SGLT2 Inhibitors and the Diabetic Kidney Fioretto, Paola; Zambon, Alberto; Rossato, Marco ...
Diabetes care,
08/2016, Volume:
39 Suppl 2, Issue:
Supplement_2
Journal Article
Peer reviewed
Open access
Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is ...established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, especially cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addition to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfiltration. Experimental studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubular cells. SGLT2 inhibitors reduced glomerular hyperfiltration in patients with type 1 diabetes, and in patients with type 2 diabetes, they caused transient acute reductions in glomerular filtration rate, followed by a progressive recovery and stabilization of renal function. Interestingly, recent studies consistently demonstrated a reduction in albuminuria. Although these data are promising, only dedicated renal outcome trials will clarify whether SGLT2 inhibitors, in addition to their glycemic and blood pressure benefits, may provide nephroprotective effects.
Although antidiabetic agents have been developed to target one or more of the core defects of type 2 diabetes mellitus (T2DM), many patients do not achieve glycemic goals. Inhibition of the ...sodium-glucose cotransporter 2 (SGLT2) induces glycosuria, reduces glucose toxicity and improves insulin sensitivity and β-cell function. As the mechanism of action of SGLT2 inhibitors is different from other agents and completely insulin-independent, the use of these drugs might potentially be efficacious alone or in combination with any other antidiabetic drug, including insulin. Dapagliflozin is a highly selective and reversible SGLT2 inhibitor approved for use in adult patients with T2DM as monotherapy in patients intolerant of metformin or as adjunctive therapy in patients inadequately controlled on existing antidiabetic medications, including insulin. A literature search conducted using PubMed identified key publications related to the use of dapagliflozin in the treatment of patients with diabetes mellitus. No date limits were applied. This review focuses on the safety and efficacy of this SGLT2 inhibitor. Dapagliflozin produces dose-related reductions in glycosylated hemoglobin (HbA1c) as monotherapy and as add-on to other antidiabetic agents, with significant reductions in body weight. Hypoglycemia is uncommon. Preliminary data from a phase 2 pharmacokinetic/pharmacodynamic study suggest that dapagliflozin may also improve glycemic control in patients with type 1 diabetes mellitus. Clinical trials published to date show that dapagliflozin is safe and effective as monotherapy or as an add-on to insulin or oral antidiabetic agents in patients with T2DM.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The clinical manifestations of diabetic nephropathy, proteinuria, increased blood pressure, and decreased glomerular filtration rate, are similar in type 1 and type 2 diabetes; however, the renal ...lesions underlying renal dysfunction in the 2 conditions may differ. Indeed, although tubular, interstitial, and arteriolar lesions are ultimately present in type 1 diabetes, as the disease progresses, the most important structural changes involve the glomerulus. In contrast, a substantial subset of type 2 diabetic patients, despite the presence of microalbuminuria or proteinuria, have normal glomerular structure with or without tubulointerstitial and/or arteriolar abnormalities. The clinical manifestations of diabetic nephropathy are strongly related with the structural changes, especially with the degree of mesangial expansion in both type 1 and type 2 diabetes. However, several other important structural changes are involved. Previous studies, using light and electron microscopic morphometric analysis, have described the renal structural changes and the structural-functional relationships of diabetic nephropathy. This review focuses on these topics, emphasizing the contribution of research kidney biopsy studies to the understanding of the pathogenesis of diabetic nephropathy and the identification of patients with a higher risk of progression to end-stage renal disease. Finally, evidence is presented that the reversal of established lesions of diabetic nephropathy is possible.
Acute kidney injury (AKI) is associated with increased mortality in most critical settings. However, it is unclear whether its mild form (i.e. AKI stage 1) is associated with increased mortality also ...in non-critical settings. Here we conducted an international study in patients hospitalized with SARS-CoV-2 infection aiming 1. to estimate the incidence of AKI at each stage and its impact on mortality 2. to identify AKI risk factors at admission (susceptibility) and during hospitalization (exposures) and factors contributing to AKI-associated mortality. We included 939 patients from medical departments in Moscow (Russia) and Padua (Italy). In-hospital AKI onset was identified in 140 (14.9%) patients, mainly with stage 1 (65%). Mortality was remarkably higher in patients with AKI compared to those without AKI (55 39.3% vs. 34 4.3%, respectively). Such association remained significant after adjustment for other clinical conditions at admission (relative risk RR 5.6; CI 3.5- 8.8) or restricting to AKI stage 1 (RR 3.2; CI 1.8-5.5) or to subjects with AKI onset preceding deterioration of clinical conditions. After hospital admission, worsening of hypoxic damage, inflammation, hyperglycemia, and coagulopathy were identified as hospital-acquired risk factors predicting AKI onset. Following AKI onset, the AKI-associated worsening of respiratory function was identified as the main contributor to AKI-induced increase in mortality risk. In conclusion, AKI is a common complication of Sars-CoV2 infection in non-intensive care settings where it markedly increases mortality risk also at stage 1. The identification of hospital-acquired risk factors and exposures might help prevention of AKI onset and of its complications.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Aim
Variability in HbA1c and blood pressure is associated with the risk of diabetic kidney disease (DKD). No evidence exists on the role of variability in lipids or serum uric acid (UA), or the ...interplay between the variability of different parameters, in renal outcomes.
Methods
Within the AMD Annals database, we identified patients with ≥5 measurements of HbA1c, systolic blood pressure (SBP) and diastolic blood pressure (DBP), total‐, high‐density lipoprotein (HDL)‐ and low‐density lipoprotein (LDL)‐cholesterol, triglycerides, and UA. Patients were followed‐up for up to 5 years. The impact of measures of variability on the risk of DKD was investigated by Cox regression analysis and recursive partitioning techniques.
Results
Four‐thousand, two‐hundred and thirty‐one patients were evaluated for development of albuminuria, and 7560 for decreased estimated glomerular filtration rate (eGFR; <60 mL/min/1.73 m2). A significantly higher risk of developing albuminuria was associated with variability in HbA1c upper quartile hazard ratio (HR) = 1.3; 95% confidence interval (CI) 1.1‐1.6. Variability in SBP, DBP, HDL‐C, LDL‐C and UA predicted the decline in eGFR, the association with UA variability being particularly strong (upper quartile HR = 1.8; 95% CI 1.3‐2.4). The concomitance of high variability in HbA1c and HDL‐C conferred the highest risk of developing albuminuria (HR = 1.47; 95% CI 1.17‐1.84), while a high variability in UA (HR = 1.54; 95% CI 1.19‐1.99) or DBP (HR = 1.47; 95% CI 1.11‐1.94) conferred the highest risk of decline in eGFR.
Conclusion
The variability of several parameters influences the development of DKD, having a different impact on albuminuria development and on the decline in GFR.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Chronic kidney disease is associated with altered lipid metabolism and lipid accumulation. Although it is though that hyperlipemia is a consequence of kidney dysfunction, several lines of evidence ...support that hyperlipidemia may contribute to the onset and progression of kidney disease, also in diabetes. This review describes the results of recent observational studies supporting the concept that glucose is only partly responsible for kidney damage onset, while a cluster of factors, including hypertriglyceridemia and low HDL-cholesterol, could play a relevant role in inducing onset and progression of DKD. We also report the results of randomized clinical trials investigating in type 2 diabetic patients the role of drug improvement of hypertriglyceridemia on renal outcomes. Finally, we discuss putative mechanisms linking hyperlipidemia (i.e. hypertriglyceridemia or low HDL cholesterol) with kidney disease.
Little information is available on the beneficial effects of cholecalciferol treatment in comorbid patients hospitalized for COVID-19. The aim of this study was to retrospectively examine the ...clinical outcome of patients receiving in-hospital high-dose bolus cholecalciferol. Patients with a positive diagnosis of SARS-CoV-2 and overt COVID-19, hospitalized from 15 March to 20 April 2020, were considered. Based on clinical characteristics, they were supplemented (or not) with 400,000 IU bolus oral cholecalciferol (200,000 IU administered in two consecutive days) and the composite outcome (transfer to intensive care unit; ICU and/or death) was recorded. Ninety-one patients (aged 74 ± 13 years) with COVID-19 were included in this retrospective study. Fifty (54.9%) patients presented with two or more comorbid diseases. Based on the decision of the referring physician, 36 (39.6%) patients were treated with vitamin D. Receiver operating characteristic curve analysis revealed a significant predictive power of the four variables: (a) low (<50 nmol/L) 25(OH) vitamin D levels, (b) current cigarette smoking, (c) elevated D-dimer levels (d) and the presence of comorbid diseases, to explain the decision to administer vitamin D (area under the curve = 0.77, 95% CI: 0.67-0.87,
< 0.0001). Over the follow-up period (14 ± 10 days), 27 (29.7%) patients were transferred to the ICU and 22 (24.2%) died (16 prior to ICU and six in ICU). Overall, 43 (47.3%) patients experienced the combined endpoint of transfer to ICU and/or death. Logistic regression analyses revealed that the comorbidity burden significantly modified the effect of vitamin D treatment on the study outcome, both in crude (
= 0.033) and propensity score-adjusted analyses (
= 0.039), so the positive effect of high-dose cholecalciferol on the combined endpoint was significantly amplified with increasing comorbidity burden. This hypothesis-generating study warrants the formal evaluation (i.e., clinical trial) of the potential benefit that cholecalciferol can offer in these comorbid COVID-19 patients.
Pancreas transplantation is the only therapeutic intervention able to achieve and maintain long-term euglycemia, without risks of hypoglycemia; this makes it possible to test the impact of ...normoglycemia in the different stages of diabetic nephropathy. Pancreas and islet transplantation in animal models prevent the development of diabetic nephropathy lesions and ameliorate or reverse established glomerular lesions. In type 1 diabetic patients, pancreas transplantation, performed simultaneously or after kidney transplantation, has been shown to prevent the recurrence of diabetic glomerulopathy lesions. The established lesions of diabetic nephropathy have been considered to be irreversible; pancreas transplantation alone allows us to test whether this is true. To this end, we studied renal structure before and 5 and 10 years after pancreas transplantation in 8 nonuremic type 1 diabetic patients. These patients, with a long diabetes duration, had established diabetic nephropathy lesions at the time of transplantation. We report that diabetic glomerulopathy lesions, unchanged at 5 years post pancreas transplantation, significantly improved after 10 years, with complete normalization of glomerular structure in most patients. Thus this study demonstrates that the lesions of diabetic nephropathy are reversed by long-term normoglycemia and that the human kidney has the potential in humans to obtain a substantial architectural remodeling of the glomerular and tubular structures toward healing.
Diabetic kidney disease (DKD) is a major burden in elderly patients with type 2 diabetes (T2DM). Low estimated glomerular filtration rate (eGFR+, < 60 mL/min/1.73 m2) and albuminuria (Alb+) are ...essential for the diagnosis of DKD, but their association with clinical variables and quality of care may be influenced by ageing.
Here we investigated the association of clinical variables and quality of care measures with eGFR+ and Alb+ in 157,595 T2DM individuals participating to the Italian Association of Clinical Diabetologists (AMD) Annals Initiative, stratified by age.
The prevalence of eGFR+ and Alb+ increased with ageing, although this increment was more pronounced for low eGFR. Irrespective of age, both the eGFR+ and Alb + groups had the worst risk factors profile when compared to subjects without renal disease, showing a higher prevalence of out-of target values of HbA1c, BMI, triglycerides, HDL-C, blood pressure and more complex cardiovascular (CVD) and anti-diabetic therapies, including a larger use of insulin In all age groups, these associations differed according to the specific renal outcome examined: male sex and smoking were positively associated with Alb+ and negatively with eGFR+; age and anti-hypertensive therapies were more strongly associated with eGFR+, glucose control with Alb+, whereas BMI, and lipid-related variables with both abnormalities. All these associations were attenuated in the older (> 75 years) as compared to the younger groups (< 65 years; 65-75 years), and they were confirmed by multivariate analysis. Notably, Q-score values < 15, indicating a low quality of care, were strongly associated with Alb+ (OR 8.54; P < 0.001), but not with eGFR+.
In T2DM patients, the prevalence of both eGFR and Albuminuria increase with age. DKD is associated with poor cardiovascular risk profile and a lower quality of care, although these associations are influenced by the type of renal abnormality and by ageing. These data indicate that clinical surveillance of DKD should not be unerestimated in old T2DM patients.
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