Improving Outcomes with SGLT2 Cotransporter Inhibitors in Challenging T2DM Patients Part 1.

Improving Outcomes with SGLT2 Cotransporter Inhibitors in Challenging T2DM Patients

Part 1

•Efficacy of SGLT2 Inhibition in T2DM and Application to Clinical Practice: Approved Agents

Ele Ferrannini, MD

Department of Clinical & Experimental Medicine

University of Pisa

Pisa, Italy

Introduction to SGLT2 Inhibitors

• Mode of action• Efficacy• Durability• Limitations



Mean plasma glucose (mg/dL)

Reprinted with permission from Ferrannini E, et al. J Clin Invest. 2014;124:499-508.

A1C (%)

6.5 7.0 7.5 8.0 8.5

SGLT2i

baseline

Effect of SGLT2 Inhibitionon Glycosuria



Time (min)

0.0

1.0

6.0

5.0

4.0

3.0

2.0

7.0

8.0

-180 -120 -60 0 60 120 180 240 300

dose

Baseline Acute

SGLT2i

Chronic SGLT2i

Meal

Reprinted with permission from Ferrannini E, et al. J Clin Invest. 2014;124:499-508.

Effect of SGLT2i on Glycosuriain T2DM

Canagliflozin in Patients with T2DM Inadequately Controlled with Metformin + Sulfonylurea over 52 Weeks

LOCF, last observation carried forward; LS least squares; SE, standard error.

Vercruysse G, et al. Presented at the 49th EASD Annual Meeting; Barcelona, Spain; Sept, 2013. Abstract 934.

-0.75%(95% CI: -0.95, -0.55)

-0.97%(95% CI: -1.17, -0.77

Proportion of subjects who achieved A1C <7.0%: canagliflozin 100 mg, 39.4%; canagliflozin 300 mg, 52.6%; placebo, 18.7%

0.2

0

-.02

-.04

-.06

-.08

-1.0

-1.2

0 6 12 18 26 34

Time point (week)

42 52

Baseline 8.1

Canagliflozin 100 mg8.1


0.01%

- 0.96%

-0.74%

Placebo

LS mean change

Change in A1C (LOCF)

1.0

0.5

0

-0.5

-1.0

-1.5

-2.0

-2.5

0 6 12 18 26 34

Time point (week)

42 52

Baseline (mmol/L) 9.4

0.6mmol/L

-1.5mmol/L

-1.1mmol/L

LS mean change

-1.6 mmol/L(95% CI: -2.1, -1.1)

-2.1 mmol/L(95% CI: -2.6, 1.6)



Change in FPG (LOCF)Placebo

Reproduced with the permission of Janssen Research & Development, LLC

Canagliflozin Monotherapy in T2DM InadequatelyControlled with Diet + Exercise over 52 weeks

Stenlöf K, et al. Presented at the 49th EASD Annual Meeting; Barcelona, Spain; Sept, 2013. Abstract 935.

Parameter Canagliflozin 100 mg

Canagliflozin 300 mg

A1C change, % -0.81 (0.07) -1.11 (0.07)

% of subjects reaching A1C <7.0% 52.4 (3.9) 64.5 (3.7)

FPG change, mmol/L -1.5 (0.1) -2.2 (0.1)

Body weight % change -3.3 (0.3) -4.4 (0.3)

Systolic BP change, mm Hg -1.4 (0.8) -3.9 (0.8)

Diastolic BP change, mm Hg -0.4 (0.6) -0.7 (0.6)

Triglycerides, % change -2.0 (3.0) -2.1 (3.0)

HDL-C % change 11.1 (1.5) 14.7 (1.5)

LDL-C % change 6.3 (2.1) 11.2 (2.1)

LDL-C/HDL-C % change -3.1 (2.1) -0.1 (2.1)

Non–HDL-C % change 1.8 (1.7) 5.6 (1.7)





A1C change, % -0.81 (0.07) -1.11 (0.07)


FPG change, mmol/L -1.5 (0.1) -2.2 (0.1)





HDL-C % change 11.1 (1.5) 14.7 (1.5)

LDL-C % change 6.3 (2.1) 11.2 (2.1)

LDL-C/HDL-C % change -3.1 (2.1) -0.1 (2.1)

Non–HDL-C % change 1.8 (1.7) 5.6 (1.7)





A1C change, % -0.81 (0.07) -1.11 (0.07)


FPG change, mmol/L -1.5 (0.1) -2.2 (0.1)





HDL-C % change 11.1 (1.5) 14.7 (1.5)

LDL-C % change 6.3 (2.1) 11.2 (2.1)

LDL-C/HDL-C % change -3.1 (2.1) -0.1 (2.1)

Non–HDL-C % change 1.8 (1.7) 5.6 (1.7)

Canagliflozin in Patients with T2DM InadequatelyControlled with Metformin + Sulfonylurea over 52 weeks

Percentage change in body weight (LOCF)

-1.3%(95% CI: -2.1, -0.5)(-1.0 kg[95% CI: -1.8, -0.2])

-2.2%(95% CI: -3.0, -1.4)(-2.1 kg[95% CI: -2.9, -1.2])

0.5

0

-.05

-1.0

-1.5

-2.0

-2.5

-3.0

-3.5

-4.0

0 6 12 18 26 34

Time point (week)

42 52

PBO

Baseline (kg) 90.8

CANA 100 mg

93.5

CANA 300 mg

93.5

-0.9%(-1.0 kg)

LS mean% change

-2.2%(-2.0 kg)

-3.2%(-3.1 kg)

Reductions in diastolic blood pressure were -2.2, 1.7, and 0.7 mm Hg with canagliflozin 100 and 300 mg and placebo, respectively. Change in pulse rate were 0.9, -1.2 and -0.4 beats per minute with canagliflozin 100 and 300 mg and placebo, respectively.

2

1

0

-1

-2

-3

-4

-5

-6

-7

0 6 12 18 26 34

Time point (week)

42 52

Baseline (mmol/L)

PBO

130.1

CANA 100 mg

130.4 130.8

0.1mmHg

--2.9mmHg-3.7mmHg

CANA 300 mg

LS mean change

Change in systolic blood pressure (LOCF)

-3.0 mmHg(95% CI: -5.5, -0.5)

-3.7 mmHg(95% CI: -6.2, -1.3)

Vercruysse G, et al. Presented at the 49th EASD Annual Meeting; Barcelona, Spain; Sept, 2013. Abstract 934.Reproduced with the permission of Janssen Research & Development, LLC

Vercruysse G, et al. Presented at the 49th EASD Annual Meeting; Barcelona, Spain; Sept, 2013. Abstract 934.

Canagliflozin in Patients with T2DM Inadequately Controlled with Metformin + Sulfonylurea over 52 WeeksParameter* CANA 100 mg CANA 300 mg PBO

A1C change, % -0.74 (0.08) -0.96 (0.08) 0.01 (0.08)

Difference vs placebo -0.75 (-0.95, -0.55) -0.97 (-1.17, -0.77)

% of subjects reaching A1C <7.0%† 39.4 (3.9) 52.6 (4.1) 18.7 (3.2)

Difference vs placebo 20.7 (10.1, 31,2) 34.0 (23.3, 44.7)

FPG change, mmol/L -1.1 (0.2) -1.5 (0.2) 0.6 (0.2)


Body weight % change -2.2 (0.3) -3.2 (0.3) -0.9 (0.3)


Systolic BP change, mm Hg -3.7 (1.0) -2.9 (1.0) 0.1 (1.0)


Diastolic BP change, mm Hg -2.2 (0.6) -1.7 (0.6) -0.7 (0.6)

Difference vs placebo -1.6 (-3.2, 0.1) -1.1 (-2.7, 0.5)

Triglycerides % change 8.5 (4.6) 6.7 (4.5) 4.7 (4.6)

Difference vs placebo 3.8 (-7.8, 15.4) 2.0 (-9.6, 13.6)

HDL-C % change 6.6 (1.3) 8.2 (1.3) 3.3 (1.3)

Difference vs placebo 3.2 (-0.1, 6.5) 4.9 (1.6, 8.2)

LDL-C % change 4.8 (2.8) 13.3 (2.8) 5.4 (2.8)

Difference vs placebo -0.6 (-7.7, 6.5) 7.9 (0.8, 15.0)

LDL-C/HDL-C % change -0.3 (2.7) 5.1 (2.8) 3.7 (2.7)

Difference vs placebo -4.0 (-10.8, 2.8) 1.4 (-5.4, 8.2)

Non–HDL-C % change 2.5 (2.1) 7.5 (2.1) 3.9 (2.1)

Difference vs placebo -1.5 (-6.9, 3.9) 3.6 (-1.8, 9.0)

Improving Outcomes with SGLT2 Cotransporter Inhibitors in Challenging T2DM Patients Part 1.

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