Exposure-Response Analysis of the Sodium-Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 Diabetes.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve markers for renal and cardiovascular outcomes in patients with and without type 2 diabetes (T2D). To assess whether individual differences in plasma drug exposure can explain inter-individual response variation, we characterized the exposure-response relationship for two SGLT2 inhibitors on several clinical and kidney hemodynamic variables. Data were obtained from two studies, RED and RECOLAR, assessing the effects of once-daily 10 mg dapagliflozin or empagliflozin, respectively, on kidney hemodynamics in patients with T2D. Individual plasma exposure was estimated using non-compartmental analyses and exposure-response relationships were assessed using linear mixed-effects models. In 23 patients participating in RED, the dapagliflozin geometric mean apparent area under the concentration-time curve during one dosing interval at steady state (AUC0-tau,ss) was 1153.1 µg/L*h (coefficient of variation (CV) 81.8%) and associated, per doubling, with decreases in body weight (0.29 kg, p < 0.001), systolic blood pressure (0.80 mmHg, p = 0.002), measured glomerular filtration rate (mGFR) (0.83 mL/min, p = 0.03), and filtration fraction (0.09%, p = 0.04). In 20 patients participating in RECOLOR, the empagliflozin geometric mean AUC0-tau,ss was 2035.7 nmol/L*h (CV 48.4%) and associated, per doubling, with decreases in body weight (0.13 kg, p = 0.002), systolic blood pressure (0.65 mmHg, p = 0.045), and mGFR (0.78 mL/min, p = 0.002). To conclude, dapagliflozin and empagliflozin plasma exposure was highly variable between patients and associated with inter-individual variation in response variables.

Mechanisms underlying the blood pressure-lowering effects of empagliflozin, losartan and their combination in people with type 2 diabetes: A secondary analysis of a randomized crossover trial.

AIM: To study the effects of the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin, the angiotensin receptor blocker (ARB) losartan, and their combination on blood pressure, while studying the mechanisms potentially involved. METHODS: A total of 24 people with type 2 diabetes (T2D) (age: 66 ± 6 years; body mass index: 31.0 ± 3 kg/m2 ; estimated glomerular filtration rate: 90 ml/min/1.73m2 ) received a 1-week treatment with empagliflozin 10 mg once daily, losartan 50 mg once daily, their combination, and placebo, in a randomized double-blind crossover design, with 4-week washout periods in between. Blood pressure, arterial stiffness, autonomic nervous system activity and plasma volume, extracellular fluid and serum albumin were assessed. RESULTS: Versus placebo (139 mmHg), empagliflozin reduced systolic blood pressure (SBP) by 8 mmHg (P = .001), losartan by 12 mmHg (P = .001) and empagliflozin + losartan by 15 mmHg (P < .001). Combination therapy had a larger SBP-lowering effect versus empagliflozin monotherapy (-7 [95% CI -12; -2] mmHg) and numerically larger effects versus losartan monotherapy (-3 [-8; 2] mmHg). Empagliflozin reduced sympathetic nervous system (SNS) activity, arterial stiffness and extracellular fluid, while increasing serum albumin. Losartan reduced SNS activity and arterial stiffness. Combination therapy induced volume contraction variables, together with a reduction in SNS activity and arterial stiffness. CONCLUSION: In people with T2D, SGLT2 inhibition in combination with an ARB had a larger blood pressure-lowering effect versus placebo than either of the drugs alone. Our data further suggest that the mechanisms underlying these blood pressure reductions at least partially differ between these agents.

The Adaptive Renal Response for Volume Homeostasis During 2 Weeks of Dapagliflozin Treatment in People With Type 2 Diabetes and Preserved Renal Function on a Sodium-Controlled Diet.

Introduction: Proximal tubule sodium uptake is diminished following sodium glucose cotransporter 2 (SGLT2) inhibition. We previously showed that during SGLT2 inhibition, the kidneys adapt by increasing sodium uptake at distal tubular segments, thereby maintaining body sodium balance. Despite continuous glycosuria, we detected no increased urine volumes. We therefore assessed the adaptive renal responses to prevent excessive fluid loss. Methods: We conducted a mechanistic open-label study in people with type 2 diabetes mellitus with preserved kidney function, who received a standardized sodium intake (150 mmol/d) to evaluate the effects of dapagliflozin on renin-angiotensin-aldosterone system (RAAS) hormones, volume-related biomarkers, urinary albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR), at start of treatment (day 4), end of treatment (day 14), and follow-up (day 18). Results: A total of 14 people were enrolled. Plasma renin and angiotensin II and urinary aldosterone and angiotensinogen were acutely and persistently increased during treatment with dapagliflozin. Plasma copeptin level was numerically increased after 4 days (21%). Similarly, fractional urea excretion was significantly decreased at start of treatment (-17%). Free water clearance was significantly decreased after 4 days (-74%) and 14 days (-41%). All changes reversed after dapagliflozin discontinuation. Conclusion: Dapagliflozin-induced osmotic diuresis triggers kidney adaptive mechanisms to maintain volume and sodium balance in people with type 2 diabetes and preserved kidney function. ClinicalTrials.gov (identification: NCT03152084).

Sodium glucose cotransporter-2 inhibitors protect the cardiorenal axis: Update on recent mechanistic insights related to kidney physiology.

Sodium glucose cotransporter-2 (SGLT2) inhibitors have acquired a central role in the treatment of type 2 diabetes, chronic kidney disease including diabetic kidney disease, and heart failure with reduced ejection fraction. SGLT2 inhibitors lower glucose levels by inducing glycosuria. In addition, SGLT2 inhibitors improve cardiovascular outcomes (3-point MACE), end-stage kidney disease, hospitalization for heart failure, and cardiovascular mortality in people with and without diabetes. The mechanisms underlying these benefits have been extensively investigated, but remain poorly understood. In this review, we first summarize recent trial evidence and subsequently focus on (1) the mechanisms by which SGLT2 inhibitors improve kidney outcomes and (2) the potential role of the kidneys in mediating the cardioprotective effects of SGLT2 inhibitors.

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.

Skin microvascular function and renal hemodynamics in overweight patients with type 2 diabetes: A cross-sectional study.

OBJECTIVE: Diabetic kidney disease is a microvascular complication of diabetes. Here, we assessed the association between skin microvascular function and renal hemodynamic function in a cohort of well-phenotyped adults with type 2 diabetes (T2D). METHODS: We included 81 overweight/obese adults (age: 62 ± 8 years; BMI: 32 ± 4 kg/m2 ) with well-controlled T2D and no renal impairment. Skin microvascular function was assessed by nailfold capillary density in rest and after arterial occlusion (ie, peak capillary density). Renal hemodynamic functions (ie, measured glomerular filtration rate [mGFR], effective renal blood flow [ERBF], filtration fraction [FF], and effective renal vascular resistance [ERVR]) were assessed by combined inulin and para-aminohippurate clearances and blood pressure measurements. RESULTS: Skin capillary density was 45 ± 10 capillaries/mm2 at baseline and 57 ± 11 capillaries/mm2 during post-occlusive peak; mGFR averaged 108 ± 20 ml/min. In multivariable regression analyses, positive associations between capillary density during post-occlusive peak and mGFR (ß = 0.224; p = 0.022) and ERBF (ß = 0.203; p = 0.020) and a positive trend for hyperemia and mGFR (ß = 0.391; p = 0.053) were observed, while a negative association for post-occlusive capillary density with ERVR (ß = -0.196; p = 0.027) was found. CONCLUSION: These findings indicate that microvascular dysfunction in overweight adults with T2D is associated with lower mGFR and ERPF and higher ERVR. We hypothesize that increased renal vascular resistance may contribute to glomerular dysfunction due to impaired renal perfusion.

Poor Taste and Smell Are Associated with Poor Appetite, Macronutrient Intake, and Dietary Quality but Not with Undernutrition in Older Adults.

BACKGROUND: Age-related declines in taste and smell function are widely assumed to contribute to the decrease in appetite and the development of undernutrition in older adults. OBJECTIVES: Here we aim to assess the associations of both taste and smell function with several nutrition-related outcomes in a single study, with poor appetite and undernutrition as primary outcomes. METHODS: This is a cross-sectional cohort study of 359 community-dwelling Dutch older adults, aged 65-93 y. Taste function was measured for all 5 basic tastes. Smell function was assessed with 3 tests: for odor identification, discrimination, and threshold. Self-reported taste and smell, appetite, energy (kcal/d) and macronutrient (% energy) intake, and covariates were assessed with extensive questionnaires. Dietary quality was calculated using the Dutch Healthy Diet index 2015, Alternative Healthy Eating Index 2010, and Mediterranean Diet Score. Body measurements included body weight (current and 2 y prior), height, and body impedance analysis. Data were analyzed via multiple logistic and linear regression. RESULTS: Of our sample, 9.2% had poor taste and 17.0% poor smell, 6.1% had poor appetite, and 21.4% were undernourished. Self-reported poor taste (OR: 8.44; 95% CI: 1.56, 45.56; P = 0.013) was associated with poor appetite, but no other taste or smell score was associated with either poor appetite or undernutrition. Some associations were found of individual taste and smell scores with macronutrient intake and dietary quality. Self-reported poor taste and smell were both consistently associated with poorer dietary quality. CONCLUSIONS: In community-dwelling older adults, specific taste and smell impairments may have diverse consequences for appetite, food intake, or dietary quality. However, this does not necessarily result in undernutrition. The consistent associations of self-reported poor taste and smell with poor dietary quality do underline the usefulness of this information when screening for nutritional risk.

Natriuretic Effect of Two Weeks of Dapagliflozin Treatment in Patients With Type 2 Diabetes and Preserved Kidney Function During Standardized Sodium Intake: Results of the DAPASALT Trial.

OBJECTIVE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk for heart failure hospitalization potentially by inducing sodium excretion, osmotic diuresis, and plasma volume contraction. Few studies have investigated this hypothesis, but none have assessed cumulative sodium excretion with SGLT2 inhibition during standardized sodium intake in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The DAPASALT trial was a mechanistic, nonrandomized, open-label study in patients with type 2 diabetes with preserved kidney function on a controlled standardized sodium diet (150 mmol/day). It evaluated the effects of dapagliflozin on sodium excretion, 24-h blood pressure, and extracellular, intracellular, and plasma volumes at the start of treatment (ST) (days 2-4), end of treatment (ET) (days 12-14), and follow-up (FU) (days 15-18). RESULTS: Fourteen patients were included in the efficacy analysis. Mean (SD) baseline sodium excretion (150 [32] mmol/24-h) did not significantly change during treatment (change at ST: -7.0 mmol/24-h [95% CI -22.4, 8.4]; change at ET: 2.1 mmol/24-h [-28.8, 33.0]). Mean baseline 24-h systolic blood pressure was 128 (10) mmHg and significantly reduced at ST (-6.1 mmHg [-9.1, -3.1]; P < 0.001) and ET (-7.2 mmHg [-10.0, -4.3]; P < 0.001). Dapagliflozin did not significantly alter plasma volume or intracellular volume, while extracellular volume changed at ST (-0.7 L [-1.3, -0.1]; P = 0.02). As expected, 24-h urinary glucose excretion significantly increased during dapagliflozin treatment and reversed during FU. CONCLUSIONS: During standardized sodium intake, dapagliflozin reduced blood pressure without clear changes in urinary sodium excretion, suggesting that factors other than natriuresis and volume changes may contribute to the blood pressure-lowering effects.

The role of renal hypoxia in the pathogenesis of diabetic kidney disease: a promising target for newer renoprotective agents including SGLT2 inhibitors?

Diabetic kidney disease is the most common cause of end-stage kidney disease and poses a major global health problem. Finding new, safe, and effective strategies to halt this disease has proven to be challenging. In part that is because the underlying mechanisms are complex and not fully understood. However, in recent years, evidence has accumulated suggesting that chronic hypoxia may be the primary pathophysiological pathway driving diabetic kidney disease and chronic kidney disease of other etiologies and was called the chronic hypoxia hypothesis. Hypoxia is the result of a mismatch between oxygen delivery and oxygen demand. The primary determinant of oxygen delivery is renal perfusion (blood flow per tissue mass), whereas the main driver of oxygen demand is active sodium reabsorption. Diabetes mellitus is thought to compromise the oxygen balance by impairing oxygen delivery owing to hyperglycemia-associated microvascular damage and exacerbate oxygen demand owing to increased sodium reabsorption as a result of sodium-glucose cotransporter upregulation and glomerular hyperfiltration. The resultant hypoxic injury creates a vicious cycle of capillary damage, inflammation, deposition of the extracellular matrix, and, ultimately, fibrosis and nephron loss. This review will frame the role of chronic hypoxia in the pathogenesis of diabetic kidney disease and its prospect as a promising therapeutic target. We will outline the cellular mechanisms of hypoxia and evidence for renal hypoxia in animal and human studies. In addition, we will highlight the promise of newer imaging modalities including blood oxygenation level-dependent magnetic resonance imaging and discuss salutary interventions such as sodium-glucose cotransporter 2 inhibition that (may) protect the kidney through amelioration of renal hypoxia.