1. Improving Outcomes with SGLT2 Cotransporter Inhibitors in Challenging T2DM Patients
Part 4 of 4

2. Incorporating SGLT2 Inhibitors into Practice:
Updates from EASD
Mark W. Stolar, MD
Associate Professor
Clinical Medicine, General Internal Medicine and Geriatrics Feinberg School of Medicine
Northwestern University Chicago, IL

3. or Special Populations
SGLT2 Inhibitors: Use in Challenging
or Special Populations
Non-insulin dependent mechanism of action allows for use in low insulin secreting or high insulin resistance type 2 diabetics
Safety/efficacy in older adults and /or renally impaired patients
Effects on weight, blood pressure and lipids

4. Determining A1C Targets
Decision-Making Elements in
Determining A1C Targets
MORE STRINGENT
LESS STRINGENT
Patient attitude and expected treatment efforts
Highly motivated, adherent, excellent self-care capacities
Less motivated, non-adherent, poor self-care capacities
High Long-standing
Short Severe
Severe
Limited
Risks potentially associated with Low
hypoglycemia, other adverse events
Disease duration
Newly diagnosed
Life expectancy
Long
Important comorbidities
Absent
Established vascular complications
Absent
Resources, support system
Readily available
Hypothetical patient. Examples are for illustrative purposes only.
Adapted from Inzucchi SE, et al. Diabetes Care. 2012;35(6):

5. Determining A1C Targets
Decision-Making Elements in
Determining A1C Targets
MORE STRINGENT
LESS STRINGENT
Patient attitude and expected treatment efforts
Highly motivated, adherent, excellent self-care capacities
Less motivated, non-adherent, poor self-care capacities
High Long-standing
Short Severe
Severe
Limited
Risks potentially associated with Low
hypoglycemia, other adverse events
Disease duration
Newly diagnosed
Life expectancy
Long
Important comorbidities
Absent
Established vascular complications
Absent
Resources, support system
Readily available
Hypothetical patient. Examples are for illustrative purposes only.
Adapted from Inzucchi SE, et al. Diabetes Care. 2012;35(6):

6. Determining A1C Targets
Decision-Making Elements in
Determining A1C Targets
MORE STRINGENT
LESS STRINGENT
Patient attitude and expected treatment efforts
Highly motivated, adherent, excellent self-care capacities
Less motivated, non-adherent, poor self-care capacities
High Long-standing
Short Severe
Severe
Limited
Risks potentially associated with Low
hypoglycemia, other adverse events
Disease duration
Newly diagnosed
Life expectancy
Long
Important comorbidities
Absent
Established vascular complications
Absent
Resources, support system
Readily available
Hypothetical patient. Examples are for illustrative purposes only.
Adapted from Inzucchi SE, et al. Diabetes Care. 2012;35(6):

7. Ominous Octet
Reprinted with permission from DeFronzo RA. Diabetes. 2009;58:

8. Increased hepatic glucose production
Reduced peripheral glucose uptake
Reduced pancreatic insulin secretion Insulin resistance
Hyperglycemia
Inhibition of glucose reabsorption from renal tubules
Urinary glucose disposal
Reduce fasting plasma
glucose
Improve glucose tolerance
A1C reduction Urinary calorie loss/
Weight Loss
Adapted from Idris I, et al. Diab Obes Metab. 2009;11:79-88.

9. Efficacy of SGLT2 Inhibitors in
Older Adults

10. Efficacy of Canagliflozin in Older
Adults: A1C and Weight
Subjects <65 years old
Subjects ≥65 years old
Efficacy Parameters*,†
Placebo (n=509)
Canagliflozin 100 mg (n=674)
Canagliflozin 300 mg (n=685)
Placebo (n = 137)
Canagliflozin 100 mg (n=159)
Canagliflozin 300 mg (n=149)
A1C change, %
-0.15 (0.04)
-0.89 (0.03)
-1.08 (0.03)
-0.05 (0.07)
-0.69 (0.07)
-0.88 (0.07)
difference vs
-0.74 (0.05)
-0.93 (0.05)
-0.64 (0.10)
-0.82 (0.10)
placebo
Body weight % change
-0.06 (0.2)
-2.8 (0.1)
-3.4 (0.1)
-0.6 (0.3)
-2.9 (0.3)
-3.8 (0.3)
-2.2 (0.2)
-2.9 (0.2)
-2.3 (0.4)
-3.2 (0.4)
Pooled data from 4 randomized, placebo-controlled, 26-week studies (N=2,313)
Sinclair A, et al. Presented at the 49th EASD Annual Meeting; Barcelona, Spain; Sept, Abstract 955.

11. Efficacy of Canagliflozin in Older Subjects: Lipid and BP effects
Subjects <65 years old
Subjects ≥65 years old
Efficacy Parameters*,†
Placebo (n=509)
Canagliflozin 100 mg (n=674)
Canagliflozin 300 mg (n=685)
Placebo (n=137)
Canagliflozin 100 mg (n=159)
Canagliflozin 300 mg (n=149)
Triglycerides % change‡
9.1 (2.2)
3.7 (2.0)
0.6 (2.0)
2.6 (3.0)
-2.4 (2.8)
-2.5 (2.9)
difference vs placebo
-5.4 (2.9)
-8.5 (2.9)
-5.2 (4.2)
LDL-C % change‡
1.5 (1.4)
6.3 (1.2)
9.8 (1.2)
0.7 (2.1)
3.5 (1.9)
6.8 (2.0)
4.8 (1.8)
8.3 (1.8)
2.8 (2.9)
6.1 (2.9)
HDL-C % change‡
4.0 (0.8)
9.2 (0.7)
10.2 (0.7)
3.7 (1.4)
9,7 (1.3)
10.7 (1.4)
5.2 (1.1)
6.2 (1.1)
6.0 (1.9)
7.1 (1.9)
LDL-C/HDL-C % change‡
-0.5 (1.4)
-0.7 (1.2)
1.3 (1.2)
-1.4 (2.3)
-4.2 (2.2)
-1.2 (2.3)
-0.2 (1.8)
1.8 (1.8)
-2.8 (3.2)
0.2 (3.2)
Non-LDL-C % change‡
1.1 (1.0)
2.6 (0.9)
4.7 (0.9)
-0.5 (1.8)
0.8 (1.7)
2.9 (1.8)
1.4 (1.4)
3.6 (1.4)
1.4 (2.5)
3.4 (2.6)
Systolic BP change, mm Hg
-0.3 (0.5)
-4.2 (0.4)
-4,.8 (0.4)
-0.8 (1.1)
-4.6 (1.0)
-5.9 (1.0)
-3.9 (0.6)
-4.5 (0.6)
-3.9 (1.4)
-5.1 (1.5)
Pooled data from 4 randomized, placebo-controlled, 26-week studies (N=2,313)
Sinclair A, et al. Presented at the 49th EASD Annual Meeting; Barcelona, Spain; Sept 2013 Abstract 955.

12. Patients with Chronic Kidney
Disease

13. Diabetes Therapy in the Setting of Impaired Renal Function
Metformin not indicated based on eGFR
Sulfonylureas should be used cautiously if at all due to hypoglycemic risk
TZD drugs are safe, but risk of edema increased with low
eGFR
DPP-4 inhibitors may require dosage adjustment
GLP-1 receptor agonists may require dosage adjustment
Insulin clearance is decreased, and risk of hypoglycemia is increased
SGLT2 inhibitors safe, but efficacy may be decreased

14. Efficacy and Safety of Canagliflozin in Patients with
T2DM and Chronic Kidney Disease: A1C and Weight
Parameter
Canagliflozin 100 mg
Canagliflozin 300 mg
Placebo
A1C change, %
-0.19 (0.10)
-0.33 (0.10)
0.07 (0.10)
Difference vs placebo
-0.27 (-0.53, 0.001)
-0.41 (-0.68, -0.14)
% of subjects reaching A1C <7.0%
23.6 (4.5)
28.1 (4.8)
18.4 (4.2)
5.2 (-7.9, 18.3)
9.7 (-3,8, 23.2)
FPG change, mmol/L
-0.1 (0.3)
-0.3 (0.3)
0.5 (0.3)
-0.7 (-1.5, 0.2)
-0.8 (-1.7, 0.1)
Body weight % change
-1.3 (0.4)
-1.0 (0.4)
0.1 (0.4)
-1.5 (-2.6, -0.4)
-1.1 (-2.2, 0.0)
Nieto J, et al. Presented at the 49th EASD Annual Meeting; Barcelona, Spain; Sept Abstract 951.

15. Lipid and Blood Pressure Effects
Efficacy and Safety of Canagliflozin in Patients with T2DM and Chronic Kidney Disease:
Lipid and Blood Pressure Effects
Parameter
Canagliflozin
100 mg
300 mg
Placebo
Systolic blood pressure change, mm Hg
-5.5 (1.5)
-6.7 (1.5)
-0.01 (1.5)
Difference vs placebo
-5.5 (-9.3, -1.7)
-6.7 (-10.5, -2.9)
Diastolic blood pressure change, mm Hg
-2.0 (1.0)
-2.4 (1.0)
-1.4 (1.0)
-0.7 (-3.1, 1.8)
-1.0 (-3.5, 1.5)
Triglycerides % change
12.4 (4.8)
9.1 (4.7)
9.9 (4.9)
2.5 (-9.9, 14.9)
-0.8 (-13.0, 11.4)
HDL-C % change
3.3 (1.9)
4.1 (1.8)
1.3 (1.9)
1.9 (-2.9, 6.8)
2.8 (-1.9, 7.6)
LDL-C % change
6.4 (3.8)
2.5 (3.7)
9.4 (3.9)
-3.0 (-12.7, 6.8)
-6.9 (-16.6, 2.8)
LDL-C/HDL-C % change
4.7 (4.1)
-1.2 (4.0)
9.0 (4.2)
-4.3 (-14.9, 6.3)
-10.2 (-20.7, 0.4)
Non-HDL-C % change
6.7 (2.9)
3.5 (2.8)
6.4 (3.0)
-0.3 (-7.9, 7.3)
-2.9(-10.3, 4.6)
Nieto J, et al. Presented at the 49th EASD Annual Meeting; Barcelona, Spain; Sept Abstract 951.

16. Change in A1C with Canagliflozin in Subjects with T2DM and Stage 3 Chronic Kidney Disease
Pooled analysis in patients with T2DM from placebo-controlled studies with eGFR >30 and <60 mL/min/1.73m2 (n=1,085) and in subgroups with eGFR >45 and <60 (n=721) or > 30 and <45 (n=364). Data presented as Least Squares
Mean (SE) change from baseline using ANCOVA and placebo-subtracted Least Squares mean (95% CI) values.
† Mean baseline age 67 years; A1C 8.1%; eGFR 48.2; body weight 91 kg. ‡ Mean baseline age 66 years; A1C 8.1%; eGFR 53.3; body weight 90 kg; §Mean baseline age 66 years; A1C 8.1%; eGFR 38.2; body weight 92 kg. ¥ P < vs placebo. P values reported for prespecified comparisons only.
Woo V, et al. Presented at American Diabetes 2013 Scientific Sessions; Chicago, IL; June Abstract 73-LB.

17. Patients with Renal Impairment
Recommended Dosing in
Patients with Renal Impairment
Canagliflozin Dapagliflozin
Increase dose to 300 mg daily if eGFR
>60 mL/min/1.73 m2
eGFR 45 to < 60 mL/min/1.73 m2: Limit dose to 100 mg daily
Do not initiate or discontinue if eGFR
< 45 mL/min/1.73 m2
Do not initiate or discontinue if eGFR
< 60 mL/min/1.73 m2
Canagliflozin [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2013.
Dapagliflozin [package insert].Princeton, NJ: Bristol-Myers Squibb Company; 2014.

18. Changes in Lipid Profiles with
SGLT2 Inhibitors

19. Changes in Lipid Profiles of Patients on Dapagliflozin
Plasma lipid changes from baseline (%, 95% CI) in pooled DAPA studies at 24 weeks
Placebo (n=1393)
Dapagliflozin 5 mg (n=1145)
Dapagliflozin 10 mg (n=1193) TC - n
989
888
834
BL mean
5.06 mmol/L
5.04 mmol/L
5.07 mmol/L
Mean change
-0.4%
+1.1%
+1.4%
(95% CI)
(-1.4, +0.6)
(0.0, +2.2)
(+0.2, +2.6)
HDL-C
990
889
1.15 mmol/L
1.16 mmol/L
1.17 mmol/L
Mean Change
+3.8%
+6.5%
+5.5%
(+2.8, +4.8)
(+5.3, +7.8)
(+4.3, +6.7)
LDL-C
985
884
828
2.97 mmol/L
2.93 mmol/L
2.95 mmol/L
-1.9%
+0.6%
+2.7%
(-3.5, -0.3)
(-1.2, +2.4)
(+0.8, +4.7) TG
984
886
831
2.12 mmol/L
2.15 mmol/L
2.19 mmol/L
-0.7%
-3.2%
-5.4%
(3.0, +1.7)
(-5.8, -0.6)
(-7.9, -2.8)
FFA
838
732
694 BL
0.56 meq/L
0.58 meq/L
mean
-5.7%
-0.5%
+1.2%
(8.9, -2.5)
(-3.7, +2.8)
(-2.4, +5.0)
12 phase 2b/3 double-blind, controlled trials for up to 24 weeks were analyzed. (n=3,731)
Hardy E, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. Sept Abstract 947.

20. Weight Loss and Blood
Pressure Effects

21. Dapagliflozin-induced Weight Loss Affects 24 Week A1C and Blood Pressure Levels
∆ BW, kg -5 -4 -3 -2 -1
Effect of other
variables
14%
17%
Added benefit of weight loss during dapagliflozin treatment that contributes to overall changes in A1C
and to changes in
blood pressure after 24 weeks of treatment -1
37% -2
Effect of ∆ In BW
49%
∆ SBP, mm Hg -3
46% -4
Non-BW ∆ related -5
37%
treatment effect -6
Dapagliflozin 10 mg
Placebo -7
Sjöström CD, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. Sept Abstract 181.

22. and Weight Loss–Associated Mechanisms
Canagliflozin Lowers A1C Through Weight Loss–Independent
and Weight Loss–Associated Mechanisms
Relationship between changes in A1C and body weight at week 26*
0.2
-0.2
-0.4
-0.6
-0.
-1.0
-1.2
-1.4
Placebo Canagliflozin 100 mg
Canagliflozin 300 mg
∆ A1C (%)
Weight loss-
independent
Weight loss- associated
Most (85%) of the A1C-lowering effect of canagliflozin is independent of weight loss
∆ body weight (%)
Across all 3 treatment groups, subjects with greater weight loss had greater reductions in A1C, and the slope associated weight loss for A1C was similar across all 3 groups.
Each 1% reduction in BW was associated with a 0.045% reduction in A1C.
*Solid symbols represent mean changes within each decile of weight change, and open symbols are mean changes in the entire
treatment group.
Pooled analysis of 4 previously reported, randomized, double-blind, 26-week, phase 3 studies (N=2,250).
Wilding L, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. Sept Abstract 946. Reproduced with the permission of Janssen Research & Development, LLC

23. and Weight Loss–Associated Mechanisms
Canagliflozin Lowers A1C Through Weight Loss–Independent
and Weight Loss–Associated Mechanisms
Relationship between changes in systolic blood pressure and body weight at Week 26* 6 4 2 -2
-4. -6 -8
-10
Placebo Canagliflozin 100 mg
Canagliflozin 300 mg
∆ SBP (mm Hg)
Weight loss contributes to
~40% of the SBP-lowering effect of canagliflozin 5
∆ body weight (%)
In each treatment group, subjects with greater weight loss had greater reductions in systolic blood pressure, with similar slopes associated with weight loss observed across all 3 groups.
Each 1% reduction in body weight was associated with a 0.62% mm Hg reduction in systolic blood pressure.
*Solid symbols represent mean changes within each decile of weight change, and open symbols are mean changes in the entire
treatment group.
Pooled analysis of 4 previously reported, randomized, double-blind, 26-week, phase 3 studies (N=2,250).
Wilding L, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. Sept Abstract 946. Reproduced with the permission of Janssen Research & Development, LLC

24. Effects of Dapagliflozin on Body Weight
Placebo + Metformin Dapagliflozin 10 mg + Metformin
0.5
1.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5
-4.0
Change in total body weight (kg)*
LOCF
Difference from placebo
-2.08 kg
(95%CI -2.84, -1.31)
P<0.0001
0 4
Sample size per time point 8 16
Study Week 24
Baseline value (kg)
Placebo 91 90 88 86
90.9
Dapagliflozin 89 85 83
92.1
Dapagliflozin reduces total body weight predominantly by reducing fat mass, visceral
adipose tissue and SC adipose tissue volume.
Reprinted with permission from Bolinder J, et al.
J Clin Endocrinol Metab (3):1020–1031.

25. Effects of Dapagliflozin on Regional Adipose Tissue Distribution
Mean change from baseline in VAT and SAT volume with treatment at 24 wk
Placebo + Metformin n=42; n=37
Dapagliflozin 10 mg + Metformin n=37; n=30
200
Change in adipose tissue volume (cm3)
-39.2
-121.4
-200
-297.5‡
-400
-306.4§
-600
-800
Visceral AT
Subcutaneous AT
Dapagliflozin reduces total body weight predominantly by reducing fat mass, visceral
adipose tissue and SC adipose tissue volume.
‡, VAT, cm3 (95 CI = to -68.6; nominal P = );
§, SAT, cm3 (95% CI = -359 to -10.1; nominal P = ).
Reprinted with permission from Bolinder J, et al.
J Clin Endocrinol Metab (3):1020–1031.

26. Summary
SGLT2 inhibitors are effective therapies in challenging patient populations
Efficacy of these therapies is reduced in older adults and renally impaired patients, but safety is maintained
Beneficial effects on weight and blood pressure are consistently seen, but clinical impact remains to be determined
Minor changes in LDL-C, but not HDL-C or triglycerides,
are observed
– Minor changes in non-HDL-C with canagliflozin
Cardiovascular outcome studies are in progress