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In the U.S., ethnic minorities with pre-diabetes, undiagnosed type 2 diabetes (T2D), and newly diagnosed T2D had a higher prevalence of microvascular complications than non-Hispanic Whites and exhibited distinct risk factors, whereas Whites had a higher rate of cardiovascular disease. • Minorities with undiagnosed and newly diagnosed T2D had higher microvascular complication prevalence than Whites. • Minorities exhibited distinct risk factors for complications, needing tailored interventions for risk factor management. [ABSTRACT FROM AUTHOR]

Background: Intravenous edetate disodium-based infusions reduced cardiovascular events in a prior clinical trial. The Trial to Assess Chelation Therapy 2 (TACT2) will replicate the initial study design.Methods: TACT2 is an NIH-sponsored, randomized, 2x2 factorial, double masked, placebo-controlled, multicenter clinical trial testing 40 weekly infusions of a multi-component edetate disodium (disodium ethylenediamine tetra-acetic acid, or Na2EDTA)-based chelation solution and twice daily oral, high-dose multivitamin and mineral supplements in patients with diabetes and a prior myocardial infarction (MI). TACT2 completed enrollment of 1000 subjects in December 2020, and infusions in December 2021. Subjects are followed for 2.5 to 5 years. The primary endpoint is time to first occurrence of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The trial has >;85% power to detect a 30% relative reduction in the primary endpoint. TACT2 also includes a Trace Metals and Biorepository Core Lab, to test whether benefits of treatment, if present, are due to chelation of lead and cadmium from patients. Design features of TACT2 were chosen to replicate selected features of the first TACT, which demonstrated a significant reduction in cardiovascular outcomes in the EDTA chelation arm compared with placebo among patients with a prior MI, with the largest effect in patients with diabetes.Results: Results are expected in 2024.Conclusion: TACT2 may provide definitive evidence of the benefit of edetate disodiumbased chelation on cardiovascular outcomes, as well as the clinical importance of longitudinal changes in toxic metal levels of participants. [ABSTRACT FROM AUTHOR]

The prevalence of hypercortisolism in persons with difficult-to-control type 2 diabetes (T2D) may be higher than currently appreciated, particularly in persons who require a greater number of antihyperglycemic agents and/or have more comorbidities. To better understand the prevalence and whether treatment of hypercortisolism may result in better control of diabetes and other hypercortisolism-associated comorbidities, we have designed CATALYST, a prospective phase 4 study in adults with difficult-to-control T2D (HbA1c 7.5–11.5%) despite receiving multiple antihyperglycemic agents. CATALYST is being conducted at about 30 sites in the United States. In Part 1, about 1000 persons with difficult-to-control T2D will be screened with a 1-mg dexamethasone suppression test (cutoff: serum cortisol >1.8 µg/dL; dexamethasone ≥140 ng/dL). Patients with ACTH-dependent hypercortisolism will be referred out of the study. The primary study endpoint—the prevalence of ACTH-independent hypercortisolism—will be evaluated in Part 1. Patients with ACTH-independent hypercortisolism may advance to Part 2, a prospective, 2:1 randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of treatment with the competitive glucocorticoid receptor antagonist mifepristone. Patients will be randomized (stratified by the presence/absence of adrenal adenomas on CT) and receive treatment for 24 weeks. The mifepristone dose will be 300 mg QD for 4 weeks, then increased to 600 mg QD for 20 weeks based on glycemic efficacy and tolerability (option to increase to mifepristone 900 mg). Secondary endpoints include changes in HbA1c from baseline to 24 weeks and changes in hypercortisolism-related comorbidities (e.g., blood pressure, weight, waist circumference, quality of life). [ABSTRACT FROM AUTHOR]

The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction–associated steatotic liver disease and metabolism dysfunction–associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes. • Obesity, diabetes, ASCVD, CKD, HF, and MASLD are closely interrelated diseases. • Two or more of these diseases are frequently present in the same individual. • Evidence supports benefits of some agents across the cardiorenal-metabolic spectrum. • The DCRM, a multispecialty task force, developed consensus recommendations. • DCRM aims to help improve the health of patients with cardiorenal-metabolic diseases. [ABSTRACT FROM AUTHOR]

Asian Americans (AA) are disproportionately affected by diabetes (DM) and its complications than non-Hispanic whites (whites). We examined white-AA disparities in glycemic, cholesterol and blood pressure control, known as 'ABCs of DM', and evaluated if acculturation plays a role in DM control in AA with DM. Using data from NHANES 2011-2016, we found AA patients were significantly less likely to meet glycemic, cholesterol and the collective 'ABCs' goals than their white counterparts. Acculturation was positively associated with glycemic goal achievement in AA patients. This study identified disparities and pointed to strategies related to acculturation to improve DM control for AA. [ABSTRACT FROM AUTHOR]

Women with Type 2 diabetes (T2D) face up to 50% higher risk of cardiovascular disease than men. This study evaluated the extent to which prediabetes and undiagnosed T2D are associated with a greater excess risk of cardiovascular disease in women versus in men. Data were pooled from 18,745 cardiovascular disease−free individuals from the Atherosclerosis Risk in Communities Study, the Multi-Ethnic Study of Atherosclerosis, and the Jackson Heart Study. The risk of coronary heart disease, ischemic stroke, and atherosclerotic cardiovascular disease (coronary heart disease or stroke) associated with prediabetes or undiagnosed T2D was estimated using Cox models adjusting for sociodemographic factors, concomitant risk factors, medication use, and menopausal status. Data were collected in 2022, and the analysis was performed in 2023. During a median follow-up of 18.6 years, the associations between prediabetes and risk of atherosclerotic cardiovascular disease were only significant in women (hazard ratio=1.18, 95% CI=1.01, 1.34, p =0.03) but not in men (hazard ratio=1.08, 95% CI=1.00, 1.28, p =0.06) (p -interaction=0.18). The associations between undiagnosed T2D and cardiovascular disease outcomes were significant in both sexes, but the effect was more pronounced in women (coronary heart disease: hazard ratio=1.83, 95% CI=1.4, 2.41, p <0.0001 in women vs hazard ratio=1.6, 95% CI=1.38, 2.07, p =0.007 in men; stroke: hazard ratio=1.99, 95% CI=1.39, 2.72, p <0.0001 vs hazard ratio=1.81, 95% CI=1.36, 2.6, p <0.0001; atherosclerotic cardiovascular disease: hazard ratio=1.86, 95% CI=1.5, 2.28, p <0.0001 vs hazard ratio=1.65, 95% CI=1.4, 1.98, p <0.0001) (all p -interactions≤0.2). Both White and Black patients exhibit similar sex differences. Prediabetes or undiagnosed T2D was associated with a greater excess risk of cardiovascular disease in women than in men. The sex differential in cardiovascular disease risk among those without the T2D diagnosis suggests the need for sex-specific guidelines in T2D screening and treatment. [ABSTRACT FROM AUTHOR]

Worldwide, both underdiagnosis and undertreatment leave many patients exposed to long periods of hyperglycemia and contribute to irreversible diabetes complications. Early glucose control reduces the risk of both macrovascular and microvascular complications, while tight control late in diabetes has little or no macrovascular benefit. Insulin therapy offers the most potent antihyperglycemic effect of all diabetes agents, and has a unique ability to induce diabetes remission when used to normalize glycemia in newly diagnosed patients. When used as a second-line therapy, basal insulin is more likely to safely and durably maintain A1C levels =7% than when insulin treatment is delayed. The use of basal insulin analogs is associated with a reduced risk of hypoglycemia and weight gain compared to NPH insulin and pre-mixed insulin. Patient selftitration algorithms can improve glucose control while decreasing the burden on office staff. Finally, recent data suggest that addition of incretin agents to basal insulin may improve glycemic control with very little, if any increased risk of hypoglycemia or weight gain. [ABSTRACT FROM AUTHOR]

Painful diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus, affecting, by some estimates, up to one quarter of diabetic patients. Since 2010, no fewer than 5 major international treatment guidelines for painful DPN have been issued, and there are meaningful differences among them. Duloxetine, pregabalin, gabapentin, and tricyclic antidepressants are the mainstays of treatment, but the choice of which class or agent to use in any given patient should be informed by patient characteristics. This review seeks to describe the differences among the recently issued guidelines, to assess the evidence on which they are based, and to offer insight into the most appropriate treatment choices based on patient characteristics. [ABSTRACT FROM AUTHOR]

Aims: This analysis evaluated HbA1c-adjusted hypoglycemia risk with glargine versus neutral protamine Hagedorn (NPH) over a 5-year study in patients with Type 2 diabetes mellitus (T2DM). Clinical significance was assessed using number needed to harm (NNH) to demonstrate the risk of one additional patient experiencing at least one hypoglycemic event. Methods: Individual patient-level data for symptomatic documented hypoglycemia and HbA1c values from a 5-year randomized study comparing once-daily glargine (n = 513) with twice-daily NPH (n = 504) were analyzed. Symptomatic hypoglycemia was categorized according to concurrent self-monitoring blood glucose levels and need for assistance. Hypoglycemic events per patient-year as a function of HbA1c were fitted by negative binomial regression using treatment and HbA1c at endpoint as independent variables. An estimate of NNH was derived from logistic regression models. Results: The cumulative number of symptomatic hypoglycemia events was consistently lower with glargine compared with NPH over 5 years. Compared with twice-daily NPH, once-daily glargine treatment resulted in significantly lower adjusted odds ratios (OR) for all daytime hypoglycemia (OR 0.74; p = 0.030) and any severe event (OR 0.64; p = 0.035), representing a 26% and 36% reduction in the odds of daytime and severe hypoglycemia, respectively. Our model predicts that, if 25 patients were treated with NPH instead of glargine, then one additional patient would experience at least one severe hypoglycemic event. Conclusions: This analysis of long-term insulin treatment confirms findings from short-term studies and demonstrates that glargine provides sustained, clinically meaningful reductions in risk of hypoglycemia compared with NPH in patients with T2DM. [ABSTRACT FROM AUTHOR]

Aims: To quantify the effect of liraglutide on systolic blood pressure (SBP) and pulse in patients with type 2 diabetes (T2D), and assess the influence of covariates on observed SBP reductions. Methods: A patient-level pooled analysis of six phase 3, randomized trials was conducted. Results: The analysis included 2792 randomized patients. In the intention-to-treat population (n = 2783), mean [±SE] SBP reductions from baseline with liraglutide 1.2 mg (2.7 [0.8] mmHg) and 1.8 mg (2.9 [0.7] mmHg) once daily were significantly greater than with placebo (0.5 [0.9] mmHg; P = 0.0029 and P = 0.0004, respectively) after 26 weeks, and were evident after 2 weeks. Liraglutide was also associated with significantly greater SBP reductions than glimepiride and, at a dose of 1.8 mg, insulin glargine and rosiglitazone. SBP reductions with liraglutide weakly correlated with weight loss (Pearson’s correlation coefficient: 0.08–0.12; P ≤ 0.0148). No dependence of these reductions on concomitant antihypertensive medications was detected (P = 0.1304). Liraglutide 1.2 and 1.8 mg were associated with mean increases in pulse of 3 beats per minute (bpm), versus a 1 bpm increase with placebo (P b 0.0001 for each dose versus placebo). Conclusions: Liraglutide reduces SBP in patients with T2D, including those receiving concomitant antihypertensive medication. © 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license [ABSTRACT FROM AUTHOR]

Background: Suboptimal blood glucose control among patients with type 2 diabetes continues to support the need for new pharmacologic approaches. Objective: The purpose of this commentary was to highlight newly available and soon-to-be available agents that are promising tools for targeting specific pathophysiologic pathways in the management of diabetes. Methods: Published evidence to support the application of novel incretin-based therapies, dipeptidyl peptidase (DPP)-4 inhibitors, sodium-glucose cotransporter (SGLT)-2 inhibitors, other oral agents and insulins for managing specific aspects of type 2 diabetes, as well as disadvantages associated with those novel medications, are discussed. Results: Several new glucagon-like peptide (GLP)-1 receptor agonists with different time frames of action, although each has unique advantages and disadvantages, have been through clinical trials. Examples of these are lixisenatide and albiglutide. Currently available DPP-4 inhibitor agents, important for inhibiting the breakdown of endogenous GLP-1, have not been associated with weight gain or hypoglycemia. SGLT-2 inhibitors, which do not depend on insulin secretion or insulin action, may be advantageous in that they appear to be broadly efficacious at all stages of diabetes. New insulin analogues, such as degludec and U-500, improve glycemic control without contributing to hypoglycemia. Conclusions: Advances in pharmacologic options offer the promise of improving glycemic control for longer periods, with limited glycemic fluctuations, hypoglycemia, and weight gain. However, the effectiveness of these agents ultimately depends on their availability to providers managing the health care of patients at high risk for poor diabetes outcomes and patients' use of them as directed. Long-term effectiveness and safety trials are ongoing. [ABSTRACT FROM AUTHOR]

Abstract: Predisposition to genital infections and urinary tract infections (UTIs) in type 2 diabetes mellitus (T2DM) results from several factors such as glucosuria, adherence of bacteria to the uroepithelium and immune dysfunction. The tendency to develop these infections could be even higher in patients with T2DM treated with the emerging class of sodium–glucose cotransporter-2 (SGLT2) inhibitors. Studies have shown that pharmacologically-induced glucosuria with SGLT2 inhibitors raises the risk of developing genital infections and, to a relatively lesser extent, UTIs. However, a definitive dose relationship of the incidence of these infections with the SGLT2 doses is not evident in the existing data. Therefore, the precise role of glucosuria as a causative factor for these infections is yet to be fully elucidated. [Copyright &y& Elsevier]

Despite a rapid increase in the number of drugs available to treat hyperglycemia there remain several unmet needs in the prevention and treatment of diabetes. There have also been tremendous advances in our understanding of the pathophysiology of type 2 diabetes, allowing the recognition of novel treatment targets. The purpose of this review is to highlight some of the novel approaches that are being developed to improve glucose control in patients with diabetes. [ABSTRACT FROM AUTHOR]

Aims: To assess efficacy and safety of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in combination therapy with metformin (≥1500 mg/day) and pioglitazone (≥30 mg/day) in patients with type 2 diabetes (T2DM) with inadequate glycemic control (hemoglobin A1c [HbA1c] ≥7.5% and ⩽11%). Methods: This placebo-controlled, double-blind study included 313 patients, mean baseline HbA1c=8.7%, who were randomized to receive sitagliptin 100 mg/day or placebo for 26 weeks. Results: The addition of sitagliptin led to significant (P b .001) mean changes from baseline relative to placebo in HbA1c (-0.7%), fasting plasma glucose (-1.0 mmol/L), and 2-h post-meal glucose (-2.2 mmol/L). In patients with baseline HbA1c ≥9.0%, mean changes from baseline in HbA1c were -1.6% and -0.8% for the sitagliptin and placebo groups, respectively (between-group difference -0.8%; P b .001). The incidences of reported adverse events were generally similar between the treatment groups. Incidences of symptomatic hypoglycemia were 7/157 [4.5%] and 6/156 [3.8%] in the sitagliptin and placebo groups, respectively (P=.786). Two patients, both in the placebo group, experienced an episode of hypoglycemia that required non-medical assistance. Conclusions: In this 26-week study, addition of sitagliptin to combination therapy with metformin and pioglitazone improved glycemic control and was generally well tolerated. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers are considered the standard of care for treatment of cardiovascular disease and chronic kidney disease. Combination therapy with both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers effectively inhibits the renin-angiotensin system as well as potentiates the vasodilatory effects of bradykinin. It has been advocated that this dual blockade approach theoretically should result in improved clinical outcomes in both cardiovascular disease and chronic kidney disease. Clinical trial evidence for the use of combination therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in cardiovascular disease has provided conflicting results in hypertension, congestive heart failure, and ischemic heart disease. Clinical trial evidence to support combination therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chronic kidney disease has largely been based on proteinuria reduction as a surrogate marker for clinically meaningful outcomes. Recent large-scale randomized clinical trials have not been able to validate protection in halting progression in chronic kidney disease with a dual blockade approach. This review serves as an appraisal on the clinical evidence of combination angiotensin-converting enzyme inhibition and angiotensin II receptor blockade in both cardiovascular disease and chronic kidney disease. [ABSTRACT FROM AUTHOR]

The kidneys play a major role in the regulation of glucose in humans, reabsorbing 99% of the plasma glucose that filters through the renal glomeruli tubules. The glucose transporter, SGLT2, which is found primarily in the S1 segment of the proximal renal tubule, is essential to this process, accounting for 90% of the glucose reabsorption in the kidney. Evidence has suggested that selective inhibition of SGLT2 induces glucosuria in a dose-dependent manner and may have beneficial effects on glucose regulation in individuals with type II diabetes. Preclinical data with SGLT2 inhibitors, such as dapagliflozin and sergliflozin, show that these compounds are highly selective inhibitors for SGLT2, have beneficial effects on the glucose utilization rate, and reduce hyperglycemia while having no hypoglycemic adverse effects. Clinical research remains to be carried out on the long-term effects of glucosuria and other potential effects of this class of drug. Nonetheless, these compounds represent a very promising approach for the treatment of diabetes.Kidney International (2009) 75, 1272–1277; doi:10.1038/ki.2009.87; published online 8 April 2009 [ABSTRACT FROM AUTHOR]

Abstract: Some β-blockers, although they are effective antihypertensive agents, may adversely effect dyslipidemia and decrease insulin sensitivity. β-blockers without adverse metabolic effects may provide an improvement in long-term hypertension therapy. Hypertensive patients (n = 568) without diabetes, not requiring lipid-lowering therapy, were randomized to once-daily extended-release carvedilol or extended-release metoprolol and titrated to target blood pressure (BP). Co-primary endpoints were comparison between groups in high-density lipoprotein (HDL) or triglycerides at 24 weeks. Extended-release carvedilol was superior to extended-release metoprolol in meeting the primary endpoint of a difference in triglycerides; the median % change in triglycerides being −8.026% (P = .0141; 97.5% confidence interval [CI], −15.35, −0.67)] from baseline to 24 weeks. Triglycerides were unchanged with carvedilol and increased with metoprolol. There was no significant difference in effect on HDL. BP was similar between treatment groups. There was a significant decrease with extended-release carvedilol vs. extended-release metoprolol in insulin (−2.56 μU/mL [P = .0213; 95% CI, −4.74 to −0.38]) and c-peptide [(−0.43 ng/mL [P = .0007; 95% CI, −0.68 to −0.18]). In hypertension, extended-release carvedilol resulted in lower triglycerides, insulin, and C-peptide levels compared with extended-release metoprolol. Similar effects were observed in high-risk subgroups. Both treatments were well tolerated. This differential metabolic profile could be useful in determining antihypertensive treatment options. [Copyright &y& Elsevier]

Abstract: Low body weight Type 2 DM/Type 2 DM-lean is a distinct clinical entity that is neither related clinically or pathophysiologically to LADA nor former fruste of Type 1DM, having absence of markers for autoimmune destruction of β-cells and good insulin and C-peptide reserve for a prolonged period of life. They constitute an independent variant of Type 2 DM with inherent peculiarities of insulin kinetics in the liver along with altered profile and behaviour of key enzymes related to carbohydrate metabolism which are marked by excess extraction of insulin in hepatic bed, hyperactive cytochrome system and non-supressible glucokinase activity. These peculiarities are reflected in the peripheral circulation as states of low circulating levels of insulin, hyperglycemia, dyslipidemia without low high density lipoprotein cholesterol (HDLc), raised triglycerides (Tg), low levels of plasma homocysteine and BMI below 19 make these diabetics less prone to develop macrovascular disease. Peripheral neuropathy and the consequences of poor glycemic control such as increased succeptibility to infections and endothelial dysfunction manifesting as proteinuria dominate the clinical picture. In view of more of infective complications and coexistent severe hyperglycemia (glucose toxicity) many of these diabetics may not respond to OHA adequately at the initiation of therapy. However, due presence of insulin resistance and good β-cell reserve for insulin, despite of lean habitus, most of them respond well to OHA for long periods of life, as may be comparable with any other phenotype of Type 2 diabetes. The insulin resistance observed in Type 2 DM-lean is not consequent to anthropometric parameters like central obesity and WHR as these diabetics are lean with poor fat depot and thus it could be an integral part of the pathogenic mechanism of Type 2 DM per se. [Copyright &y& Elsevier]

Abstract: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, and when activated by their ligands, they induce perixosome proliferation. Three receptors have been identified: PPAR γ, PPAR δ, and PPAR α, all with different tissue expression. PPAR γ is predominantly expressed in adipose tissue and regulates the formation of fat cells and their function. The effect of PPAR γ activation is to enhance the action of insulin in insulin-sensitive tissue by increasing peripheral glucose disposal and decreasing hepatic glucose production. The thiazolidinediones (TZDs) are a class of medications used for treatment and possibly the prevention of type 2 diabetes, which are potent agonists for the PPAR γ receptor. Because the thiazolidinediones target insulin resistance, these agents may improve many of the risk factors associated with obesity and insulin resistance including dyslipidemia, hypertension, impaired fibrinolysis, and atherosclerosis. The impact of the thiazolidinediones on cardiovascular mortality is currently unclear but it appears that the thiazolidinediones exert numerous non-glycemic effects that may improve cardiovascular outcomes. Several non-TZD PPAR γ agonists and combined PPAR γ/α effect on cardiovascular disease are also being evaluated. These drugs have anti-inflammatory and vascular properties and are currently the subject of numerous studies targeting the primary and secondary prevention of macrovascular disease in patients with diabetes and insulin resistance and might be developed as anti-atherogenic agents on the basis of their actions. [Copyright &y& Elsevier]

Abstract: Background:: The natural course of type 2 diabetes mellitus (DM) is characterized by insulin resistance followed by a progressive decline in β-cell function, which results in relative insulin deficiency. At diagnosis, a patient with tvpe 2 DM has only 50%, of β-cell function remaining. Given this inevitable decline in β-cell function and insulin secretion, most patients with type 2 DM will require insulin therapy at some point. Objective:: The objective of this article was to provide a brief overview of physiologic insulin secretion and to discuss the role of basal insulin therapy in patients with type 2 DM. Methods:: Materials for this article were identified through searches (2000–2005) of MEDLINE and Google, as well as from the author''s personal files. Search terms included basal insulin, titration, hypoglycemia, glycemic control, and basal-bolus therapy. Results:: The cfficacy of insulin either as nmonotherapy or in combination with oral agents in type 2 DM is well established. Insulin therapy has also been show to improve insulin sensitivity and, in some cases, reverse insulin resistance, possibly by elimination of glucose toxicity. In recent years, the availability of insulin formulations with more favorable pharmacokinetic profiles has reduced concerns about hvpoglycemia and weight gain, facilitating the use of insulin in patients with type 2 DM. For insulin-naive patients who are inadequately controlled on oral antidiabetic drugs, the addition of a single basal insulin dose at bedtime has been found to reduce glycosylated hemoglobin (A1C levels,with a low risk of nocturnal hypoglycemia. Basal insulins. (ie, glargine, detemir) have also been shown to induce less weight gain a significant concern for both patients and providers. The use of long-acting basal insulins may also reduce intrapatient variability in fasting blood glucose values. Moreover, the long-acting basal insulins such as glargine and detemir can be administered QD, which may enhance the potential for patient compliance. Aggressive titration of insulin doses based on a target fasting plasma glucose level of 100 to 120 mg/dL is essential to achieving target A1C levels (<7.0%,). As β-cell function declines, patients may require switch to basal-bolus insulin therapy. Although the long- and intermediate-acting insulin formulations are comparable with regard to efficacy as the basal component in basal-bolus therapy, the long-acting insulins have been associated with lower rates of nocturnal hypoglycemia, which can have a positive effect on glycemic control during the daytime. Conclusion:: Basal insulins, both intermediate- and long-acting formulations, are playing an increasingly important role in the treatment of type 2 DM. [Copyright &y& Elsevier]

Abstract: Objective: The aim of this study was to determine the effect of basal insulin, alone or with a sensitizer, or a combination of oral agents on nontraditional risk factors for cardiovascular disease (CVD). Research design and methods: We randomized 57 patients with T2DM to either (1) continuous subcutaneous basal Lispro insulin at a single rate using an insulin pump (basal insulin) or (2) basal insulin and oral pioglitazone 30 mg daily (basal insulin +Pio) or (3) a sulfonylurea and metformin (SU+M). We measured glycosylated hemoglobin (HbA1c), plasma high-sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitor-1 (PAI-1), 8-epi-prostaglandin F2 α (PGF2α), serum lipoprotein (a) [Lp (a)], and lipoprotein profile at baseline and after 20 weeks of treatment. Results: HbA1c decreased by ≥2% (P<.001) and to comparable levels (P=NS) in all groups. Despite improved glycemia, hsCRP did not change in any group, whereas plasma PAI-1 fell with basal insulin +Pio (P<.02) and SU+M (P<.01). PGF2α declined with basal insulin (P<.02) and SU+M (P<.001). High-density lipoprotein cholesterol (HDL-C) increased only with basal insulin +Pio (18.2%, P<.05). Lp (a) increased with basal insulin therapy alone (P<.01). Data were pooled from all groups to determine the overall effect of glycemic control—there was a significant (P<.001) decline in HbA1c, PAI-1, and PGF2α and an increase in HDL-C (P<.001). There was no correlation between HbA1c reduction and changes in these parameters. Conclusions: We conclude that excellent glycemic control per se does not impact nontraditional risk factors for CVD equally, but various diabetes medications have different effects on these risk factors. These findings may have implications for making appropriate therapeutic choices for patients with Type 2 diabetes, although larger studies with more appropriate treatment comparisons may be necessary. [Copyright &y& Elsevier]

The past decade has witnessed a dramatic increase in the prevalence of obesity. Comorbidities of obesity include type 2 diabetes mellitus, hypertension, and lipid abnormalities, all of which contribute to cardiovascular disease (CVD) and are associated with endothelial dysfunction. These abnormalities frequently cluster in individuals, and the term metabolic syndrome is now widely used to define this cluster. The syndrome is frequently (although not invariably) associated with insulin resistance and CVD. Diabetes is associated with CVD, which may be asymptomatic in some cases, particularly when associated with autonomic neuropathy. This has implications for guidelines on the evaluation of patients with erectile dysfunction (ED) and CVD. Treatment of ED in men with diabetes has been revolutionized by the introduction of phosphodiesterase 5 inhibitors. However, men with diabetes tend to respond less positively to these agents, at least as currently prescribed. This decreased responsiveness may be related to the severity of endothelial function in patients with diabetes. Additional therapeutic strategies may be needed to overcome this problem. [Copyright &y& Elsevier]

Abstract: Homocysteine (Hcy) is a metabolite of the essential amino acid methionine. Hyperhomocysteinemia is associated with vascular disease, particularly carotid stenosis. Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor γ, attenuates balloon catheter–induced carotid intimal hyperplasia in type 2 diabetic rats. We studied 4 groups (n = 7 per group) of adult female Sprague-Dawley rats fed (a) powdered laboratory chow (control), (b) control diet with rosiglitazone (3.0 mg/kg/d), (c) diet containing 1.0% l-methionine, and (d) diet containing methionine and rosiglitazone. After 1 week on high methionine diet, the rats were administered an aqueous preparation of rosiglitazone by oral gavage. One week after initiation of rosiglitazone, balloon catheter injury of the carotid artery was carried out using established methods, and the animals continued on their respective dietary and drug regimens for another 21 days. At the end of the experimental period, blood samples were collected, and carotid arteries and liver were harvested. Serum Hcy increased significantly on methionine diet compared with controls (28.9 ± 3.2 vs 6.3 ± 0.04 μmol/L). Development of intimal hyperplasia was 4-fold higher in methionine-fed rats; this augmentation was significantly reduced (P < .018) in rosiglitazone-treated animals. Rosiglitazone treatment significantly (P < .001) suppressed Hcy levels and increased the activity of the Hcy metabolizing enzyme, cystathionine-β-synthase in the liver samples. Hcy (100 μmol/L) produced a 3-fold increase in proliferation of rat aortic vascular smooth muscle cells; this augmentation was inhibited by incorporating rosiglitazone (10 μmol/L). After balloon catheter injury to the carotid artery of animals on a high methionine diet, there was an increase in the rate of development of intimal hyperplasia consistent with the known effects of Hcy. It is demonstrated for the first time that the peroxisome proliferator-activated receptor γ agonist rosiglitazone can attenuate the Hcy-stimulated increase in the rate of development of intimal hyperplasia indirectly by increasing the rate of catabolism of Hcy by cystathionine-β-synthase and directly by inhibiting vascular smooth muscle cell proliferation. These findings may have important implications for the prevention of cardiovascular disease and events in patients with hyperhomocysteinemia (HHcy). [Copyright &y& Elsevier]

The pathogenesis of type 2 diabetes mellitus is multifactorial and complex, and it is influenced by both genetic and environmental factors. This metabolic disorder results from insulin resistance in target tissues and impairment of pancreatic insulin secretion. The purpose of this review is to examine our current understanding of the pathophysiology of type 2 diabetes, identify therapeutic targets, and highlight recent advances in addressing this complex disorder. [Copyright &y& Elsevier]

Patients with diabetes have a greatly increased relative risk of developing cardiovascular disease when compared with patients without diabetes. Much of this risk is related to insulin resistance and is associated with both traditional and nontraditional cardiovascular risk factors. Therapy for diabetes must address these risk factors in an attempt to prevent and adequately treat cardiovascular disease. Pharmacologic therapy directed toward dyslipidemia and hypertension has a beneficial effect on risk factors and has been shown to decrease cardiovascular events. The effects of insulin and oral hypoglycemic agents on insulin resistance are variable, and their direct effect on cardiovascular disease is less clear. Metformin is the only oral hypoglycemic agent shown to decrease cardiovascular events independent of glycemia. The thiazolidinediones directly improve insulin resistance, decrease plasma insulin concentration, and have the potential to decrease the risk of cardiovascular disease in patients with diabetes. A number of studies have demonstrated that the thiazolidinediones produce changes in several cardiovascular risk factors associated with the insulin resistance syndrome, including lowering blood pressure, correcting diabetic dyslipidemia, improving fibrinolysis, and decreasing carotid artery intima-medial thickness. These agents bind a newly described class of receptors, peroxisome proliferator-activated receptors, which may have implications for atherosclerosis. Although these drugs increase low-density lipoprotein (LDL) cholesterol, they induce a favorable change in the LDL particle size and susceptibility to oxidation. Long-term clinical trials are being conducted to determine the effect that thiazolidinediones have on cardiovascular events in individuals with type 2 diabetes. [Copyright &y& Elsevier]

Objective: To determine whether plasma homocysteine (tHcy) levels were related to insulin resistance and obesity in subjects without diabetes or vascular disease. Research design and methods: We studied correlates of plasma tHcy in 26 subjects covering a wide spectrum of obesity and insulin sensitivity (SI). The measurement of in vivo insulin sensitivity was performed using the minimal model analysis of the frequently sampled intravenous glucose tolerance test (FSIVGTT). Results: There was no relationship between tHcy and body mass index. There was a significant relationship between plasma tHcy and SI (r=0.53, P=0.006), demonstrating that the more insulin sensitive subjects had higher levels of tHcy. On log transformation of the plasma insulin values, log insulin correlated negatively with plasma tHcy (r=−0.47; P=0.02). None of the subjects were deficient in vitamin B12 and folate. Plasma vitamin B12 was significantly related to plasma tHcy (r=−0.44, P=0.017), although we found no significant relationship between plasma folate and tHcy (r=−0.21, P=0.27). SI correlated significantly with vitamin B12 (r=0.4, P=0.045) whereas, we found no significant relationship between SI and plasma folate (r=0.27, P=0.2). On multiple linear regression using tHcy as the dependent variable, SI and vitamin B12 remained significant predictors of plasma tHcy, whereas, age and plasma folate were not predictors of tHcy. Conclusions: We conclude that in vitamin replete lean and obese individuals, insulin sensitivity correlates significantly with plasma tHcy. This relationship may need to be considered when evaluating the role of plasma homocysteine as a risk factor in patients with obesity and type 2 diabetes. [Copyright &y& Elsevier]

Emerging data suggest that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve kidney outcomes for people with type 2 diabetes (T2D). Direct comparisons of the kidney and cardiovascular effectiveness of GLP-1 RA with sodium-glucose cotransporter 2 inhibitors (SGLT2i), a first-line therapy for this population, are needed. The authors compared kidney and cardiovascular outcomes for new users of SGLT2i and GLP-1 RAs with T2D. Using propensity score overlap weighting, we analyzed electronic health record data from 20 U.S. health systems contributing to PCORnet between 2015 and 2020. The primary kidney outcome was a composite of sustained 40% estimated glomerular filtration rate (eGFR) decline, incident end-stage kidney disease, or all-cause mortality over 2 years or until censoring. In addition, we examined cardiovascular and safety outcomes. The weighted study cohort included 35,004 SGLT2i and 47,268 GLP-1 RA initiators. Over a median of 1.2 years, the primary outcome did not differ between treatments (HR: 0.91; 95% CI: 0.81-1.02), although SGLT2i were associated with a lower risk of 40% eGFR decline (HR: 0.77; 95% CI: 0.65-0.91). Risks of mortality (HR: 1.08; 95% CI: 0.92-1.27), a composite of stroke, myocardial infarction, or death (HR: 1.03; 95% CI: 0.93-1.14), and heart failure hospitalization (HR: 0.95; 95% CI: 0.80-1.13) did not differ. Genital mycotic infections were more common for SGLT2i initiators, but other safety outcomes did not differ. The results were similar regardless of chronic kidney disease status. SGLT2i and GLP-1 RAs led to similar kidney and cardiovascular outcomes in people with T2D, though SGLT2i initiation was associated with a lower risk of 40% eGFR decline. (Evaluating Comparative Effectiveness of Empagliflozin in Type 2 Diabetes Population With and Without Chronic Kidney Disease; NCT05465317) [ABSTRACT FROM AUTHOR]

The economic and psychological consequences of diabetes-related hypoglycemic events are multifold and shared across various parties, including patients and their family or caregivers, payors, and employers. Hypoglycemic events contribute to increased morbidity, mortality, and a substantial portion of diabetes economic burden. Both severe and non-severe hypoglycemic episodes contribute to economic and psychological burden, and can have short-term consequences, such as emergency services, hospitalization, clinic visits, and increased use of diabetes supplies. Severe hypoglycemic events also generate additional follow-up costs, and are likely to occur again. Left untreated, hypoglycemia can have long-term consequences including, death, cardiovascular events, and cognitive issues. Costs vary geographically based on the treatment protocols which focus on outpatient treatment versus increased in-patient hospitalization. Certain types of medications are also associated with increased hypoglycemia, which requires closer monitoring of the patient, such as with basal insulin initiation. Some individuals with diabetes may be more vulnerable to hypoglycemia, such as the elderly, postoperative bariatric patients, and adolescent females. Measures to mitigate hypoglycemia are essential to ease the economic burden of these events. Medication management, optimal glucose control, lifestyle modifications and frequent glucose monitoring are some interventions which may help prevent hypoglycemia. [ABSTRACT FROM AUTHOR]

Diabetes management with achievement and maintenance of good glycemic control is very challenging in patients requiring multiple daily injections. This article is focusing on broader use of recently approved fixed ratio combination therapies, basal insulin and glucagon-like peptide-1 receptor agonists (GLP1 RA). These combination therapy improve patient compliance and adherence with the therapy, decrease burden of multiple injection, target multiple abnormalities in the pathophysiology of diabetes, decrease postprandial hypoglycemia, assist in weight loss and decrease weight related comorbidities. These combinations were recently approved for use as first injectables after failure of oral agents. Review of combination treatment with existing fixed doses of basal insulin with GLP1 RA opens door for further clinical trials for other dose combinations that can be used, particularly for patients who need higher doses of insulin. [ABSTRACT FROM AUTHOR]

The Notre-Dame de Paris fire offers anthropologists in the field of critical heritage studies a rich opportunity for fieldwork and conceptual innovation. This paper examines the social repercussions of a monument's destruction, ranging from emotional responses and public involvement to local and global consequences. The paper also includes the project lines of a broader comparative survey on reactions to the destruction of cultural heritage. A team of social scientists created a comparative grid in order to describe and analyze a series of case studies: Notre-Dame de Paris (France, fire in 2019), the National Museum (Brazil, fire in 2018), Notre-Dame de la Merci (France, fire in 2017), and Coventry Cathedral (UK, bombed in 1940 during WWII). The comparative grid is as follows: - Practices and Reactions: Emotion and Mobilization Regimes Heritage disasters provoke a wide range of privately and collectively expressed reactions that frame these events as a social construction. How do citizens and institutions navigate the outpouring of emotion elicited by the destruction of a monument? - Consequences: The Nature of Heritage Items and Their Social Impact Laypersons and authorities assign different meanings to heritage items according to their cultural and political significance and material and intangible features. How does such representations of a ravaged monument influence its reconstruction process and future relevance? - The Social Fabrication of Memory and Narrative The destruction of a heritage object rapidly triggers a series of narratives, including legal documents and authorities' statements, that constitute a textual memory of the disaster. What standards define catastrophe narratives, and what do their retellings of the event reveal or obscure? - Heritage in Crisis: Catastrophe as Social Construction of Heritage Fragility Heritage is by nature fragile and requires continuous preservation. How does the destruction of monuments galvanize collective representations of the endangerment of heritage? - Temporality and Spatiality: Catastrophe as an Event in Time and Space Although the destruction event is often short-lived and localized, it reveals enduring values and concepts of past and future, as well as geographic place. How are temporality and spatiality reimagined after the loss of a heritage object? - The Right to Heritage: Reconstruction, Citizenship, and Cultural Policies Although often conceptualized as isolated events, the destruction of heritage objects is deeply embedded in their economic, cultural, and social context. What do the destruction and reconstruction of heritage reveal about power dynamics and economic inequalities? - The Limits of Reflexivity: Researchers as Actors Facing the Politics of Mourning As researchers, balancing personal commitment with heritage and ethical scientific inquiry is crucial to sound analysis and to the validity of research results. How should scholars simultaneously manage the experience of and the study of emotional responses such as rage or grief? This paper illustrates these points using vignettes from selected case studies. The project is part of the working group EMOBI, a broader ethnographic project on collective emotions and mobilization following the Paris cathedral fire (social sciences working group of Chantier Scientifique Notre-Dame , supported by the CNRS and the Ministry of Culture). The goal is to provide a comparative study of the stakes and repercussions of devastated heritage. [ABSTRACT FROM AUTHOR]