- Sodium-glucose cotransporter 2 inhibition: cardioprotection by treating diabetes-a translational viewpoint explaining its potential salutary effects. [JOURNAL ARTICLE]
- Eur Heart J Cardiovasc Pharmacother 2016 Apr 18.
Diabetes is a growing epidemic worldwide characterized by an elevated concentration of blood glucose, associated with a high incidence of cardiovascular disease and mortality. Although in general reduction of hyperglycaemia is considered a therapeutic goal, hypoglycaemic therapies do not necessarily reduce cardiovascular mortality and may even aggravate cardiovascular risk factors, such as body weight. A new class of antidiabetic drugs acts by inhibition of the sodium-glucose cotransporter 2 (SGLT2), which (partially) prevents reabsorption of glucose from the renal filtrate. The induction of glucose excretion via the urine (glycosuria) was turned into an effective strategy to reduce blood glucose. Ancillary advantages are the caloric and volumetric loss and thereby the reduction of body weight and blood pressure. Additionally, SGLT2 inhibition has been suggested to exert direct cardioprotective effects by the reduction of cardiac fibrosis, inflammation, and oxidative stress. This article summarizes the functional consequences of SGLT2 inhibition on the diabetic and hyperglycaemic organism. We especially focused on the effects on the kidney and the cardiovascular system as described in experimental studies. The interesting observations in experimental studies may extend to clinical medicine, as a recent trial reported a decrease in heart failure outcomes in patients at high cardiovascular risk. In conclusion, SGLT2 inhibition represents a novel treatment, which might be a promising target not only to (further) reduce blood glucose but also to target other cardiovascular risk factors. More research and long-term follow-ups will reveal the specific influence of SGLT2 inhibition on the circulatory system and cardiovascular outcomes.
- Genitourinary infections in diabetic patients in the new era of diabetes therapy with sodium-glucose cotransporter-2 inhibitors. [REVIEW, JOURNAL ARTICLE]
- Nutr Metab Cardiovasc Dis 2016 Jul 12.
To review prevalence and significance of urinary tract (UTI) and genital infections (GI) in diabetes and the effects of sodium glucose cotransporter 2 (SGLT-2) inhibitors on these complications.The prevalence of asymptomatic bacteriuria (ASB) is 2-3 times higher in diabetic than in non-diabetic women. The treatment of ASB has no impact on the development of UTIs and/or a decline in renal function. Therefore, there is no indication for screening for and/or treatment of ASB. The incidence of UTI is higher and frequently complicated in diabetic patients, particularly in those with longer duration of disease and of older age. There is no consistent evidence of an association between A1c levels, glycosuria and the risk of ASB and/or UTIs. Diabetes is a known risk factor for Candida colonization and GI, and a poor glycemic control is associated with a higher risk. While patients treated with SGLT-2 inhibitors may have a non-significant increased risk of UTI, they have a clearly increased risk of GI; most of these infections are mild, easy to treat, and the rate of recurrence is low.Diabetic patients are at high risk of UTIs and of GI. Only GI are associated with poor glycemic control. Although patients treated with SGLT-2 inhibitors have an increased 3-5 fold risk of GI, proper medical education can reduce this risk.
- Impact of protease inhibitors on the evolution of urinary markers: Subanalyses from an observational cross-sectional study. [Journal Article]
- Medicine (Baltimore) 2016 Aug; 95(32):e4507.
Kidney injury (defined as the presence of albuminuria, proteinuria, glycosuria [without hyperglycemia], hematuria, and/or renal hypophosphatemia) is an emerging problem in human immunodeficiency virus (HIV)-infected patients, although few data are available on the role of protease inhibitors (PIs) in this condition.To determine the time to kidney injury in a cohort of HIV-infected patients receiving a PI-containing regimen.We report the results of a subanalysis of a published cross-sectional study. The subanalysis included only patients receiving PI-containing regimens for more than 6 months (377 of the overall 970 patients). We determined associated factors and constructed receiver operating characteristic curves to estimate time to kidney injury depending on the PI used.The percentage of patients with kidney injury was 27.7% for darunavir, 27.9% for lopinavir, and 30% for atazanavir. Time to kidney injury was as follows: 229 days for atazanavir/ritonavir (area under the curve [AUC], 0.639; sensitivity, 0.89; specificity, 0.41); 332 days for atazanavir/ritonavir plus tenofovir (AUC, 0.603; sensitivity, 0.75; and specificity, 0.29); 318 days for nonboosted atazanavir (AUC, 0.581; sensitivity, 0.89; and specificity, 0.29); 478 days for lopinavir/ritonavir (AUC, 0.566; sensitivity, 0.864; and specificity, 0.44); 1339 days for lopinavir/ritonavir plus tenofovir (AUC, 0.667; sensitivity, 0.86; and specificity, 0.77); 283 days for darunavir/ritonavir (AUC, 0.523; sensitivity, 0.80; and specificity, 0.261); and 286 days for darunavir/ritonavir plus tenofovir (AUC, 0.446; sensitivity, 0.789; and specificity, 0.245). The use of lopinavir/ritonavir without tenofovir was a protective factor (odds ratio = 1.772; 95%CI, 1.070-2.93; P = 0.026).For all PIs, the percentage of patients with kidney injury exceeded 27%, irrespective of tenofovir use. The longest time to kidney injury was recorded with lopinavir/ritonavir. These results demonstrate the need for renal monitoring, including urine samples, in patients receiving a PI-based regimen, even when tenofovir is not used concomitantly.
- [OP.5C.03] HIGHER PREVALENCE OF HYPERTENSION IN MIGRANTS IN ITALY: A SNAPSHOT OF THE 2012 AND 2013C WORLD KIDNEY DAY. [Journal Article]
- J Hypertens 2016 Sep.:e60-1.
Among the many health-related challenges posed by the increased number of Migrants, cardiovascular risk evaluation has been less extensively evaluated than communicable disease prevention and treatment. Ethnic background is one of the many non-modifiable determinants of cardiovascular disease, whereas stress and modifiable factors such as dietary habits and smoking are very likely to be profoundly altered in the migrant population.To compare the prevalence of hypertension in Italian residents as compared with Migrants, a total of 6027 voluntary subjects underwent medical interview, body weight, height and blood pressure (BP) measurement, risk factor evaluation and urine analysis during the National Kidney Day survey held in 2012 and 2013 by the Federazione Italiana del Rene (FIR).Migrants were 445/6027 (7.38%), with a rate remarkably similar to the percentage of non-Italian residents (8.09%). A wide heterogeneity was evident, with 53 different nationalities, subdivided in Eastern Europe (38.2%), Northern Africa (17.6%), Center and Southern Africa (12.9%), Latin America (12.8%), Indian subcontinent (9.6%), Far East (5.5%), Middle East (3.4%) macro-areas. Gender distribution and body mass index were comparable in the Italian and in the Migrant groups. Despite a 10-year age difference (50 ± 12 vs. 41 ± 15 years; p <0.001), the overall prevalence of hypertension was similar in the two groups (44.7% in Italians vs. 43.4% in Migrants), as defined by BP>140/90 mmHg and/or current antyhypertensive treatment. When stratified by age, Migrants presented significantly higher BP values, the prevalence of hypertension being at least 10% higher than in Italian residents in any decade group. A similar trend was observed for awareness, active treatment and satisfactory BP control rates. Also the rate of proteinuria and glycosuria was higher in the spot urine sample analysis.In Migrants, hypertension prevalence, treatment rate and control rate are significantly higher than in the Italian resident population. In the future years this will inevitably increase the burden of cardiovascular disease on society and health system. These data underscore the urgent need of prevention and intervention in this special population, trying to take into proper account all the involved social, cultural, economic and health-related factors.
- Proximal tubular nephropathy in two dogs diagnosed with lead toxicity. [Case Reports]
- Aust Vet J 2016 Aug; 94(8):280-4.
Lead toxicity was diagnosed in two dogs presenting with vague clinical symptoms. Complete blood count, biochemical testing and imaging changes showed a metarubricytosis in dog 1, but were largely normal in dog 2. Both dogs had glucosuria and proteinuria on urinalysis consistent with damage to the proximal renal tubules. Both animals returned elevated blood lead levels. A history of ingestion of lead was reported by the owner in one dog and elucidated from the second owner once the animal had recorded elevated blood lead levels.Lead toxicity is rarely reported in the human literature as a cause of proximal tubular dysfunction. To the author's knowledge this is the first case report specifically examining this in the dog. The clinical awareness that lead is a potential cause of proximal renal tubular dysfunction offers another tool to assist the clinician in the diagnostic process. This is particularly important given that the clinical signs and minimum database findings in animals with lead toxicosis are highly variable. Evidence of proximal tubular dysfunction should trigger the clinician to closely examine the history for a potential source of lead exposure and consider submitting samples to test blood lead levels.
- Multiple daily injection of insulin regimen for a 10-month-old infant with type 1 diabetes mellitus and diabetic ketoacidosis. [Journal Article]
- Ann Pediatr Endocrinol Metab 2016 Jun; 21(2):96-8.
The incidence of type 1 diabetes is increasing worldwide, and the greatest increase has been observed in very young children under 4 years of age. A case of infantile diabetic ketoacidosis in a 10-month-old male infant was encountered by these authors. The infant's fasting glucose level was 490 mg/dL, his PH was 7.13, his pCO2 was 15 mmHg, and his bicarbonate level was 5.0 mmol/L. The glycosylated hemoglobin level had increased to 9.4%. Ketonuria and glucosuria were detected in the urinalysis. The fasting C-peptide and insulin levels had decreased. The infant was positive for anti-insulin and antiglutamic acid decarboxylase antibodies. Immediately after the infant's admission, fluid therapy and intravenous insulin infusion therapy were started. On the second day of the infant's hospitalization and after fluid therapy, he recovered from his lethargic condition, and his general condition improved. Feeding was started on the third day, and he was fed a formula 5 to 7 times a day and ate rice, vegetables, and lean meat. Due to the frequent feeding, the frequency of rapid-acting insulin injection was increased from 3 times before feeding to 5 times, adjusted according to the feeding frequency. The total dose of insulin that was injected was 0.8-1.1 IU/kg/day, and the infant was discharged on the 12th day of his hospitalization. The case is presented herein with a brief review of the relevant literature.
- Empagliflozin (an SGLT2 inhibitor), alone or in combination with linagliptin (a DPP-4 inhibitor), prevents steatohepatitis in a novel mouse model of non-alcoholic steatohepatitis and diabetes. [Journal Article]
- Diabetol Metab Syndr 2016.:45.
Sodium-glucose co-transporter-2 (SGLT2) inhibitors are new oral antidiabetic drugs that reduce hyperglycemia by promoting urinary glucose excretion. Glycosuria produced by SGLT2 inhibitors is associated with weight loss, mainly due to reduced fat volume. We investigated the effects of empagliflozin (selective SGLT2 inhibitor) and linagliptin (DPP-4 inhibitor) on steatohepatitis and fibrosis in a mouse model of non-alcoholic steatohepatitis (NASH) with diabetes.A novel NASH model was generated by administration of streptozotocin to C57BL/6J mice at 2 days old, with a high-fat diet from 4 weeks. NASH mice aged 6 weeks were divided into four groups of 6 animals: vehicle, linagliptin (10 mg/kg), empagliflozin (10 mg/kg), and linagliptin + empagliflozin. The histological non-alcoholic fatty liver disease activity score was significantly lower in the empagliflozin and linagliptin + empagliflozin groups than in the vehicle or linagliptin groups. Hepatic expression of inflammatory genes (tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1) was decreased in the empagliflozin and linagliptin + empagliflozin groups compared with the vehicle group. The collagen deposition with Sirius red staining was significantly reduced in the linagliptin + empagliflozin group compared with the linagliptin or the empagliflozin group. Immunohistochemistry showed that expression of α-smooth muscle actin, a marker of myofibroblasts (fibrosis), was reduced in the linagliptin + empagliflozin group compared with the vehicle group, as was expression of type 1 and 3 collagen mRNA. Linagliptin + empagliflozin decreased expression of mRNAs for genes related to fatty acid synthesis, but did not increase mRNAs for β-oxidation-related genes.While empagliflozin alone attenuates development of NASH showing anti-steatotic and anti-inflammatory effects, combined administration of empagliflozin and linagliptin can synergistically ameliorates NASH with stronger anti-fibrotic effects.
- Vascular effects of Linagliptin in Non Obese Diabetic (NOD) mice are glucose-independent and involve positive modulation of Endothelial Nitric Oxide Synthase (eNOS)/caveolin-1 (CAV-1) pathway. [JOURNAL ARTICLE]
- Diabetes Obes Metab 2016 Jul 27.
The molecular mechanism through which dipeptidyl peptidase 4 inhibitors (DPP4i) exert their beneficial effects on cardiovascular function is still unclear. Since DPP4i are not effective on type 1 diabetes (T1DM), we tested the effect of Linagliptin in Non Obese Diabetic (NOD) mice, a murine model of T1DM, to unveil a possible direct cardiovascular action of DPP4i beyond glycemia control.NOD mice are grouped according to glycosuria levels as NODI: null; NODII: high; NODIII: severe, and enrolled for Linagliptin treatments once they reach NODII levels. Vascular reactivity is assessed ex vivo on aorta harvested from mice upon reaching NODIII level. In a separate set of experiments, Linagliptin effect is tested directly in vitro on vessels harvested from untreated NODIII, glucagone like polypeptide 1 receptor knockout (GLP1R(-/-) ) and soluble guanylyl cyclase-α1 knockout (sGCα1 (-/-) ) mice. Molecular and cellular studies were performed on endothelial and eNOS-transfected cells.In ex vivo vascular study, endothelium-dependent vasorelaxation is ameliorated and eNOS/NO/sGC signaling enhanced. In the in vitro vascular study, Linagliptin exerts a direct vasodilating activity, on vessels harvested from both normo- or hyper-glycaemic mice. The effect is independent from GLP1/GLP1R interaction and requires eNOS/NO/sGC pathway activation. Molecular studies performed on endothelial cells show that Linagliptin rescues eNOS from caveolin-1 binding in a calcium independent manner.Linagliptin, by interfering with the protein-protein interaction caveolin-1/eNOS, leads to an increased eNOS availability, thus enhancing NO production. This mechanism accounts for the vascular effect of Linagliptin that is independent from glucose control and GLP-1/GLP1R interaction.
- The potential of SGLT2 inhibitors in phase II clinical development for treating type 2 diabetes. [JOURNAL ARTICLE]
- Expert Opin Investig Drugs 2016 Aug 5.:1-20.
There is now an abundance of anti-diabetic agents. However, only few patients achieve glycemic targets. Moreover, current glucose-lowering agents mainly depend upon insulin secretion or function. Sodium glucose co-transporter type 2 (SGLT2) inhibitors present a novel glucose-lowering therapy, inducing glycosuria in an insulin-independent fashion.In this review, the authors discuss the key efficacy and safety data from phase II clinical trials in type 2 diabetes mellitus (T2DM) of the main SGLT2 inhibitors approved or currently in development, and provide a rationale for their use in T2DM.Despite the very promising characteristics of this new therapeutic class, a number of issues await consideration. One important question is what to expect from head-to-head comparison data. We also need to know if dual inhibition of SGLT1/SGLT2 is more efficacious in reducing HbA1c and how this therapy affects metabolic and cardiovascular parameters. Additionally, several SGLT2 agents that have not yet come to market have hitherto been evaluated in Asian populations, whereas approved SGLT2 inhibitors have been frequently studied in other populations, including Caucasian subjects. Thus, we need more information on the potential role of ethnicity on their efficacy and safety.