain was observed, and no other adverse events were detected, which allowed continuing the chosen glucose-lowering therapy. Strategic perspectives of the prescribed therapy were determined — reducing cardio- and cerebrovascular risk and improving the patient’s prognosis.

Treatment modification after initiating second-line medication for type 2 diabetes.

To describe changes in antidiabetic medication (ADM) use and characteristics associated with changes in ADM use after initiation of noninsulin second-line therapy. Retrospective cohort study. This study analyzed private health plan claims for adults with type 2 diabetes who initiated 1 of 5 index ADM classes: sulfonylureas, dipeptidyl peptidase 4 inhibitors (DPP4is), sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), or thiazolidinediones. Analyses evaluated 3 treatment modification outcomes-discontinuation, switching, and intensification-over 12-month follow-up. Of 82,624 included adults, nearly two-thirds (63.6%) experienced any treatment modification. Discontinuation was the most common modification (38.6%), especially among patients prescribed GLP-1 RAs (50.3%). Switching occurred in 5.2% of patients and intensification in 19.8%. In adjusted analysis, compared with patients prescribed sulfonylureas, discontinuation risk was 7% higher (HR, 1.07; 95% CI, 1.04-1.10) among patients prescribed DPP4is and 28% higher (HR, 1.28; 95% CI, 1.23-1.33) among patients prescribed GLP-1 RAs. Compared with sulfonylureas, all other index ADM classes had higher risks of switching and lower risks of intensification. Younger age group and female sex were both associated with higher risks of all modifications. Compared with index ADM prescription by a family medicine or internal medicine physician, index prescription by an endocrinologist was associated with both lower discontinuation risk and higher intensification risk. Most patients experienced a treatment modification within 1 year. Results highlight the need for new prescribing approaches and patient supports that can maximize medication adherence and reduce health system waste.

Lower Incidence of Leukemia in Sodium Glucose Cotransporter-2 Inhibitor-Treated Patients with Type 2 Diabetes Mellitus: Result from Large Real-World Cohorts

Objective: Leukemia is the among the top ten most common cancer in the United States of America, with incidence of 14.0 per 100,000 people. While the incidence of non-Hodgkin lymphoma has significantly decreased, the incidence of leukemia has been stable during 2014-2018 [1]. In the meantime, sodium-glucose cotransporter-2 inhibitors (SGLT-2i), a comparatively new class of anti-diabetic medication, has gained significant popularity among clinician due to its cardioprotective and renoprotective properties. Several observational studies and meta-analyses explored the relationship between SGLT-2i and solid tumor, including bladder cancer and breast cancer [2, 3]. Nevertheless, contemporary data for SGLT-2i and leukemia are limited. This large cohort study was aimed to investigate the association between SGLT-2i and the risk of leukemia. Methods: This was a retrospective cohort study including patients with T2DM from 92 hospitals across the United States between 2015 and 2023. Inclusion criteria were patients with T2DM aged 18 years or older who newly initiated treatment with SGLT-2i or DPP-4i. Patients with a history of type 1 diabetes or malignancies were excluded. Propensity score matching was applied to each group to account for confounding factors, including demographic characteristics, comorbidities, laboratory data, and medication history. The primary outcome of interest was the occurrence of incident leukemia, including lymphoid leukemia, myeloid leukemia and monocytic leukemia. Kaplan-Meier analysis and log-rank tests were used to compare the outcomes across the cohorts, while hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated using the Cox proportional hazard regression model. Results: A total of 718,276 SGLT-2i initiators were matched to 1,159,112 DPP4i initiators diagnosed with T2DM. Among these, 3,429 incidents of leukemia were identified, with 1,148 occurring in the SGLT2i groups and 2,281 in the DPP-4i group after matching.The baseline characteristics, including ethnicity, comorbidities and medication history, were well-balanced between the two cohorts. SGLT-2i initiators demonstrated a significantly reduced risk of new-onset leukemia compared to those using DPP-4i, including myeloid leukemia (HR, 0.676; 95% CI, 0.589 to 0.776, p < 0.001) and lymphoid leukemia (HR, 0.846; 95% CI, 0.753-0.950, p = 0.005). There was no significant difference in the occurrence of monocytic leukemia (aHR 0.836; 95% CI, 0.556 to 1.257, p = 0.388). Conclusion: This population-based propensity-score matched cohort study showed that SGLT-2i is associated with lower in the risk of developing leukemia when compared to those treated with DPP-4i. These findings highlight the potential therapeutic value of SGLT-2i in the prevention of hematological malignancies in patients with T2DM. Further clinical trials are necessary to explore and validate the potential applications. Reference 1. Cronin, K.A., et al., Annual report to the nation on the status of cancer, part 1: National cancer statistics. Cancer, 2022. 128(24): p. 4251-4284. 2. Garcia, M., et al., SGLT2 Inhibitors and Bladder Cancer: Analysis of Cases Reported in the European Pharmacovigilance Database. J Clin Pharmacol, 2021. 61(2): p. 187-192. 3. Tang, H., et al., SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials. Diabetologia, 2017. 60(10): p. 1862-1872.

Changes in Cardiovascular and Renal Biomarkers Associated with SGLT2 Inhibitors Treatment in Patients with Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus is a major health problem worldwide with a steadily increasing prevalence reaching epidemic proportions. The major concern is the increased morbidity and mortality due to diabetic complications. Traditional but also nontraditional risk factors have been proposed to explain the pathogenesis of type 2 diabetes mellitus and its complications. Hyperglycemia has been considered an important risk factor, and the strict glycemic control can have a positive impact on microangiopathy but not macroangiopathy and its related morbidity and mortality. Thus, the therapeutic algorithm has shifted focus from a glucose-centered approach to a strategy that now emphasizes target-organ protection. Sodium-glucose transporter 2 inhibitors is an extremely important class of antidiabetic medications that, in addition to their glucose lowering effect, also exhibit cardio- and renoprotective effects. Various established and novel biomarkers have been described, reflecting kidney and cardiovascular function. In this review, we investigated the changes in established but also novel biomarkers of kidney, heart and vascular function associated with sodium-glucose transporter 2 inhibitors treatment in patients with type 2 diabetes mellitus.

Role of metformin in the management of type 2 diabetes: recent advances.

Metformin is one of the oldest antidiabetic medications, commonly used in the management of type 2 diabetes. Its mechanism of action is based on reducing glucose production in the liver, decreasing insulin resistance, and increasing insulin sensitivity. The drug has been studied extensively and has been shown to be effective in lowering blood glucose levels without increasing the risk of hypoglycemia. It has been used for the treatment of obesity, gestational diabetes, and polycystic ovary syndrome. According to current guidelines, metformin can be used as the first‑line agent in the management of diabetes; however, in individuals with type 2 diabetes who would benefit from cardio‑renal protection, newer agents, such as sodium‑glucose cotransporter‑2 inhibitors and glucagon‑like peptide‑1 receptor agonists, are favored as the first‑line therapy. The novel classes of antidiabetic medications have demonstrated significant positive effects on glycemia with added benefits in patients with obesity, renal disease, heart failure, and cardiovascular disease. The emergence of these more effective agents has significantly altered the way diabetes is managed, thus prompting re‑evaluation of metformin as the initial therapy for all patients with diabetes.

Renal protection and safety of sodium-glucose cotransporter-2 inhibitors in chronic kidney disease.

Chronic kidney disease (CKD) has a clinical characteristic of progressive loss of kidney function and becomes a serious health and social concern. SGLT2i (sodium-glucose cotransporter 2 inhibitors), a class of anti-diabetic medications, is shown to reduce cardiovascular and renal events. This systematic review and meta-analysis aimed to assess whether SGLT2i could become a new treatment strategy for CKD for its renal protection and safety. Based on predetermined criteria, a bibliographical search was performed on May 31, 2022, by searching the following databases: ISI Web of Science, Embase, PubMed, and the Cochrane Library. Statistical analysis was conducted to assess renal protection and safety of SGLT2i by using Cochrane Review Manager Version 5.3. Thirty randomised controlled trials fulfilled the inclusion criteria and were eligible for this meta-analysis. Our study found that the SGLT2i can sustainably reduce the urine albumin/creatinine ratio (UACR) at different time points and prevent the progression to macroalbuminuria. Before 24 weeks, SGLT2i can decrease the estimated glomerular filtration rate (eGFR) compared to the control group. Interestingly, after 24 weeks, SGLT2i can continuously maintain the increase in eGFR when compared with the control group. Furthermore, SGLT2i can reduce the event rates of incident or worsening nephropathy, a decline in estimated eGFR of ≥ 50%, doubling of serum creatinine level, acute renal failure and renal failure. Interestingly, the renoprotective effects of SGLT2i are independent of its glycemic effects. SGLT2i can reduce the morbidity rate of any related adverse events, any related severe adverse events and SGLT2i have not increased the event rates of urinary tract infection, bone fractures, amputation, and acute pancreatitis when compared with the control group. SGLT2i can protect renal function and are safe drug for CKD. SGLT2i are promising therapeutic agents for CKD patients.

Effectiveness of the Lilly Connected Care Program in Improving Glycemic Management Among Patients With Type 2 Diabetes in China: Retrospective Real-world Study.

Type 2 diabetes mellitus (T2DM) is a worldwide public health concern. Mobile health management platforms could be a potential way to achieve effective glycemic control. This study aimed to evaluate the real-world effectiveness of the Lilly Connected Care Program (LCCP) platform in glycemic control among patients with T2DM in China. This retrospective study included Chinese patients with T2DM (aged ≥18 years) from April 1, 2017, to January 31, 2020, for the LCCP group and from January 1, 2015, to January 31, 2020, for the non-LCCP group. Propensity score matching was used to match the LCCP and non-LCCP groups to reduce confounding, with covariates including age, sex, the duration of diabetes, baseline hemoglobin A1c (HbA1c), and the number of oral antidiabetic medication classes. HbA1c reduction over 4 months, the proportions of patients achieving an HbA1c reduction of ≥0.5% or ≥1%, and the proportions of patients reaching to target HbA1c level of ≤6.5% or <7% were compared between the LCCP and non-LCCP groups. Multivariate linear regression was used to assess factors associated with HbA1c reduction. A total of 923 patients were included, among whom 303 pairs of patients were well matched after propensity score matching. HbA1c reduction during the 4-month follow-up was significantly larger in the LCCP group than the non-LCCP group (mean 2.21%, SD 2.37% vs mean 1.65%, SD 2.29%; P=.003). The LCCP group had a higher proportion of patients with an HbA1c reduction of ≥1% (209/303, 69% vs 174/303, 57.4%; P=.003) and ≥0.5% (229/303, 75.6% vs 206/303, 68%; P=.04). The proportions of patients reaching the target HbA1c level of ≤6.5% were significantly different between the LCCP and non-LCCP groups (88/303, 29% vs 61/303, 20.1%; P=.01), whereas the difference in the proportions of patients reaching the target HbA1c level of <7% was not statistically significant (LCCP vs non-LCCP: 128/303, 42.2% vs 109/303, 36%; P=.11). LCCP participation and higher baseline HbA1c were associated with a larger HbA1c reduction, whereas older age, longer diabetes duration, and higher baseline dose of premixed insulin analogue were associated with a smaller HbA1c reduction. The LCCP mobile platform was effective in glycemic control among patients with T2DM in China in the real world.

Management of diabesity: Current concepts.

The global prevalence of obesity is increasing rapidly with an exponential rise in incidence of type 2 diabetes mellitus in recent years. 'Diabesity', the term coined to show the strong interlink between obesity and diabetes, is the direct cons-equence of the obesity pandemic, and poses significant challenges in the management of the disease. Without addressing the clinical and mechanistic complications of obesity such as metabolic-associated fatty liver disease and obstructive sleep apnoea, a rational management algorithm for diabesity cannot be developed. Several classes of anti-diabetic medications including insulins, sulphonylureas, thiazolidinediones and meglitinides are associated with the risk of weight gain and may potentially worsen diabesity. Therefore, appropriate selection of antidiabetic drug regimen is crucial in the medical management of diabesity. The role of non-pharmacological measures such as dietary adjustments, exercise interventions and bariatric procedures should also be emphasised. Unfortunately, the importance of appropriate and optimal management of diabesity is often overlooked by medical professionals when achieving adequate glycemic control which results in inappropriate management of the disease and its complications. This review provides a narrative clinical update on the evidence behind the management of diabesity.

Comparison of decision tree with common machine learning models for prediction of biguanide and sulfonylurea poisoning in the United States: an analysis of the National Poison Data System

BackgroundBiguanides and sulfonylurea are two classes of anti-diabetic medications that have commonly been prescribed all around the world. Diagnosis of biguanide and sulfonylurea exposures is based on history taking and physical examination; thus, physicians might misdiagnose these two different clinical settings. We aimed to conduct a study to develop a model based on decision tree analysis to help physicians better diagnose these poisoning cases.MethodsThe National Poison Data System was used for this six-year retrospective cohort study.The decision tree model, common machine learning models multi layers perceptron, stochastic gradient descent (SGD), Adaboosting classiefier, linear support vector machine and ensembling methods including bagging, voting and stacking methods were used. The confusion matrix, precision, recall, specificity, f1-score, and accuracy were reported to evaluate the model’s performance.ResultsOf 6183 participants, 3336 patients (54.0%) were identified as biguanides exposures, and the remaining were those with sulfonylureas exposures. The decision tree model showed that the most important clinical findings defining biguanide and sulfonylurea exposures were hypoglycemia, abdominal pain, acidosis, diaphoresis, tremor, vomiting, diarrhea, age, and reasons for exposure. The specificity, precision, recall, f1-score, and accuracy of all models were greater than 86%, 89%, 88%, and 88%, respectively. The lowest values belong to SGD model. The decision tree model has a sensitivity (recall) of 93.3%, specificity of 92.8%, precision of 93.4%, f1_score of 93.3%, and accuracy of 93.3%.ConclusionOur results indicated that machine learning methods including decision tree and ensembling methods provide a precise prediction model to diagnose biguanides and sulfonylureas exposure.

Associations between antidiabetic medication use and breast cancer survival outcomes among medicare beneficiaries

Abstract Objective This study examined the associations between mortality (all-cause and breast cancer-specific) and different antidiabetic medication use before breast cancer diagnosis. Methods This study used a longitudinal, retrospective cohort design. Linked Surveillance, Epidemiology and End Results (SEER)-Medicare databases from 2007 to 2013 were used to identify female beneficiaries who had continuous Medicare enrollment, a new breast cancer diagnosis between 2008 and 2013, and exposure to the antidiabetic medication. Different classes of antidiabetic medications from one year before their breast cancer diagnosis were considered as users while all other non-users were excluded. Both all-cause mortality and breast cancer-specific mortality were treated as outcomes. Cox proportional hazards models for all-cause mortality and sub-distribution hazards models for breast cancer-specific mortality were employed to estimate both unadjusted and adjusted hazard ratios and 95% confidence intervals (CI) for risks of survival outcomes, controlling for severity of diabetes and other covariates. Key findings A total of 1715 women with breast cancer used antidiabetic medications one year before their breast cancer diagnosis. Compared to metformin, women using insulin, sulfonylurea and combination treatments before their breast cancer diagnosis had a higher risk for all-cause mortality (adjusted Hazard Ratio, aHR: 1.64, 95% CI 1.29, 2.07; aHR: 1.35, 95% CI 1.04, 1.75 and aHR: 1.44, 95% CI 1.14, 1.83, respectively). Women with advanced-stage breast cancer and higher levels of diabetes severity were more likely to get all-cause mortality (all P &amp;lt; 0.05). Women with combination treatments had a statistically higher risk of breast cancer-specific mortality (aHR: 1.52, 95% CI 1.05, 2.19) than metformin users. Conclusions Among women with breast cancer, mortality risk is associated with pre-diagnosis exposure to different types of antidiabetic medications.

Glucagon-like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes in Youth.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have gained traction for the management of type 2 diabetes and obesity. Unlike several classes of antidiabetic medications that contribute to weight gain, GLP-1RAs not only reduce haemoglobin A1c, but also promote weight loss. While there is a large body of evidence supporting its safety and efficacy in adults, paediatric clinical trial data have only emerged in recent years. This review will discuss the limited treatment options for paediatric type 2 diabetes and the mechanism of action of GLP-1RAs as it pertains to physiological pathways relevant for type 2 diabetes, obesity and their related comorbidities. The outcomes of paediatric trials evaluating liraglutide, exenatide, semaglutide and dulaglutide in paediatric type 2 diabetes and obesity will be closely examined, including differences compared with adult studies. Finally, potential barriers and strategies to expanding GLP-1RA access in adolescents will be discussed. Future studies are needed to determine if the cardio-and renal-protective benefits of GLP-1RAs apply to youth-onset type 2 diabetes.

An Overview of the Potential of Medicinal Plants Used in the Development of Nutraceuticals for the Management of Diabetes Mellitus: Proposed Biological Mechanisms

Diabetes mellitus (DM) is a chronic metabolic disorder in which the pancreas does not produce enough insulin or the body cannot effectively use it. The prevalence of diabetes is increasing steadily, making it a global public health problem. Several serious complications are associated with this disease. There are a number of different classes of antidiabetic medications. Interestingly, traditional medicine can also be used for the development of novel classes of hypoglycemic therapeutics. This article summarizes an update of the potential of various important medicinal plants used in the development of nutraceuticals for the management of diabetes mellitus, and a proposal of their biological mechanisms.

Dapagliflozin Attenuates Sympathetic and Pressor Responses to Stress in Young Prehypertensive Spontaneously Hypertensive Rats.

SGLT2i (sodium-glucose cotransporter 2 inhibitor), a class of anti-diabetic medications, is shown to reduce blood pressure (BP) in hypertensive patients with type 2 diabetes. Mechanisms underlying this action are unknown but SGLT2i-induced sympathoinhibition is thought to play a role. Whether SGLT2i reduces BP and sympathetic nerve activity (SNA) in a nondiabetic prehypertension model is unknown. Accordingly, we assessed changes in conscious BP using radiotelemetry and alterations in mean arterial pressure and renal SNA during simulated exercise in nondiabetic spontaneously hypertensive rats during chronic administration of a diet containing dapagliflozin (0.5 mg/kg per day) versus a control diet. We found that dapagliflozin had no effect on fasting blood glucose, insulin, or hemoglobin A1C levels. However, dapagliflozin reduced BP in young (8-week old) spontaneously hypertensive rats as well as attenuated the age-related rise in BP in adult spontaneously hypertensive rat up to 17-weeks of age. The rises in mean arterial pressure and renal SNA during simulated exercise (exercise pressor reflex activation by hindlimb muscle contraction) were significantly reduced after 4 weeks of dapagliflozin (Δmean arterial pressure: 10±7 versus 25±14 mm Hg, Δrenal SNA: 31±17% versus 68±39%, P<0.05). Similarly, rises in mean arterial pressure and renal SNA during mechanoreflex stimulation by passive hindlimb stretching were also attenuated by dapagliflozin. Heart weight was significantly decreased in dapagliflozin compared with the control group. These data demonstrate a novel role for SGLT2i in reducing resting BP as well as the activity of skeletal muscle reflexes, independent of glycemic control. Our study may have important clinical implications for preventing hypertension and hypertensive heart disease in young prehypertensive individuals.

High throughput screen of small molecules as potential countermeasures to galactic cosmic radiation induced cellular dysfunction

Space travel increases galactic cosmic ray exposure to flight crews and this is significantly elevated once travel moves beyond low Earth orbit. This includes combinations of high energy protons and heavy ions such as 56Fe or 16O. There are distinct differences in the biological response to low-energy transfer (x-rays) or high-energy transfer (High-LET). However, given the relatively low fluence rate of exposure during flight operations, it might be possible to manage these deleterious effects using small molecules currently available. Virtually all reports to date examining small molecule management of radiation exposure are based on low-LET challenges. To that end an FDA approved drug library (725 drugs) was used to perform a high throughput screen of cultured cells following exposure to galactic cosmic radiation. The H9c2 myoblasts, ES-D3 pluripotent cells, and Hy926 endothelial cell lines were exposed to a single exposure (75 cGy) using the 5-ion GCRsim protocol developed at the NASA Space Radiation Laboratory (NSRL). Following GCR exposure cells were maintained for up to two weeks. For each drug (@10µM), a hierarchical cumulative score was developed incorporating measures of mitochondrial and cellular function, oxidant stress and cell senescence. The top 160 scores were retested following a similar protocol using 1µM of each drug. Within the 160 drugs, 33 are considered to have an anti-inflammatory capacity, while others also indirectly suppressed pro-inflammatory pathways or had noted antioxidant capacity. Lead candidates came from different drug classes that included angiotensin converting enzyme inhibitors or AT1 antagonists, COX2 inhibitors, as well as drugs mediated by histamine receptors. Surprisingly, different classes of anti-diabetic medications were observed to be useful including sulfonylureas and metformin. Using a hierarchical decision structure, we have identified several lead candidates. That no one drug or even drug class was completely successful across all parameters tested suggests the complexity of managing the consequences of galactic cosmic radiation exposure.

Dapagliflozin Attenuates Sympathetic and Pressor Responses to Stress in Young Prehypertensive Spontaneously Hypertensive Rats

Sodium‐glucose cotransporter 2 inhibitor (SGLT2i) is a class of anti‐diabetic medications approved for lowering blood glucose in type 2 diabetes mellitus (T2DM) and reducing cardiovascular risks in heart failure patients with or without T2DM. SGLT2i is also known to reduce blood pressure (BP) in hypertensive patients with T2DM. Mechanisms underlying these benefits of SGLT2i are unclear, but sympathetic overactivation is known to play a major role in the pathogenesis and progression of hypertension and heart failure. Whether SGLT2i reduces sympathetic nerve activity (SNA) and BP in a non‐diabetic prehypertension model is undetermined. Therefore, we conducted studies to determine effects of a SGLT2i, dapagliflozin (DAPA), on conscious BP as well as SNA in prehypertensive spontaneously hypertensive rats (SHRs) during physical stress. Accordingly, we randomly assigned 4‐week‐old non‐diabetic SHRs to either a normal powdered food treated (control) group or a normal powdered food containing DAPA treated (0.5mg/kg/day) group. After 4 weeks on the diet, we measured conscious BP in both groups of rats using radiotelemetry. We also assessed changes in mean arterial pressure (MAP) and renal SNA (RSNA) in response to hindlimb muscle contraction (ie, activation of the exercise pressor reflex, EPR), passive muscle stretch (ie, activation of the mechanically sensitive component of the EPR, known as the mechanoreflex), and intra‐arterial capsaicin injection (ie, activation of the metabolically sensitive component of the EPR, known as the metaboreflex) in a separate group of decerebrate control and DAPA SHRs. We found that fasting blood glucose levels were not significantly different between DAPA and control groups (65±27 vs. 78±20 mg/dL). Heart weight and heart weight‐to‐tibial length was significantly (all P&lt;0.01) decreased by 19% and 16%, respectively in DAPA rats compared to control rats. We also found that daytime/nighttime MAP were markedly lower in DAPA SHRs than control SHRs (daytime: 120±5 vs. 130±6 mmHg, nighttime: 123±6 vs. 132±6 mmHg, P&lt;0.05). A significant reduction in HR in DAPA rats was also observed compared to control rats (daytime: 299±15 vs. 337±20 bpm, nighttime: 320±12 vs. 357±12 bpm, P&lt;0.01). Similarly, the rises in MAP and RSNA during EPR activation were significantly attenuated in DAPA SHRs compared to control SHRs (ΔMAP: 10±5 vs. 29±15 mmHg, ΔRSNA: 43±17 vs. 96±48 %, P&lt;0.05). The pressor and sympathetic responses to mechanoreflex stimulation were also markedly lower in DAPA than control (ΔMAP: 10±7 vs. 25±14 mmHg, ΔRSNA: 31±17 vs. 68±39 %, P&lt;0.05). There was a tendency for MAP and RSNA responses to metaboreflex activation to be lower in the DAPA group, but the difference did not reach statistical significance (ΔMAP: 38±18 vs. 58±24 mmHg, P=0.07, ΔRSNA: 58±29 vs. 95±45 %, P=0.08). In conclusion, our data demonstrate a novel role for SGLT2i in reducing resting BP as well as the activity of skeletal muscle reflexes, independent of blood glucose. Our study may have important clinical implications for preventing hypertension and related cardiovascular damage in young prehypertensive individuals.

Medication Optimization Among People With Type 2 Diabetes Participating in a Continuous Glucose Monitoring-Driven Virtual Care Program: Prospective Study.

BackgroundThe Onduo virtual care program for people with type 2 diabetes (T2D) includes a mobile app, remote lifestyle coaching, connected devices, and telemedicine consultations with endocrinologists for medication management and prescription of real-time continuous glucose monitoring (RT-CGM) devices. In a previously described 4-month prospective study of this program, adults with T2D and baseline glycated hemoglobin (HbA1c) ≥8.0% to ≤12.0% experienced a mean HbA1c decrease of 1.6% with no significant increase in hypoglycemia.ObjectiveThe objective of this analysis was to evaluate medication optimization and management in the 4-month prospective T2D study.MethodsStudy participants received at least 1 telemedicine consultation with an Onduo endocrinologist for diabetes medication management and used RT-CGM intermittently to guide therapy and dosing. Medication changes were analyzed.ResultsOf 55 participants, 48 (87%) had a medication change consisting of a dose change, addition, or discontinuation. Of these, 15 (31%) participants had a net increase in number of diabetes medication classes from baseline. Mean time to first medication change for these participants was 36 days. The percentage of participants taking a glucagon-like peptide-1 receptor agonist increased from 25% (12/48) to 56% (n=27), while the percentages of participants taking a sulfonylurea or dipeptidyl peptidase 4 inhibitor decreased from 56% (n=27) to 33% (n=16) and 17% (n=8) to 6% (n=3), respectively. Prescriptions of other antidiabetic medication classes including insulin did not change significantly.ConclusionsThe Onduo virtual care program can play an important role in providing timely access to guideline-based diabetes management medications and technologies for people with T2D.Trial RegistrationClinicalTrials.gov NCT03865381; https://clinicaltrials.gov/ct2/show/NCT03865381