A Review of the Dose Justification of Phase 3 Trials to Regulatory Authorities for Drugs Intended for the Treatment of Type 2 Diabetes in Europe

Aims: Cardiovascular outcome trials with anti-diabetic drugs suggest that additional cardiovascular benefit can be achieved independent of improving glycaemic control. Nonetheless, dose selection of anti-diabetic drugs is typically based solely on glycaemic effects. We evaluated whether off-target drug effects are currently considered for dose justification to regulatory agencies. Methods: In the European Union, anti-diabetic drugs are registered by the European Medicines Agency. We extracted available information regarding dose selection from public assessment reports and marketing application dossiers. Descriptive statistics were used to summarise the extracted information. Results: In total, 14 drugs of three drug classes were included; sodium-glucose co-transporter-2 inhibitors (n = 4), dipeptidyl peptidase-4 inhibitors (n = 4) and glucagon-like peptide-1 receptor agonists (n = 6). For these drugs, 21 dose-finding trials were submitted including results of multiple off-target effects, of which body weight (n = 18) and low-density lipoprotein cholesterol (n = 14) were most frequently reported. Dose-response curves for off-target effects appeared to be different compared to the glycaemic dose-response curve. Glycated hemoglobin (100%) and fasting plasma glucose (42.9%), were used most frequently for the dose justification, but generally off-target effects (<25%) were not. Conclusions: Dose justification to regulatory authorities was mainly based on glycaemic effects. The dose-response relationship for the off-target effects did not necessarily follow the dose-response relationship of the on-target effects suggesting that selection of the optimal anti-diabetic dose could benefit from including off-target effects in the dose selection process as well

Increased serum potassium affects renal outcomes: a post hoc analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial

To assess the effect of an angiotensin receptor blocker (ARB) on serum potassium and the effect of a serum potassium change on renal outcomes in patients with type 2 diabetes and nephropathy. We performed a post hoc analysis in patients with type 2 diabetes participating in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Renal outcomes were defined as a composite of doubling of serum creatinine or end-stage renal disease. At month 6, 259 (38.4%) and 73 (10.8%) patients in the losartan group and 151 (22.8%) and 34 (5.1%) patients in the placebo group had serum potassium a parts per thousand yen5.0 mmol/l and a parts per thousand yen5.5 mmol/l, (p <0.001), respectively. Losartan was an independent predictor for serum potassium a parts per thousand yen5.0 mmol/l at month 6 (OR 2.8; 95% CI 2.0-3.9). Serum potassium at month 6 a parts per thousand yen 5.0 mmol/l was in turn associated with increased risk for renal events (HR 1.22; 95% CI 1.00-1.50), independent of other risk factors. Adjustment of the overall treatment effects for serum potassium augmented losartan's renoprotective effect from 21% (6-34%) to 35% (20-48%), suggesting that the renoprotective effects of losartan are offset by its effect on serum potassium. In this study, we found that treatment with the ARB losartan is associated with a high risk of increased serum potassium levels, which is in turn associated with an increased risk of renal outcomes in patients with diabetes and nephropathy. Whether additional management of high serum potassium would further increase the renal protective properties of losartan is an important clinical question

The Potential Roles of Osmotic and Nonosmotic Sodium Handling in Mediating the Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Heart Failure

Concomitant type 2 diabetes and chronic kidney disease increases the risk of heart failure. Recent studies demonstrate beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on chronic kidney disease progression and heart failure hospitalization in patients with and without diabetes. In addition to inhibiting glucose reabsorption, SGLT2 inhibitors decrease proximal tubular sodium reabsorption, possibly leading to transient natriuresis. We review the hypothesis that SGLT2 inhibitor’s natriuretic and osmotic diuretic effects mediate their cardioprotective effects. The degree to which these benefits are related to changes in sodium, independent of the kidney, is currently unknown. Aside from effects on osmotically active sodium, we explore the intriguing possibility that SGLT2 inhibitors could also modulate nonosmotic sodium storage. This alternative hypothesis is based on emerging literature that challenges the traditional 2-compartment model of sodium balance to provide support for a 3-compartment model that includes the binding of sodium to glycosaminoglycans, such as those in muscles and skin. This recent research on nonosmotic sodium storage, as well as direct cardiac effects of SGLT2 inhibitors, provides possibilities for other ways in which SGLT2 inhibitors might mitigate heart failure risk. Overall, we review the effects of SGLT2 inhibitors on sodium balance and sensitivity, cardiac tissue, interstitial fluid and plasma volume, and nonosmotic sodium storage

Feasibility Study to Assess Canagliflozin Distribution and Sodium-Glucose Co-Transporter 2 Occupancy Using [18F]Canagliflozin in Patients with Type 2 Diabetes

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, including canagliflozin, reduce the risk of cardiovascular and kidney outcomes in patients with and without type 2 diabetes, albeit with a large inter-individual variation. The underlying mechanisms for this variation in response might be attributed to differences in SGLT2 occupancy, resulting from individual variation in plasma and tissue drug exposure and receptor availability. We performed a feasibility study for the use of [ 18 F]Canagliflozin positron emission tomography (PET) imaging to determine the association between clinical canagliflozin doses and SGLT2 occupancy in patients with type 2 diabetes. We obtained two 90-min dynamic PET scans with diagnostic intravenous [ 18 F]Canagliflozin administration and a full kinetic analysis in seven patients with type 2 diabetes. Patients received 50, 100 or 300mg oral canagliflozin (n=2:4:1) 2.5 hours before the second scan. Canagliflozin pharmacokinetics and urinary glucose excretion were measured. The apparent SGLT2 occupancy was derived from the difference between the apparent volume of distribution of [ 18 F]Canagliflozin in the baseline and post-drug PET scans. Individual canagliflozin area under the curve from oral dosing until 24-hours (AUC P0-24h ) varied largely (range 1715-25747 μg/L*h, mean 10580 μg/L*h) and increased dose dependently with mean values of 4543, 6525 and 20012 μg/L*h for 50, 100 and 300mg respectively (P=0.046). SGLT2 occupancy ranged between 65 and 87%, but did not correlate with canagliflozin dose, plasma exposure or urinary glucose excretion. We report the feasibility of [ 18 F]Canagliflozin PET imaging to determine canagliflozin kidney disposition and SGLT2 occupancy. This suggests the potential of [ 18 F]Canagliflozin as a tool to visualize and quantify clinically SGLT2 tissue binding. </p

Moderate dietary sodium restriction added to angiotensin converting enzyme inhibition compared with dual blockade in lowering proteinuria and blood pressure: randomised controlled trial

Objective To compare the effects on proteinuria and blood pressure of addition of dietary sodium restriction or angiotensin receptor blockade at maximum dose, or their combination, in patients with non-diabetic nephropathy receiving background treatment with angiotensin converting enzyme (ACE) inhibition at maximum dose

[18F]FDG and [18F]NaF as PET markers of systemic atherosclerosis progression:A longitudinal descriptive imaging study in patients with type 2 diabetes mellitus

BACKGROUND: While [18F]-fluordeoxyglucose ([18F]FDG) uptake is associated with arterial inflammation, [18F]-sodium fluoride ([18F]NaF) is a marker for arterial micro-calcification. We aimed to investigate the prospective correlation between both PET markers over time and whether they are prospectively ([18F]FDG) and retrospectively ([18F]NaF) related to progression of systemic arterial disease in a longitudinal study in patients with type 2 diabetes mellitus (T2DM). METHODS: Baseline [18F]FDG PET/Low Dose (LD) Computed Tomography (CT) scans of ten patients with early T2DM without cardiovascular history (70% men, median age 63 years) were compared with five-year follow-up [18F]NaF/LDCT scans. Systemic activity was expressed as mean target-to-background ratio (meanTBR) by dividing the maximal standardized uptake value (SUVmax) of ten arteries by SUVmean of the caval vein. CT-assessed macro-calcifications were scored visually and expressed as calcified plaque (CP) score. Arterial stiffness was assessed with carotid-femoral pulse wave velocity (PWV). Five-year changes were expressed absolutely with delta (Δ) and relatively with %change. RESULTS: Baseline meanTBR[18F]FDG was strongly correlated with five-year follow-up meanTBR[18F]NaF (r = 0.709, P = .022). meanTBR[18F]NaF correlated positively with ΔCPscore, CPscore at baseline, and follow-up (r = 0.845, P = .002 and r = 0.855, P = .002, respectively), but not with %change in CPscore and PWV. CONCLUSION: This proof-of-concept study demonstrated that systemic arterial inflammation is an important pathogenetic factor in systemic arterial micro-calcification development

Effects of empagliflozin on renal sodium and glucose handling in patients with acute heart failure

Aims Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve clinical outcome in patients with heart failure (HF), but the mechanisms behind their beneficial effects are not yet fully understood. We examined the effects of empagliflozin on renal sodium and glucose handling in patients with acute HF. Methods and results This study was a pre-defined sub-study of a double-blind, randomized, placebo-controlled, multicentre study (EMPA-RESPONSE-AHF). Patients were allocated within 24 h of an acute HF admission to either empagliflozin 10 mg/day (n = 40) or placebo (n = 39) for 30 days. Markers of glucose and sodium handling were measured daily during the first 96 h and at day 30. Patients were 76 (range 38-89) years old and 33% had diabetes. The use of loop diuretics during the first 96 h was similar in both groups. Empagliflozin increased fractional glucose excretion with a peak after 24 h (21.8% vs. 0.1%; P 0.3 for all). However, empagliflozin increased plasma osmolality (delta osmolality at 72 h: 5 +/- 8 vs. 2 +/- 5 mOsm/kg; P = 0.049). Finally, there was an early decline in estimated glomerular filtration rate with empagliflozin vs. placebo (-10 +/- 12 vs. -2 +/- 12 mL/min/1.73 m(2); P = 0.009), which recovered within 30 days. Conclusion In patients with acute HF, empagliflozin increased fractional glucose excretion and plasma osmolality, without affecting fractional sodium excretion or urine osmolality and caused a temporary decline in estimated glomerular filtration rate. This suggests that empagliflozin stimulates osmotic diuresis through increased glycosuria rather than natriuresis in patients with acute HF

Efficacy and Safety of Dapagliflozin in Patients with Chronic Kidney Disease across the Spectrum of Frailty

BACKGROUND: A sizeable proportion of patients with chronic kidney disease (CKD) are reported to be frail. Here we examined the safety and efficacy of dapagliflozin in patients with CKD by frailty level. METHODS: Adults with CKD, with/without type 2 diabetes, with estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m 2 and urinary albumin-to-creatinine ratio 200-5000 mg/g were randomized to dapagliflozin (10 mg/day) or placebo. The primary endpoint was composite of sustained ≥50% eGFR decline, end-stage kidney disease (ESKD) or death from kidney or cardiovascular (CV) causes. RESULTS: Frailty index (FI), assessed by Rockwood cumulative deficit approach, was calculable in 4303/4304 (99.9%) patients: 1162 (27.0%) in not-to-mildly frail(FI≤0.210), 1642 (38.2%) in moderately frail(FI 0.211-0.310), and 1499 (34.8%) in severely frail categories (FI>0.311). Dapagliflozin reduced the risk of the primary composite endpoint across all FI categories (hazard ratios [95% CI]: 0.50 [0.33-0.76], 0.62 [0.45-0.85], and 0.64 [0.49-0.83], respectively (P-interaction =0.67). Results were similar for secondary outcomes including kidney composite outcome (sustained ≥50% eGFR decline, ESKD or death from kidney cause; P-interaction=0.44), CV endpoint (heart failure hospitalization or CV death; P-interaction=0.63), and all-cause mortality (P-interaction p=0.42). Results were consistent when using FI as a continuous variable. Occurrence of serious adverse events was numerically lower in patients receiving dapagliflozin vs. placebo in all FI categories (16.9% vs. 20.1%, 26.3% vs. 30.7%, and 42.9% vs 47.8%, in not-to-mildly, moderately and severely frail categories, respectively). CONCLUSIONS: The relative benefit of dapagliflozin for all outcomes was consistent across all frailty categories, with no difference in associated safety

POS-255 EFFECT OF DAPAGLIFLOZIN ON BLOOD PRESSURE IN PATIENTS WITH CKD: A PRE-SPECIFIED ANALYSIS FROM DAPA-CKD

Introduction: Hypertension is common in patients with chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibitors decrease blood pressure in patients with type 2 diabetes, but the consistency and magnitude of blood pressure lowering with dapagliflozin in patients with CKD is unknown. We performed a pre-specified analysis of the DAPA-CKD trial to investigate the effect of dapagliflozin on systolic blood pressure in patients with CKD, with and without type 2 diabetes. Methods: We randomized 4,304 adults with baseline eGFR 25–75 mL/min/1.73m2and urinary albumin-to-creatinine ratio (UACR) 200–5,000 mg/g to either dapagliflozin 10 mg or placebo once daily; median follow-up was 2.4 years. The primary outcome was a composite of sustained ≥50% eGFR decline, end-stage kidney disease, or death from a kidney or cardiovascular cause. Change in systolic blood pressure was a pre-specified endpoint. Subgroup analyses were performed according to baseline type 2 diabetes status. Results: Baseline mean (SD) systolic blood pressure was 137.1 mmHg (17.4); in participants with and without type 2 diabetes 139.2 mmHg (17.3) and 132.6 mmHg (16.7), respectively. By week 2, dapagliflozin compared to placebo reduced systolic blood pressure by 3.6 mmHg (95%CI 2.8, 4.4; p\u3c0.001), an effect maintained over the duration of the trial, with similar reductions in patients with and without type 2 diabetes (Table). The reduction in systolic blood pressure with dapagliflozin explained 7.6% (95%CI 1.8, 20.9) of the effect on the primary composite outcome, with similar proportions explained in patients with and without type 2 diabetes. Conclusions: In participants with CKD, dapagliflozin lowered systolic blood pressure with a consistent effect in participants with and without type 2 diabetes. The modest reduction in blood pressure explained a small proportion of the benefit of dapagliflozin on the primary outcome. Conflict of interest Potential conflict of interest: HLH received grant funding and honoraria for consultancy as a member of the steering committee of the DAPA-CKD trial from AstraZeneca. Honoraria for steering committee membership paid to his institution from Janssen, Gilead, Bayer, Chinook, CSL Pharma honoraria for consultancy paid to his institution from Abbvie, Boehringer Ingleheim, Retrophin, Novo Nordisk honoraria for advisory board participation paid to his institution from Janssen, Merck, Mitsubishi Tanabe and Munipharma lecture fees received from AstraZeneca and Mitsubishi Tanabe and grant support received from Boehringer Ingelheim