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1.
Arterioscler Thromb Vasc Biol ; : ATVBAHA120314129, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32404008

RESUMO

OBJECTIVE: In mice fed a high-fat diet, impairment of insulin signaling in endothelium is an early phenomenon that precedes decreased insulin sensitivity of skeletal muscle, adipose tissue, and liver. We assessed in humans whether short-term overfeeding affects insulin-induced microvascular recruitment in skeletal muscle and adipose tissue before changes occur in glucose uptake and lipolysis. Approach and Results: Fifteen healthy males underwent a hypercaloric and subsequent hypocaloric diet intervention. Before, during, and after the hypercaloric diet, and upon return to baseline weight, all participants underwent (1) a hyperinsulinemic-euglycemic clamp to determine insulin-induced glucose uptake and suppression of lipolysis (2) contrast-enhanced ultrasonography to measure insulin-induced microvascular recruitment in skeletal muscle and adipose tissue. In addition, we assessed insulin-induced vasodilation of isolated skeletal muscle resistance arteries by pressure myography after the hypercaloric diet in study participants and controls (n=5). The hypercaloric diet increased body weight (3.5 kg; P<0.001) and fat percentage (3.5%; P<0.001) but did not affect glucose uptake nor lipolysis. The hypercaloric diet increased adipose tissue microvascular recruitment (P=0.041) and decreased the ratio between skeletal muscle and adipose tissue microvascular blood volume during hyperinsulinemia (P=0.019). Insulin-induced vasodilation of isolated skeletal muscle arterioles was significantly lower in participants compared with controls (P<0.001). The hypocaloric diet reversed all of these changes, except the increase in adipose tissue microvascular recruitment. CONCLUSIONS: In lean men, short-term overfeeding reduces insulin-induced vasodilation of skeletal muscle resistance arteries and shifts the distribution of tissue perfusion during hyperinsulinemia from skeletal muscle to adipose tissue without affecting glucose uptake and lipolysis. REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02628301.

2.
J Nephrol ; 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32356231

RESUMO

Glucagon-like peptide (GLP)-1 receptor agonists are the cornerstone in the treatment of hyperglycemia in many people suffering from type 2 diabetes (T2D). These drugs have potent glucose-lowering actions and, additionally, lower body weight through satiety induction while reducing blood pressure and dyslipidemia. Partly through these actions, GLP-1 receptor agonism was shown to reduce cardiovascular disease (CVD) in people with T2D with previous CVD or at high-risk thereof. In these cardiovascular safety trials, in secondary or exploratory analyses, GLP-1 receptor agonists were also shown to reduce macro-albuminuria, an accepted surrogate marker for diabetic kidney disease (DKD), a condition that still represents a major unmet medical need. In this review we will discuss the evidence which suggests renoprotection induced by GLP-1 receptor agonists and the potential mechanisms that may be involved. These include mitigation of hyperglycemia, overweight and insulin resistance, systemic and glomerular hypertension, dyslipidemia, sodium retention, inflammation and renal hypoxia. The recently initiated large-sized FLOW trial investigating the effects of semaglutide on hard renal outcomes in patients with DKD will provide clarity whether GLP-1 receptor agonists may reduce the burden of DKD in addition to their other beneficial metabolic and cardiovascular effects.

3.
Diabetes Obes Metab ; 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32329160

RESUMO

AIMS: Data regarding the albuminuria-lowering effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in patients with diabetes and chronic kidney disease are limited. We examined the albuminuria-lowering effect of exenatide once weekly (EQW) compared with active glucose-lowering comparators in patients with type 2 diabetes (T2D) and increased urine albumin-to-creatinine ratio (uACR). METHODS: Six randomized double-blind and open-label phase III studies were pooled in a post-hoc, exploratory analysis to evaluate the efficacy and safety of EQW versus non-GLP1 comparators in patients with T2D and baseline uACR ≥30 mg/g. Treatment groups were EQW versus all comparators pooled. Efficacy outcomes were percent change from baseline to week 26/28 in uACR and absolute change in glycated haemoglobin (HbA1c), systolic blood pressure (SBP), body weight (BW) and estimated glomerular filtration rate (eGFR). RESULTS: Baseline characteristics were generally similar between the two treatment groups (EQW: N = 194, All comparators: N = 274). Relative to the comparator group, EQW changed albuminuria by -26.2% (95% CI -39.5 to -10). Similar improvements were observed with EQW versus oral glucose-lowering drugs (-29.6% [95% CI -47.6 to -5.3) or insulin (-23.8% [95% CI -41.8 to -0.2]). The effect of EQW on uACR was independent of baseline RASi usage. Adjusted mean decreases in HbA1c, SBP and BW were more pronounced in the EQW versus the comparator group. Adjustment for changes in HbA1c, eGFR and SBP did not substantially affect the uACR-lowering effect of EQW. When also adjusting for changes in BW, the uACR lowering effect was reduced to -13.0% [95% CI -29.9 to 7.8]. CONCLUSION: EQW reduced uACR in patients with T2D and elevated albuminuria compared to commonly used glucose-lowering drugs. This article is protected by copyright. All rights reserved.

5.
Kidney Int ; 97(4): 806, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32200865
6.
Nephrol Dial Transplant ; 35(Supplement_1): i24-i32, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32003832

RESUMO

Diabetic kidney disease (DKD) is a common complication of type 1 diabetes (T1D) and a major risk factor for premature death from cardiovascular disease (CVD). Current treatments, such as control of hyperglycaemia and hypertension, are beneficial, but only partially protect against DKD. Finding new, safe and effective therapies to halt nephropathy progression has proven to be challenging. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated, in addition to glycaemic lowering, impressive protection against DKD and CVD progression in people with type 2 diabetes. Although these beneficial cardiorenal effects may also apply to people with T1D, supporting data are lacking. Furthermore, the increased rates of euglycaemic diabetic ketoacidosis may limit the use of this class in people with T1D. In this review we highlight the pathophysiology of DKD in T1D and the unmet need that exists. We further detail the beneficial and adverse effects of SGLT2 inhibitors based on their mechanism of action. Finally, we balance the effects in people with T1D and indicate future lines of research.

7.
Expert Rev Endocrinol Metab ; 15(1): 13-27, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32066294

RESUMO

Introduction: Cardiometabolic diseases (CMD) are a group of interrelated disorders such as metabolic syndrome, type 2 diabetes mellitus and cardiovascular diseases (CVD). As the prevalence of these diseases increases globally, efficient new strategies are necessary to target CMD and modifiable risk factors. In the past decade, evidence has accumulated regarding the influence of gut microbiota (GM) on CMD, providing new targets for therapeutic interventions.Areas covered: This narrative review discusses the pathophysiologic link between CMD, GM, and potential microbiota-based targets against atherosclerosis and modifiable risk factors for atherosclerosis. Low-grade inflammation can be induced through GM and its derived metabolites. CMD are influenced by GM and microbiota-derived metabolites such as short-chain fatty acids (SCFA), secondary bile acids, trimethylamine N-oxide (TMAO), and the composition of GM can modulate host metabolism. All of the above can lead to promising therapeutic targets.Expert opinion: Most data are derived from animal models or human association studies; therefore, more translational and interventional research in humans is necessary to validate these promising findings. Reproduced findings such as aberrant microbiota patterns or circulating biomarkers could be targeted depending on individual metabolic profiles, moving toward personalized medicine in CMD.

8.
Diabetes Obes Metab ; 22(6): 988-996, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32026592

RESUMO

AIM: To dissect the effects of the sodium-glucose linked transporter 2 inhibitor dapagliflozin on lipid metabolism and assess whether these effects could potentially offset cardiovascular benefit with this drug-class. MATERIALS AND METHODS: We assessed the effect of dapagliflozin on lipid metabolism in 11 adults with uncomplicated type 2 diabetes. After 4 weeks of statin wash-out and 4 weeks of rosuvastatin 10 mg treatment, participants were treated with dapagliflozin 10 mg once-daily for 5 weeks. Before and after dapagliflozin, plasma lipids were measured and very low-density lipoprotein (VLDL)-1 and VLDL-2 apolipoprotein (Apo)B fluxes were assessed using (5.5.5-2 H3 )-leucine tracer infusion. In addition, hepatic and peripheral insulin sensitivity as well as insulin-mediated inhibition of peripheral lipolysis were measured during a two-step hyperinsulinemic-euglycaemic clamp using (6,6-2 H2 )-glucose and (1,1,2,3,3-2 H5 )-glycerol tracers. RESULTS: Rosuvastatin decreased all plasma lipids significantly: total cholesterol from 4.5 (3.2-6.2) to 3.1 (2.5-3.8) mmol/L, LDL cholesterol from 2.6 (1.7-3.4) to 1.5 (1.1-2.2) mmol/L, HDL cholesterol from 1.34 (0.80-2.02) to 1.19 (0.74-1.89) mmol/L and triglycerides from 0.92 (0.31-3.91) to 0.79 (0.32-2.10) mmol/L. The addition of dapaglifozin to rosuvastatin did not raise either LDL cholesterol or total cholesterol, and only increased HDL cholesterol by 0.08 (-0.03-0.13) mmol/L (P = 0.03). In line with this, dapagliflozin did not affect VLDL-1 or VLDL-2 ApoB fluxes. Fasting endogenous glucose production tended to increase by 0.9 (-3.4-3.1) µmol kg-1 min-1 (P = 0.06), but no effect on hepatic and peripheral insulin sensitivity or on peripheral lipolysis was observed. CONCLUSIONS: Dapagliflozin has no effect on plasma LDL-cholesterol levels or VLDL-apoB fluxes in the context of optimal lipid-lowering treatment, which will thus not limit cardiovascular benefit when lipids are adequately controlled.

9.
Diabetologia ; 63(3): 597-610, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31915895

RESUMO

AIMS/HYPOTHESIS: The pathophysiology of type 1 diabetes has been linked to altered gut microbiota and more specifically to a shortage of intestinal production of the short-chain fatty acid (SCFA) butyrate, which may play key roles in maintaining intestinal epithelial integrity and in human and gut microbial metabolism. Butyrate supplementation can protect against autoimmune diabetes in mouse models. We thus set out to study the effect of oral butyrate vs placebo on glucose regulation and immune variables in human participants with longstanding type 1 diabetes. METHODS: We administered a daily oral dose of 4 g sodium butyrate or placebo for 1 month to 30 individuals with longstanding type 1 diabetes, without comorbidity or medication use, in a randomised (1:1), controlled, double-blind crossover trial, with a washout period of 1 month in between. Participants were randomly allocated to the 'oral sodium butyrate capsules first' or 'oral placebo capsules first' study arm in blocks of five. The clinical investigator received blinded medication from the clinical trial pharmacy. All participants, people doing measurements or examinations, or people assessing the outcomes were blinded to group assignment. The primary outcome was a change in the innate immune phenotype (monocyte subsets and in vitro cytokine production). Secondary outcomes were changes in blood markers of islet autoimmunity (cell counts, lymphocyte stimulation indices and CD8 quantum dot assays), glucose and lipid metabolism, beta cell function (by mixed-meal test), gut microbiota and faecal SCFA. The data was collected at the Amsterdam University Medical Centers. RESULTS: All 30 participants were analysed. Faecal butyrate and propionate levels were significantly affected by oral butyrate supplementation and butyrate treatment was safe. However, this modulation of intestinal SCFAs did not result in any significant changes in adaptive or innate immunity, or in any of the other outcome variables. In our discussion, we elaborate on this important discrepancy with previous animal work. CONCLUSIONS/INTERPRETATION: Oral butyrate supplementation does not significantly affect innate or adaptive immunity in humans with longstanding type 1 diabetes. TRIAL REGISTRATION: Netherlands Trial Register: NL4832 (www.trialregister.nl). DATA AVAILABILITY: Raw sequencing data are available in the European Nucleotide Archive repository (https://www.ebi.ac.uk/ena/browse) under study PRJEB30292. FUNDING: The study was funded by a Le Ducq consortium grant, a CVON grant, a personal ZONMW-VIDI grant and a Dutch Heart Foundation grant.

10.
MAGMA ; 33(1): 73-80, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31471702

RESUMO

OBJECTIVES: Increased renal sinus fat (RSF) is associated with hypertension and chronic kidney disease, but underlying mechanisms are incompletely understood. We evaluated relations between RSF and gold-standard measures of renal hemodynamics in type 2 diabetes (T2D) patients. METHODS: Fifty-one T2D patients [age 63 ± 7 years; BMI 31 (28-34) kg/m2; GFR 83 ± 16 mL/min/1.73 m2] underwent MRI-scanning to quantify RSF volume, and subcutaneous and visceral adipose tissue compartments (SAT and VAT, respectively). GFR and effective renal plasma flow (ERPF) were determined by inulin and PAH clearances, respectively. Effective renal vascular resistance (ERVR) was calculated. RESULTS: RSF correlated negatively with GFR (r = - 0.38; p = 0.006) and ERPF (r = - 0.38; p = 0.006) and positively with mean arterial pressure (MAP) (r = 0.29; p = 0.039) and ERVR (r = 0.45, p = 0.001), which persisted after adjustment for VAT, MAP, sex, and BMI. After correction for age, ERVR remained significantly related to RSF. CONCLUSIONS: In T2D patients, higher RSF volume was negatively associated to GFR. In addition, RSF volume was positively associated with increased renal vascular resistance, which may mediate hypertension and CKD development. Further research is needed to investigate how RSF may alter the (afferent) vascular resistance of the renal vasculature.

11.
Nephrology (Carlton) ; 25(4): 290-297, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31429150

RESUMO

AIM: Increased plasma uric acid (PUA) concentrations are associated with chronic kidney disease in type 2 diabetes (T2D) patients. The mechanisms involved remain unclear. We investigated the relation between PUA and (intra)renal haemodynamics in T2D patients without overt kidney disease. METHODS: Eighty-eight white men and women with T2D were included (age 64 (58-68) years; body mass index 30.9 (28.3-33.6) kg/m2 ; glycated haemoglobin 7.1 (6.8-7.6)%). Plasma UA and fractional excretion of UA were measured, while glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were assessed by inulin and PAH-clearance techniques, respectively. Effective renal vascular resistance was calculated (ERVR). Renal afferent and efferent arteriolar resistances and glomerular hydrostatic pressure were estimated. Relationships between PUA and fractional excretion of UA and (intra)renal haemodynamic parameters were evaluated by multivariable linear regression analyses. RESULTS: Plasma UA concentrations were at the higher end of the normal range in most participants: 342 ± 68 µmol/L or 5.7 ± 1.1 mg/dL (mean ± SD). In multivariable analyses, PUA concentrations were negatively associated with GFR (r = -0.471; P = 0.001), ERPF (r = -0.436; P = 0.003) and glomerular hydrostatic pressure (r = -0.427; P = 0.003). In contrast, PUA concentrations had a positive correlation with ERVR (r = 0.474; P = 0.001), but not with efferent vascular resistance. Fractional excretion of UA was not related to renal haemodynamics. CONCLUSION: Plasma UA was negatively associated to GFR, ERPF but positively related to ERVR in T2D patients without overt renal impairment. Plasma UA-related increase in ERVR may be related to increased arterial afferent tone, which may put the kidney at risk for renal damage through ischaemia.

12.
Diabetes Care ; 43(1): 228-234, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31662305

RESUMO

OBJECTIVE: Impaired insulin sensitivity is associated with hyperfiltration (i.e., elevated glomerular filtration rate [GFR]) in adolescents with type 2 diabetes (T2D) and adults with prediabetes. Yet, these relationships are based on studies that relied on estimated GFR (eGFR), estimates of insulin sensitivity, or both. We aimed to verify the relationship between insulin sensitivity and renal hemodynamic function by gold standard methods in adults with T2D. RESEARCH DESIGN AND METHODS: Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp (M value) (glucose infusion rate in mg/kglean/min) and renal hemodynamic function by urinary inulin (GFR) and para-aminohippuric acid (effective renal plasma flow [ERPF]) clearances in participants with T2D without overt kidney disease. Filtration fraction (FF) (GFR/ERPF) was calculated. Relationships between insulin sensitivity and renal hemodynamic parameters were examined by multivariable linear regression. Renal hemodynamic parameters were examined across tertiles of M values. RESULTS: We tested 44 adults with T2D, of whom 77% were male, with mean ± SD age 63 ± 7 years, BMI 31.2 ± 4.0 kg/m2, and HbA1c 7.4 ± 0.6%. Average GFR was 110 ± 26 mL/min, with an FF of 22.1 ± 2.8% and median 24-h urinary albumin excretion of 11.3 mg (interquartile range 5.8-17.0). Average M value was 5.6 ± 2.9 mg/kglean/min. Insulin sensitivity inversely correlated with GFR (r = -0.44, P < 0.01) and FF (r = -0.40, P < 0.01), and these associations remained significant after multivariable adjustments for age, sex, renin-angiotensin system inhibitor use, and HbA1c. In addition, GFR, FF, and urinary albumin excretion were highest in the participants in the lowest M value tertile. CONCLUSIONS: For the first time, we demonstrate that impaired insulin sensitivity is associated with intrarenal hemodynamic dysfunction by gold standard techniques in adults with T2D treated with metformin monotherapy.

13.
Diabetes Care ; 43(1): 235-243, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31719053

RESUMO

OBJECTIVE: Poor sleep has been identified as a risk factor for poor glycemic control in individuals with type 2 diabetes (T2D). As optimal sleep can be characterized in several ways, we evaluated which sleep characteristics are most strongly associated with glycated hemoglobin A1c (HbA1c). RESEARCH DESIGN AND METHODS: A total of 172 patients with T2D completed 7-day wrist-actigraphy and sleep questionnaires. Linear regression was used to evaluate associations between sleep measures (total sleep duration, variability in sleep duration, midsleep time, variability in midsleep time, sleep efficiency, subjective sleep quality, and subjective insomnia symptoms) and HbA1c, individually and in concert. RESULTS: Variability in sleep duration was individually most strongly associated with HbA1c (ß = 0.239; P = 0.002; R 2 = 4.9%), followed by total sleep duration (U-shaped: ß = 1.161/ß2 = 1.044; P = 0.017/0.032; R 2 = 4.3%), subjective sleep quality (ß = 0.191; P = 0.012; R 2 = 3.6%), variability in midsleep time (ß = 0.184; P = 0.016; R 2 = 3.4%), and sleep efficiency (ß = -0.150; R 2 = 2.3%). Midsleep time and subjective insomnia symptoms were not associated with HbA1c. In combination, variability in sleep duration, total sleep duration, and subjective sleep quality were significantly associated with HbA1c, together explaining 10.3% of the variance in HbA1c. Analyses adjusted for covariates provided similar results, although the strength of associations was generally decreased and showing total sleep duration and subjective sleep quality to be most strongly associated with HbA1c, together explaining 6.0% of the variance in HbA1c. CONCLUSIONS: Sleep in general may be a modifiable factor of importance for patients with T2D. The prevention of sleep curtailment may serve as a primary focus in the sleep-centered management of T2D.

14.
Kidney Int ; 97(1): 202-212, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31791665

RESUMO

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve hard renal outcomes in type 2 diabetes. This is possibly explained by the fact that SGLT2i normalize the measured glomerular filtration rate (mGFR) by increasing renal vascular resistance, as was shown in young people with type 1 diabetes and glomerular hyperfiltration. Therefore, we compared the renal hemodynamic effects of dapagliflozin with gliclazide in type 2 diabetes. The mGFR and effective renal plasma flow were assessed using inulin and para-aminohippurate clearances in the fasted state, during clamped euglycemia (5 mmol/L) and during clamped hyperglycemia (15 mmol/L). Filtration fraction and renal vascular resistance were calculated. Additionally, factors known to modulate renal hemodynamics were measured. In 44 people with type 2 diabetes on metformin monotherapy (Hemoglobin A1c 7.4%, mGFR 113 mL/min), dapagliflozin versus gliclazide reduced mGFR by 5, 10, and 12 mL/min in the consecutive phases while both agents similarly improved Hemoglobin A1c (-0.48% vs -0.65%). Dapagliflozin also reduced filtration fraction without increasing renal vascular resistance, and increased urinary adenosine and prostaglandin concentrations. Gliclazide did not consistently alter renal hemodynamic parameters. Thus, beyond glucose control, SGLT2i reduce mGFR and filtration fraction in type 2 diabetes. The fact that renal vascular resistance was not increased by dapagliflozin suggests that this is due to post-glomerular vasodilation rather than pre-glomerular vasoconstriction.

15.
Endocr Rev ; 41(2)2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31633153

RESUMO

Diabetic kidney disease remains the most common cause of end-stage kidney disease in the world. Despite reductions in incidence rates of myocardial infarction and stroke in people with diabetes over the past 3 decades, the risk of diabetic kidney disease has remained unchanged, and may even be increasing in younger individuals afflicted with this disease. Accordingly, changes in public health policy have to be implemented to address the root causes of diabetic kidney disease, including the rise of obesity and diabetes, in addition to the use of safe and effective pharmacological agents to prevent cardiorenal complications in people with diabetes. The aim of this article is to review the mechanisms of pathogenesis and therapies that are either in clinical practice or that are emerging in clinical development programs for potential use to treat diabetic kidney disease.

17.
Curr Opin Nephrol Hypertens ; 29(1): 103-111, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31714285

RESUMO

PURPOSE OF REVIEW: Incretin-based therapies mimic or augment the gut-hormone glucagon-like peptide (GLP)-1 and, due to their glucose-lowering potential and beneficial safety profile, as well as their cardiovascular safety and/or protection, are prescribed on a large scale to treat individuals with type 2 diabetes (T2D). However, whether the two drug-classes that belong to this category, respectively GLP-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors, also reduce the risk of diabetic kidney disease (DKD) is at present heavily debated. This review aims to discuss the current evidence. RECENT FINDINGS: Evidence from land-mark cardiovascular safety trials, conducted in people with T2D at high-cardiovascular risk but with normal kidney function, suggest that both drug-classes have excellent renal safety profiles. In contrast to DPP-4 inhibitors, it seems that GLP-1 receptor agonists reduce albuminuria and possibly induce a reduction of estimated glomerular filtration rate decline. However, the trials were not properly designed to test renal outcomes. SUMMARY: A dedicated renal trial involving a GLP-1 receptor agonist has recently commenced and will answer the question whether these drugs will be effective to reduce DKD. Moreover, ongoing mechanism-of-action studies are focusing on the renal physiological effects of GLP-1, as the effects on particularly albuminuria reduction remain currently unexplained.

18.
Diabetes Obes Metab ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31742881

RESUMO

AIMS: Renin-angiotensin system inhibitors (RASi) are the most effective treatments for diabetic kidney disease but significant residual renal risk remains, possibly because of other mechanisms of kidney disease progression unrelated to RAS that may be present. Sodium-glucose co-transporter-2 inhibitors reduce albuminuria and may complement RASi by offering additional renal protection. This post hoc analysis investigated the effects of dapagliflozin on cardio-renal risk factors in patients with type 2 diabetes (T2D) with increased albuminuria treated with or without RASi at baseline. MATERIALS AND METHODS: We evaluated the effects of dapagliflozin 10 mg/day over 12-24 weeks across 13 placebo-controlled studies in patients with T2D with a urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g at baseline. Patients were divided into two subgroups based on treatment with or without RASi at baseline. RESULTS: Compared with patients with RASi at baseline (n = 957), patients without RASi (n = 302) were younger, had a shorter duration of diabetes (7 vs. 12 years), higher estimated glomerular filtration rate (eGFR) and lower UACR, serum uric acid (sUA), body weight and systolic blood pressure. Placebo-adjusted treatment effects of dapagliflozin on UACR, eGFR, glycated haemoglobin and haematocrit over 24 weeks were similar across groups. Mean reductions in body weight and sUA were more distinct in patients without RASi treatment at baseline. CONCLUSIONS: Treatment with dapagliflozin over 24 weeks provides similar clinically relevant improvements in metabolic and haemodynamic parameters, and similar reductions in UACR, in patients with T2D with elevated albuminuria treated with or without RASi at baseline.

19.
Nutrition ; 67-68: 110524, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31415908

RESUMO

OBJECTIVES: Excessive sodium intake, despite current dietary advice, remains a global issue with cardiovascular and renal consequences. The aim of this study was to determine whether glucagon-like peptide receptor agonists (GLP-1 RAs), used as antihyperglycemic agents for type 2 diabetes (T2DM) management, may reduce salt cravings as they are known to reduce hedonic feeding behavior and are involved in sodium homeostasis by increasing renal sodium excretion. METHODS: We performed exploratory analyses using data from two randomized, clinical crossover trials, which primarily aimed to assess the effects of GLP-1 RAs on central satiety and reward circuits and subsequent related feeding behavior. In study A, healthy, obese individuals and patients with T2DM were randomly assigned to receive intravenous administration of placebo or GLP-1 RA exenatide with or without concurrent GLP-1 receptor blockade, on separate testing days. In study B, individuals with T2DM randomly received GLP-1 RA liraglutide (titrated up to 1.8 mg daily) or titrated insulin glargine for 12 wk. In both studies, participants received an ad libitum mixed meal that served to calculate sodium intake. Moreover, salt craving was scored using a Likert scale. RESULTS: In study A, acute exenatide, parallel to reduced total food intake, reduced sodium intake in all studied groups by up to 30%. In study B, prolonged liraglutide treatment did not affect sodium or total caloric intake. Neither acute exenatide nor prolonged liraglutide treatment affected salt craving as measured by the Likert scale. CONCLUSION: Acute exenatide reduced sodium intake in light of a generalized reduction in food ingestion, while prolonged intervention with liraglutide did not lower sodium intake. Neither intervention affected salt craving. Given the known effects of these drugs on renal sodium excretion, blood pressure, and renal and cardiovascular outcome, it seems plausible to perform dedicated mechanistic studies in humans to assess the effects of GLP-1 RA administration on sodium balance.

20.
Ther Adv Endocrinol Metab ; 10: 2042018819865398, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31384419

RESUMO

Diabetic kidney disease (DKD) remains the main cause for chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide. Both CKD and ESKD lead to major increases in risk of cardiovascular disease and death in people with diabetes. Despite optimal management of lifestyle, glucose levels and hypertension, residual risk remains high, indicating that additional therapies to mitigate the burden of the disease are desired. In past decades, new treatment options for the management of diabetes have emerged, of which some have showed promising renoprotective potential. This review discusses current understanding of the renal effects of glucagon-like peptide receptor agonists and their potential use in prevention and treatment of DKD.

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