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This review summarizes the complex relationship between medications used to treat type 2 diabetes and bone health. T2DM patients face an increased fracture risk despite higher bone mineral density; thus, we analyzed the impact of key drug classes, including Metformin, Sulphonylureas, SGLT-2 inhibitors, DPP-4 inhibitors, GLP-1 agonists, and Thiazolidinediones. Metformin, despite promising preclinical results, lacks a clear consensus on its role in reducing fracture risk. Sulphonylureas present conflicting data, with potential neutral effects on bone. SGLT-2 inhibitors seem to have a transient impact on serum calcium and phosphorus, but evidence on their fracture association is inconclusive. DPP-4 inhibitors emerge as promising contributors to bone health, and GLP-1 agonists exhibit positive effects on bone metabolism, reducing fracture risk. Thiazolidinediones, however, demonstrate adverse impacts on bone, inducing loss through mesenchymal stem cell effects. Insulin presents a complex relationship with bone health. While it has an anabolic effect on bone mineral density, its role in fracture risk remains inconsistent. In conclusion, a comprehensive understanding of diabetes medications' impact on bone health is crucial. Further research is needed to formulate clear guidelines for managing bone health in diabetic patients, considering individual profiles, glycemic control, and potential medication-related effects on bone. [ABSTRACT FROM AUTHOR]

A connection between diabetes and an increased risk of epilepsy has been suggested by observational studies. Animal studies have also shown that antihyperglycemic drugs can improve seizures. However, it is unclear whether antihyperglycemic drugs have a causal role in epilepsy in humans. To investigate this potential causal relationship, a Mendelian randomisation study was conducted using International League Against Epilepsy data as the discovery set and FinnGen data as the replication set. It was discovered that three antidiabetic drug target genes, ETFDH, CYP21A2 and CYP2D6, were involved in the occurrence of epilepsy. In particular, ETFDH was identified as a target gene in both the discovery set (inverse variance weighting [IVW], odds ratio [OR] = 1.018, 95% confidence interval [CI], 1.004–1.033, p = 0.009) and replication set (IVW, OR = 1.074, 95% CI, 1.034–1.114, p = 0.00016), and CYP21A2 was identified in the discovery set (IVW, OR = 1.029, 95% CI, 1.005–1.053, p = 0.016) and replication set (IVW, OR = 1.057, 95% CI, 1.001–1.116, p = 0.045) as having a causal association with an increased risk of epilepsy. Conversely, the CYP2D6 gene was found to be a protective factor for epilepsy in both the discovery set (IVW, OR = 0.0984, 95% CI, 0.969–0.998, p = 0.025) and replication set (IVW, OR = 0.977, 95% CI, 0.955–1.000, p = 0.046). A search of DrugBank revealed that metformin, an anti-glucose drug, is an inhibitor of the ETFDH gene and may have a potential therapeutic effect on epilepsy. [ABSTRACT FROM AUTHOR]

Cellular stress, notably oxidative, inflammatory, and endoplasmic reticulum (ER) stress, is implicated in the pathogenesis of cardiovascular disease. Modifiable risk factors for cardiovascular disease such as diabetes, hypercholesterolemia, saturated fat consumption, hypertension, and cigarette smoking cause ER stress whereas currently known cardioprotective drugs with diverse pharmacodynamics share a common pleiotropic effect of reducing ER stress. Selective targeting of oxidative stress with known antioxidative vitamins has been ineffective in reducing cardiovascular risk. This "antioxidant paradox" is partially attributed to the unexpected aggravation of ER stress by the antioxidative agents used. In contrast, some of the contemporary antihyperglycemic drugs inhibit both oxidative stress and ER stress in human coronary artery endothelial cells. Unlike sulfonylureas, meglitinides, α glucosidase inhibitors, and thiazolidinediones, metformin, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors are the only antihyperglycemic drugs that reduce ER stress caused by pharmacological agents (tunicamycin) or hyperglycemic conditions. Clinical trials with selective ER stress modifiers are needed to test the suitability of ER stress as a therapeutic target for cardiovascular disease. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the relationships between health literacy, unrealistic optimism, and adherence to glycometabolic disease management related to erectile dysfunction (ED) in male patients with type 2 diabetes (T2D) or preDM. Materials and Methods: This prospective observational study enroled 167 consecutive patients with T2D and ED. All patients underwent the following examinations: (a) medical history collection; (b) Body Mass Index (BMI) determination; (c) hormonal and biochemical assessment; (d) duration of T2D, complications and treatment; (e) International Index of Erectile Function‐5 questionnaire to assess ED; and (f) validated questionnaire to evaluate health literacy, unrealistic optimism, and treatment adherence. Results: Overall, mean age was 62.5 ± 9.4 years (range: 20–75) and mean BMI was 28.4 ± 4.8 kg/m2 (range: 18.4–46.6). The mean IIEF‐5 score was 15.4 ± 5.2 (range: 5–25). The majority of patients showed high health literacy. However, low health literacy was found in patients with higher IIEF‐5 scores and high BMI. Unrealistic optimism was low in most patients. Higher adherence to treatment was found in patients who reported regular physical activity, who followed a diet, and in patients with a family history of T2D. Regarding anti‐diabetic treatment, patients treated with insulin showed higher health literacy than patients not treated with other medications, whereas higher adherence was found in patients using SGLT2‐i. Conclusions: This study highlighted the close relationship between metabolic compensation, BMI, ED, and psychological attitudes, including health literacy and unrealistic optimism. [ABSTRACT FROM AUTHOR]

The study aimed to evaluate dual liquid chromatography (LC) coupled to high-resolution mass spectrometry (HRMS) for the simultaneous analysis of small and large molecule drugs by development and application of a validated bioanalytical method. The oral antihyperglycemic drugs (OAD) dapagliflozin, empagliflozin, glibenclamide, glimepiride, metformin, pioglitazone, repaglinide, saxagliptin, sitagliptin, and vildagliptin, as well as the antihyperglycemic peptides exenatide, human insulin, insulin aspart, insulin degludec, insulin detemir, insulin glargine, insulin glulisine, insulin lispro, and semaglutide were included in the analytical procedure. Analytes were extracted using a combination of protein precipitation and solid-phase extraction. Two identical reversed-phase columns were used for separation followed by Orbitrap high-resolution mass spectrometry. The whole procedure was validated according to international recommendations. Different MS parameters had to be used for the two analyte groups, but dual LC separation allowed elution of all analytes within 12 min using the same column type. The analytical procedure was accurate and precise for most of the compounds except for exenatide, semaglutide, and insulin glargine, which were included qualitatively in the method. Analysis of proof-of-concept samples revealed OAD concentrations mostly within their therapeutic range, insulins could be detected in five cases but at concentrations below the lower limit of quantification except for one case. Dual LC in combination with HRMS was shown to be a suitable platform to analyze small and large molecules in parallel and the current method allowed the determination of a total of 19 antihyperglycemic drugs in blood plasma within 12 min. [ABSTRACT FROM AUTHOR]

Abstract Background The reno-protective effect of second-line treatments in type 2 diabetes has been assessed by clinical trials but generalizability to routine clinical practice is still uncertain. We aimed to assess the effectiveness of these treatments, when added to metformin, on the risk of chronic kidney disease (CKD). Methods A real-world, hospital-based, type 2 diabetes cohort was retrospectively assembled at Ramathibodi Hospital from 2010 to 2019. Patients who received sulfonylureas (SU), thiazolidinediones (TZD), dipeptidyl peptidase-4 inhibitors (DPP4i), or sodium-glucose cotransporter-2 inhibitors (SGLT2i), as second-line antihyperglycemic treatment were included. Treatment effect models with inverse probability weighting and regression adjustment were used to estimate CKD risk according to treatment. Results CKD was identified in 4,132 of the 24,777 patients with type 2 diabetes (16.7%). The CKD incidence (95% CI) was 4.1% (2.2%, 6.9%), 13.5% (12.5%, 14.6%), 14.8% (13.5%, 16.1%), and 18.0% (17.4%, 18.5%) for patients receiving SGLT2i, DPP4i, TZD, and SU treatment, respectively. The average treatment effects (i.e., the difference in CKD risk) for SGLT2i, DPP4i, and TZD compared to SU were − 0.142 (− 0.167, − 0.116), − 0.046 (− 0.059, − 0.034), and − 0.004 (− 0.023, 0.014), respectively, indicating a significant reduction in CKD risk of 14.2% and 4.6% in the SGLT2i and DPP4i groups, respectively, compared to the SU group. Furthermore, SGLT2i significantly reduced CKD risk by 13.7% (10.6%, 16.8%) and 9.5% (6.8%, 12.2%) when compared to TZD and DPP4i, respectively. Conclusions Our study identified 14.2%, 13.7%, and 9.5% reduced CKD risk in Thai patients with type 2 diabetes who were treated with SGLT2i compared to those treated with SU, TZD, and DPP4i, respectively, in real-world clinical data. Previous evidence of a reno-protective effect of SGLT2i reported in other populations is consistent with our observations in this Southeast Asian cohort.

This review summarizes the complex relationship between medications used to treat type 2 diabetes and bone health. T2DM patients face an increased fracture risk despite higher bone mineral density; thus, we analyzed the impact of key drug classes, including Metformin, Sulphonylureas, SGLT-2 inhibitors, DPP-4 inhibitors, GLP-1 agonists, and Thiazolidinediones. Metformin, despite promising preclinical results, lacks a clear consensus on its role in reducing fracture risk. Sulphonylureas present conflicting data, with potential neutral effects on bone. SGLT-2 inhibitors seem to have a transient impact on serum calcium and phosphorus, but evidence on their fracture association is inconclusive. DPP-4 inhibitors emerge as promising contributors to bone health, and GLP-1 agonists exhibit positive effects on bone metabolism, reducing fracture risk. Thiazolidinediones, however, demonstrate adverse impacts on bone, inducing loss through mesenchymal stem cell effects. Insulin presents a complex relationship with bone health. While it has an anabolic effect on bone mineral density, its role in fracture risk remains inconsistent. In conclusion, a comprehensive understanding of diabetes medications’ impact on bone health is crucial. Further research is needed to formulate clear guidelines for managing bone health in diabetic patients, considering individual profiles, glycemic control, and potential medication-related effects on bone.

Background: Erectile dysfunction is recognized as one of the complications of diabetes mellitus. To date, awide gap of knowledge is present on the efficacy of pharmacological treatments of diabetes mellitus on erectile function, acting not only through metabolic control. Similarly, the effects of different diet regimens on erectile dysfunction are still debated. Objectives:We aimed to explore the effects of diet and antihyperglycemic drugs, considering both old and novel therapeutic approaches, on erectile function. Materials/methods:We performed a systematic review, following the PRISMA guidelines. The research was conducted on studies reporting erectile dysfunction assessment in subjects with diabetes and the relationship with diet and antihyperglycemic drugs. Results: The Mediterranean diet was effective in most studies for the protection of erectile function. Furthermore, antihyperglycemic drugs seem to show an overall protective role on erectile function. Discussion/conclusion: Although encouraging results are present for all classes of antihyperglycemic drugs, several studies are needed in humans, mainly on acarbose, pioglitazone, dipeptidyl-peptidase-4 inhibitors, and sodium-glucose cotransporter-2 inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: The cardiovascular benefits of multiple antihyperglycemic drugs as add-on therapies to metformin in the real-practice are unclear. This study aimed to directly compare major adverse cardiovascular events (CVE) associated with these multiple drugs. Methods: An emulation of a target trial was conducted using a retrospective-cohort data of type 2 diabetesmellitus (T2DM) prescribed with second-line drugs on top of metformin, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i), thiazolidinediones (TZD) and sulfonylureas (SUs). We applied inverse probability weighting and regression adjustment using intention-to-treat (ITT), per-protocol analysis (PPA) and modified ITT. Average treatment effects (ATE) were estimated using SUs as the reference. Results and Discussion:: Among 25,498 patients with T2DM, 17,586 (69.0%), 3,261 (12.8%), 4,399 (17.3%), and 252 (1.0%) received SUs, TZD, DPP4i, and SGLT2i. Median follow-up time was 3.56 (1.36-7.00) years. CVE was identified in 963 patients. The ITT and modified ITT approaches showed similar results; the ATE (i.e., the difference of CVE risks) for SGLT2i, TZD, and DPP4i compared to SUs were -0.020(-0.040, -0.0002), -0.010(-0.017, -0.003), and -0.004(-0.010, 0.002), respectively, indicating 2% and 1% significant absolute risk reduction in CVE in SGLT2i and TZD compared to SUs. These corresponding effects were also significant in the PPA with ATEs of -0.045(-0.060, -0.031), -0.015(-0.026, -0.004), and -0.012(-0.020, -0.004). In addition, SGLT2i had 3.3% significant absolute risk reduction in CVE relative to DPP4i. Our study demonstrated benefits of SGLT2i and TZD in reducing CVE in T2DM patients compared to SUs when added to metformin. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate the prevalence of DM among patients with ED and the impact of glycometabolic compensation and antihyperglycemic treatment on ED severity. Methods: In total, 1332 patients with ED were enrolled. The diagnosis was performed through the International-Index-of-Erectile-Function questionnaire. ED severity was considered according to presence/absence of spontaneous erections, maintenance/achievement deficiency and response to PDE5-i. DM patients were clustered according to antihyperglycemic treatment: "metformin"/"insulin"/"old antihyperglycemic drugs"/"new antihyperglycemic drugs". Results: The prevalence of DM patients was 15.8% (Group A, patients with ED and DM). Among these, the prevalence of spontaneous erections (21.0%) was lower than in the remaining patients (Group B, patients with ED without DM) (32.0%, p < 0.001). The prevalence of poor response to PDE5-i was lower in Group B (10.0%) than in Group A (35.0%, p < 0.001). Patients with good response to PDE5-i therapy showed lower HbA1c values than patients with poor/no response (6.6 ± 1.1% vs. 7.7 ± 1.9%, p = 0.02). The prevalence of absent response to PDE5-i was higher in patients treated with old antidiabetic drugs than in the population treated with new drugs (p = 0.03). Conclusion: The severity of ED and lower response to PDE5-i were higher in DM patients. A better glycometabolic profile, as well as new antihyperglycemic drugs, seem to have a positive effect on ED. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease in China, which greatly negatively impacts public health and patients' quality of life. Recently, multiple guidelines have updated their recommendations to optimize the treatment and management of individuals with DKD. New antihyperglycemic drugs offer new options for DKD. Traditional Chinese medicine (TCM) has a long history in treating DKD, and relevant theories have been continuously enriched and developed. Along with the increasing application of evidence-based medicine in TCM research, the benefits of TCM treatments in DKD have been gradually recognized and valued, such as relieving fatigue, edema, backache and other symptoms, lowering protein in the urine, protecting kidney function, enhancing treatment efficiency, reducing the risk of end-stage renal disease, and improving the long-term prognosis. This article gave a summary and strengths analysis of the latest advances in TCM and Western medicine treatments for DKD.

Abstract The COVID-19 pandemic led to an unprecedented crisis, and early on, it has been shown that diabetes is an important risk factor for complications and mortality in infected patients, as demonstrated by several studies. Moreover, hyperglycemia, regardless of whether patients have diabetes, is associated with poorer outcomes, which suggests that adequate monitoring and treatment of elevated glycemia in the hospital setting can improve patient outcomes. In patients with COVID-19, glycemic control may be impaired as a consequence of the infection itself (aggravating pre-existing diabetes and potentially precipitating new-onset diabetes), inflammation, or corticosteroid use—a well-established therapy to reduce COVID-19 complications, especially in the intensive care unit. This article reviews the link between diabetes and hyperglycemia, and COVID-19, with a brief review of potential mechanisms, along with emerging evidence on the effect of glycemic control on COVID-19 outcomes, especially in hospital settings.

IntroductionThe cardiovascular benefits of multiple antihyperglycemic drugs as add-on therapies to metformin in the real-practice are unclear. This study aimed to directly compare major adverse cardiovascular events (CVE) associated with these multiple drugs.MethodsAn emulation of a target trial was conducted using a retrospective-cohort data of type 2 diabetes mellitus (T2DM) prescribed with second-line drugs on top of metformin, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i), thiazolidinediones (TZD) and sulfonylureas (SUs). We applied inverse probability weighting and regression adjustment using intention-to-treat (ITT), per-protocol analysis (PPA) and modified ITT. Average treatment effects (ATE) were estimated using SUs as the reference.Results and DiscussionAmong 25,498 patients with T2DM, 17,586 (69.0%), 3,261 (12.8%), 4,399 (17.3%), and 252 (1.0%) received SUs, TZD, DPP4i, and SGLT2i. Median follow-up time was 3.56 (1.36-7.00) years. CVE was identified in 963 patients. The ITT and modified ITT approaches showed similar results; the ATE (i.e., the difference of CVE risks) for SGLT2i, TZD, and DPP4i compared to SUs were -0.020(-0.040, -0.0002), -0.010(-0.017, -0.003), and -0.004(-0.010, 0.002), respectively, indicating 2% and 1% significant absolute risk reduction in CVE in SGLT2i and TZD compared to SUs. These corresponding effects were also significant in the PPA with ATEs of -0.045(-0.060, -0.031), -0.015(-0.026, -0.004), and -0.012(-0.020, -0.004). In addition, SGLT2i had 3.3% significant absolute risk reduction in CVE relative to DPP4i. Our study demonstrated benefits of SGLT2i and TZD in reducing CVE in T2DM patients compared to SUs when added to metformin.

Background: The reno-protective effect of second-line treatments in type 2 diabetes has been assessed by clinical trials but generalizability to routine clinical practice is still uncertain. We aimed to assess the effectiveness of these treatments, when added to metformin, on the risk of chronic kidney disease (CKD). Methods: A real-world, hospital-based, type 2 diabetes cohort was retrospectively assembled at Ramathibodi Hospital from 2010 to 2019. Patients who received sulfonylureas (SU), thiazolidinediones (TZD), dipeptidyl peptidase-4 inhibitors (DPP4i), or sodium-glucose cotransporter-2 inhibitors (SGLT2i), as second-line antihyperglycemic treatment were included. Treatment effect models with inverse probability weighting and regression adjustment were used to estimate CKD risk according to treatment. Results: CKD was identified in 4,132 of the 24,777 patients with type 2 diabetes (16.7%). The CKD incidence (95% CI) was 4.1% (2.2%, 6.9%), 13.5% (12.5%, 14.6%), 14.8% (13.5%, 16.1%), and 18.0% (17.4%, 18.5%) for patients receiving SGLT2i, DPP4i, TZD, and SU treatment, respectively. The average treatment effects (i.e., the difference in CKD risk) for SGLT2i, DPP4i, and TZD compared to SU were − 0.142 (− 0.167, − 0.116), − 0.046 (− 0.059, − 0.034), and − 0.004 (− 0.023, 0.014), respectively, indicating a significant reduction in CKD risk of 14.2% and 4.6% in the SGLT2i and DPP4i groups, respectively, compared to the SU group. Furthermore, SGLT2i significantly reduced CKD risk by 13.7% (10.6%, 16.8%) and 9.5% (6.8%, 12.2%) when compared to TZD and DPP4i, respectively. Conclusions: Our study identified 14.2%, 13.7%, and 9.5% reduced CKD risk in Thai patients with type 2 diabetes who were treated with SGLT2i compared to those treated with SU, TZD, and DPP4i, respectively, in real-world clinical data. Previous evidence of a reno-protective effect of SGLT2i reported in other populations is consistent with our observations in this Southeast Asian cohort. [ABSTRACT FROM AUTHOR]

Background. The purpose of this study was to evaluate the effect of diet and antihyperglycemic drugs on erectile dysfunction (ED) in a setting of subjects affected by diabetes mellitus (DM) or preDM. Methods. This is a prospective observational study on 163 consecutive subjects with preDM or DM. All patients have undergone a medical evaluation (age, Body Mass Index (BMI), family history of DM, duration of DM, smoking, physical activity, dyslipidemia, cardiovascular comorbidities, and testosterone and HbA1c levels) and the International Index of Erectile Function (IIEF)-5 questionnaire. Results. Overall, the mean age was 62.8 ± 9.3 years, and the mean BMI was 28.4 ± 4.6 kg/m2. The IIEF-5 score mean value was 14.4 ± 6.2 (range 4–25). Among all confounders investigated for their association with the IIEF-5 score, only age and the duration of DM among diabetic patients showed a significant trend. The IIEF-5 score was higher in patients using GLP-1a compared to insulin (16.7 ± 4.7 vs. 12.9 ± 6.2; p = 0.02). This association was confirmed after adjustment for age and duration of DM (p = 0.01). All other treatments were similar (14.9 ± 6.2, 14.8 ± 9.2, 15.3 ± 5.4, and 13.6 ± 6.8 for metformin, sulfonylureas (SU), dipeptidyl-peptidase-4 inhibitors (DPP-4i), and sodium-glucose cotransporter-2 inhibitors (SGLT2i) treatment, respectively). Conclusions. This prospective observational study increases attention and focus on the effect of antihyperglycemic drugs and diet on ED, above all about the role of new classes, showing a significant higher IIEF-5 mean value in patients using GLP-1a compared to patients on insulin treatment. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic led to an unprecedented crisis, and early on, it has been shown that diabetes is an important risk factor for complications and mortality in infected patients, as demonstrated by several studies. Moreover, hyperglycemia, regardless of whether patients have diabetes, is associated with poorer outcomes, which suggests that adequate monitoring and treatment of elevated glycemia in the hospital setting can improve patient outcomes. In patients with COVID-19, glycemic control may be impaired as a consequence of the infection itself (aggravating pre-existing diabetes and potentially precipitating new-onset diabetes), inflammation, or corticosteroid use—a well-established therapy to reduce COVID-19 complications, especially in the intensive care unit. This article reviews the link between diabetes and hyperglycemia, and COVID-19, with a brief review of potential mechanisms, along with emerging evidence on the effect of glycemic control on COVID-19 outcomes, especially in hospital settings. [ABSTRACT FROM AUTHOR]

The management of diabetes in cirrhosis and liver transplantation can be challenging. There is difficulty in diagnosis and monitoring of diabetes as fasting blood sugar values are low and glycosylated hemoglobin may not be a reliable marker. The challenges in the management of diabetes in cirrhosis include the likelihood of cognitive impairment, risk of hypoglycemia, altered drug metabolism, frequent renal dysfunction, risk of lactic acidosis, and associated malnutrition and sarcopenia. Moreover, calorie restriction and an attempt to lose weight in obese diabetics may be associated with a worsening of sarcopenia. Many commonly used antidiabetic drugs may be unsafe or be associated with a high risk of hypoglycemia in cirrhotics. Post-transplant diabetes is common and may be contributed by immunosuppressive medication. There is inadequate clinical data on the use of antidiabetic drugs in cirrhosis, and the management of diabetes in cirrhosis is hampered by the lack of guidelines focusing on this issue. The current review aims at addressing the practical management of diabetes by a hepatologist. [ABSTRACT FROM AUTHOR]

Aims: The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) binds to the ACE2 component of the renin‐angiotensin aldosterone system (RAAS) and infects the human cells. The aims of the present review were to look at the role and alteration of the RAAS components in SARS‐CoV‐2 infection, therapeutic approaches, and clinical trials in this field. Methods: We surveyed the literature (PubMed, Web of Science, and Scopus) till August 18, 2021, and 59 published papers regarding the components of the RAAS and their role and alterations in SARS‐CoV‐2 infection along with various COVID‐19 therapies based on the RASS components were included in the study. Results: ACE inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor inhibitors are agents that significantly enhance the ACE2 and Ang‐(1‐7) levels, which can be suggestive for their role as therapeutics against SARS‐CoV‐2 infection. Beta‐adrenergic blockers, which negatively regulate renin release from juxtaglomerular cells, and vitamin D, as a regulator of the RAAS and renin expression, are proposed therapeutics in the treatment of COVID‐19. Some antihyperglycemic agents could be potentially protective against COVID‐19‐induced lung injury. Also, the inhibition of the Janus kinase/signal transducer and activator of the transcription pathway as a potential treatment for COVID‐19 has been suggested. Finally, resveratrol, an antioxidant that can suppress Ang II, has been suggested as an adjunct to other therapies. Conclusion: Regarding the suggested potential therapies for COVID‐19, there are many clinical trials whose results might change the treatment strategies of SARS‐CoV‐2 infection. So, the results of well‐organized clinical trials on the efficacy and safety of the mentioned agents in the treatment of COVID‐19 will be useful in the management and therapy of the disease. [ABSTRACT FROM AUTHOR]

Abstract Aims The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) binds to the ACE2 component of the renin‐angiotensin aldosterone system (RAAS) and infects the human cells. The aims of the present review were to look at the role and alteration of the RAAS components in SARS‐CoV‐2 infection, therapeutic approaches, and clinical trials in this field. Methods We surveyed the literature (PubMed, Web of Science, and Scopus) till August 18, 2021, and 59 published papers regarding the components of the RAAS and their role and alterations in SARS‐CoV‐2 infection along with various COVID‐19 therapies based on the RASS components were included in the study. Results ACE inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor inhibitors are agents that significantly enhance the ACE2 and Ang‐(1‐7) levels, which can be suggestive for their role as therapeutics against SARS‐CoV‐2 infection. Beta‐adrenergic blockers, which negatively regulate renin release from juxtaglomerular cells, and vitamin D, as a regulator of the RAAS and renin expression, are proposed therapeutics in the treatment of COVID‐19. Some antihyperglycemic agents could be potentially protective against COVID‐19‐induced lung injury. Also, the inhibition of the Janus kinase/signal transducer and activator of the transcription pathway as a potential treatment for COVID‐19 has been suggested. Finally, resveratrol, an antioxidant that can suppress Ang II, has been suggested as an adjunct to other therapies. Conclusion Regarding the suggested potential therapies for COVID‐19, there are many clinical trials whose results might change the treatment strategies of SARS‐CoV‐2 infection. So, the results of well‐organized clinical trials on the efficacy and safety of the mentioned agents in the treatment of COVID‐19 will be useful in the management and therapy of the disease.

Background: Although type 2 diabetes mellitus (T2DM) patients with coronavirus disease 2019 (COVID‐19) develop a more severe condition compared to those without diabetes, the mechanisms for this are unknown. Moreover, the impact of treatment with antihyperglycemic drugs and glucocorticoids is unclear. Methods: From 1584 COVID‐19 patients, 364 severe/critical COVID‐19 patients with clinical outcome were enrolled for the final analysis, and patients without preexisting T2DM but elevated glucose levels were excluded. Epidemiological data were obtained and clinical status evaluation carried out to assess the impact of T2DM and its management on clinical outcomes. Results: Of 364 enrolled severe COVID‐19 inpatients, 114 (31.3%) had a history of T2DM. Twenty‐seven (23.7%) T2DM patients died, who had more severe inflammation, coagulation activation, myocardia injury, hepatic injury, and kidney injury compared with non‐DM patients. In severe COVID‐19 patients with T2DM, we demonstrated a higher risk of all‐cause fatality with glucocorticoid treatment (adjusted hazard ratio [HR], 3.61; 95% CI, 1.14‐11.46; P =.029) and severe hyperglycemia (fasting plasma glucose ≥11.1 mmol/L; adjusted HR, 11.86; 95% CI, 1.21‐116.44; P =.034). Conclusions: T2DM status aggravated the clinical condition of COVID‐19 patients and increased their critical illness risk. Poor fasting blood glucose (≥ 11.1 mmol/L) and glucocorticoid treatment are associated with poor prognosis for T2DM patients with severe COVID‐19. [ABSTRACT FROM AUTHOR]

Background: There is a conflicting literature on the association between the use of antihyperglycemic drugs and dementia risk.Objective: The goal of this case-control study was to analyze the association between the use of antihyperglycemic drugs and dementia risk in patients followed in general practices in Germany.Methods: This study included patients with type 2 diabetes mellitus who had received a first dementia diagnosis in 972 general practices in Germany between January 2013 and December 2017 (index date). Controls without dementia were matched (1:1) to cases by age, gender, index year, and physician. Two multivariate regression models were used to study the association between the use of antihyperglycemic drugs and dementia risk. Model 1 included all antihyperglycemic drugs prescribed to patients regardless of the prescription duration, whereas Model 2 only included the longest therapy prescribed to each patient.Results: There were 8,276 diabetes patients with dementia and 8,276 diabetes patients without dementia included in this study. In Model 1, glitazones were associated with a decreased dementia risk (odds ratio [OR] = 0.80), whereas insulin was associated with an increased risk of developing the condition (OR = 1.34). In Model 2, metformin, prescribed as monotherapy (OR = 0.71) or as dual therapy with sulfonylureas (OR = 0.90), was associated with a decrease in the likelihood of subsequently being diagnosed with dementia. By contrast, the combination of basal insulin and bolus insulin (OR = 1.47) and premix insulin (OR = 1.33) were risk factors for dementia.Conclusion: Metformin and glitazones were negatively associated with dementia, while insulin was positively associated with dementia. [ABSTRACT FROM AUTHOR]

• Prescriptions of GLP-1 RA and SGLT2i increased from 2015 to 2021 in older diabetics. • Use of GLP-1 RA and SGLT2i increased mainly in older diabetics with CVD. • Use of sulfonylureas and glinides decreased from 2015 to 2021 in older diabetics. • One fourth of T2DM patients over 80 years were still treated with sulfonylureas. • There is still room to improve the management in older people with diabetes. To describe glucose-lowering drugs prescribing pattern in a large population of older diabetics from 2010 to 2021. Using linkable administrative health databases, we included patients aged 65–90 years treated with glucose-lowering drugs. Prevalence rate of drugs was collected within each study year. A stratified analysis by gender, age and coexistence of cardiovascular disease (CVD) was conducted. A total of 251 737 and 308 372 patients were identified in 2010 and 2021, respectively. Use of metformin (68.4% to 76.6%), DPP-4i (1.6% to 18.4%), GLP-1-RA (0.4% to 10.2%), SGLT2i (0.6% to 11.1%) increased, while sulfonylureas (53.6% to 20.7%) and glinides (10.5% to 3.5%) decreased over time. Metformin, glitazones, GLP1-RA, SGLT2i and DPP4i (except for 2021) usage decreased with aging, in contrast to sulfonylureas, glinides and insulin. The coexistence of CVD was associated with a higher prescription of glinides, insulin, DPP-4i, GLP1-RA and SGLT2i, particularly in 2021. We found a significant increase in the prescriptions of GLP-1 RA and SGLT2i in older diabetics, mainly in those with CVD. However, drugs without CV benefits including sulfonylureas and DPP-4i continued to be highly prescribed in older patients. There is still room to improve the management in this population according to recommendations. [ABSTRACT FROM AUTHOR]

Diabetes mellitus type 2 is a chronic progressive disease which leads to specific vascular complications - microangiopathy and macroangiopathy. These complications are the reason of increased cardiovascular mortality, which is 4-5 times higher in patients with type 2 diabetes mellitus than in the general population.

Background Antihyperglycemic drugs have been linked to new-onset atrial fibrillation ( NAF). However, the effect of the different classes of antihyperglycemic drugs on the development of NAF in elderly patients has not been well studied. In this study, we investigated the association between different classes of antihyperglycemic drugs and NAF in elderly patients. Materials and methods This was a nested case-control study performed using the database of National Health Insurance programme in Taiwan. Each participant aged 65 years and older who were NAF from 2005 to 2012 were assigned to the NAF group, whereas case was sex-, age-, diabetes duration-, index date-matched, and Charlson Comorbidity Index score-matched randomly selected participant without NAF were assigned to the non- NAF group. Multivariable logistic regression model was used for the estimation of odds ratios ( ORs) and 95% confidence intervals ( CIs) of NAF associated with use of different classes of antihyperglycemic agents. Nonusers served as the reference group. Results We identified 1958 cases and 7832 controls. The risk of NAF after adjusting for sex, age, comorbidities and concurrent medication was higher among the users of insulin than among the nonusers ( OR, 1·58; 95% CI, 1·37-1·82). Patients who took dipeptidyl peptidase 4 inhibitors were at lower risk of developing NAF than the nonusers ( OR, 0·65; 95% CI, 0·45-0·93). Conclusions In this population, use of dipeptidyl peptidase 4 inhibitor was associated with a low risk of NAF. Insulin use was associated with a significant increase in the risk of NAF during the long-term follow-up. [ABSTRACT FROM AUTHOR]

Aims: Diabetes treatments aim at preventing undesirable metabolic effects of hyperglycemia and at preventing/reducing tissue damage, including cardiovascular (CV) events. For approval, novel diabetes drugs undergo early systematic investigation to assess CV safety. This review provides an updated analysis of the results of recent studies examining novel diabetes medications and CV outcomes.Data Synthesis: The new regulatory guidelines enforce adjudication of all CV events when testing novel diabetes drugs. Endpoints of CV mortality, myocardial infarction (MI), stroke and hospitalization for heart failure (HF) were included in the most recent clinical studies on novel antihyperglycemics. These are: the incretin mimetics glucagon-like peptide 1 (GLP-1) receptor agonists (GLP1-RA), the incretin enhancers dipeptidylpeptidase-4 (DPP-4) inhibitors (DPP4-I or gliptins), and the sodium-glucose cotransporter (SGLT2) inhibitors (SGLT2-I or gliflozins). The studies ELIXA and EXAMINE, testing lixisenatide and alogliptin, respectively, revealed non-inferiority versus placebo in terms of CV safety. The SAVOR-TIMI 53 results confirmed overall CV safety of saxagliptin, but raised a warning related to the increase in the risk of hospitalization for HF in the saxagliptin group. Recently, TECOS revealed a particularly favorable CV profile for sitagliptin while EMPA-REG showed a significant CV risk reduction in empagliflozin treated subjects. Ongoing studies will provide additional data on CV safety for other GLP1-RAs, DPP4-I and SGLT2-I.Conclusions: Results of safety outcome studies focused on CV events, including HF and mortality for CV causes, are not homogeneous. A critical analysis of these studies may help cardiologists and diabetes specialists to adapt their therapeutic choices to individual patients. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is the world's fastest growing disease with high morbidity and mortality rates, predominantly as a result of heart failure. A significant number of diabetic patients exhibit diabetic cardiomyopathy; that is, left ventricular dysfunction independent of coronary artery disease or hypertension. The pathogenesis of diabetic cardiomyopathy is complex, and is characterized by dysregulated lipid metabolism, insulin resistance, mitochondrial dysfunction and disturbances in adipokine secretion and signaling. These abnormalities lead to impaired calcium homeostasis, ultimately resulting in lusitropic and inotropic defects. This article discusses the impact of these hallmark factors in diabetic cardiomyopathy, and concludes with a survey of available and emerging therapeutic modalities. [ABSTRACT FROM AUTHOR]

Abstract: To estimate the prevalence of type 2 diabetes in Italy and to investigate patient-related variables associated with the use of different antihyperglycemic therapies. This study was conducted between the years 2000–2003 from a source population comprising a cumulative sample of 394,719 patients from 320 General Practitioners across Italy, who provide information to the Health Search/Thales Database (HSD). A total sample of 23,729 of patients with type 2 diabetes age 15 years or older was selected from the source population. During the study years, the prevalence of type 2 diabetes increased from 4.7 to 6.0%. A significant increase in the use of antihyperglycemic therapy was also observed between 2000 and 2003. In particular, the use of biguanides increased. During the same period, the use of sulfonylurea monotherapy, oral combination therapy and insulin with oral combination therapy decreased. The results from the multivariate analysis revealed that healthier patients were more likely to be prescribed biguanide and sulfonylurea monotherapy, whereas patients with more diabetes complications and poorer glycemic control were more likely to be prescribed oral combination therapy or insulin (monotherapy or combination therapy). In conclusion, the study results appear to suggest that the prescribing patterns of Italian GPs and the predictors of different antihyperglycemic drug use are consistent with recent scientific evidence. [Copyright &y& Elsevier]

Simultaneous determination of two antidiabetic drugs, metformin and glyburide, in pharmaceutical tablet formulations were investigated. Normal phase thin layer chromatography plate (silica gel 60 F254) was used as stationary phase and water/methanol/ammonium sulfate (2/1/0.5 w/ v) as mobile phase to determine two pharmaceutically active ingredients, in three different formulations of Glucovance®. This system gave a good resolution for metformin ( R f value of 0.43 ± 0.01) and glyburide ( R f value of 0.64 ± 0.02). Determination was by densitometry in the absorbance mode at 237 nm. The linear regression data for the calibration plot showed a good relationship with r = 0.99581 and 0.99982 for metformin and glyburide, respectively. The method was validated for precision and recovery. The limits of detection and quantification were 25.24 and 84.12 ng spot−1 for metformin and 12.26 and 40.86 ng spot−1 for glyburide, respectively. Stability study has been carried out for samples and standard solutions. [ABSTRACT FROM AUTHOR]

Abstract Background:: Trials have shown that intensive therapy to control bloodglucose levels results in lower rates of microvascular complications and myocardial infarction among patients with type 2 diabetes. They have also demonstrated the economic and quality-of-life benefits of improved glycemic control among this patient population. Glycemic control achievable in controlled settings, however, may differ from that observed in actual practice settings, in part due to the patient''s autonomy in determining whether, or to what extent, adherence to the prescribed regimen is acceptable. Objective:: The goal of this study was to determine adherence with pharmacotherapy for type 2 diabetes among newly treated working-aged adults (ie, those aged 18–64 years) who had employer-sponsored health insurance. Adherence was defined as the regular refilling of prescriptions as indicated, such that an appropriate supply of medication is available over time. Methods: A retrospective cohort study of newly treated patients (aged18–64 years) was conducted using an administrative claims database with coverage from 1997 through 2000. Eligibility required at least12 months of history before and after the index prescription date. Earlynonpersistence (failure to fill a second prescription for the index drug or any other antihyperglycemic medication) and 12-month non-persistence rates were calculated, as was nonadherence based on a medication possession ratio (MPR) &#60;80%. Survival and logistic regression models were used to examine adherence rates and behavior predictors. Results:: A total of 6090 patients (median age, 51.0 years; 3263 men, 2827 women) were included. After the first prescription, 10.5% of patients (95% CI, 9.8–11.3) failed to fill a second prescription for the initial or any other antihyperglycemic medication. At 12 months after the initial prescription date, 37.0% of patients (95% CI, 35.8–38.2) had discontinued pharmacotherapy. During the period of persistence (the time interval during which prescriptions were beingfilled), 46.2% of patients (95% CI, 44.7–47.7) were nonadherent according to the MPR-based analysis. After adjustment for covariates, younger age (ie, 18–24 years) and female gender were foundto be risk factors for early nonpersistence (odds ratio [OR], 1.77 [95% CI, 1.07–2.94] and OR, 1.47 [95% CI, 1.25–1.73], respectively) and for discontinuation over time (hazard ratio [HR], 2.44 [95% CI, 1.89–3.15] and HR, 1.18 [95% CI, 1.09–1.28], respectively). Another risk factor for early nonpersistence and discontinuation over time was initial treatment using insulin (OR, 3.00 [95% CI, 2.30–3.91]; HR, 2.68 [95% CI, 2.31–3.10]) or an α-glucosidase inhibitor (OR, 2.07 [95% CI, 1.11–3.84]; HR, 1.57 [95% CI, 1.11–2.22]). Conclusions:: Adherence with antihyperglycemic pharmacotherapy was poor among working-aged patients newly treated for type 2 diabetes. Patients prescribed insulin as initial pharmacotherapy were less likely to persist on medication than those initially prescribed oral agents. [Copyright &y& Elsevier]

α-Lipoic acid [5-[1,2]-dithiolan-3-yl-pentanoic acid (LA)] is a natural antioxidant and cofactor of several enzymes. It increases the glucose transport activity in skeletal muscles and adipocytes in a non-insulin dependent manner. Therefore, LA is widely used in Type 2 diabetic patients as an oral auxiliary drug. However, large doses of LA (0.8–1.8 gr/day po) are required due to its unfavorable pharmacokinetic parameters. In order to improve these parameters, we synthesized ester and amide LA derivates. Two of these newly synthesized compounds, 5-[1,2]-dithiolan-3-yl-pentanoic acid 3-(5-[1,2]dithiolan-3yl-pentanoylamino)-propyl]-amide (AN-7) and 5-[1,2]-dithiolan-3-yl-pentanoic acid 3-(5-[1,2]-dithiolan-3yl-pentanoyloxy)-propyl ester (AN-8) augmented the rate glucose transport in myotubes in culture in the absence or presence of insulin. Their potency was 12-fold higher than that of the parent compound; their maximal stimulatory effect was 1.5-fold higher than that of LA. When tested in vivo in streptozotocin-diabetic C57/Black mice, AN-7 (10 mg/kg/day for 2 weeks, sc) reduced blood glucose level by 39% while a higher dose of LA (50 mg/kg/day for 2 weeks, sc) lowered it by 30%. These results indicate that AN-7 is more potent than LA in augmenting glucose transport in skeletal muscles and reducing blood glucose in diabetic animals. [Copyright &y& Elsevier]

Diabetes is a chronic progressive metabolic disease caused by insulin deficiency or insulin resistance. In spite of the availability of several antihyperglycaemics, there is a need for the development of safer antidiabetic drugs due to their undesirable effects. Sodium-glucose cotransporter-2 inhibitors are a class of antidiabetics, which hinder the reabsorption of glucose in the kidneys, causing excretion of glucose via urine. Sodium-glucose cotransporter-2 inhibitors are a well-tolerated class with no significant adverse effects and are found to be favorable in certain conditions, which may be rudimentary to cardiovascular and renal diseases. The current advancements in their design and development, their mechanism of action, structure-activity relationship, synthesis and in silico development along with their auxiliary roles have been extensively reviewed.

Growing evidence indicates that oxidative and endoplasmic reticular stress, which trigger changes in ion channels and inflammatory pathways that may undermine cellular homeostasis and survival, are critical determinants of injury in the diabetic kidney. Cells are normally able to mitigate these cellular stresses by maintaining high levels of autophagy, an intracellular lysosome-dependent degradative pathway that clears the cytoplasm of dysfunctional organelles. However, the capacity for autophagy in both podocytes and renal tubular cells is markedly impaired in type 2 diabetes, and this deficiency contributes importantly to the intensity of renal injury. The primary drivers of autophagy in states of nutrient and oxygen deprivation-sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia-inducible factors (HIF-1 α and HIF-2 α )-can exert renoprotective effects by promoting autophagic flux and by exerting direct effects on sodium transport and inflammasome activation. Type 2 diabetes is characterized by marked suppression of SIRT1 and AMPK, leading to a diminution in autophagic flux in glomerular podocytes and renal tubules and markedly increasing their susceptibility to renal injury. Importantly, because insulin acts to depress autophagic flux, these derangements in nutrient deprivation signaling are not ameliorated by antihyperglycemic drugs that enhance insulin secretion or signaling. Metformin is an established AMPK agonist that can promote autophagy, but its effects on the course of CKD have been demonstrated only in the experimental setting. In contrast, the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors may be related primarily to enhanced SIRT1 and HIF-2 α signaling; this can explain the effects of SGLT2 inhibitors to promote ketonemia and erythrocytosis and potentially underlies their actions to increase autophagy and mute inflammation in the diabetic kidney. These distinctions may contribute importantly to the consistent benefit of SGLT2 inhibitors to slow the deterioration in glomerular function and reduce the risk of ESKD in large-scale randomized clinical trials of patients with type 2 diabetes., (Copyright © 2020 by the American Society of Nephrology.)

Background and Objective: Elderly patients with type 2 diabetes represent a growing and heterogeneous group of subjects where treatment targets and antihyperglycemic drugs prescriptions should be tailored according to coexisting illnesses, functional and social domains., Methods: We carried-out a national cross-sectional study (from February 2014 to December 2014) to assess prescription patterns and treatment inadequacy in patients with type 2 diabetes older than 65 years with at least 6 months of treatment with antihyperglycemic drugs., Results: We included a total of 4,917 patients cared by 2,100 family physicians and 450 specialists. Diabetes prescriptions were monotherapy (21.2%), dual therapy (58.1%) and triple therapy (20.6%). The most common prescription patterns were metformin in monotherapy (66.5%), metformin plus DPP4 inhibitors in dual therapy (77.3%) and, in triple therapy, oral drugs (45.5%) and oral drugs plus insulin (45.8%). A total of 1,272 (25.9%) patients were at risk of serious hypoglycemia, 643 of them due to treatment with secretagogues (25%) or treatment with human insulin types (25.6%)., Conclusions: Elderly patients with type 2 diabetes often receive antihyperglycemic therapy with higher risk of hypoglycemia. Substitution of secretagogues and human insulin therapy for safer medication could significantly reduce the adverse effects of diabetes treatment in this population., (Copyright © 2019. Publicado por Elsevier España, S.L.U.)

Individuals with diabetes have a two- to four-fold increased risk of coronary artery disease (CAD) and higher mortality rates than those without diabetes. Because not only microvascular but also macrovascular disease in patients with diabetes are known to predispose patients to a lower quality of life as well as lead to higher mortality rates, identifying and managing risk factors of CAD is of clinical relevance in diabetes care. A number of antihyperglycemic drugs are currently approved for the treatment of hyperglycemia in patients with type 2 diabetes mellitus (T2DM), with several new drugs having been developed during the last decade. Diabetes-related complications have been substantially reduced worldwide. However, in view of the current situation in which both the prevalence of obesity and glucose abnormality have increased worldwide, including Japan, diet and exercise remain the crucial means of treatment for patients with diabetes. Furthermore, predicting the development of CAD is essential. This review summarizes data from recent studies on cardiovascular disease in patients with T2DM, focusing on clinical trials and big data, including studies involving Japanese individuals.

Current therapy directed at delaying the progression of diabetic nephropathy includes intensive glycemic and optimal blood pressure control, renin angiotensin-aldosterone system blockade and multifactorial intervention. However, the renal protection provided by these therapeutic modalities is incomplete. There is a scarcity of studies analysing the nephroprotective effect of antihyperglycaemic drugs beyond their glucose lowering effect and improved glycaemic control on the prevention and progression of diabetic nephropathy. This article analyzes the exisiting data about older and newer drugs as well as the mechanisms associated with hypoglycemic drugs, apart from their well known blood glucose lowering effect, in the prevention and progression of diabetic nephropathy. Most of them have been tested in humans, but with varying degrees of success. Although experimental data about most of antihyperglycemic drugs has shown a beneficial effect in kidney parameters, there is a lack of clinical trials that clearly prove these beneficial effects. The key question, however, is whether antihyperglycemic drugs are able to improve renal end-points beyond their antihyperglycemic effect. Existing experimental data are post hoc studies from clinical trials, and supportive of the potential renal-protective role of some of them, especially in the cases of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. Dedicated and adequately powered renal trials with renal outcomes are neccessary to assess the nephrotection of antihyperglycaemic drugs beyond the control of hyperglycaemia.