Kidney hemodynamic profile and systemic vascular function in adults with type 2 diabetes: Analysis of three clinical trials.

AIMS: Glomerular hyperfiltration plays a key role in the pathophysiology of diabetic kidney disease (DKD). Mechanisms underlying this adverse hemodynamic profile are incompletely understood. We hypothesized that systemic vascular pathology, including endothelial dysfunction and arterial stiffness, relates to glomerular hyperfiltration indicated by filtration fraction (FF). METHODS: Baseline data of three trials of overweight adults with type 2 diabetes (TD2, n = 111) with relatively well preserved kidney function were analyzed. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and FF, were assessed with gold-standard clearance techniques. Systemic vascular resistance (SVR), an indicator of endothelial dysfunction, and pulse pressure (PP), a measure of arterial stiffness, were derived from continuous beat-to-beat monitoring. RESULTS: SVR related negatively to GFR (ß: -0.382, p < 0.001) and ERPF (ß: -0.475, p < 0.001), and positively to FF (ß:0.369, p < 0.001). Associations between SVR, ERPF and FF persisted after multivariable adjustments.. PP was negatively related to ERPF (ß: -0.252, p = 0.008), and positively to FF (ß: 0.257, p = 0.006), of which the latter remained significant in multivariable regression. CONCLUSION: Parameters of systemic vascular pathology, including endothelial dysfunction and arterial stiffness, relate to an adverse kidney hemodynamic profile characterized by glomerular hyperfiltration, which predisposes to the development of DKD.

Postprandial renal haemodynamic effects of the dipeptidyl peptidase-4 inhibitor linagliptin versus the sulphonylurea glimepiride in adults with type 2 diabetes (RENALIS): A predefined substudy of a randomized, double-blind trial.

AIM: To determine the effect of the dipeptidyl peptidase-4 inhibitor linagliptin on postprandial glomerular hyperfiltration compared with the sulphonylurea glimepiride in adults with type 2 diabetes (T2D). MATERIALS AND METHODS: In this predefined substudy within a randomized, double-blind, parallel-group, intervention trial, overweight people with T2D without renal impairment were treated with once-daily linagliptin 5 mg (N = 10) or glimepiride 1 mg (N = 13) as an add-on to metformin for 8 weeks. After a standardized liquid protein-rich meal, the glomerular filtration rate (GFR) and effective renal plasma flow were determined by inulin and para-aminohippuric acid clearance, respectively, based on timed urine sampling. Intrarenal haemodynamics were estimated using the Gomez equations. Glucoregulatory/vasoactive hormones, urinary pH and fractional excretions (FE) of sodium, potassium and urea were measured. RESULTS: Compared with glimepiride, linagliptin increased the postprandial filtration fraction (FF; mean difference 2.1%-point; P = .016) and estimated glomerular hydraulic pressure (mean difference 3.0 mmHg; P = .050), and tended to increase GFR (P = .08) and estimated efferent renal arteriolar resistance (RE ; P = .08) from baseline to week 8. No differences in FE were noted. Glimepiride reduced HbA1c more than linagliptin (mean difference -0.40%; P = .004), without between-group differences in time-averaged postprandial glucose levels. In the linagliptin group, change in FF correlated with change in mean arterial pressure (R = 0.807; P = .009) and time-averaged mean glucagon (R = 0.782; P = .008), but not with changes in glucose, insulin, intact glucagon-like peptide-1, renin or FENa . Change in glucagon was associated with change in RE (R = 0.830; P = .003). CONCLUSIONS: In contrast to our hypothesis, compared with glimepiride, linagliptin does not reduce postprandial hyperfiltration, yet appears to increase FF after meal ingestion by increasing blood pressure or RE .

The effect of liraglutide and sitagliptin on oxidative stress in persons with type 2 diabetes.

Glucagon-like peptide 1 receptor agonists have shown cardioprotective effects which have been suggested to be mediated through inhibition of oxidative stress. We investigated the effect of treatment with a glucagon-like peptide 1 receptor agonist (liraglutide) on oxidative stress measured as urinary nucleic acid oxidation in persons with type 2 diabetes. Post-hoc analysis of two independent, randomised, placebo-controlled and double-blinded clinical trials. In a cross-over study where persons with type 2 diabetes and microalbuminuria (LIRALBU, n = 32) received liraglutide (1.8 mg/day) or placebo for 12 weeks in random order, separated by 4 weeks of wash-out. In a parallel-grouped study where obese persons with type 2 diabetes (SAFEGUARD, n = 56) received liraglutide (1.8 mg/day), sitagliptin (100 mg/day) or placebo for 12 weeks. Endpoints were changes in the urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG)) and RNA oxidation [8-oxo-7,8-dihydroguanosine (8-oxoGuo)]. In LIRALBU, we observed no significant differences between treatment periods in urinary excretion of 8-oxodG [0.028 (standard error (SE): 0.17] nmol/mmol creatinine, p = 0.87) or of 8-oxoGuo [0.12 (0.12) nmol/mmol creatinine, p = 0.31]. In SAFEGUARD, excretion of 8-oxodG was not changed in the liraglutide group [2.8 (- 8.51; 15.49) %, p = 0.62] but a significant decline was demonstrated in the placebo group [12.6 (- 21.3; 3.1) %, p = 0.02], resulting in a relative increase in the liraglutide group compared to placebo (0.16 nmol/mmol creatinine, SE 0.07, p = 0.02). Treatment with sitagliptin compared to placebo demonstrated no significant difference (0.07 (0.07) nmol/mmol creatinine, p = 0.34). Nor were any significant differences for urinary excretion of 8-oxoGuo liraglutide vs placebo [0.09 (SE: 0.07) nmol/mmol creatinine, p = 0.19] or sitagliptin vs placebo [0.07 (SE: 0.07) nmol/mmol creatinine, p = 0.35] observed. This post-hoc analysis could not demonstrate a beneficial effect of 12 weeks of treatment with liraglutide or sitagliptin on oxidatively generated modifications of nucleic acid in persons with type 2 diabetes.

Kidney hemodynamic function in men and postmenopausal women with type 2 diabetes and preserved kidney function.

The progression of kidney disease may differ between sexes in type 2 diabetes (T2D), with previous studies reporting a slower decline in women. Glomerular hyperfiltration is a key factor driving the kidney function decline. The current study aimed to investigate the differences in kidney hemodynamic function between men and women with T2D. A cross-sectional analysis of pooled data from three studies compared kidney hemodynamic function between men and postmenopausal women with T2D without overt nephropathy. The outcome measures were glomerular filtration rate (GFR; inulin clearance), effective renal plasma flow (ERPF; p-aminohippurate clearance), filtration fraction (GFR/ERPF), and renal vascular resistance (RVR; mean arterial pressure/renal blood flow). Glomerular hydraulic pressure (PGLO) as well as afferent and efferent vascular resistance were estimated by Gomez formulae. Sex differences were assessed with linear regression models adjusted for systolic blood pressure, glucose, use of renin-angiotensin system blockers, and body mass index. In total, 101 men [age: 63 (58-68) yr, body mass index: 31.5 ± 3.9 kg/m2, GFR: 111 ± 18 mL/min, HbA1c: 7.4 ± 0.7%] and 27 women [age: 66 (62-69) yr, body mass index: 30.9 ± 4.5 kg/m2, GFR: 97 ± 11 mL/min, HbA1c: 7.1 ± 0.5%] were included. GFR was higher in men versus women [11.0 mL/min (95% confidence interval: 3.6, 18.4)]. Although statistically nonsignificant, PGLO trended higher in men [1.9 mmHg (95% confidence interval: -0.1, 4.0)], whereas RVR [-0.012 mmHg/L/min (95% confidence interval: -0.022, -0.002)] and afferent vascular resistance were lower [-361 dyn/s/cm5 (95% confidence interval: -801, 78)]. In conclusion, in adults without overt nephropathy, GFR was higher in men compared with women. PGLO also trended to be higher in men. Both findings are possibly related to afferent vasodilation and suggest greater prevalence of hyperfiltration. This could contribute to accelerated GFR loss over time in men with T2D.NEW & NOTEWORTHY In adults with type 2 diabetes, men had higher markers of hyperfiltration, which could potentially explain the accelerated progression of diabetic kidney disease in men compared with women.

Effects of DPP-4 Inhibitor Linagliptin Versus Sulfonylurea Glimepiride as Add-on to Metformin on Renal Physiology in Overweight Patients With Type 2 Diabetes (RENALIS): A Randomized, Double-Blind Trial.

OBJECTIVE: To compare effects of the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin with those of a sulfonylurea on renal physiology in metformin-treated patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: In this double-blind randomized trial, 46 overweight T2DM patients without renal impairment received once-daily linagliptin (5 mg) or glimepiride (1 mg) for 8 weeks. Fasting glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid clearances. Fractional excretions, urinary damage markers, and circulating DPP-4 substrates (among others, glucagon-like peptide 1 and stromal cell-derived factor-1α [SDF-1α]) were measured. RESULTS: HbA1c reductions were similar with linagliptin (-0.45 ± 0.09%) and glimepiride (-0.65 ± 0.10%) after 8 weeks (P = 0.101). Linagliptin versus glimepiride did not affect GFR, ERPF, estimated intrarenal hemodynamics, or damage markers. Only linagliptin increased fractional excretion (FE) of sodium (FENa) and potassium, without affecting FE of lithium. Linagliptin-induced change in FENa correlated with SDF-1α (R = 0.660) but not with other DPP-4 substrates. CONCLUSIONS: Linagliptin does not affect fasting renal hemodynamics compared with glimepiride in T2DM patients. DPP-4 inhibition promotes modest natriuresis, possibly mediated by SDF-1α, likely distal to the macula densa.

Effects of dipeptidyl peptidase-4 inhibitor linagliptin versus sulphonylurea glimepiride on systemic haemodynamics in overweight patients with type 2 diabetes: A secondary analysis of an 8-week, randomized, controlled, double-blind trial.

AIM: To determine the glucose-independent effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin versus the sulphonylurea glimepiride on systemic haemodynamics in the fasting and postprandial state in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: In this prespecified secondary analysis of a phase IV, double-blind trial, 46 metformin-treated, overweight patients with T2D were included and randomly assigned (1:1) to once-daily linagliptin (5 mg) or glimepiride (1 mg) for 8 weeks. In a sub-study involving 26 patients, systemic haemodynamics were also assessed following a standardized liquid meal (Nutridrink Yoghurt style). Systemic haemodynamics (oscillometric device and finger photoplethysmography), arterial stiffness (applanation tonometry) and cardiac sympathovagal balance (heart rate variability [HRV]) were measured in the fasting state and repetitively following the meal. Ewing tests were performed in the fasting state. RESULTS: From baseline to week 8, linagliptin compared with glimepiride did not affect systemic haemodynamics, arterial stiffness or HRV in the fasting state. Linagliptin increased parasympathetic nervous activity, as measured by the Valsalva manoeuvre (P = .021) and deep breathing test (P = .027) compared with glimepiride. Postprandially, systolic blood pressure (SBP) dropped an average of 7.6 ± 1.6 mmHg. Linagliptin reduced this decrease to 0.7 ± 2.3 mmHg, which was significant to glimepiride (P = .010). CONCLUSIONS: When compared with glimepiride, linagliptin does not affect fasting blood pressure. However, linagliptin blunted the postprandial drop in SBP, which could benefit patients with postprandial hypotension.

Renal sinus fat and renal hemodynamics: a cross-sectional analysis.

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.

Plasma uric acid and renal haemodynamics in type 2 diabetes patients.

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.

The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial.

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.

GLP-1 receptor agonists do not affect sodium intake: Exploratory analyses from two randomized clinical trials.

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.

Assessment of real-time and quantitative changes in renal hemodynamics in healthy overweight males: Contrast-enhanced ultrasonography vs para-aminohippuric acid clearance.

OBJECTIVE: To determine the ability of renal contrast-enhanced ultrasonography (CEUS) to detect acute drug-induced changes in renal perfusion (using the glucagon-like peptide (GLP)-1 receptor agonist exenatide and nitric oxide [NO]-synthase inhibitor L-NG -monomethyl arginine [l-NMMA]), and assess its correlation with gold standard-measured effective renal plasma flow in humans. METHODS: In this prespecified exploratory analysis of a placebo-controlled cross-over study, renal hemodynamics was assessed in 10 healthy overweight males (aged 20-27 years; BMI 26-31 kg/m2 ) over two separate testing days; during placebo (isotonic saline) and subsequent exenatide infusion (Day-A), and during l-NMMA, and subsequent exenatide plus l-NMMA infusion (Day-B). Renal cortical microvascular blood flow was estimated following microbubble infusion and CEUS destruction-refilling-sequences. Renal cortical microvascular blood flow was compared with simultaneously measured effective renal plasma flow in humans, derived from para-aminohippuric acid-clearance methodology. RESULTS: On Day-A, effective renal plasma flow increased by 68 [26-197] mL/min/1.73 m2 during exenatide vs placebo infusion (+17%; P = .015). In parallel, exenatide increased renal cortical microvascular blood flow, from 2.42 × 10-4 [6.54 × 10-5 -4.66 × 10-4 ] AU to 4.65 × 10-4 [2.96 × 10-4 -7.74 × 10-4 ] AU (+92%; P = .027). On Day-B, effective renal plasma flow and renal cortical microvascular blood flow were reduced by l-NMMA, with no significant effect of concomitant exenatide on renal hemodynamic-indices assessed by either technique. Effective renal plasma flow correlated with renal cortical microvascular blood flow on Day-A (r = .533; P = .027); no correlation was found on Day-B. CONCLUSIONS: Contrast-enhanced ultrasonography can detect acute drug-induced changes human renal hemodynamics. CEUS-assessed renal cortical microvascular blood flow moderately associates with effective renal plasma flow, particularly when perfusion is in normal-to-high range. Renal CEUS cannot replace effective renal plasma flow measurements, but may be a complementary tool to characterize regional kidney perfusion.

Renal tubular effects of prolonged therapy with the GLP-1 receptor agonist lixisenatide in patients with type 2 diabetes mellitus.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are well-established glucose-lowering drugs for type 2 diabetes mellitus (T2DM) management. Acute GLP-1RA administration increases urinary excretion of sodium and other electrolytes. However, the renal tubular effects of prolonged GLP-1RA treatment are largely unknown. In this secondary analysis of a randomized trial, we determined the renal tubular effects of 8-wk treatment with 20 µg lixisenatide, a short-acting (prandial) GLP-1RA, versus titrated once-daily insulin glulisine in 35 overweight T2DM-patients on stable insulin glargine background therapy (age: 62 ± 7 yr, glycated hemoglobin: 8.0 ± 0.9%, estimated glomerular filtration rate: >60 ml·min-1·1.73 m-2). After a standardized breakfast, lixisenatide increased absolute and fractional excretions of sodium, chloride, and potassium and increased urinary pH. In contrast, lixisenatide reduced absolute and fractional excretions of magnesium, calcium, and phosphate. At week 8, patients treated with lixisenatide had significantly more phosphorylated sodium-hydrogen exchanger isoform 3 (NHE3) in urinary extracellular vesicles than those on insulin glulisine treatment, which suggested decreased NHE3 activity in the proximal tubule. A rise in postprandial blood pressure with lixisenatide partly explained the changes in the urinary excretion of sodium, potassium, magnesium, and phosphate and the changes in urinary pH. In conclusion, lixisenatide affects postprandial urinary excretion of several electrolytes and increases urinary pH compared with insulin glulisine in T2DM patients after 8 wk of treatment. This is most likely explained by a drug-induced rise in blood pressure or direct inhibitory effects on NHE3 in the proximal tubule.

Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial.

BACKGROUND: The results of the ELIXA trial demonstrated the cardiovascular safety of lixisenatide, a short-acting glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes and acute coronary syndrome. In this exploratory analysis of ELIXA, we investigate the effect of lixisenatide on renal outcomes. METHODS: ELIXA was a randomised, double-blind, placebo-controlled trial, done at 828 sites in 49 countries. Patients with type 2 diabetes and a recent coronary artery event were randomly assigned (1:1) to a daily subcutaneous injection of lixisenatide (10-20 µg) or volume-matched placebo, in addition to usual care, until at least 844 patients had an adjudicated major adverse cardiovascular event included in the primary outcome. Patients, study staff, and individuals involved in analysis of trial data were masked to treatment assignment. The primary and secondary endpoints of this trial have been reported previously. Here, in an exploratory analysis of ELIXA, we investigated percentage change in urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) according to prespecified albuminuria status at baseline (normoalbuminuria [UACR <30 mg/g]; microalbuminuria [≥30 to ≤300 mg/g]; and macroalbuminuria [>300 mg/g]) using a mixed-effect model with repeated measures. Time to new-onset macroalbuminuria and doubling of serum creatinine were also assessed with Cox proportional hazards models. The ELIXA trial is registered with ClinicalTrials.gov, number NCT01147250, and is completed. FINDINGS: Of 6068 patients randomly allocated between July 9, 2010, and Aug 2, 2013, baseline UACR data were available for 5978 (99%). Median follow-up time was 108 weeks. 4441 (74%; 2191 assigned to placebo and 2250 assigned to lixisenatide) had normoalbuminuria, 1148 (19%; 596 assigned to placebo and 552 assigned to lixisenatide) had microalbuminuria, and 389 (7%; 207 assigned to placebo and 182 assigned to lixisenatide) had macroalbuminuria. After 108 weeks, the placebo-adjusted least-squares mean percentage change in UACR from baseline with lixisenatide was -1·69% (95% CI -11·69 to 8·30; p=0·7398) in patients with normoalbuminuria, -21·10% (-42·25 to 0·04; p=0·0502) in patients with microalbuminuria, and -39·18% (-68·53 to -9·84; p=0·0070) in patients with macroalbuminuria. Lixisenatide was associated with a reduced risk of new-onset macroalbuminuria compared with placebo when adjusted for baseline HbA1c (hazard ratio [HR] 0·808 [95% CI 0·660 to 0·991; p=0·0404]) or baseline and on-trial HbA1c (HR 0·815 [0·665 to 0·999; p=0·0491]); point estimates were similar when adjusted for other traditional renal risk factors. At week 108, the largest eGFR decline from baseline was observed in the macroalbuminuric group, but no significant differences were observed between the two treatment groups. No significant differences in eGFR decline were identified between treatment groups in any UACR subgroup. In the trial safety population, doubling of serum creatinine occurred in 35 (1%) of 3032 patients in the placebo group and 41 (1%) of 3031 patients in the lixisenatide group (HR 1·163, 95% CI 0·741-1·825; p=0·5127). As previously reported in the ELIXA trial, the proportion of patients with renal adverse events was low (48 [1·6%] of 3032 patients in the placebo group vs 48 [1·6%] of 3031 patients in the lixisenatide group) and did not significantly differ between treatment groups. INTERPRETATION: Lixisenatide reduces progression of UACR in macroalbuminuric patients, and is associated with a lower risk of new-onset macroalbuminuria after adjustment for baseline and on-trial HbA1c and other traditional renal risk factors. FUNDING: Sanofi.

Lixisenatide Versus Insulin Glulisine on Fasting and Postbreakfast Systemic Hemodynamics in Type 2 Diabetes Mellitus Patients.

The prolonged treatment effects of a short-acting GLP-1RA (glucagon-like peptide-1 receptor agonist), such as lixisenatide, on fasting and postprandial systemic hemodynamics in type 2 diabetes mellitus patients are unknown. In this secondary analysis, we included 34 overweight insulin glargine-treated type 2 diabetes mellitus patients (mean±SD age, 62±7 years; HbA1c, 8.0±0.9%; systolic blood pressure [BP], 133.9±16.1 mm Hg; diastolic BP, 75.4±8.39 mm Hg) that were randomized to once-daily lixisenatide 20 µg or once-daily titrated insulin glulisine for 8 weeks. Systemic hemodynamics (oscillometric device and finger photoplethysmography), arterial stiffness (applanation tonometry), and cardiac sympathovagal balance (heart rate variability) were measured in the fasting state and repetitively (up to minute 175) after a standardized mixed breakfast. Acetaminophen was given orally to estimate gastric emptying rate. Lixisenatide did not affect fasting systemic hemodynamics compared with insulin glulisine from baseline to week 8. Postbreakfast overall, lixisenatide compared with insulin glulisine tended to increase systolic BP by 5.2±2.9 mm Hg (P=0.087) and increased diastolic BP by 5.4±1.4 mm Hg (P<0.001), with respective maximal differences of +10.2±3.7 mm Hg (P=0.007) and +7.2±1.5 mm Hg (P<0.001). Lixisenatide increased systemic vascular resistance (P<0.001) and arterial stiffness (P=0.007). No between-group differences in overall postbreakfast heart rate, cardiac output, or cardiac sympathovagal balance, and circulating catecholamines, angiotensin II, or aldosterone were observed. Both treatments lowered HbA1c similarly, whereas lixisenatide achieved greater reductions in postbreakfast plasma glucose excursions. Lixisenatide slowed gastric emptying rate, which statistically explained changes in postbreakfast BP. Lixisenatide compared with once-daily titrated insulin glulisine for 8 weeks does not affect fasting but increases postbreakfast BP in insulin glargine-treated type 2 diabetes mellitus patients. This effect could, at least in part, be explained by reduced passage rate of nutrients and water and activation of the gastrovascular reflex.

Effect of immediate and prolonged GLP-1 receptor agonist administration on uric acid and kidney clearance: Post-hoc analyses of four clinical trials.

AIMS: To determine the effects of glucagon-like peptide (GLP)-1 receptor agonists (RA) on uric acid (UA) levels and kidney UA clearance. MATERIAL AND METHODS: This study involved post-hoc analyses of 4 controlled clinical trials, which assessed actions of GLP-1RA administration on kidney physiology. The immediate effects of GLP-1RA exenatide infusion vs placebo were determined in 9 healthy overweight men (Study-A) and in 52 overweight T2DM patients (Study-B). The effects of 12 weeks of long-acting GLP-1RA liraglutide vs placebo in 36 overweight T2DM patients (Study-C) and of 8 weeks of short-acting GLP-1RA lixisenatide vs once-daily titrated insulin glulisine in 35 overweight T2DM patients (Study-D) were also examined. Plasma UA, fractional (inulin-corrected) and absolute urinary excretion of UA (UEUA ) and sodium (UENa ), and urine pH were determined. RESULTS: Median baseline plasma UA level was 5.39 to 6.33 mg/dL across all studies (17%-22% of subjects were hyperuricaemic). In Study-A, exenatide infusion slightly increased plasma UA (+0.07 ± 0.02 mg/dL, P = .04), and raised absolute-UEUA (+1.58 ± 0.65 mg/min/1.73 m2 , P = .02), but did not affect fractional UEUA compared to placebo. Fractional UEUA and absolute UEUA correlated with increases in urine pH (r:0.86, P = .003 and r:0.92, P < .001, respectively). Fractional UEUA correlated with increased fractional UENa (r:0.76, P = .02). In Study-B, exenatide infusion did not affect plasma UA, but increased fractional UEUA (+0.76 ± 0.38%, P = .049) and absolute UEUA (+0.75 ± 0.27 mg/min/1.73 m2 , P = .007), compared to placebo. In regression analyses, both parameters were explained by changes in urine pH and, in part, by changes in UENa . In Study-C, liraglutide treatment did not affect plasma UA, UEUA, UENa or urine pH, compared to placebo. In Study-D, lixisenatide treatment increased UENa and urine pH from baseline, but did not affect plasma UA or UEUA . CONCLUSION: Immediate exenatide infusion increases UEUA in overweight healthy men and in T2DM patients, probably by inhibiting Na+ /H+ -exchanger type-3 in the renal proximal tubule. Prolonged treatment with a long-acting or short-acting GLP-1RA does not affect plasma UA or UEUA in T2DM patients with normal plasma UA levels and at relatively low cardiovascular risk. Our results suggest that the cardio-renal benefits of GLP-1RA are not mediated through changes in UA.

GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes.

The gastrointestinal tract - the largest endocrine network in human physiology - orchestrates signals from the external environment to maintain neural and hormonal control of homeostasis. Advances in understanding entero-endocrine cell biology in health and disease have important translational relevance. The gut-derived incretin hormone glucagon-like peptide 1 (GLP-1) is secreted upon meal ingestion and controls glucose metabolism by modulating pancreatic islet cell function, food intake and gastrointestinal motility, amongst other effects. The observation that the insulinotropic actions of GLP-1 are reduced in type 2 diabetes mellitus (T2DM) led to the development of incretin-based therapies - GLP-1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors - for the treatment of hyperglycaemia in these patients. Considerable interest exists in identifying effects of these drugs beyond glucose-lowering, possibly resulting in improved macrovascular and microvascular outcomes, including in diabetic kidney disease. As GLP-1 has been implicated as a mediator in the putative gut-renal axis (a rapid-acting feed-forward loop that regulates postprandial fluid and electrolyte homeostasis), direct actions on the kidney have been proposed. Here, we review the role of GLP-1 and the actions of associated therapies on glucose metabolism, the gut-renal axis, classical renal risk factors, and renal end points in randomized controlled trials of GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM.