ROLE OF KIDNEY AND SGLT-2 INHIBITOR IN GLUCOSE HOMEOSTASIS

Transcription

1 ROLE OF KIDNEY AND SGLT-2 INHIBITOR IN GLUCOSE HOMEOSTASIS Prof. Dato Dr. Mafauzy Mohamed Professor of Medicine / Senior Consultant Endocrinologist Health Campus, UniversiB Sains Malaysia

2 The Kidneys Maintain Homeostasis by Filtration, Reabsorption, Secretion and Excretion Human kidneys together receive ~25% of cardiac output 1 (1.5 L/min in a 70-kg adult male) Afferent arteriole Efferent arteriole Bowman s capsule Glomerular capillaries Distal convoluted tubule Proximal convoluted tubule Collecting duct Nephron (~1.5 million per kidney) Loop of Henle 1 Balat A. Kidney is in trouble with mediators. Bosn J Basic Med Sci 2010;10:S29 36.

3 Contribution of Kidney to Glucose Homeostasis Production of glucose Utilization of glucose Reabsorption of glucose from glomerular filtrate Gerich JE. G. Bolli, Diabet presented Med at EASD 2010;27: September 2008

4 The Liver and the Kidney Both Contribute to Glucose Production Gluconeogenesis 20 25%* Glucose production ~70 g/day Gluconeogenesis 25 30%* Glycogenolysis 45 50%* *post-absorptive state Gerich JE. Diabet Med 2010;27:

5 The Kidney Filters and Reabsorbs a Large Proportion of the Glucose Present in the Body Net ~0 g/day Glucose input ~250 g/day: Dietary intake ~180 g/day Glucose production ~70 g/day Gluconeogenesis Glycogenolysis Glucose utilization ~250 g/day: Brain ~125 g/day Rest of body ~125 g/day Glucose pool in body ~450 g Glucose filtered ~180 g/day Glucose reabsorbed ~180 g/day Wright EM, et al. J Int Med 2007;261:32 43.

6 The renal proximal tubule responsible for the reabsorption of glucose Manski D. Accessed December 6, Abdul-Ghani MA, et al. Endocr Pract. 2008;14(6): Marsenic O. Am J Kidney Dis. 2009;53(5):

7 Renal Glucose Handling Glomerulus 180 g glucose filtered each day SGLT2: up to ~90%* of glucose is reabsorbed from the S1/S2 segments Proximal tubule SGLT1: ~10%* of glucose is reabsorbed from the S3 segment Excretion: minimal glucose Wright EM. Am J Physiol Renal Physiol 2001;280:F10 8; Lee YJ, et al. Kidney Int Suppl 2007;106:S27 35; Brown GK. J Inherit Metab Dis 2000;23: *based on animal data 732HQ10NP027

8 Major Glucose Transporters GLUT family Facilitative glucose transporters. Passive bidirectional transport. 13 members (GLUT1 12 and H+/ myoinositol transporter [HMIT]). GLUT1 (widespread incl. kidney). GLUT2 (kidneys and pancreas). SGLT family Sodium glucose co-transporters. Active unidirectional transport. 6 members (SGLT1 6). SGLT1 (brush border of small intestine and S3 of proximal tubule). SGLT2 (proximal tubule S1 & S2). Extracellular space! Extracellular space! NH 2! COOH! 1! 2! 3! 4! 5! 6! 7! 8! 9! 10! 11! 12! 1! 2! 3! 4! 5! 6! 7! 8! 9! 10! 11! 12! 13!14! NH 2! COOH! Intracellular space! Intracellular space! Zhao F, Keating AF. Curr Genomics 2007;8:

9 Sodium Glucose Co-transporters (SGLTs) Transporter Major site of action Function SGLT1 Small intestine, heart, trachea and kidney Co-transports sodium, glucose and galactose across the brush border of the intestine and proximal tubule of the kidney SGLT2 Kidney Co-transports sodium and glucose in the S1 segment of the proximal tubule of the kidney SGLT3 SGLT4 Small intestine, uterus, lungs, thyroid and testis Small intestine, kidney, liver, stomach and lung Transports sodium (not glucose) Transports glucose and mannose SGLT5 Kidney Unknown SGLT6 Spinal cord, kidney, brain and small intestine Transports myoinositol and glucose Bays H. Curr Med Res Opin 2009;25: Charles SH, et al. Am J Physiol Cell Physiol 2010.

10 SGLT2 and SGLT1 their relative roles in glucose reabsorption 1,2 1. Abdul-Ghani MA, et al. Endocr Pract. 2008;14(6): Washburn WN. J Med Chem. 2009;52(7):

11 SGLT2 the major glucose transporter in the renal proximal tubule Washburn WN. J Med Chem. 2009;52(7): Marsenic O. Am J Kidney Dis. 2009;53(5): Vallon V, et al. Curr Opin Nephrol Hyperten. 2010;19: (5): Abdul Ghani MA, et al. Endocr Pract. 2008;14(6):

12 SGLT1 a minor glucose transporter in the renal proximal tubule1-3

13 SGLT2 and GLUT2 Mechanism of Transport Tubular lumen Interstitial space Adapted from Wright EM, et al. Physiology 2004;19:370 6.

14 Reabsorption of glucose helps sustain hyperglycemia1,2 1. Washburn WN. J Med Chem. 2009;52(7): Marsenic O. Am J Kidney Dis. 2009;53(5):

15 In Type 2 Diabetes Mellitus, Counterproductive Increases in SGLT2 Upregulation and Glucose Reabsorption Occur Normalized levels Transporter protein expression Healthy Type 2 diabetes mellitus * * AMG uptake (CPM) Glucose uptake into tubular epithelial cells * 0 0 SGLT2 GLUT2 Healthy Type 2 diabetes mellitus *p<0.05; from human exfoliated proximal tubular epithelial cells (HEPTECs) Rahmoune H, et al. Diabetes 2005;54:

16 Implications of an increased glucose threshold in type 2 diabetes An adaptive response to conserve glucose (i.e. for energy needs) becomes maladaptive in diabetes Moreover, the ability of the diabetic kidney to conserve glucose may be augmented in absolute terms by an increase in the renal re-absorption of glucose De Fronzo RA. Diabetes. 2009;58:

17 Beyond a certain plasma glucose threshold, saturation of glucose transporters results in glucosuria Rate of glucose filtration / reabsorption / excretion (mmol/min) Excretion threshold Glucose filtration rate is normally proportional to plasma glucose concentration Splay Saturation threshold Glucosuria starts to occur Transport Maximum for Glucose (TmG) Filtered glucose Reabsorbed glucose No excretion Excreted glucose mmol/l mg/dl Adapted from Chao EC, et al. Nat Rev Drug Discov 2010;9: ; Marsenic O. Am J Kidney Dis 2009;53: Plasma glucose HQ11NP HQ10NP027

18 Familial Renal Glucosuria Glucose reabsorption Theoretical Observed Normal Type B Type A reduced affinity of SGLT2 transporter for glucose decreased TmG reduced amount of normal SGLT2 protein Type O complete absence of renal glucose transport Plasma glucose concentration (mg/dl) 300 Santer R, et al. Clin J Am Soc Nephrol 2010;5:

19 Familial Renal Glucosuria Glucosuria varies from 0.6 to 202 g/1.73 m 2 /day between affected individuals 1 Glucosuria <100 g/1.73 m 2 /day is generally asymptomatic but the following features have been reported in some individuals 2 : Polyuria, enuresis, mild growth and pubertal maturation delay Increased incidence of urinary tract infections Activation of renin angiotensin aldosterone system secondary to natriuresis Severe glucosuria >100 g/1.73 m 2 /day occurs especially in type O individuals 2 Episodic dehydration and ketosis can occur during pregnancy or starvation Drug-induced glucosuria with SGLT2 inhibitors <70 g/1.73 m 2 /day usually g/1.7 3m 2 /day 1 Santer R, et al. J Am Soc Nephrol 2003;14: ; 2 Santer R, et al. Clin J Am Soc Nephrol 2010;5:

20 Renal SGLT2 inhibition an insulin-independent target in type 2 diabetes Washburn WN. J Med Chem. 2009;52(7): Bailey CJ. Curr Diab Rep. 2009;9(5): Srinivasan BT, et al. Postgrad Med J. 2008;84(996): Rajesh R, et al. Int J Pharma Sci Res. 2010;1(2):

21 SGLT2 Inhibition: Potential Clinical Benefit in Type 2 Diabetes Mellitus Glucose lowering Prevention of microvascular morbidity 1 Decrease in glucotoxicity 2 Urinary glucose excretion decreases as hyperglycemia decreases, resulting in a low risk of hypoglycemia 2 Insulin-independent mechanism 3 Ability to work at all stages of disease Ability to combine with other classes of antihyperglycemics 2 Stable control in combination with insulin and insulin secretagogues 2 Osmotic diuresis Initial weight loss 2 Decrease in blood pressure 2 Loss of excess calories in the urine 2,3 Sustained weight loss 2 Mitigation of weight gain from other classes of antihyperglycemics 2 1 Holman RR, et al. N Engl J Med 2008;359: ; 2 Neumiller JJ. Drugs 2010;70:377 85; 3 Lo MC, et al. Am J Ther 2010 [Epub ahead of print]

22 Development of SGLT2 inhibitors The search for a potent, selective SGLT2 inhibitor.from apple trees to candidate drugs HQ11NP068

23 Discovery of phlorizin by French chemists in the early 1800s Isolated from apple tree bark (1835) Glycosuric effect revealed (1865) Renal effects identified in rat (1903) and man (1933) Antidiabetic effect discovered (1987) Found to inhibit SGLT1 and SGLT2 Ehrenkranz JRL, et al. Diabetes Metab Rev 2005;21: HQ11NP068

24 In the 1880s-1890s, phlorizin was shown to induce glycosuria In 1886, Von Mering observed that dogs receiving doses of phlorizin above 1.0 g developed glycosuria Cited in Joel RL, et al. Diabetes Metab Res Rev 2005;21: In a diabetic with g of glucose per litre of blood, the injection of 50 mg of phlorizin was also followed by a slight decrease, to g, while glycosuria increased by 115 to 140 g (Émile) Charles Achard, HQ11NP068

25 In 1987, phlorizin was found to prevent hyperglycaemia and restore insulin sensitivity in partially pancreatectomised rats Rats treated with phlorizin (0.13 g/kg) every 8 h for 4 5 weeks after 90% partial pancreatectomy: Glycosuria increased 10-fold 400 Fasting blood glucose Fed blood glucose ** Oral glucose tolerance test and meal tolerance test responses normalised Insulin sensitivity (reduced by onset of hyperglycaemia) restored Rossetti L, et al. J Clin Invest 1987;79: Blood glucose (mg/dl) *p<0.05; **p<0.001 * Sham Diabetic Diabetic + phlorizin ** Sham + phlorizin Phlorizin stop HQ11NP068

26 A single dose of the selective SGLT2 inhibitor dapagliflozin induced cumulative urinary glucose excretion in healthy volunteers Mean Cumulative Urinary Glucose (g) Komoroski BJ, et al. Clin Pharmacol Ther 2009;85: mg 5 mg 10 mg 20 mg 50 mg 100 mg 250 mg 500 mg Placebo Time after dose (h) HQ11NP068

27 Sustained long-term efficacy of dapagliflozin as add-on to metformin (1) Mean change from baseline in HbA1c (102 weeks) Week 24 Week 50 Week 102 Adjusted mean change from baseline at week 102 (95% CI) 0.02 (-0.20,0.23) Adjusted mean change from baseline in HbA1c (%) (-0.68, -0.29) (-0.77, -0.39) (-0.97, -0.60) Placebo Time (weeks) Bailey CJ, et al. Lancet 2010;375: Bailey CJ et al. 71 st ADA Scientific Sessions, San Diego, June, 2011 [Abstract 988-P]. 2.5 mg/d 5 mg/d 10 mg/d HQ11NP068

28 Add-on to Met Compared to SU (Glipizide) HbA1c adjusted mean change from baseline with dapagliflozin was statistically non-inferior to glipizide (both 0.52%) at 52 weeks. 3 Initial HbA1c reduction at 52 weeks was sustained with dapagliflozin but this effect had attenuated with glipizide at 104 weeks (Figure 2). HbA1c difference vs glipizide at 104 weeks 0.18% (95% CI; 0.33, 0.03). Change in HbA1c over Time Nauck M, et al. Diabetologia. 2010;53(1):S107

29 Dapagliflozin induced significantly less hypoglycaemia than glipizide at 104 weeks 10 fold difference in hypoglycaemic episodes with glipizide compared to dapagliflozin The majority of first episodes of hypoglycaemia occurred in the first year No major hypoglycaemic episodes reported with dapagliflozin, versus 3 with glipizide No discontinuation due to hypoglycaemia with dapagliflozin, whereas 7 patients discontinued study treatment with glipizide. Proportion of Patients with Hypoglycaemia, % 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Hypoglycaemic episodes 4.2% Dapagliflozin + Metformin First event weeks First event 0-52 week 45.8% Glipizide + Metformin Nauck M, et al. 71 st ADA Scientific Sessions, San Diego, June, 2011 Abstract 40-LB.

30 Consistent decreases in HbA1c from baseline at week 24 across all dapagliflozin studies Baseline HbA1c Monotherapy 1 Add-on to Met 2 Add-on to Glim 3 Add-on to Pio 4 Add-on to Ins Dapa + Met XR Primary endpoint for 24-week adjusted Δ from baseline HbA1c (%) * * * * * *p <0.001 compared with placebo * 1 Ferrannini E, et al. Diabetes Care 2010;33: Bailey CJ, et al. Lancet 2010;375: Strojek K, et al. Diabetes Obes Metab 2011;13: Rosenstock J, et al. 71 st ADA Scientific Sessions, San Diego, June, 2011 Abstract 0986-P. 5 Wilding J, et al. Diabetes. 2010;59 (Suppl 1):A21-A22. Abstract 0078-OR. 6 Henry R, et al. 71 st ADA Scientific Sessions, San Diego, June, 2011 Abstract 307-OR HQ11NP068

31 Dapagliflozin reduces total body weight and fat mass at week 24 DXA: dual X-ray absorptiometry Langkilde A.M, Study D1690C Internal Presentation January, HQ11NP068

32 Sustained body weight reduction of add-on dapagliflozin vs. add-on glipizide in patients on metformin Baseline weight DAPA + MET : 88.4 kg GLIP + MET : 87.6 kg 3.0 Week 104 weight Change in total body weight (kg) GLI + MET (n = 401) DAPA + MET (n = 400) kg (0.88, 1.84) Between-group difference: 5.06 kg (95% CI; 5.73, 4.4) -3.70kg (-4.16, -3.24) Nauck M, et al. 71 st ADA Scientific Sessions, San Diego, June, 2011 [Abstract 40-LB].

33 Consistent reductions in body weight with dapagliflozin Baseline Weight 24-wk Monotherapy 24-wk add-on to Met 2 52-wk add-on to Met 3 24-wk add-on to Glim 4 24 wk-add-on to Ins 5 24-wk add-on to Pio 6 24-wk Dapa + Met XR kg 88kg 85.9kg 81.1kg 93.8kg 86.3kg 81.1kg 24- and 52-week adjusted Δ from baseline weight (kg) NS * *p <0.001 vs. comparator NS: not significant * Ferrannini E, et al. Diabetes Care 2010;33: ; 2 Bailey CJ, et al. Lancet 2010;375: ; 3 Nauck MA, et al. Diabetes Care 2011;34: ; 4 Strojek K, et al. Diabetes Obes Metab 2011;13: Wilding J, et al. Diabetes 2010;59 (Suppl 1):A21 A22 [Abstract 0078-OR]; 6 Rosenstock J, et al. 71 st ADA Scientific Sessions, San Diego, June, 2011 [Abstract 0986-P]; 7 Henry R, et al. 71 st ADA Scientific Sessions, San Diego, June, 2011 Abstract 307-OR. * * * * HQ11NP068

34 Blood pressure reductions consistently observed with dapagliflozin in phase III studies Mean changes in systolic blood pressure (mmhg) Monotherapy AM only 1 Add-on to Met vs. SU 2 Add-on to Met 3 Add-on to SU 4 Add-on to TZD 5 48 week add-on to insulin 6 2 Week 24 or 48 mean change from baseline mmhg Ferrannini E, et al. Diabetes Care 2010;33: ; 2 Nauck MA, et al. Diabetes Care 2011;34: ; 3 Bailey CJ, et al. Lancet 2010;375: ; 4 Strojek K, et al. Diabetes Obes Metab 2011;13:928-38; 5 Rosenstock J, et al. 71st ADA Scientific Sessions, San Diego, June, 2011 [Abstract 0986-P]; 6 Wilding J, et al. Diabetes 2010;59 (Suppl 1):A21-A22 [Abstract 0078-OR] HQ11NP068

35 Events of Volume Depletion at 24 Weeks Frequency of reactions related to volume depletion* All events Dapagliflozin 10 mg 0.8% Control 0.4% *Including dehydration, hypovolaemia, or hypotension. Serious events occurred in <0.2% of patients and were comparable between groups Dapagliflozin is not recommended for initiation of therapy in patients who are volume depleted. Temporary interruption of dapagliflozin is recommended for patients who develop volume depletion until the depletion is corrected. Dapagliflozin. Summary of product characteristics. Bristol-Myers Squibb/AstraZeneca EEIG, 2012

36 Adverse Events of Hypotension/ Hypovolemia/ Dehydration* % of Patients Dapa 2.5 mg N = 814 Dapa 5 mg N = 1145 Dapa 10 mg N = 1193 PBO N = 1393 Total Subjects with an Event Hypotension Syncope <0.1 Dehydration <0.1 0 Orthostatic Hypotension *Includes data after rescue. A decrease from supine to standing of >20 mmhg in systolic blood pressure or >10 mm Hg in diastolic blood pressure N=number of treated agents Ptaszynska et al. ADA 2012

37 Genital infections - summary of pooled data up to 24 weeks The rate of clinically diagnosed vaginitis and other related genital infection was higher in the 10 mg dapagliflozin group than with placebo Events were more frequently experienced by women than by men All events were mild to moderate in intensity Most events did not recur with time Percentage of subjects with clinical diagnosis of genital infection Placebo DAPA 10 mg Most events responded to the initial course of standard therapy List J, et al. 71 st ADA Scientific Sessions, San Diego, June, 2011 [Poster # 985-P]. 0 Total Women Men HQ11NP068

38 Urinary tract infections - summary of pooled data up to 24 weeks The rates of clinically diagnosed UTI were slightly higher in the dapagliflozin 10 mg group than with placebo and these events were more frequent in women than men All events were mild to moderate in intensity Most events did not recur with time Most events responded to the initial course of standard therapy Percentage of subjects with clinical diagnosis of UTI Placebo DAPA 10 mg Upper UTI was rare and balanced between groups Parikh SJ, et al. 71 st ADA Scientific Sessions, San Diego, June 24-28, 2011 [abstract 984-P]. 0 Total Women Men HQ11NP068

39 Treatment with an SGLT2 inhibitor: clinical benefits in type 2 diabetes mellitus Sustained glucose lowering Potential prevention of microvascular morbidity 1 Decrease in glucotoxicity 2 Insulin-independent mechanism 3 Efficacy at all stages of the disease Possibility of combination with antihyperglycaemics of other classes 2 Stable control in combination with insulin and insulin secretagogues 2 SGLT2 Osmotic diuresis Initial weight loss 2 Decrease in blood pressure 2 Loss of excess calories 2,3 Sustained weight loss 2 Mitigation of weight gain caused by antihyperglycaemics of other classes 2 1 Holman RR, et al. N Engl J Med 2008;359: ; 2 Neumiller JJ. Drugs 2010;70:377-85; 3 Lo MC, et al. Am J Ther 2010 [Epub ahead of print] HQ11NP068