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AACE Presentations of SGLT-2 Inhibitor Data

David Joffe, BSPharm, CDE, Editor-in-chief, Diabetes In Control
Lauren Self, University of Florida College of Pharmacy, PharmD Candidate
When the finest, most talented endocrinologists get together for a conference, you can bet that there will be a lot of great information on the latest in diabetes care. This year it seems that research on the SGLT2-Inhibitor class was the most important and garnered the most attention. We have pulled together all of the presentations and abstracts from this year’s AACE meeting for you to review.

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EMPAGLIFLOZIN, A SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITOR, LOWERS BLOOD PRESSURE IN PATIENTS WITH TYPE 2 DIABETES

Thomas Hach1, Hiddo Lambers Heerspink2, Egon Pfarr1, Soeren Lund1, Ludwin Ley1, Uli Broedl1, Hans Woerle1

1. Boehringer Ingelheim Pharma GmbH & Co. KG; 2. University Medical Center Groningen, University of Groningen

Objective: Analyze the effects of the Empagliflozin (EMPA) doses tested in Phase III trials (10 mg qd and 25 mg qd) on BP using pooled data from two Phase II trials.

Methods: Data were pooled from two randomized, placebo (PBO)-controlled 12-week trials that examined EMPA as monotherapy (N=408) or as add-on to metformin (N=495) in patients with T2DM. Changes from baseline to week 12 in BP (last observation carried forward) measured as a safety assessment were analyzed using ANCOVA with study, treatment, and baseline BP as fixed effects and country as a random effect in patients receiving PBO (n=153), EMPA 10 mg (n=152), or EMPA 25 mg (n=152). Data from patients with systolic BP (SBP)>140 mmHg at baseline were analyzed as a sub-group (PBO, n=33; EMPA 10 mg, n=27; EMPA 25 mg, n=38).

Results: Median age (years) and mean±SD BMI (kg/m2) for PBO, EMPA 10 mg and 25 mg were 59.0, 59.5 and 58.0 and 30.3±4.8, 29.9±4.4 and 30.1±5.0, respectively. The majority (67.8%) took antihypertensive medication at baseline. Baseline mean±SD SBP was 134.3±15.9 mmHg, 131.3±13.8 mmHg and 132.5±14.6 mmHg for PBO, EMPA 10 mg and 25 mg, respectively. Adjusted mean±SE changes from baseline in SBP were -1.2±1.0 mmHg for PBO vs -3.8±1.0 mmHg and -4.5±1.0 mmHg for EMPA 10 mg and 25 mg, respectively (both p<0.05 vs PBO). Reductions from baseline to week 12 in diastolic BP (DBP) were not significantly different from placebo in either EMPA group (adjusted mean±SE changes: -1.8±0.6 mmHg for PBO, -2.3±0.6 mmHg for EMPA 10 mg, -2.7±0.6 mmHg for EMPA 25 mg). In patients with baseline SBP >140 mmHg, baseline mean± SD SBP was 157.2±13.6 mmHg, 152.8±8.9 mmHg, and 151.1±8.7 mmHg for PBO, EMPA 10 mg and 25 mg, respectively and adjusted mean (SE) changes from baseline were -10.4±2.4 mmHg, -17.0±2.6 mmHg, and -13.4±2.3 mmHg, respectively (p=NS). Including the number of antihypertensive medications at baseline in the ANCOVA did not alter the effect of EMPA on BP versus placebo. Blood pressure changes did not correlate with pulse rate changes. The number of patients with AEs was comparable across groups (34.6% for PBO, 34.2% for EMPA 10 mg, 31.6% for EMPA 25 mg).

Discussion: Treatment with EMPA was well tolerated and provided statistically significant and clinically meaningful reductions in SBP. Reductions in SBP were more pronounced in patients with SBP >140 mmHg, but due to the small sample size, the differences in this sub-group did not reach statistical significance.

Conclusion: EMPA 10 mg or 25 mg for 12 weeks provided statistically significant and clinically meaningful reductions in SBP without increases in pulse rate.

 

CANAGLIFLOZIN (CANA), A SODIUM GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITOR, IMPROVES INDICES OF BETA-CELL FUNCTION (Beta-CF) IN PATIENTS WITH TYPE 2 DIABETES MELLITUS (T2DM) ON METFORMIN (MET) PLUS SULFONYLUREA (SU)

David Polidori, PhD1, Frank Vercruysse2, Eleuterio Ferrannini3

1. Janssen Research & Development, LLC; 2. Janssen Research & Development; 3. University of Pisa School of Medicine

Objective: Assess the effects of CANA on Beta-CF by evaluating indices of Beta-CF in a Phase 3 study of patients with T2DM inadequately controlled with MET + SU. Progressive loss of Beta-CF is thought to underlie the pathophysiology of T2DM. CANA, an inhibitor of SGLT2, is in development for the treatment of T2DM. In hyperglycemic, partially pancreatectomized rats, Beta-CF can be restored when normoglycemia is achieved with SGLT2 inhibitor treatment.

Methods: This 26-week, randomized, double-blind, placebo (PBO)-controlled study evaluated CANA 100 and 300 mg compared with PBO as add-on therapy to MET + SU in patients with T2DM (N = 469; mean baseline characteristics: age, 57 years; A1C, 8.1%; BMI, 33.0 kg/ m2; duration of T2DM, 9.6 years). A subset of patients (n = 168) were given a meal tolerance test at baseline and Week 26 and plasma glucose (G) and serum C-peptide (C) were measured at 7 time points over 3 hours. Beta-CF was assessed using the AUCC/AUCG ratio and a model-based method relating the insulin secretion rate (ISR; obtained by deconvolution of C) to concomitant G using linear regression. Beta-cell glucose sensitivity as the slope of ISR vs G relationship and ISR at 9 mM G were calculated. All changes are reported as PBO-subtracted least squares (LS) mean changes using an ANCOVA model.

Results: At Week 26, CANA 100 and 300 mg significantly reduced A1C from baseline compared with PBO (ΔA1C, -0.71% and -0.92%, respectively; P <0.001) and were generally well tolerated. The ISR vs G relationship was unchanged with PBO and was shifted upwards (indicating increased ISR at each PG concentration) with both CANA doses. Mean values of all calculated indices of Beta-CF increased with both CANA doses versus PBO, although some of the changes did not reach statistical significance.

Mean AUCC/AUCG increased by ~20% from baseline values of 123-132 pM/mM (increases of 27.1 (95% CI: -0.2; 54.4; P = 0.051) and 27.4 (-0.7; 55.6; P = 0.056) for CANA 100 and 300mg). Mean ISR at 9mMG increased by ~50-60% from baseline values of 114-117 pmol/min/m2 (increases of 54.6 (7.7; 101.5; P = 0.02) and 69.2 (19.7; 118.9; P = 0.007) for CANA 100 and 300 mg). Mean Beta-cell glucose sensitivity increased by ~20% from baseline values of 31-34 pmol●min-1●m-2●mM-1 (increases of 7.6 (-2.6; 17.9; P = 0.14) and 6.7 (-4.1; 17.5; P = 0.22) for CANA 100 and 300 mg).

Conclusion: In T2DM patients (mean T2DM duration of 9.6 years) on background MET + SU, CANA 100 and 300 mg improved glycemic control and measures of Beta-CF compared with PBO after 26 weeks of treatment.

EMPAGLIFLOZIN (EMPA), A SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITOR FOR 90 WEEKS PROVIDES SUSTAINED GLYCEMIC CONTROL AND WEIGHT LOSS IN PATIENTS WITH TYPE 2 DIABETES (T2DM)

Ele Ferrannini, University of Pisa School of Medicine (presented by Thomas Hach, MD, Boehringer Ingelheim)

The investigative sodium glucose cotransporter-2 (SGLT2) inhibitor empagliflozin appears to improve key diabetes parameters and also seems to meaningfully reduce weight, researchers said here.

When used as monotherapy in patients with type 2 diabetes, the 10-mg dose of empagliflozin reduced glycosylated hemoglobin A1c (HbA1c) an average of 0.51 percentage points from baseline in a 90-week trial and the 25-mg dose was associated with an average 0.60-percentage-point decrease, while comparator metformin reduced HbA1c by a mean 0.64 percentage points.

When employed as an add-on to metformin, the lower dose of empagliflozin reduced HbA1c by an average 0.61 percentage points, the higher dose reduced HbA1c by an average 0.74 percentage points, and sitagliptin (Januvia) reduced HbA1c by an average 0.45 percentage points. The changes in fasting glucose levels showed a similar pattern, with both treatment arms showing sustained decreases over the course of the 12-week double-blind study and the 78-week extension trial in which placebo patients were re-randomized into active agent groups.

In addition to the glucose-lowering effects, patients on the low dose of empagliflozin in the monotherapy trial lost an average of 4.59 lbs. (2.08 kg) of weight in the 3-month study.  Weight loss was 4.12 lbs. (1.87 kg) with the high dose of empaglifozin. Patients on monotherapy metformin lost 1.98 lbs. (0.9 kg).

When used as an add-on medication, low-dose empagliflozin was associated with a 6.28-lb. (2.85-kg) weight loss; high-dose empagliflozin was associated with an 8.42-lb. (3.82-kg) weight loss; and sitagliptin was associated with a 1.34-lb. (0.61-kg) weight loss.

Empagliflozin is being developed as an oral treatment of type 2 diabetes by Boehringer Ingelheim and Eli Lilly. It inhibits SGLT2, which accounts for about 90% of glucose reabsorption into the blood. Blocking SGLT-2 causes blood glucose to be eliminated through the urine.

In the monotherapy trial, 82 patients were assigned to low-dose empagliflozin, 82 patients were assigned to the high-dose empagliflozin, and 80 were treated with metformin.

In the add-on trial, 71 patients got low-dose empagliflozin, 70 got the higher dose, and 71 patients received sitagliptin.

The adverse event profiles of the drugs were similar, although it appeared that there were a few more genital infections related to use of empagliflozin than with metformin or sitagliptin.

Because empagliflozin is eliminated through the kidneys, the researchers looked closely at glomerular filtration rates, but did not see any alarming decreases when empagliflozin was used as either monotherapy or as an add-on to metformin.

 

RENAL GLUCOSE HANDLING: IMPACT OF CHRONIC KIDNEY DISEASE AND SODIUM GLUCOSE COTRANSPORTER 2 INHIBITION IN PATIENTS WITH TYPE 2 DIABETES.

Ferrannini E, Veltkamp SA, Smulders RA, Kadokura T.

Objective: Assess the pharmacodynamics of ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 2 diabetes (T2DM) having impaired renal function.Research design and methods: Glycosuria was measured before and after a single ipragliflozin dose in 8 nondiabetic subjects and 57 T2DM patients (age 62 ± 9 years, fasting glucose 133 ± 39 mg/dL, mean ± SD) with normal renal function (assessed as the estimated glomerular filtration rate [eGFR]) (eGFR1 ≥90 mL · min(-1) · 1.73 m(-2)), mild (eGFR2 ≥60 to <90), moderate (eGFR3 ≥30 to <60), or severe reduction in eGFR (eGFR4 ≤15 to <30). Results: Ipragliflozin significantly increased urinary glucose excretion in each eGFR class (P < 0.0001). However, ipragliflozin-induced glycosuria declined (median [IQR]) across eGFR classes (from 46 mg/min [33] in eGFR1 to 8 mg/min [7] in eGFR4, P < 0.001). Ipragliflozin-induced fractional glucose excretion (excretion/filtration) was 39% [27] in the T2DM patients (pooled data), similar to that of the nondiabetic subjects (37% [17], P = ns). In bivariate analysis of the pooled data, ipragliflozin-induced glycosuria was directly related to eGFR and fasting glucose (P < 0.0001 for both, r(2) = 0.55), predicting a decrement in 24-h glycosuria of 15 g for each 20 mL/min decline in eGFR and an increase of 7 g for each 10 mg/dL increase in glucose above fasting normoglycemia. Conclusions: In T2DM patients, ipragliflozin increases glycosuria in direct, linear proportion to GFR and degree of hyperglycemia, such that its amount can be reliably predicted in the individual patient. Although absolute glycosuria decreases with declining GFR, the efficiency of ipragliflozin action (fractional glucose excretion) is maintained in patients with severe renal impairment.

PMID: 23359360 [PubMed – in process] PMCID: PMC3631866 [Available on 2014/5/1]