This Review covers the rationale, physiological consequences and clinical application of pharmacological sodium-glucose cotransporter 2 (SGLT2) inhibition. In patients with type 2 diabetes mellitus, ...in whom renal glucose reabsorption might be upregulated, orally active, selective SGLT2 inhibitors improve glycaemic control to a therapeutically useful extent. Chronic administration of several SGLT2 inhibitors dose-dependently lowers HbA(1c) levels by 0.5-1.5% without causing hypoglycaemia. The unique mechanism of action of SGLT2 inhibitors-which does not hinge upon β-cell function or tissue insulin sensitivity-means that they can exert their antihyperglycaemic effects in combination with any other oral antidiabetic drug as well as insulin. Available phase III studies confirm a good tolerability profile. Weight loss owing to urinary calorie leakage may be less than expected, but the negative energy balance offers a valuable clinical benefit. Offloading of sodium can assist blood pressure control. The progressive loss of efficacy in patients with reduced glomerular function will have to be balanced against the possibility of renal protection. The safety issues of genitourinary infections and cancer risk requires careful, proactive monitoring and analysis of robust exposure data, particularly in elderly, frail patients and in patients with impaired kidney function and/or high cardiovascular/cancer risk, who represent an increasing fraction of the population with diabetes mellitus.
Aim
To update the available evidence on the impact of periodontitis on diabetes control, incidence and complications.
Methods
Observational studies on the effect of periodontitis on diabetes, ...published after 2012, were identified through electronic databases and hand‐searched journals. Findings were summarized by evidence tables, using PRISMA statement. Quality of the included studies was evaluated through the Newcastle Ottawa scale.
Results
Healthy individuals with periodontitis exhibit a poor glycaemic control and a higher risk of developing diabetes. Individuals affected by diabetes show a deterioration of glycaemic control if also affected by periodontitis and significantly higher prevalence of diabetes‐related complications. Limited evidence is available on gestational diabetes and type 1 diabetes.
Conclusions
Periodontitis has a significant impact on diabetes control, incidence and complications. Nevertheless, the heterogeneity and quality of the included publications suggest that caution should be exercised when interpreting the data and that there remains an important need for additional evidence.
In the last ten years, knowledge on pathophysiology of type 2 diabetes (T2DM) has significantly increased, with multiple failures (decreased incretin effect, increased lipolysis, increased glucagon ...secretion, neurotransmitters dysfunction) recognized as important contributors, together with decreased insulin secretion and reduced peripheral glucose uptake. As a consequence, the pharmacologic therapy of T2DM has been progressively enriched by several novel classes of drugs, trying to overcome these defects. The last, intriguing compounds come into the market are SGLT2 inhibitors, framing the kidney in a different scenario, not as site of a harmful disease complication, but rather as the means to correct hyperglycemia and fight the disease. This review aims to offer a short, updated overview of the role of these compounds in the treatment of T2DM, focusing on efficacy, ancillary albeit relevant clinical effects, safety, potential cardiovascular protection, positioning in common therapeutic algorithms.
Approximately half of all patients with type 2 diabetes (T2D) develop a certain degree of renal impairment. In many of them, chronic kidney disease (CKD) progresses over time, eventually leading to ...end-stage kidney disease (ESKD) requiring dialysis and conveying a substantially increased risk of cardiovascular morbidity and mortality. Even with widespread use of renin-angiotensin system blockers and tight glycemic control, a substantial residual risk of nephropathy progression remains. Recent cardiovascular outcomes trials investigating sodium-glucose cotransporter 2 (SGLT2) inhibitors have suggested that these therapies have renoprotective effects distinct from their glucose-lowering action, including the potential to reduce the rates of ESKD and acute kidney injury. Although patients in most cardiovascular outcomes trials had higher prevalence of existing cardiovascular disease compared with those normally seen in clinical practice, the proportion of patients with renal impairment was similar to that observed in a real-world context. Patient cardiovascular risk profiles did not relevantly impact the renoprotective benefits observed in these studies. Benefits were observed in patients across a spectrum of renal risk, but were evident also in those without renal damage, suggesting a role for SGLT2 inhibition in the prevention of CKD in people with T2D. In addition, recent studies such as CREDENCE and DAPA-CKD offer a greater insight into the renoprotective effects of SGLT2 inhibitors in patients with moderate-to-severe CKD. This review outlines the evidence that SGLT2 inhibitors may prevent the development of CKD and prevent and delay the worsening of CKD in people with T2D at different levels of renal risk.
Aims/hypothesis
The strict rules applied in Italy during the recent COVID-19 pandemic, with the prohibition to attend any regular outdoor activity, are likely to influence the degree of metabolic ...control in patients with type 2 diabetes. We explored such putative effect immediately after the resolution of lockdown rules, in the absence of any variation of pharmacologic treatment.
Methods
One-hundred and fourteen patients with adequate metabolic control took part in this single-centre, prospective, observational study. The metabolic profile tested 1 week after the end of the lockdown was compared with the last value and the mean of the last three determinations performed before the pandemic emergency (from 6 months to 2 years before).
Results
After 8 weeks of lockdown, an increase of HbA1c > 0.3% (mean +0.7%) was observed in 26% of the participants; these were also characterized by a persistent elevation in serum triglycerides able to predict the worsening of glucose control.
Conclusions
Lockdown determined a relevant short-term metabolic worsening in approximately one-fourth of previously well-controlled type 2 diabetic individuals; pre-lockdown triglycerides were the only parameter able to predict such derangement of glucose control.
Sodium-glucose cotransporter-2 inhibitors reduce blood pressure (BP) and renal and cardiovascular events in patients with type 2 diabetes through not fully elucidated mechanisms. Aim of this study ...was to investigate whether dapagliflozin is able to acutely modify systemic and renal vascular function, as well as putative mechanisms.
Neuro-hormonal and vascular variables, together with 24 h diuresis, urinary sodium, glucose, isoprostanes and free-water clearance were assessed before and after a 2-day treatment with dapagliflozin 10 mg QD in sixteen type 2 diabetic patients; data were compared with those obtained in ten patients treated with hydrochlorothiazide 12.5 mg QD. Brachial artery endothelium-dependent and independent vasodilation (by flow-mediated dilation) and pulse wave velocity were assessed. Renal resistive index was obtained at rest and after glyceryl trinitrate administration. Differences were analysed by repeated measures ANOVA, considering treatment as between factor and time as within factor; Bonferroni post hoc comparison test was also used.
Dapagliflozin decreased systolic BP and induced an increase in 24 h diuresis to a similar extent of hydrochlorothiazide; 24 h urinary glucose and serum magnesium were also increased. 24 h urinary sodium and fasting blood glucose were unchanged. Oxidative stress was reduced, as by a decline in urinary isoprostanes. Flow-mediated dilation was significantly increased (2.8 ± 2.2 to 4.0 ± 2.1%, p < 0.05), and pulse-wave-velocity was reduced (10.1 ± 1.6 to 8.9 ± 1.6 m/s, p < 0.05), even after correction for mean BP. Renal resistive index was reduced (0.62 ± 0.04 to 0.59 ± 0.05, p < 0.05). These vascular modifications were not observed in hydrochlorothiazide-treated individuals.
An acute treatment with dapagliflozin significantly improves systemic endothelial function, arterial stiffness and renal resistive index; this effect is independent of changes in BP and occurs in the presence of stable natriuresis, suggesting a fast, direct beneficial effect on the vasculature, possibly mediated by oxidative stress reduction.
Diabetes is a worldwide emergency. Its chronic complications impose a heavy burden on patients, health systems, and on society as a whole. Diabetic retinopathy is one of the most common and serious ...complications of diabetes, and an established risk factor for blindness in adults. Over 15 years of investigation led to the identification of vascular endothelial growth factor (VEGF) as a main pathogenic factor in diabetic retinopathy and to the introduction of highly effective anti-VEGF-based therapies, such as the monoclonal antibody bevacizumab or its fragment ranibizumab, which helped to prevent diabetes-related blindness in millions of patients. Recently, a pathogenic role for uncontrolled increases in the extracellular ATP concentration (eATP) and for overactivation of the purinergic receptor P2X7 (P2X7R) has been suggested. The P2X7R is an eATP-gated plasma membrane channel expressed in multiple tissues and organs, with a pleiotropic function in inflammation, immunity, cancer, and hormone and growth factor release. P2X7R stimulation or overexpression positively regulate the secretion and buildup of VEGF, thus promoting neo-angiogenesis in a wide variety of disease processes. In this review, we explore current evidence that supports the role of P2X7R receptor signaling in the pathogenesis of diabetic retinopathy, as well as the most appealing current therapeutical options for P2X7R targeting.
Loss of pancreatic beta cells is a central feature of type 1 (T1D) and type 2 (T2D) diabetes, but a therapeutic strategy to preserve beta cell mass remains to be established. Here we show that the ...death receptor TMEM219 is expressed on pancreatic beta cells and that signaling through its ligand insulin-like growth factor binding protein 3 (IGFBP3) leads to beta cell loss and dysfunction. Increased peripheral IGFBP3 was observed in established and at-risk T1D/T2D patients and was confirmed in T1D/T2D preclinical models, suggesting that dysfunctional IGFBP3/TMEM219 signaling is associated with abnormalities in beta cells homeostasis. In vitro and in vivo short-term IGFBP3/TMEM219 inhibition and TMEM219 genetic ablation preserved beta cells and prevented/delayed diabetes onset, while long-term IGFBP3/TMEM219 blockade allowed for beta cell expansion. Interestingly, in several patients' cohorts restoration of appropriate IGFBP3 levels was associated with improved beta cell function. The IGFBP3/TMEM219 pathway is thus shown to be a physiological regulator of beta cell homeostasis and is also demonstrated to be disrupted in T1D/T2D. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes.
Along the obesity pandemic, the prevalence of non-alcoholic fatty liver disease (NAFLD), often regarded as the hepatic manifestation of the metabolic syndrome, increases worldwide representing now ...the prevalent liver disease in western countries. No pharmacotherapy is approved for the treatment of NAFLD and, currently, the cornerstone treatment is lifestyle modifications focusing on bodyweight loss, notoriously difficult to obtain and even more difficult to maintain. Thus, novel therapeutic approaches are highly demanded. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are approved for the treatment of type 2 diabetes and obesity. They exert their body weight-lowering effect by reducing satiety and food intake. GLP-1RAs have also been shown to reduce liver inflammation and fibrosis. Furthermore, glucagon receptor agonism is being investigated for the treatment of NAFLD due to its appetite and food intake-reducing effects, as well as its ability to increase lipid oxidation and thermogenesis. Recent studies suggest that glucagon receptor signaling is disrupted in NAFLD, indicating that supra-physiological glucagon receptor agonism might represent a new NAFLD treatment target. The present review provides (1) an overview in the pathophysiology of NAFLD, including the potential involvement of GLP-1 and glucagon, (2) an introduction to the currently available GLP-1RAs and (3) outlines the potential of emerging GLP-1RAs and GLP-1/glucagon receptor co-agonists in the treatment of NAFLD.
Aim
To evaluate the changes in renal endpoints in type 2 diabetes patients treated with dapagliflozin versus other glucose‐lowering medications in routine clinical practice.
Materials and Methods
...DARWIN‐T2D was a retrospective study conducted at 46 outpatient diabetes clinics in Italy. An automated software collected data on 17 285 patients who received dapagliflozin, glucagon‐like peptide‐1 receptor agonists, dipeptidyl peptidase‐4 inhibitors, or gliclazide, 6751 of whom had a follow‐up visit. We analysed changes in albumin excretion rate (AER) and estimated glomerular filtration rate (eGFR).
Results
Patients who received dapagliflozin (n = 473) were younger, more obese, and had a poorer glucose control than those who received a comparator (n = 2973). After ~6 months, median (interquartile range) AER declined by 37%, from 19.5 (7.5–78.2) to 13.2 (6.5–45.0) mg/g (P < 0.0001) in the dapagliflozin group and did not change in the comparator group. After adjusting for confounders, therapy with dapagliflozin versus comparators was associated with an AER reduction of 26.4 ± 13.1 mg/g (P = 0.045), and eGFR (mL/min/1.73 m2) diminished by 1.1 ± 0.5 (P = 0.049) in the dapagliflozin group and by 0.6 ± 9.1 (P = 0.002) in the comparator group (P = 0.35 between groups). No patient treated with dapagliflozin versus four patients treated with comparators experienced a doubling of serum creatinine.
Conclusions
The antiproteinuric effect of dapagliflozin is confirmed here for the first time by real‐world data. Despite a mild decline in eGFR, there was no evidence of clinically relevant worsening in renal function.
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