Class Of Oral Hypoglycemic Agents Research Articles

Sodium-glucose transport protein 2 inhibitor use in the management of insulin dysregulation in ponies and horses.

Laminitis is a common and painful condition of the equine foot and approximately 90% of cases are associated with insulin dysregulation (ID) that is a central feature of the common endocrine disorder equine metabolic syndrome (EMS) and occurs in a subset of animals with pituitary pars intermedia dysfunction. Additional features of EMS include obesity, altered circulating concentrations of adipokines (particularly adiponectin and leptin) and hypertriglyceridaemia. Obesity, ID, hypoadiponectinaemia, hyperleptinaemia and an altered plasma lipid profile are also features of human metabolic syndrome (HMS) alongside hyperglycaemia. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel class of oral hypoglycaemic agents used in combination with lifestyle changes in the management of HMS. SGLT2 receptors are responsible for 90% of the renal glucose reabsorption that occurs in the proximal convoluted tubule. Thus, these drugs increase urinary glucose excretion by suppressing glucose reabsorption from the glomerular filtrate resulting in urinary calorie loss with consequent weight loss and improvements in ID, hyperglycemia, hypoadiponectinaemia and hyperleptinaemia. There are no licenced veterinary drugs available for treating ID and preventing insulin-associated laminitis in horses. Thus, the use of SGLT2i for the control of equine hyperinsulinaemia with the goal of improving recovery from associated active laminitis or preventing future laminitis has recently been advocated. There are a small number of published studies reporting the use of the SGLT2i canagliflozin, ertugliflozin and velagliflozin to aid the management of equine ID. However, the doses used are largely extrapolated from human studies with limited consideration of species-specific variations. In addition, there is limited evaluation of the fundamental differences between ID in horses and humans, particularly the fact that most horses with ID remain hyperinsulinaemic but normoglycaemic such that increased urinary loss of glucose may not explain the beneficial effects of these drugs. Further study of the potential deleterious effects of treatment-associated hypertriglyceridaemia is required together with the effect of SGLT2i therapy on circulating concentrations of adipokines in horses.

Sodium-glucose transport protein 2 inhibitor use in the management of insulin dysregulation in ponies and horses.

Laminitis is a common and painful condition of the equine foot and approximately 90% of cases are associated with insulin dysregulation (ID) that is a central feature of the common endocrine disorder equine metabolic syndrome (EMS) and occurs in a subset of animals with pituitary pars intermedia dysfunction. Additional features of EMS include obesity, altered circulating concentrations of adipokines (particularly adiponectin and leptin) and hypertriglyceridaemia. Obesity, ID, hypoadiponectinaemia, hyperleptinaemia and an altered plasma lipid profile are also features of human metabolic syndrome (HMS) alongside hyperglycaemia. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel class of oral hypoglycaemic agents used in combination with lifestyle changes in the management of HMS. SGLT2 receptors are responsible for 90% of the renal glucose reabsorption that occurs in the proximal convoluted tubule. Thus, these drugs increase urinary glucose excretion by suppressing glucose reabsorption from the glomerular filtrate resulting in urinary calorie loss with consequent weight loss and improvements in ID, hyperglycemia, hypoadiponectinaemia and hyperleptinaemia. There are no licenced veterinary drugs available for treating ID and preventing insulin-associated laminitis in horses. Thus, the use of SGLT2i for the control of equine hyperinsulinaemia with the goal of improving recovery from associated active laminitis or preventing future laminitis has recently been advocated. There are a small number of published studies reporting the use of the SGLT2i canagliflozin, ertugliflozin and velagliflozin to aid the management of equine ID. However, the doses used are largely extrapolated from human studies with limited consideration of species-specific variations. In addition, there is limited evaluation of the fundamental differences between ID in horses and humans, particularly the fact that most horses with ID remain hyperinsulinaemic but normoglycaemic such that increased urinary loss of glucose may not explain the beneficial effects of these drugs. Further study of the potential deleterious effects of treatment-associated hypertriglyceridaemia is required together with the effect of SGLT2i therapy on circulating concentrations of adipokines in horses.

ASPECTS OF THE USE OF ANTIDIABETIC DRUGS IN PHARMACEUTICAL PRACTICE ON THE BASIS OF RATIONAL PHARMACOTHERAPY

The aim of the article. To study of the incidence of diabetes mellitus in Ukraine and to determine the prospects for the use and pharmaceutical development of antidiabetic drugs. Materials and methods. Data from the State Registers of Medicinal Products of Ukraine, of Wholesale and Retail Prices for Medicinal Products declared in Ukraine under an international non-proprietary or generic name (01.01.2024). Were used: systematic and comparative analysis, processing and synthesis, and generalization to determine the forecasted prospects. Results. In Ukraine the number of diabetes patients increased by 11% in the group of children and adolescents; in the group of elderly patients – by 12.5%, among the adult working – 20%, diabetes of the II type predominates. The trend of increase in the number of studies on the search for therapeutic alternatives for the treatment of type II diabetes and list of medicines on the pharmaceutical market has been revealed. In Ukraine drugs for oral use include APIs of the following pharmacological groups: sulfonylureas; meglitinides; biguanides; thiazolidinedione; α-glucosidase inhibitors; DPP-4 inhibitors; SGLT-2 inhibitors. Mechanism of action of the new class of oral hypoglycemic agents, approved by the FDA, consists in blocking SGLT-2 proteins from the proximal convoluted tubule in the kidney, leads to the prevention of reabsorption and excretion of the glucose molecule. This allows its use in combination with insulin and other antidiabetic drugs for the treatment of type I and II diabetes in patients of various age categories. According to the volume of clinical studies, SGLT-2 inhibitor SGLT-2 derivative gliflozin API drugs are the second largest group of antidiabetic drugs recommended for use by FDA and EMA regulatory bodies. Conclusions. The pharmaceutical development of mono and combined drugs with APIs SGLT-2 inhibitors gliflozin derivatives in combination with APIs with metformin, DPP-4 inhibitors, APIs thiazolidinedione derivatives is promising for solving the problem of diabetes treatment and prevention of complications for patients of different age groups including working population in Ukraine.

Effect of Crospovidone, Croscaramellose Sodium in Combination on the Drug Release of Anti diabetic Medication in Tablet Form

Objective: The current study’s objective is to check the impact of superdisintegrants on the drug release of Vildagliptin by developing oral disintegrating tablets (ODT). Vildagliptin, new class of oral hypoglycemic agent. It acts by inhibiting dipeptidyl peptidase-4. Conventional Vildagliptin tablets are (due to its first pass effect) unsuitable where quicker onset of action is required Hence, it is necessary to develop oral disintegrating tablet, in order to obtain improved patient compliance. Methods: Using Oral disintegrating tablets of Vildagliptin were prepared using various quantities of Crospovidone & Croscaramellose sodium as Superdisintegrants by direct compression method. Nine trials were developed by varying the quantities of Crospovidone, Croscaramellose sodium such as 6 ± 1.5 mg i.e. 4.5, 6, 7.5 mg respectively. Prepared formulations were assessed for Pharmaceutical Product Performance as per official methods such as hardness, friability, weight variation, drug content, wetting time, disintegration time, and drug release studies. Results: Findings indicate that all formulations meet the acceptance criteria such as good mechanical strength (>4.3 kg/cm2), less friable (<0.65%), uniform drug content (>98%) and kinetic modeling was applied to the in-vitro dissolution profiles. Conclusion: The best formulation (F1), which is likewise identical to the marketed product (Galvus-50) (f2= 89.01, f1= 1.85), contained 7.5 mg of Crospovidone and 7.5 mg of Croscaramellose sodium. Formulation (F1) follow first order, whereas release mechanism found to be Fickian type (n= 0.323).

Particularities of Urinary Tract Infections in Diabetic Patients: A Concise Review.

Diabetes mellitus is a chronic disease that, untreated or poorly controlled, can lead to serious complications, reducing life expectancy and quality. Diabetic patients are more likely to develop infections, including many common infections, but also pathognomonic ones such as emphysematous pyelonephritis, malignant otitis externa, mucormycosis and Fournier's gangrene. Considering the fact that diabetic patients experience more frequently urinary tract infections (UTIs) with a worse prognosis than non-diabetic people, we conducted a review study based on data in the literature, following the particularities of UTIs in this group of patients, the risk factors, the mechanisms involved and the challenges in their management. The findings highlight that UTI in diabetic patients have some particularities, including a more frequent evolution to bacteremia, increased hospitalizations, and elevated rates of recurrence and mortality than non-diabetic patients. The possible risk factors identified seem to be female gender, pregnancy, older age, UTI in the previous six months, poor glycemic control and duration of diabetes. The mechanisms involved are related to glucosuria and bladder dysfunction, factors related to bacterial strains and host response. The bacterial strains involved in UTIs in diabetic patients and their antibiotic susceptibility profile are, with some exceptions, similar to those in non-diabetic people; however, the antimicrobial agents should be carefully chosen and the duration of the treatment should be as those required for a complicated UTI. The data related to the risk of developing UTIs in patients treated with SGLT-2 inhibitors, a new class of oral hypoglycaemic agents with cardiovascular and renal benefits, are controversial; overall, it was evidenced that UTIs occurred at the initiation of the treatment, recurrent infection was uncommon and the majority of UTIs responded to treatment with standard antibiotics. Moreover, interruption or discontinuation of SGLT-2 inhibitor as a result of UTI was rare and SGLT-2 inhibitors did not increase the risk of severe infections such as urosepsis and pyelonephritis.

Sodium-dependent glucose co-transporter-2 inhibitor empagliflozin exerts neuroprotective effects in rotenone-induced Parkinson’s disease model in zebrafish; mechanism involving ketogenesis and autophagy

Sodium-dependent glucose co-transporter-2 (SGLT2) inhibitor empagliflozin (EMP), is the new class of oral hypoglycemic agent approved as a treatment for Type 2 diabetes. SGLT2 inhibitors may induce ketogenesis through inhibiting the renal reabsorption of glucose. In recent years, positive effects of ketogenic diets on neurodegenerative diseases such as Parkinson's disease (PD) have been reported by improving autophagy. We aimed to evaluate the effects of EMP treatment as a SGLT2 inhibitor that can mimic the effects of ketogenic diet, in rotenone induced PD model in zebrafish focusing on ketogenesis, autophagy, and molecular pathways related with PD progression including oxidative stress and inflammation. Adult zebrafish were exposed to rotenone and EMP for 30 days. Y-Maze task and locomotor analysis were performed. Neurotransmitter levels were determined by liquid chromatography tandem- mass spectrometry (LC-MS/MS). Lipid peroxidation (LPO), nitric oxide (No), alkaline phosphatase, superoxide dismutase, glutathione, glutathione S-transferase (GST), sialic acid, acetylcholinesterase, and the expressions of autophagy, ketogenesis and PD-related genes were determined. Immunohistochemical staining was performed for the microglial marker L-plastin (Lcp1) and tyrosine hydroxylase (Th). EMP treatment improved DOPAC/DA ratio, Y-Maze task, locomotor activity, expressions of Th and Lcp-1, autophagy and inflammation related (mTor, atg5, tnfα, sirt1, il6, tnfα); PD-related (lrrk2, park2, park7, pink1), and ketone metabolism-related genes (slc16a1b, pparag, and pparab), and oxidant-damage in brain in the rotenone group as evidenced by decreased LPO, No, and improved antioxidant molecules. Our results showed benefical effects of EMP as a SGLT2 inhibitor in neurotoxin-induced PD model in zebrafish. We believe our study, will shed light on the mechanism of the effects of SGLT2 inhibitors, ketogenesis and autopahgy in PD.

Improvement of Global Longitudinal Strain and Myocardial Work in Type 2 Diabetes Patients on Sodium-Glucose Cotransporter 2 Inhibitors Therapy.

Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) are a novel class of oral hypoglycemic agents currently used among patients with type 2 diabetes mellitus (T2DM). The effects of SGLT2-i inhibitors on cardiac structure and function are not fully understood. The aim of this study is to evaluate the echocardiographic changing among patients with well-controlled T2DM treated with SGLT2-i in real-world setting. Thirty-five well-controlled T2DM patients (65 ± 9 years, 43.7% male) with preserved left ventricular ejection fraction (LVEF) and 35 age and sex-matched controls were included. T2DM patients underwent clinical and laboratory evaluation; 12-lead surface electrocardiogram; 2-dimensional color Doppler echocardiography at enrolment, before SGLT2-i administration, and at 6 months follow-up after an uninterrupted 10 mg once daily of empagliflozin (n: 21) or dapagliflozin (n: 14). Standard echocardiographic measurements, LV global longitudinal strain (LV-GLS), global wasted work, and global work efficiency were calculated. T2DM patients showed higher E\E' ratio (8.3 ± 2.5 vs. 6.3 ± 0.9; P < 0.0001 ) and lower LV-GLS (15.8 ± 8.1 vs. 22.1 ± 1.4%; P < 0.0001 ) and global myocardial work efficiency (91 ± 4 vs. 94 ± 3%; P: 0.0007 ) compared with age and sex-matched controls. At 6-month follow-up, T2DM patients showed a significant increase in LVEF (58.9 ± 3.2 vs. 62 ± 3.2; P < 0.0001 ), LV-GLS (16.2 ± 2.8 vs. 18.7 ± 2.4%; P = 0.003 ), and global work efficiency (90.3 ± 3.5 vs. 93.3 ± 3.2%; P = 0.0004 ) values; conversely, global wasted work values (161.2 ± 33.6 vs. 112.72 ± 37.3 mm Hg%; P < 0.0001 ) significantly decreased. Well-controlled T2DM patients with preserved LVEF who are treated with a SGLT2-i on top of the guidelines direct medical therapy showed a favorable cardiac remodeling, characterized by the improvement of LV-GLS and myocardial work efficiency.

Abstract #1385190: Empagliflozin Induced Acute Pancreatitis

Acute pancreatitis is a rapid onset inflammatory process of the pancreas which may have local and systemic manifestations. The most common causes of acute pancreatitis are gallstones and alcohol use. Other causes include drug-induced. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of oral hypoglycemic agents which is approved by the FDA for treating diabetes and for heart failure. 56-year-old, female patient known to have uncontrolled type 2 diabetes. Presented with a complaint of acute epigastric pain radiating to the back and then become a generalized abdominal pain, moderate in severity, not relieved by analgesic, associated with nausea and vomiting. The patient denied any history of alcohol, smoking use. A review of her medication list included sitagliptin 100 mg, metformin 2g, gliclazide 60 mg and more recently, empagliflozin 10 mg which was started seven weeks prior to symptoms onset. Physical examination was significant for tenderness in epigastric area. Laboratory workup revealed an elevated serum lipase 3851 units/L, serum amylase 3755 units\L abdominal CT scan shows mild fatty atrophy and mild peri-pancreatic fat stranding and free fluid adjacent to the tale and body suggesting evidence of acute pancreatitis. Abdominal ultrasound shows the gall bladder was without stones. The patient was admitted with diagnosis of mild acute pancreatitis and underwent conservative management. Patient condition was improved and discharged on same pre-admission antidiabetic medication with OPD follow-up. 3 weeks later she presented to the emergency department complaining from acute epigastric pain radiating to the back and association of nausea and vomiting. With tenderness in epigastric area laboratory workup revealed an elevated serum lipase and amylase. Abdominal CT scan confirmed acute interstitial pancreatitis. After 3 days of conservative management she was improved and discharged but this time her diabetologist discontinue empagliflozin and she was started on insulin. She was following up with her diabetologist in outpatient clinic and there was no history of recurrence of pancreatitis. Drug induce pancreatitis are rare cause but must be considered. It is therefore important to determine the underlying etiology of acute pancreatitis to prevent occurrence, recurrence, and the complications of pancreatitis. FDA and Health Canada have identified a potential safety issue and possible association between SGLT-2 inhibitors and acute pancreatitis but Further studies are required to investigate this association. This case report emphasized the possible association between SGLT2 inhibitors and acute pancreatitis. Physicians must be aware about this side effect as a possible cause of acute pancreatitis after exclusion of most common etiologies. Also, physician should inform the patient about the side effects of SGLT2 and the symptoms of acute pancreatitis and advised them to stop SGLT-2 inhibitors use in case such symptoms occur. Further studies are required to investigate this association.

Role of Dipeptidyl peptidase inhibitors in lung ischemia-reperfusion injury

Lung ischemia-reperfusion injury (LIRI)is a common complication after lung transplantation and cardiopulmonary bypass. It is an important factor affecting the success rate of transplantation. Its specific pathogenesis has not yet been fully elucidated. It is very significant to find the targets and drugs for the prevention and treatment of LIRI in order to improving the utilization rate of "marginal donor lung" and the long-term survival rate of lung transplant patients. Dipeptidyl peptidase 4(DPP4) inhibitors are a class of oral hypoglycemic agents. Previous studies have shown that DPP4 inhibitors have a variety of pharmacological activities, including anti-inflammatory, anti-fibrotic, immunomodulatory and other extrapancreatic functions. Recent studies have shown that DPP4 inhibitors may alleviate LIRI through various mechanisms, including inhibiting inflammatory responses, reducing oxidative stress, regulating blood glucose levels, and activating autophagy. This article reviewed the clinical and preclinical applications and mechanisms of DPP4 inhibitors in LIRI.

Considerations for Choosing First-Line Urate-Lowering Treatment in Older Patients with Comorbid Conditions.

Gout is the most common inflammatory arthritis in adults. The prevalence of gout increases with age. Urate-lowering treatment (ULT) among older patients is often challenging in that patients frequently suffer insufficient effectiveness or adverse events due to comorbidities, concurrentmedications, and altered pharmacokinetics. The large-scale randomized controlled trials (RCTs) directly investigating gout patients regarding cardiovascular (CV) safety have only recently been introduced; CARES and FAST compared the CV safety of the two xanthine oxidase inhibitors (XOis), febuxostat versus allopurinol, in patients with gout. Based on the CARES trial that showed CV concerns with febuxostat, the current international guidelines recommend allopurinol as first-line ULT in gout, while preserving other agents as a second-line treatment, despite a higher potency of febuxostat. XOis would be more suitable than uricosurics to treat older patients with gout due to the high prevalence of chronic kidney disease (CKD) in older patients. However, allopurinol alone might not achieve the target serum uric acid levels below 6 mg/dL and CKD might confer an increased risk of allopurinol induced cutaneous adverse reactions in older patients. Furthermore, as well as the later analysis of CARES participants who were lost to follow-up, data from the FAST trial and real-world studies suggest non-inferior CV safety for febuxostat compared to allopurinol even in the presence of CV diseases. Thus, febuxostat use in older patients with renal impairment may be more positively considered. The combination therapy of a novel uricosuric, verinurad, plus febuxostat reduced albuminuria in hyperuricemic patients with type 2 diabetes and CKD in a phase 2a trial, and further RCTs are awaited. Finally, the sodium-glucose cotransporter-2 inhibitor class of oral hypoglycemic agents, known to exert beneficial CV and renal effects independent of glycemic control, have shown a uricosuric effect and could be used as adjunctive therapy in older patients with cardiorenal comorbidities.

Abstract #1316800: Acute Pancreatitis as a Rare Side Effect of Using Empagliflozin

Acute pancreatitis is a rapid onset inflammatory process of the pancreas. The most common causes are gallstones and alcohol use. Other causes include drug-induced, hypertriglyceridemia, trauma, infectious. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of oral hypoglycemic agents which is approved by the FDA for treating diabetes and heart failure. SGLT2 inhibitors function through a novel mechanism of reducing renal tubular glucose reabsorption, producing a reduction in blood glucose without stimulating insulin release.

463-P: Effects of Imeglimin, a New Oral Hyperglycemic Agent, on High Glucose and Low Glucose–Induced Cell Death and Mitochondrial Dysfunction in Schwann Cells

It is known that hyperglycemia-induced oxidative stress is a major cause of the pathogenesis of diabetic neuropathy, and hyperglycemia-induced mitochondrial ROS production is considered as one pivotal mechanism of increased oxidative stress. On the other hand, imeglimin is a new class of oral hypoglycemic agents called “glymines” containing tetrahydrotriazines, which targets mitochondrial dysfunction. We investigated the effects of imeglimin on cell death and mitochondrial dysfunction induced by high glucose and low glucose in Schwann cells. Immortalized adult mouse Schwann (IMS32) cells were cultured for 1 hour in the medium with normal glucose concentration of 5.5 mM, low glucose of 2.5 mM, and high glucose of 25 mM. Compared to normal glucose, not only high glucose but also low glucose decreased cell viability of IMS32 cells and increased mitochondrial oxidative stress. Mitochondrial membrane potential was also decreased either by high glucose or low glucose. In addition, mitochondrial oxygen consumption rate (OCR) was increased by low glucose as well as high glucose. Mitochondria isolated from IMS32 cells exposed to high glucose and low glucose for 1 hour exhibited increased activity of complex I. The expression of complex I protein was unchanged by high glucose for 1 hour. Imeglimin ameliorated the decrease in cell viability and improved the mitochondrial dysfunctions via inhibiting the increase of mitochondrial oxidative stress, OCR and the activity of complex I caused by high glucose and low glucose. These results indicate that hyperglycemia and hypoglycemia induce mitochondrial dysfunction in nerves, and that imeglimin may prevent against diabetic neuropathy by attenuation mitochondrial dysfunction and cell death in Schwann cells. Disclosure T. Himeno: None. J. Nakamura: None. H. Kamiya: Research Support; Abbott Japan Co., Ltd., Eli Lilly and Company, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Terumo Corporation. Speaker's Bureau; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. K. Sango: None. K. Kato: None.

Effects of an SGLT Inhibitor on the Production, Toxicity, and Elimination of Gut-Derived Uremic Toxins: A Call for Additional Evidence.

Sodium–glucose cotransporter (SGLT) inhibitors are a class of oral hypoglycemic agents, which, in recent years, have been shown to improve renal and cardiovascular outcomes in patients with diabetic and non-diabetic chronic kidney disease. There remains considerable debate regarding the potential glucose-independent mechanisms by which these benefits are conferred. SGLT inhibitors, to a variable extent, impair small intestinal glucose absorption, facilitating the delivery of glucose into the colon. This suppresses protein fermentation, and thus the generation of uremic toxins such as phenols and indoles. It is acknowledged that such a shift in gut microbial metabolism yields health benefits for the host. SGLT inhibition, in addition, may be hypothesized to foster the renal clearance of protein-bound uremic toxins. Altered generation and elimination of uremic toxins may be in the causal pathway between SGLT inhibition and improved cardiometabolic health. Present review calls for additional research.

Impacto de dapagliflozina en los factores de riesgo cardiovascular. Más allá del control de la glucemia

Sodium–glucose transport protein 2 (SGLT2) inhibitors are a new class of oral hypoglycemic agents that increase urinary glucose excretion independently of insulin secretion, although an apparently simple mechanism, but with multiple metabolic effects.Dapagliflozin was the first SGLT2 inhibitor marketed in Europe in 2012 for the treatment of patients with type 2 diabetes, and consequently, with the greatest clinical experience. The results of different clinical trials and real-life studies have demonstrated its effectiveness in glycemic control, as they reduce glycosylated hemoglobin, while achieving a decrease in body weight and blood pressure, among others, providing a comprehensive metabolic protection.

Sodium-Glucose Co-transporter-2 Inhibitors and Nephroprotection in Diabetic Patients: More Than a Challenge.

Diabetic nephropathy is the most common cause of end-stage renal disease worldwide. Control of blood glucose and blood pressure (BP) reduces the risk of developing this complication, but once diabetic nephropathy is established, it is then only possible to slow its progression. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a novel class of oral hypoglycemic agents that increase urinary glucose excretion by suppressing glucose reabsorption at the renal proximal tubule. SGLT2is lower glycated hemoglobin (HbA1c) without increasing the risk of hypoglycemia, induce weight loss and improve various metabolic parameters including BP, lipid profile, albuminuria and uric acid. Several clinical trials have shown that SGLT2is (empagliflozin, dapagliflozin canagliflozin, and ertugliflozin) improve cardiovascular and renal outcomes and mortality in patients with type 2 diabetes. Effects of SGLT2is on the kidney can be explained by multiple pathways. SGLT2is may improve renal oxygenation and intra-renal inflammation thereby slowing the progression of kidney function decline. Additionally, SGLT2is are associated with a reduction in glomerular hyperfiltration, an effect which is mediated by the increase in natriuresis, the re-activation of tubule-glomerular feedback and independent of glycemic control. In this review, we will focus on renal results of major cardiovascular and renal outcome trials and we will describe direct and indirect mechanisms through which SGLT2is confer renal protection.

Long-term safety and efficacy of alogliptin, a DPP-4 inhibitor, in patients with type 2 diabetes: a 3-year prospective, controlled, observational study (J-BRAND Registry)

IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research...

Use of antidiabetic medications and risk of chronic obstructive pulmonary disease exacerbation requiring hospitalization: a disease risk score-matched nested case\u2013control study

BackgroundExacerbation of chronic obstructive pulmonary disease (COPD) severely impacts the quality of life and causes high mortality and morbidity. COPD is involved with systemic and pulmonary inflammation, which may be attenuated with antidiabetic agents exerting anti-inflammatory effects. Real-world evidence is scant regarding the effects of antidiabetic agents on COPD exacerbation. Accordingly, we conducted a disease risk score (DRS)-matched nested case–control study to systemically assess the association between each class of oral hypoglycemic agents (OHAs) and risk of severe COPD exacerbation in a nationwide COPD population co-diagnosed with diabetes mellitus (DM).MethodsWe enrolled 23,875 COPD patients receiving at least one OHA for management of DM by analyzing the Taiwan National Health Insurance claims database between January 1, 2000, and December 31, 2015. Cases of severe exacerbation were defined as those who had the first hospital admission for COPD. Each case was individually matched with four randomly-selected controls by cohort entry date, DRS (the estimated probability of encountering a severe COPD exacerbation), and COPD medication regimens using the incidence density sampling approach. Conditional logistic regressions were performed to estimate odds ratios (OR) of severe COPD exacerbation for each type of OHAs.ResultsWe analyzed 2700 cases of severe COPD exacerbation and 9272 corresponding controls after DRS matching. Current use of metformin versus other OHAs was associated with a 15% (adjusted OR [aOR], 0.85; 95% confidence interval [CI] 0.75–0.95) reduced risk of severe COPD exacerbation, whereas the reduced risk was not observed with other types of antidiabetic agents. When considering the duration of antidiabetic medication therapy, current use of metformin for 91–180 and 181–365 days was associated with a 28% (aOR, 0.72; 95% CI 0.58–0.89) and 37% (aOR, 0.63; 95% CI 0.51–0.77) reduced risk of severe COPD exacerbation, respectively. Similarly, 91–180 days of sulfonylureas therapy led to a 28% (aOR, 0.72; 95% CI 0.58–0.90) lower risk, and longer treatments consistently yielded 24–30% lower risks. Current use of thiazolidinediones for more than 181 days yielded an approximately 40% decreased risk.ConclusionsDuration-dependent beneficial effects of current metformin, sulfonylurea, and thiazolidinedione use on severe COPD exacerbation were observed in patients with COPD and DM.

Efficacy and Cardiovascular Safety of Meglitinides.

Meglitinides are a group of oral hypoglycemic medications currently approved for the treatment of type 2 diabetes mellitus (T2DM). Two meglitinide molecules, Repaglinide and Nateglinide, are presently in use. Repaglinide is preferred because of its superior glycemic efficacy. They have modest efficacy with a mean decrement of glycosylated haemoglobin (HbA1c) ranging between -0.2 to -1.50% with individual therapy. Additional HbA1c reduction can occur with combination therapy with other oral hypoglycemics. This class of drugs is effective in controlling postprandial hyperglycemia with minimal risk of hypoglycemia. It is also useful in patients with variable meal timings, especially in the elderly, and in patients with renal failure. There are a dearth of long-term studies on meglitinides to assess cardiovascular outcomes or mortality in T2DM, although the Nateglinide and Valsartan in Impaired Glucose ToleranceOutcomes Research (NAVIGATOR) study showed no difference between Nateglinide and placebo with regard to the core composite cardiovascular outcomes. Based on a PubMed literature search using key words: 'meglitinides', 'repaglinide', 'nateglinide', 'HbA1c', 'glycated haemoglobin', 'cardiovascular safety', 'cardiovascular events', 'cardiovascular outcome trials', 'type 2 diabetes mellitus' and heart failure, and combining the search terms using Boolean operators 'AND', 'OR' and 'NOT' as needed we compiled current evidence for use of these oral hypoglycemic agents in clinical use. This article is an attempt to review the efficacy and cardiovascular (CV) safety of Meglitinides to help clinicians to use this class of oral hypoglycaemic agents prudently.

Nephroprotective Effects of 2nd Type Sodium-Glucose Co-Transporter Inhibitors: A Literature Review

Introduction: A wide range of oral hypoglycemic drugs with various mechanisms of effect are available forthe treatment of patients with 2nd type diabetes mellitus today. Despite the high effectiveness of these agentsin the normalization of glycemia, they cause different chronic complications in many patients with 2nd typediabetes mellitus. However, during the last years, a range of principal new data has been accumulated onthe pleiotropic effects of the last classes of oral hypoglycemic agents — inhibitors of the 2nd type sodiumglucosecotransporter (SGLT2).Materials and Method: Three electronic databases were checked to find out studies reporting the data onthe mechanisms and clinical significance of the nephroprotective effect of inhibitors of the sodium-glucosecotransporter of 2nd type (glyphlozines) in patients with 2nd type diabetes mellitus. The primary outcomewas to learn the worldwide tendency on this matter and to compare the results of different researchers.Results: We found 25 studies as eligible for our review. The review presents data on the mechanisms andclinical significance of the nephroprotective effect of inhibitors of the sodium-glucose cotransporter of 2ndtype (glyphlozines). The effects associated with the influence of representatives of this pharmacologicalgroup on the glomerular filtration rate, glycemia, diuresis, ketogenesis and other factors are discussed. Theresults of recent experimental and clinical studies aimed at studying certain aspects of the nephroprotectiveeffect of SGLT2 inhibitors in 2nd type diabetes mellitus and other pathological conditions were analyzed.Conclusion. SGLT2 inhibitors associate with a multicomponent nephroprotective effect, which confirmedby the results of both experimental and clinical studies. The nephroprotective potential of SGLT2 inhibitorsis maximally realized in the presence of diabetes and remains not entirely clear in the case of another kidneypathology.

Phenanthridine Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Design, Synthesis and Biological Evaluation.

Diabetes mellitus is a chronic metabolic disorder, characterized by hyperglycemia over a prolonged period, disturbance of fat, protein, and carbohydrate metabolism, resulting from defective insulin secretion, insulin action or both. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are relatively a new class of oral hypoglycemic agents that reduce the deterioration of gutderived endogenous incretin hormones secreted in response to food ingestion to stimulate the secretion of insulin from beta cells of the pancreas. In this study, synthesis, characterization, and biological assessment of twelve novel phenanthridine sulfonamide derivatives 3a-3l as potential DPP-IV inhibitors were carried out. The target compounds were docked to study the molecular interactions and binding affinities against the DPP-IV enzyme. The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and MS. Quantum-polarized ligand docking (QPLD) was also performed. In vitro biological evaluation of compounds 3a-3l reveals comparable DPP-IV inhibitory activities ranging from 10%-46% at 100 μM concentration, where compound 3d harboring ortho- fluoro moiety exhibited the highest inhibitory activity. QPLD study shows that compounds 3a-3l accommodate DPP-IV binding site and form H-bonding with the R125, E205, E206, S209, F357, R358, K554, W629, S630, Y631, Y662, R669, and Y752 backbones Conclusion: In conclusion, phenanthridine sulfonamides could serve as potential DPP-IV inhibitors that require further structural optimization in order to enhance their inhibitory activity.