Nima Soleymanlou

Renal Hemodynamic Effect of Sodium-Glucose Cotransporter 2 Inhibition in Patients With Type 1 Diabetes Mellitus

Background— The primary objective of this mechanistic open-label, stratified clinical trial was to determine the effect of 8 weeks’ sodium glucose cotransporter 2 inhibition with empagliflozin 25 mg QD on renal hyperfiltration in subjects with type 1 diabetes mellitus (T1D). Methods and Results— Inulin (glomerular filtration rate; GFR) and paraaminohippurate (effective renal plasma flow) clearances were measured in individuals stratified based on having hyperfiltration (T1D-H, GFR ≥ 135 mL/min/1.73m2, n=27) or normal GFR (T1D-N, GFR 90–134 mL/min/1.73m2, n=13) at baseline. Renal function and circulating levels of renin-angiotensin-aldosterone system mediators and NO were measured under clamped euglycemic (4–6 mmol/L) and hyperglycemic (9–11 mmol/L) conditions at baseline and end of treatment. During clamped euglycemia, hyperfiltration was attenuated by −33 mL/min/1.73m2 with empagliflozin in T1D-H, (GFR 172±23–139±25 mL/min/1.73 m2, P<0.01). This effect was accompanied by declines in plasma NO and effective renal plasma flow and an increase in renal vascular resistance (all P<0.01). Similar significant effects on GFR and renal function parameters were observed during clamped hyperglycemia. In T1D-N, GFR, other renal function parameters, and plasma NO were not altered by empagliflozin. Empagliflozin reduced hemoglobin A1c significantly in both groups, despite lower insulin doses in each group (P⩽0.04). Conclusions— In conclusion, short-term treatment with the sodium glucose cotransporter 2 inhibitor empagliflozin attenuated renal hyperfiltration in subjects with T1D, likely by affecting tubular-glomerular feedback mechanisms. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01392560.

Sodium-glucose cotransporter 2 inhibition and glycemic control in type 1 diabetes: results of an 8-week open-label proof-of-concept trial.

OBJECTIVE Adjunctive-to-insulin therapy with sodium-glucose cotransporter 2 (SGLT2) inhibition may improve glycemic control in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS We evaluated the glycemic efficacy and safety of empagliflozin 25 mg daily in 40 patients treated for 8 weeks in a single-arm open-label proof-of-concept trial (NCT01392560). RESULTS Mean A1C decreased from 8.0 ± 0.9% (64 ± 10 mmol/mol) to 7.6 ± 0.9% (60 ± 10 mmol/mol) (P < 0.0001), fasting glucose from 9.0 ± 4.3 to 7.0 ± 3.2 mmol/L (P = 0.008), symptomatic hypoglycemia (<3.0 mmol/L) from 0.12 to 0.04 events per patient per day (P = 0.0004), and daily insulin dose from 54.7 ± 20.4 to 45.8 ± 18.8 units/day (P < 0.0001). Mean urinary excretion of glucose increased from 19 ± 19 to 134 ± 61 g/day (P < 0.0001). Weight decreased from 72.6 ± 12.7 to 70.0 ± 12.3 kg (P < 0.0001), and waist circumference decreased from 82.9 ± 8.7 to 79.1 ± 8.0 cm (P < 0.0001). CONCLUSIONS This proof-of-concept study strongly supports a randomized clinical trial of adjunctive-to-insulin empagliflozin in patients with T1D.

Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1).

To investigate the pharmacodynamics, efficacy and safety of empagliflozin as adjunct to insulin in patients with type 1 diabetes.

Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration

Abbreviations ΔPF Filtration pressure across the glomerular capillaries πG Glomerular oncotic pressure FENa Fractional excretion of sodium KFG Ultrafiltration coefficient PGLO Glomerular hydrostatic pressure RA Afferent renal arteriolar resistances RAAS Renin–angiotensin–aldosterone system RE Efferent renal arteriolar resistances SGLT2 Sodium–glucose co-transporter 2 T1D-N Type 1 diabetic patients with renal normofiltration T1D-H Type 1 diabetic patients with renal hyperfiltration

Sodium glucose cotransport-2 inhibition and intrarenal RAS activity in people with type 1 diabetes

To the Editor: Recently, Musetti et al. commented on the potential renal effects of sodium glucose co-transport-2 inhibition (SGLT2-i), as reviewed by Gilbert.1, 2 They specifically elaborated on Gilbert’s hypothesis that SGLT2-i may be reminiscent of renin–angiotensin system (RAS) blockade, indicating that such an intervention may also downregulate the RAS, thereby increasing the risk of hyperkalemia and hemodynamic kidney injury.

Diurnal Glycemic Patterns during an 8-Week Open-Label Proof-of-Concept Trial of Empagliflozin in Type 1 Diabetes

Background We recently reported improved glycemic control with reduced insulin dose in subjects with type 1 diabetes treated with the sodium glucose co-transporter-2 inhibitor empagliflozin. To further characterize the effects, we analyzed diurnal glycemic patterns by continuous glucose monitoring (CGM). Methods In an 8-week single-arm open-label pilot study of empagliflozin, we compared ambulatory glucose profiles produced from CGM data during 2-week intervals in a placebo run-in baseline period, end-of-treatment, and post-treatment. Change in glycemic exposure was evaluated by area under the median curve according to time of day (AUCTOTAL 12:00am-11:55pm; AUCDAY 7:05am-10:55pm, AUCNIGHT 11:00pm-7:00am), as well as glycemic variability, glycemic stability and time-in-target (≥70 to ≤140mg/dL). Results The 40 patients (26 on insulin pump) were aged 24±5 years and BMI 24.5±3.2 kg/m2. Consistent with the observed HbA1c decrease (8.0±0.9% to 7.6±0.9%, p<0.0001), normalized AUCTOTAL CGM decreased from 153.7±25.4 to 149.0±30.2mg/dL∙h at end-of-treatment (p = 0.31), and significantly increased post-treatment (164.1±29.5mg/dL∙h, p = 0.02). The numerical decrease in normalized AUCNIGHT (152.0±36.6 to 141.9±34.4mg/dL∙h, p = 0.13) exceeded AUCDAY (154.5±24.5 to 152.6±30.4mg/dL∙h, p = 0.65). Trends toward lower glycemic variability (83.1±18.9 to 75.6±28.6mg/dL, p = 0.06) and little change in glycemic stability (10.8±3.6 to 10.3±4.5mg/dL/h, p = 0.51) were observed. When empagliflozin was discontinued, these worsened relative to baseline (89.3±19.3mg/dL, p = 0.04 and 11.8±3.7mg/dL/hr, p = 0.08). Time-in-target numerically increased (40.2±11.9 to 43.1±13.5%, p = 0.69) at end-of-treatment but reversed post-treatment. Findings were similar on stratification of pump and MDI subjects. Conclusions We observed that empagliflozin was associated with patterns of improved nighttime glycemia more prominent than daytime. Trial Registration Clinicaltrials.gov NCT01392560

Incidence and prevalence of diabetic ketoacidosis (DKA) among adults with type 1 diabetes mellitus (T1D): a systematic literature review

Objectives To summarise incidence and prevalence of diabetic ketoacidosis (DKA) in adults with type 1 diabetes (T1D) for the overall patient population and different subgroups (age, sex, geographical region, ethnicity and type of insulin administration). Design Systematic literature review (SLR). Data sources Medline (via PubMed) and Embase (1 January 2000 to 23 June 2016). Study selection Peer-reviewed observational studies with reported data on the incidence or prevalence of DKA in T1D adults were included. A single reviewer completed the study screening and selection process and a second reviewer performed an additional screening of approximately 20% of the publications; two reviewers independently conducted the quality assessment; the results were narratively synthesised. Results Out of 1082 articles, 19 met the inclusion and exclusion criteria, with two additional studies identified that did not specify the patient age range and are therefore not included in the SLR. Overall, eight studies reported incidence with a range of 0–56 per 1000 person-years (PYs), with one outlying study reporting an incidence of 263 per 1000 PYs. Eleven studies reported prevalence with a range of 0–128 per 1000 people. Prevalence of DKA decreased with increasing age. Subgroup analyses were performed using data from no more than two studies per subgroup. There was a higher prevalence of DKA reported in women, non-whites and patients treated with insulin injections compared with men, whites and patients using continuous subcutaneous insulin infusion pumps, respectively. Conclusions To our knowledge, this is the first SLR on the epidemiology of DKA in T1D adults. Despite an increasing prevalence of T1D in recent years, DKA in adults has been poorly characterised. In an era when the benefit–risk profiles of new antidiabetic therapies are being evaluated, including the potential risk of DKA, there is a clear need to better elucidate the expected rate of DKA among T1D adults.

Glucose Exposure and Variability with Empagliflozin as Adjunct to Insulin in Patients with Type 1 Diabetes: Continuous Glucose Monitoring Data from a 4-Week, Randomized, Placebo-Controlled Trial (EASE-1)

BACKGROUND We evaluated the effect of empagliflozin as adjunct to insulin on 24-h glucose exposure and variability in patients with type 1 diabetes. METHODS Patients (N = 75) with HbA1c ≥7.5% to ≤10.5% were randomized to receive empagliflozin 2.5 mg, empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily as adjunct to insulin for 4 weeks. Insulin dose was to be kept as stable as possible during week 1 of treatment and was freely adjustable thereafter. Markers of glucose exposure and variability were assessed from 7-day blinded continuous glucose monitoring intervals. This study is completed ( ClinicalTrials.gov NCT01969747). RESULTS Empagliflozin reduced hourly mean glucose area under the median curve over 24 h versus placebo within week 1 (adjusted mean differences: -12.2 mg/dL·h [95% confidence interval -23.9 to -0.5], -30.2 mg/dL·h [-42.2 to -18.2], and -33.0 mg/dL·h [-44.8 to -21.1] with empagliflozin 2.5, 10, and 25 mg, respectively; all P < 0.05) and increased time in glucose target range (>70 to ≤180 mg/dL). Results were sustained to week 4 with empagliflozin 25 mg. All empagliflozin doses significantly reduced glucose variability (interquartile range and mean amplitude of glucose excursions) versus placebo at weeks 1 and 4. Except for small increases in hours per day with glucose ≤70 mg/dL during the stable insulin period, empagliflozin did not increase time in hypoglycemia compared with placebo. CONCLUSIONS In patients with type 1 diabetes, empagliflozin as adjunct to insulin decreased glucose exposure and variability and increased time in glucose target range.

Population Pharmacokinetic– Pharmacodynamic Analysis to Characterize the Effect of Empagliflozin on Renal Glucose Threshold in Patients With Type 1 Diabetes Mellitus

Sodium glucose cotransporter 2 inhibitors increase urinary glucose excretion (UGE) by lowering the renal threshold for glucose (RTG). We aimed to quantify the effect of the sodium glucose cotransporter inhibitor empagliflozin on renal glucose reabsorption in patients with type 1 diabetes mellitus (T1DM) using a mechanistic population pharmacokinetic–pharmacodynamic (PK‐PD) model and to compare results with analyses in patients with type 2 diabetes mellitus (T2DM). The PK‐PD model was developed using data from a randomized phase 2 study in which patients with T1DM received oral once‐daily empagliflozin 2.5 mg, empagliflozin 10 mg, empagliflozin 25 mg, or placebo as an adjunct to insulin. The model assumed that UGE was dependent on plasma glucose and renal function and that empagliflozin lowered RTG. The final model was evaluated using visual predictive checks and found to be consistent with observed data. Calculated RTG with placebo was 181 mg/dL, and with empagliflozin (steady state) 1 mg and 2.5 mg was 53.4 mg/dL and 12.5 mg/dL, respectively. Empagliflozin 10 mg and 25 mg yielded negative RTG values, implying RTG was reduced to a negligible value. Although estimated PK‐PD parameters were generally comparable between patients with T1DM and patients with T2DM, slight differences were evident, leading to lower RTG and higher UGE in patients with T1DM compared with patients with T2DM. In conclusion, the model provided a reasonable description of UGE in response to administration of empagliflozin and placebo in patients with T1DM.

Empagliflozin as adjunct to insulin in Japanese participants with type 1 diabetes: Results of a 4-week, double-blind, randomized, placebo-controlled phase 2 trial

This phase 2, double‐blind, randomized, placebo‐controlled trial (ClinicalTrials.gov NCT02702011) with 4 sites in Japan investigated the pharmacodynamics (PD), pharmacokinetics (PK) and safety profile of empagliflozin in Japanese participants with type 1 diabetes mellitus (T1DM) as adjunctive therapy to insulin.