1. SGLT2 inhibitors Ian Gallen Consultant Community Diabetologist
Royal Berkshire Hospital
Reading UK

2. Diabetes from Ancient Greek διαβήτης (diabētēs) which literally means "a passer through; a siphon.
Asklepieion of Kos Ἀσκληπιεῖον

3. Main classes of oral drugs available
Biguanides (Metformin)
Sulphonylureas (Gliclazide, Glimiperide, Glibencalmide etc)
Thiozolendinediones (Pioglitazone)
Glinides (Replaglinide, nataglinide)
Alpha-glucosidase inhibitors (Acarbose)
DDP-4 inhibitors or Gliptins (Sitagliptin, Saxagliptin,Linagliptin, Vildagliptin, Allogliptin)
SGLT2 inhibitor agents (empagliflozin, cangligliflozin, dapagliflozin)
Coming soon dual SGLT1/2 inhibitor agents
Ian Gallen

4. What would your ideal diabetes drug do?
Effective in lowering HbA1c
No hypoglycaemia
No effect on weight/ weight loss?
Reduce CV risk
Also reduce lipids and B.P.?
Few/ no side effects
Safe
Ian Gallen

5. SGLT2 is a sodium glucose cotransporter1,2
Segment S1–2
Basolateral membrane
SGLT2
GLUT2
Glucose Na+
Glucose
Glucose Na+
Na+ K+ K+
Na+/K+ ATPase pump
Lateral intercellular space
The SGLTs are a family of transmembrane glucose transporters providing an active transport of glucose, or other small molecules, against their concentration gradient using a concentration gradient of sodium ions, generated by the sodium‐potassium ATP‐pump, as their motive force.
SGLTs transfer glucose and sodium (Na+:glucose coupling ratio for SGLT2 = 1:1) from the lumen into the cytoplasm of tubular cells through a secondary active transport mechanism.
At the basolateral membrane, GLUT2 transfers the intracellular glucose to the interstitium and plasma by a facilitated transport process (via a Na+/K+ ATPase).
SGLTs transfer glucose and sodium (Na+:glucose coupling ratio for SGLT1 = 2:1 and for SGLT2 = 1:1) from the lumen into the cytoplasm of tubular cells through a secondary active transport mechanism
GLUT, glucose transporter; SGLT, sodium glucose cotransporter.
1. Wright EM, et al. Physiology. 2004;19:370– Bakris GI, et al. Kidney Int. 2009;75:1272– Mather A, Pollock C. Kidney Int Suppl. 2011;120:S1–S6.

6. Renal glucose re-absorption in patients with diabetes1,2
Filtered glucose load > 180 g/day
When blood glucose increases above the renal threshold (~ 11 mmol/L), the capacity of the transporters is exceeded, resulting in urinary glucose excretion
SGLT2
~ 90%
At a certain glucose concentration the glucose flux is to high and the glucose transport system becomes saturated . All the filtered glucose in excess of this threshold is excreted In the urine.
SGLT1
~ 10%
SGLT, sodium glucose cotransporter.
1. Adapted from: Gerich JE. Diabet Med. 2010;27:136–142; 2. Bakris GL, et al. Kidney Int. 2009;75;1272–1277.

7. Urinary glucose excretion via SGLT2 inhibition1
Filtered glucose load > 180 g/day
SGLT2 inhibitors reduce glucose re-absorption in the proximal tubule, leading to urinary glucose excretion* and osmotic diuresis
SGLT2 inhibitor
SGLT2
SGLT2 inhibition lowers the Tm – the maximum re-absorptive capacity of the proximal tubule and lower the renal threshold for Glucose. Therefore, treated subjects will start to renally excrete glucose. The amount of excreted glucose is dependent on the Glucose filtration and therefore dependent on the blood glucose values. In the hypoglycaemic Range the amount of Glucose which is excreted will be very small and with rising blood Glucose the excreted glucose will also increase. Subjects with high baseline glucose will have a much higher glucose excretion rate than subjects which are near normal. In the PK/PD studies a UGE (urinary glucose excretion) of around 80 g/day was measured. The Glucose loss is associated with fluid loss (increase in urine volume), osmotic diuresis and of with caloric loss. (average of 240 cal/day)
SGLT1
SGLT, sodium glucose cotransporter.
*Loss of ~ 80 g of glucose per day = 240 cal/day.
1. Bakris GL, et al. Kidney Int. 2009;75;1272–1277.

8. Renal glucose re-absorption and excretion
Glucose re-absorption is increased in T2D...
The amount of glucose filtered increases linearly with increasing plasma glucose concentration
Glucose filtration
Glucose excretion
Tmax is the transport maximum for glucose (maximum glucose re-absorption)
...reducing the amount of glucose excreted at a given level of blood glucose
Tmax
Glucose re-absorption
SGLT2 inhibitors lower the amount of glucose that can be re-absorbed, i.e., lower the renal threshold/Tmax
Above a certain threshold of plasma glucose, glucose appears in the urine
Glucose flux
Glucose re-absorption on SGLT2 inhibition
As the level of glucose in the blood rises, the amount of Glucose which is filtered in the kidney increase (yellow). The re-absorption rate progressively increases up to the point marked Tmax (red line). At plasma glucose concentrations below this level, all the filtered glucose is re-absorbed (observe that the ‘filtered’ and ‘re-absorbed’ curves are superimposed below this point. As the filtered and re-absorption curves separate, the point marked ‘threshold’ is reached, and the body starts to excrete glucose into the urine (green line) (i.e. as the plasma glucose concentration rises, there comes a point where the maximum re-absorptive capacity of the proximal tubule is exceeded). Above this point, the ‘excreted’ curve rises with increasing plasma glucose concentration. In T2D the Tmax is slightly increased due to up regulation of SGLT2, therefore the renal Glucose excretion is shifted to the right (green line). Inhibition of SGLT2 changes the titration curve of renal glucose absorption. SGLT2 inhibition lowers the Tm – the maximum re-absorptive capacity of the proximal tubule – and such an individual will start to renally excrete up to 80 g glucose per day (see graph). As the Tm is lowered, the excreted curve is left shifted and also the threshold where Glucose will occur in the urine is shifted to a hypoglycaemic range.
This increases glucose excretion 90
180
270
360
450
540
Plasma glucose (mg/dL)
SGLT2, sodium glucose cotransporter 2; T2D, Type 2 Diabetes; Tmax, transport maximum.
Nair S, Wilding JPH. J Clin Endocrinol Metab. 2010;95:34–42.

9. Comparison with placebo
24-week empagliflozin monotherapy versus placebo and sitagliptin Change in HbA1c at Week 24
Empagliflozin
Comparison with placebo
-0.74
(95% CI: , -0.59)
p <
EMPA-REG MONO: study
-0.73
(95% CI: , -0.59)
p <
(95% CI: , -0.71)
p <
Placebo
EMPA 10 mg
EMPA 25 mg
SITA 100 mg
Mean baseline HbA1c (%)
7.91
7.87
7.86
7.85
Mean baseline HbA1c (mmol/mol)
63.0
62.5
62.4
62.3
End HbA1c (%)
7.98
7.21
7.09
7.20
End HbA1c (mmol/mol)
63.7
55.3
54.0
55.2
CI, confidence interval; EMPA, empagliflozin; HbA1c, glycosylated haemoglobin; QD, once daily; SITA, sitagliptin.
ANCOVA, FAS (LOCF).
Roden M, et al. Lancet Diabetes Endocrinol. 2013;1:208–219.

10. 24-week empagliflozin monotherapy versus placebo and sitagliptin Change from baseline in HbA1c over time
EMPA-REG MONO: study
Baseline
Week
Placebo
Empagliflozin 10 mg QD
Empagliflozin 25 mg QD
Sitagliptin
Number of patients analysed
Placebo
212
211
186
173
158
EMPA 10 mg QD
215
206
203
EMPA 25 mg QD
221
208
204
Sitagliptin
220
219
213
198
EMPA, empagliflozin; HbA1c, glycosylated haemoglobin; QD, once daily; SE, standard error.
MMRM results, FAS (OC).
Roden M, et al. Lancet Diabetes Endocrinol. 2013;1:208–219.

11. 24-week empagliflozin monotherapy versus placebo and sitagliptin Change in FPG (mmol/L) over time
Baseline
Week
-1.0
(95% CI:
-1.3, -0.7)
p <
-2.0
(95% CI:
-2.3, -1.7)
p <
-1.7
(95% CI:
-2.0, -1.4)
p <
EMPA-REG MONO: study
Number of patients analysed
Placebo
211
183
169
154
EMPA 10 mg QD
215
214
210
205
201
EMPA 25 mg QD
220
217
206
203
200
Sitagliptin
218
216
193
CI, confidence interval; EMPA, empagliflozin; FPG, fasting plasma glucose; QD, once daily.
MMRM, FAS (OC).
Roden M, et al. Lancet Diabetes Endocrinol. 2013;1:208–219.

12. Comparison with placebo
24-week empagliflozin monotherapy versus placebo and sitagliptin Change in body weight at Week 24
Empagliflozin
Placebo
(n = 228)
10 mg QD
(n = 224)
25 mg QD
Sitagliptin 100 mg QD
(n = 223)
Comparison with placebo
0.5
(95% CI: 0.0, 1.0)
p =
-1.9
(95% CI: -2.4, -1.5)
p <
EMPA-REG MONO: study
-2.2 (95% CI: -2.6, -1.7)
p <
Mean baseline
78.2
78.4
77.8
79.3
CI, confidence interval; QD, once daily.
ANCOVA, FAS (LOCF).
Roden M, et al. Lancet Diabetes Endocrinol. 2013;1:208–219.

13. 24-week empagliflozin monotherapy versus placebo and sitagliptin Adverse events of special interest
OL empagliflozin
25 mg QD
(n = 87)
10 mg QD
(n = 224)
Confirmed hypoglycaemia*
1 (< 1%)
1 (1%)
Urinary tract infections
12 ( 5)
15 ( 7)
11 ( 5)
3 ( 3)
Male†
3 (2)
2 (1)
4 (3)
2 (3)
Female‡
9 (9)
12 (15)
10 (13)
7 (9)
1 (4)
Genital infections
0 ( 0.0)
7 ( 3)
9 ( 4)
2 ( 1)
1 ( 1)
1 (1)
1 (2)
3 (4)
EMPA-REG MONO: study
No urinary tract infections or genital infections were reported as serious adverse events.
QD, once daily; OL, open label.
*Plasma glucose ≤ 70 mg/dL and/or requiring assistance.
†Percentage of males in group.
‡Percentage of females in group.
Roden M, et al. Lancet Diabetes Endocrinol. 2013;1:208–219.

14. placebo and sitagliptin
52-week extension of empagliflozin monotherapy versus placebo and sitagliptin Change from baseline in HbA1c at Week 76
Empagliflozin
Comparison with
placebo and sitagliptin
p < 0.001
p < 0.001
p < 0.001
EMPA-REG EXTENDTM MONO
p = 0.131
p = 0.005
Placebo
EMPA 10 mg
EMPA 25 mg
SITA 100 mg
Mean baseline HbA1c (%)
7.91
7.87
7.86
7.85
EMPA, empagliflozin; HbA1c, glycosylated haemoglobin; SE, standard error; SITA, sitagliptin.
ANCOVA in FAS (LOCF).
Roden M, et al. ADA 2014, Abstract 264-OR.

15. Adjusted mean (SE) HbA1c (%)
52-week extension of empagliflozin monotherapy versus placebo and sitagliptin HbA1c over time
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
Sitagliptin
Adjusted mean (SE) HbA1c (%)
EMPA-REG EXTENDTM MONO 41 52 64 76
Week
Number of patients analysed
Placebo
212
211
186
173
158 96 81 73 65
EMPA 10 mg
215
206
203
156
144
134
132
EMPA 25 mg
221
208
204
147
143
138
Sitagliptin
220
219
213
198
123
114
108
EMPA, empagliflozin; HbA1c, glycosylated haemoglobin; SE, standard error.
MMRM in FAS (OC).
Roden M, et al. ADA 2014, Abstract 264-OR.

16. Adjusted mean (SE) HbA1c (%)
52-week extension of empagliflozin as add-on to metformin in T2D HbA1c over time
Placebo
Empagliflozin 10 mg QD
Empagliflozin 25 mg QD
Adjusted mean (SE) HbA1c (%)
EMPA-REG EXTENDTM MET
Baseline 41 52 64 76
Week
Number of patients analysed
Placebo
199
195
190
173
156 96 86 74 70
EMPA 10 mg QD
216
213
212
201
198
153
144
138
130
EMPA 25 mg QD
205
204
197
191
186
135
122
118
EMPA, empagliflozin; HbA1c, glycosylated haemoglobin; QD, once daily; SE, standard error; T2D, Type 2 Diabetes.
MMRM in FAS (OC).
Merker L, et al. ADA 2014, Abstract 1074-P.

17. Adjusted mean (SE) change from baseline in body weight (kg)
52-week extension of empagliflozin as add-on to metformin in T2D Change from baseline in body weight over time
Placebo
Empagliflozin 10 mg QD
Empagliflozin 25 mg QD
Week 24 52 76
Adjusted mean (SE) change from baseline in body weight (kg)
EMPA-REG EXTENDTM MET
Number of patients analysed
Placebo
158 85 70
EMPA 10 mg QD
197
147
130
EMPA 25 mg QD
185
133
121
EMPA, empagliflozin; QD, once daily; SE, standard error; T2D, Type 2 Diabetes.
MMRM in FAS (OC).
Merker L, et al. ADA 2014, Abstract 1074-P.

18. 104-week study with empagliflozin H2H versus glimepiride Change in HbA1c over time
Difference in change from baseline at Week 104: -0.11% (95% CI: -0.21, -0.01) p = 0.026
EMPA-REG H2H-SU™: study
Observed cases means data observed before anti-diabetic rescue medication.
The impact of missing data and important protocol violations and robustness of the primary or secondary analyses were assessed using sensitivity analyses (mixed model repeated measures [MMRM] analyses). MMRM analyses were performed in the full analysis set using observed cases, with data after a change in metformin dose or additional anti-diabetes therapy set to missing (OC). The MMRM model included baseline eGFR, region, treatment, visit, and treatment-by-visit interaction as fixed effects and baseline HbA1c as a linear covariate. The same model was used for key secondary endpoints but with the baseline value for the endpoint in question as an additional linear covariate. 65 78 91
104
Analysed patients
Glimepiride
761
758
738
699
660
609
562
524
494
461
Empagliflozin
759
751
734
702
672
646
624
593
568
548
CI, confidence interval; H2H, head-to-head; HbA1c, glycosylated haemoglobin; QD, once daily.
MMRM. FAS (OC).
Ridderstråle M, et al. Lancet Diabetes Endocrinol. 2014;2:691‒700.

19. 104-week study with empagliflozin H2H versus glimepiride
Change in body weight over time 12 28 52 78
104
Week
-4.6 kg (95% CI:
-5.0, -4.2)
p <
EMPA-REG H2H-SU™: study
Observed cases means data observed before anti-diabetic rescue medication.
Analysed patients
Glimepiride
745
743
703
610
526
462
Empagliflozin
739
737
706
643
595
555
CI, confidence interval; H2H, head-to-head; QD, once daily; SE, standard error.
MMRM. FAS (OC). Ridderstråle M, et al. Lancet Diabetes Endocrinol. 2014;2:691‒700.

20. 104-week study with empagliflozin H2H versus glimepiride
Change in body weight over time 12 28 52 78
104
Week
-4.6 kg (95% CI:
-5.0, -4.2)
p <
EMPA-REG H2H-SU™: study
Observed cases means data observed before anti-diabetic rescue medication.
Analysed patients
Glimepiride
745
743
703
610
526
462
Empagliflozin
739
737
706
643
595
555
CI, confidence interval; H2H, head-to-head; QD, once daily; SE, standard error.
MMRM. FAS (OC). Ridderstråle M, et al. Lancet Diabetes Endocrinol. 2014;2:691‒700.

21. and SGLT2 agonist do this too!
N Engl J Med 2015; 373:

22. Across all studies and empagliflozin
Improves Glycaemic control
Reduction of HbA1c as monotherapy
or with Metformin, Pioglitazone
and as part of triple therapy
or with insulin
Sustained weight loss
Reduction in SBP and DBP
Well tolerated
Reduce death rates (RRR 32% in Empa-Reg)

23. SGLT2 Use In Berkshire Number 265 Male 158 Female 98 Age 58.3±0.5
BMI (kg/m2)
33.7±0.5
Source IG Eclipse audit 3/8/2016

24. Outcomes of SGLT2 Use In Berkshire
Start
6 months
P Value
HbA1c %
9.33±0.1
8.47±0.1
P < 0.001
Weight Kg
±1.3
±1.3
Total cholesterol (mmol/l)
3.93±0.07
4.02±0.07 NS
Triglycerides (mmol/l)
0.8±0.1
0.56±0.1
eGRF (ml/min)
63.5±0.6
70.3±0.9
Haemoglobin (g/dl)
13.9±0.1
14.1±0.1
ALT (iU/L)
42.4±1.1
40.1±1.0
P < 0.03
ALT (iU/L) Raised at start
76.1±5.0
66.4±5.0
Source IG Eclipse audit 3/8/2016

25. ABCD nationwide audit of dapagliflozin
By December 2015, 138 contributors from 57 centres had submitted data on 1,725 dapagliflozin treated patients (56.5% males, mean (±SD) age 57.3 (±9.3)years,
Weight (±23.2) kg, BMI 37.0 (±6.8)kg/m2 and HbA1c 9.5 (±1.4)%),
Duration of diabetes 9.7( ) years.
Co-medications
80.4% metformin,
26.1% insulin(11.0% basal insulin, 12.3% basal bolus, 2.8% insulin mixtures),
29.0% sulphonylurea,
25.5% GLP-1 receptor analogues,
12.4% DPP-4 inhibitors,
5.9% pioglitazone
1.5% other agents.
Dapagliflozin reduced HbA1c, weight, BMI and systolic blood pressure by clinically and statistically significant amounts
These improvements were increased to the second follow up.

26. ABCD nationwide audit of dapagliflozin
Abstract ADA 2016

27. ABCD nationwide audit of dapagliflozin
LFTs
Abstract ADA 2016