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

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

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

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

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;19:370–376. 2. Bakris GI, et al. Kidney Int. 2009;75:1272–1277. 3. Mather A, Pollock C. Kidney Int Suppl. 2011;120:S1–S6.

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.

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.

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.

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: -0.88, -0.59) p < 0.0001 EMPA-REG MONO: study 1245.20 -0.73 (95% CI: -0.88, -0.59) p < 0.0001 -0.85 (95% CI: -0.99, -0.71) p < 0.0001 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.

24-week empagliflozin monotherapy versus placebo and sitagliptin Change from baseline in HbA1c over time EMPA-REG MONO: study 1245.20 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.

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 < 0.0001 -2.0 (95% CI: -2.3, -1.7) p < 0.0001 -1.7 (95% CI: -2.0, -1.4) p < 0.0001 EMPA-REG MONO: study 1245.20 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.

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 = 0.0355 -1.9 (95% CI: -2.4, -1.5) p < 0.0001 EMPA-REG MONO: study 1245.20 -2.2 (95% CI: -2.6, -1.7) p < 0.0001 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.

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 1245.20 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.

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.

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.

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.

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.

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 1245.28 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.

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 < 0.0001 EMPA-REG H2H-SU™: study 1245.28 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.

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 < 0.0001 EMPA-REG H2H-SU™: study 1245.28 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.

and SGLT2 agonist do this too! N Engl J Med 2015; 373:2117-2128

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)

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

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 103.19.33±1.3 100.59.33±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

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 105.9 (±23.2) kg, BMI 37.0 (±6.8)kg/m2 and HbA1c 9.5 (±1.4)%), Duration of diabetes 9.7(30-14.0) 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.

ABCD nationwide audit of dapagliflozin Abstract ADA 2016

ABCD nationwide audit of dapagliflozin LFTs Abstract ADA 2016