SGLT2 Inhibitors From Discovery to Clinical Practice

Transcription

1 SGLT2 Inhibitors From Discovery to Clinical Practice Sunder Mudaliar, MD, FRCP (Edin), FACP, FACE Clinical Professor of Medicine University of California, San Diego Staff Physician VA San Diego Healthcare System Co-Investigator Diabetes Prevention Program, NIH GRADE Study

2 Conflict of Interest Disclosure: Consultant/Advisory Board Member: Astra-Zeneca Research Support: NIH, Intarcia Pharmaceuticals, Janssen Pharmaceuticals, Astra-Zeneca

3 Objectives Describe the Emerging Role of SGLT2 Inhibitors in the Management of Diabetes From the Apple Tree Bark to a Novel Therapy for Diabetes Clinical Efficacy Safety Bone Fractures, Bladder Ca, Ketoacidosis Extra Glycemic Benefits Renal, CVD Place in Current Treatment Algorithms

4 Pathophysiology of Type 2 Diabetes Ominous Octet Intestine Kidney Adipose Tissue Incretin Signaling Glucose reabsorption Pancreas Lipolysis Glucose uptake Altered adipokine signaling Hyperglycemia Insulin secretion Glucagon secretion Brain Altered neuronal signaling Muscle Glucose uptake Liver Gluconeogenesis Adapted from DeFronzo RA. Diabetes. 2009;58:

5 The Kidney Consumes Glucose Makes Glucose Filters and Reabsorbs Glucose

6 Normal renal glucose handling Majority of glucose is reabsorbed by SGLT2 (90%) Proximal tubule SGLT2 Glucose Glucose filtration Remaining glucose is reabsorbed by SGLT1 (10%) Minimal to no glucose excretion 6 SGLT, sodium-glucose co-transporter. 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10 18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27 35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14 21.

7 SGLT-2 Inhibition: A novel insulin-independent approach to remove excess glucose Reduced glucose reabsorption SGLT2 SGLT-2 i Proximal tubule SGLT-2 i SGLT2 Glucose Glucose filtration Increased urinary excretion of excess glucose (~70 g/day, corresponding to 280 kcal/day*) Selectively inhibit SGLT2 in the renal proximal tubule 7 *Increases urinary volume by only ~1 additional void/day (~375 ml/day) in a 12-week study of healthy subjects and patients with Type 2 diabetes Wright EM. Am J Physiol Renal Physiol 2001;280:F10 18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27 35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14 21; 4. Dapa For discussion purposes. Summary of product characteristics. Bristol-Myers Squibb/AstraZeneca EEIG, only. Not intended for promotional use. Any promotional claims will need to be supported by label and clinical data and dependent upon global

8 Familial Renal Glucosuria Phenotype Affected individuals exhibit urinary glucose excretion of g/day at normal plasma glucose levels Clinical manifestations are rarely observed Usually asymptomatic Rare propensity for hypoglycemia, polyuria, and hypovolemia Severe clinical consequences have not been reported No increase in the incidence of chronic kidney disease 1. Calado J, et al. Kidney Int 2011;79(Suppl 120):S7-S Wright EM. J Intern Med 2007;261: Santer R, et al. J Am Soc Nephrol 2003;14: Francis J, et al. Nephrol Dial Transplant 2004;19: Calado J, et al. Nephrol Dial Transplant 2008;23:

9 From apple bark to a novel therapeutic option

10 LX Sotagliflozin

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12 SGLT2 inhibitors Clinical Indications Type 2 Diabetes Monotherapy Add-on to other oral agents Add-on to Insulin

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14 Clinical Use of SGLT2 Inhibitors Potential advantages Reduction in HbA1C (~0.5 to 1.2%) Low risk of hypoglycaemia Weight loss (75g urine glucose = 300kcal/day = ~ 1lb/week) Reduction in body fat (VAT) Blood pressure lowering Renal/CVD Effects? Reduction of Liver Fat in NASH Effects independent of insulin

15 Clinical Use of SGLT2 Inhibitors Concerns Polyuria/Hypovolemia Electrolyte disturbances Bacterial urinary tract infections Fungal genital infections Increase in LDL Cholesterol Bladder/Breast cancer Bone Effects Canagliflozin Unexpected effects Euglycemic Ketoacidosis

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18 Clinical Use of SGLT2 Inhibitors Concerns Polyuria/Hypovolemia? Electrolyte disturbances Bacterial urinary tract infections Fungal genital infections Increase in LDL Cholesterol Bladder/Breast cancer Bone Effects Canagliflozin Unexpected effects Euglycemic Ketoacidosis

19 Bone Effects

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22 Renal Effects

23 Changes in Renal Function with SGLT-2 Inhibitors Initial in e-gfr, then towards baseline Reversibility after discontinuation Decrease in the urinary albumin/creatinine ratio

24 Use in Type 1 DM

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26 Effects of Dapagliflozin on Urinary Glucose and MAGE in Type 1 Diabetes Henry RR et al. Diabetes Care Sep 30. pii: DC_ [Epub ahead of print]

27 Euglycemic Keto-Acidosis

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29 Peters A et al. Diabetes Care Jun 15. pii: dc [Epub ahead of print]

30 Peters A et al. Diabetes Care Jun 15. pii: dc [Epub ahead of print]

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32 Multiple Mechanisms Contribute to DKA/EKA with SGLT2i: Glucagon Insulin Insulin:Glucagon Ratio Acute illness PO intake Carbohydrate Intake Alcohol Intake

33 Measures to Prevent DKA/EKA: Do not use SGLT2i in patients with Type 1 DM Education of Providers/Patients: Use like Metformin stop before surgery and acute illness Recognize Signs & Symptoms: Nausea, vomiting, shortness of breath, malaise Promptly evaluate for urine and/or plasma ketones at home or in a medical setting, even if glucose levels are nearly normal Encourage adequate fluid/carbohydrate intake Do not STOP insulin

34 Optimal Drug for Type 2 Diabetes Effectively lower glucose levels Minimize risk of hypoglycemia Reduce body weight Improve insulin sensitivity Improve β-cell function Durable effect

35 Death from cardiovascular causes: 38% relative risk reduction (3.7% vs. 5.9%) Hospitalization for heart failure: 35% relative risk reduction (2.7% vs 4.1%) Death from any cause 32% relative risk reduction (5.7% vs 8.3%)

36 SGLT2 Inhibitor Cardiovascular Outcomes Studies Drug Trial Name No. of Patients Completion Date Empagliflozin EMPA REG Canagliflozin CANVAS Dapagliflozin DECLARE TIMI Ertugliflozin MK

37 Potential Multi Dimensional Mechanisms Underlying CVD Benefits in EMPA REG Changes in: arterial stiffnes, cardiac function, and cardiac oxygen demand (in the absence of sympathetic-nerve activation) Cardiorenal effects: reduction in albuminuria, uric acid Known effects on hyperglycemia, body weight, visceral adiposity, and blood pressure Zinman B et al. N Engl J Med Sep 17. [Epub ahead of print]

38 Questions??? The art of medicine consists of amusing the patient while nature cures the disease.

39 Use in NASH/NAFLD??

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42 Does the Combination of SGLT2 Inhibitors and Incretins Blunt the Glucagon Rise??

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44 Triple Combination Metformin + Saxagliptin + Dapagliflozin 0.9% 1.2% 1.5% Rosenstock et al. Diabetes Care Oct 28. pii: DC_ [Epub ahead of print]

45 Hansen L et al. Endocr Pract Nov;20(11):

46 Effects on Albuminuria

47 Percentage of patients moving by at least one category between normo-albuminuria, micro-albuminuria and macro-albuminuria (ST + LT) Normo-albuminuria: 0 < 3.4 mg/mmol; micro-albuminuria: 3.4 < 33.9 mg/mmol; macro-albuminuria: 33.9 mg/mmol. A. Ptaszynska, T. Mansfield, E. Johnsson, S.J. Parikh, Y. Yavin, J.F. List. ADA P

48 48 and local Cherney promotional et guidance al Circulation. and regulatory 2014;129: practices and policies.

49 Tubulo-Glomerular Feedback 49 Cherney et al Circulation. 2014;129:

50 Potential Mechanisms of Nephroprotection with SGLT-2 Inhibitors Decrease in Intra-glomerular Pressure Tubulo-Glomerular Feedback Limiting Uptake of Glucose by Proximal Tubules Weight Loss Lowering Blood Pressure Increase in Hematocrit Stanton RC. Circulation 2014;129:

51 Renal Function: egfr Mean Change from Baseline Mean egfr decreased initially by week 1 and then gradually increased toward egfr baseline values over several weeks; mean egfr values remained stable thereafter Week 24 Week PBO n= DAPA 10 mg n = EMDAC Background For discussion document. purposes only. Available Not intended at: for promotional use. Any promotional claims will need to be supported by label and clinical data and dependent upon global

52 Bone Mineral Density at Week 102 DXA body composition study At 1 and 2 years no effect on bone mineral density measured at Lumbar spine (L1-L4), Femoral neck, Total hip Dapa 10mg N = 91 Placebo N = 91 Patients in 102 wk DXA eval. n = 68 n = 71 Bone Mineral Density (BMD) Difference Dapa vs. Placebo % Change from Baseline (%) 95% CI p-value BMD Lumbar Spine (L1-4) (-0.89, 1.34) BMD Femoral Neck (-2.21, 0.35) BMD Total Hip (-1.32, 0.43) CI = confidence interval; Dapa = dapagliflozin; MET = metformin Study D1690C00012, DXA Body Composition Study EMDAC Background For discussion document. purposes only. Available Not intended at: for promotional use. Any promotional claims will need to be supported by label and clinical data and dependent upon global

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56 Laboratory data: Electrolytes 1-3 Dapagliflozin had no clinically relevant impact on serum electrolytes No clinically meaningful changes from baseline were observed in mean serum sodium, potassium, calcium, bicarbonate or chloride after 24 weeks of treatment Small changes from baseline in mean serum phosphorous and magnesium were observed There was no increased risk of hyperkalaemia with dapagliflozin Sodium (MEQ/L) Mean change from baseline (SD) Potassium (MEQ/L) Mean change from baseline (SD) Calcium, total, (mg/dl) Mean change from baseline (SD) Bicarbonate, (MEQ/L) Mean change from baseline (SD) Chloride, serum (MEQ/l) Mean change from baseline (SD) Magnesium, serum (MEQ/l) Mean change from baseline (SD) Phosphorous, inorganic (mg/dl) Mean change from baseline (SD) Placebo-controlled pool (short term) Dapagliflozin 10 mg (n=2360) n= (3.172) n= (0.454) n= (0.493) n= (3.047) n= (3.227) n= (0.192) n= (0.509) Placebo (n=2295) n= (3.192) n= (0.433) n= (0.523) n= (2.907) n= (3.176) n= (0.164) n= (0.647) MEQ, molar equivalent; SD, standard deviation. 1. AZ data on file; 2. EMDAC Background document. Available at: Last accessed March Ptaszynska A, Johnsson KM, Parikh SJ, de Bruin TW, Apanovitch AM, List JF. Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events. Drug Safety 2014 Oct;37(10):

57 Events of fracture 1,2 The proportions of patients with fractures were small and balanced for dapagliflozin versus placebo Placebo-controlled pool (short-term) Placebo-controlled pool (short + long term) Dapagliflozin 10 mg (n=2360) Placebo (n=2295) Dapagliflozin 10 mg (n=2026) Placebo (n=1956) Events, n 8 (0.3%) 17 (0.7%) 23 (1.1%) 32 (1.6%) 1. EMDAC Background document. Available at: Last accessed March Ptaszynska A, Johnsson KM, Parikh SJ, de Bruin TW, Apanovitch AM, List JF. Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events. Drug Safety 2014 Oct;37(10):

58 Events of fracture The dapagliflozin groups had higher rates of neuropathy and orthostatic hypotension at baseline, conceivably predisposing them to falls. No increase in fractures was observed in pooled data from patients across the dapagliflozin clinical studies with stage 3A CKD, or in patients with normal to mildly impaired renal function. Dapagliflozin has been shown to have no effect on bone mineral density or on markers of bone turnover in patients with normal to mildly impaired renal function. Placebo (n=84) Dapagliflozin 5 mg (n=83) Dapagliflozin 10 mg (n=85) Fracture* 0 (0.0%) 5 (6.0%) 8 (9.4%) *randomized, double-blind, placebo-controlled study patients with inadequately controlled type 2 diabetes and moderate renal impairment Through 104 weeks, 13 (7.7%) patients experienced fracture in the dapagliflozin groups (5 at 5mg and 8 at 10 mg) vs. 0 on placebo. Many of the fractures were in places not suggestive of bone health issues (for example, toes and patella). Kohan DE, Fioretto P, Tang W and List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 2014 Apr;85(4):

59 Laboratory data: Electrolytes 1-3 Dapagliflozin had no clinically relevant impact on serum electrolytes No clinically meaningful changes from baseline were observed in mean serum sodium, potassium, calcium, bicarbonate or chloride after 24 weeks of treatment Small changes from baseline in mean serum phosphorous and magnesium were observed There was no increased risk of hyperkalaemia with dapagliflozin Sodium (MEQ/L) Mean change from baseline (SD) Potassium (MEQ/L) Mean change from baseline (SD) Calcium, total, (mg/dl) Mean change from baseline (SD) Bicarbonate, (MEQ/L) Mean change from baseline (SD) Chloride, serum (MEQ/l) Mean change from baseline (SD) Magnesium, serum (MEQ/l) Mean change from baseline (SD) Phosphorous, inorganic (mg/dl) Mean change from baseline (SD) Placebo-controlled pool (short term) Dapagliflozin 10 mg (n=2360) n= (3.172) n= (0.454) n= (0.493) n= (3.047) n= (3.227) n= (0.192) n= (0.509) Placebo (n=2295) n= (3.192) n= (0.433) n= (0.523) n= (2.907) n= (3.176) n= (0.164) n= (0.647) MEQ, molar equivalent; SD, standard deviation. 1. AZ data on file; 2. EMDAC Background document. Available at: Last accessed March Ptaszynska A, Johnsson KM, Parikh SJ, de Bruin TW, Apanovitch AM, List JF. Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events. Drug Safety 2014 Oct;37(10):

60 Events of fracture 1,2 The proportions of patients with fractures were small and balanced for dapagliflozin versus placebo Placebo-controlled pool (short-term) Placebo-controlled pool (short + long term) Dapagliflozin 10 mg (n=2360) Placebo (n=2295) Dapagliflozin 10 mg (n=2026) Placebo (n=1956) Events, n 8 (0.3%) 17 (0.7%) 23 (1.1%) 32 (1.6%) 1. EMDAC Background document. Available at: Last accessed March Ptaszynska A, Johnsson KM, Parikh SJ, de Bruin TW, Apanovitch AM, List JF. Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events. Drug Safety 2014 Oct;37(10):

61 Events of fracture The dapagliflozin groups had higher rates of neuropathy and orthostatic hypotension at baseline, conceivably predisposing them to falls. No increase in fractures was observed in pooled data from patients across the dapagliflozin clinical studies with stage 3A CKD, or in patients with normal to mildly impaired renal function. Dapagliflozin has been shown to have no effect on bone mineral density or on markers of bone turnover in patients with normal to mildly impaired renal function. Placebo (n=84) Dapagliflozin 5 mg (n=83) Dapagliflozin 10 mg (n=85) Fracture* 0 (0.0%) 5 (6.0%) 8 (9.4%) *randomized, double-blind, placebo-controlled study patients with inadequately controlled type 2 diabetes and moderate renal impairment Through 104 weeks, 13 (7.7%) patients experienced fracture in the dapagliflozin groups (5 at 5mg and 8 at 10 mg) vs. 0 on placebo. Many of the fractures were in places not suggestive of bone health issues (for example, toes and patella). Kohan DE, Fioretto P, Tang W and List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 2014 Apr;85(4):

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70 Cellular Mechanism of Renal Glucose Reabsorption TUBULAR LUMEN Glucose Apical Membrane SGLT2 S1 Proximal Tubule Glucose Basolateral Membrane GLUT2 INTERSTITIAL FLUID Na + Na + Na + /K + ATPase K + Glucose SGLT1 S3 Proximal Tubule Glucose GLUT1 Na + Na + Na + /K + ATPase K + GLUT = glucose transporter; SGLT = sodium glucose cotransporter 1. Adapted from Santer R, et al. Clin J Am Soc Nephrol 2010;5:

71 Normalized Glucose Transporter Levels Counts per minute Glucose Transporter Expression and Activity Are Increased in Type 2 Diabetes 8 SGLT2 GLUT2 AMG Uptake * * * NGT T2DM NGT T2DM NGT T2DM 0 *P <0.05 AMG = methyl- -D-[U 14 C]-glucopyranoside; GLUT = glucose transporter; NGT = normal glucose tolerance; SGLT = sodium glucose co-transporter; T2DM = type 2 diabetes mellitus 1. Rahmoune H, et al. Diabetes 2005;54:

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74 DPP-4 Inhibitors GLP-1 Agonists SGLT2 Inhibitors A1C Lowering ~0.5% -1.0% ~0.8% -1.9% ~0.5% -1.2% Hypoglycemia Risk Low Low Low Weight effect Neutral Weight loss Weight Loss Blood Pressure Neutral Modest Modest Common AEs - Nausea, vomiting UTI/GTI/Volume Depletion SAEs of Interest Severe Joint Pains Pancreatitis/Pancreatic Ca Medullary Thyroid Ca Euglycemic Ketosis Administration Oral Injection Oral Represents authors collective analysis, evaluation, and opinion, not official association opinion.

75 Reduced Hypoglycemia 5.4 % vs yrs 3 Major Hypos with SU vs None with Dapa Del Prato S, et al. Diabetes Obes Metab Jun;17(6):

76 Dapagliflozin Versus Sulfonylurea as Add-on to Metformin: Change in Weight Over 208 Weeks Change in weight (kg)* 3 Dapagliflozin + Metformin Glipizide + Metformin Sample size (excluding data after rescue) n Week 208 Values: Dapagliflozin + Metformin: kg (95% CI: -4.3, -3.01) Glipizide + Metformin: 0.73 kg (95% CI: 0.06, 1.40) Treatment Difference: kg (95% CI: -5.31, -3.46) Study week DAPA+MET GLIP+MET *Data are adjusted mean change from baseline ±95% CI derived from a longitudinal repeated-measures mixed model. Del Prato S, et al. Diabetes Obes Metab Jun;17(6):

77 Potential Mechanisms Leading to DKA with SGLT2i Taylor SI, Blau JE, Rother KI. J Clin Endocrinol Metab Jun 18:jc [Epub ahead of print]

78 Other Contributing Factors Role of acute illness/alcohol Intake PO intake Carbohydrate Intake

79 Events of Fracture The proportions of patients with fractures were small and balanced for dapagliflozin versus placebo Placebo-controlled pool (short-term) Placebo-controlled pool (short- plus long-term) Events, n (%) DAPA 10 mg PBO DAPA 10 mg PBO N=2360 N=2295 N=2026 N= (0.3) 17 (0.7) 23 (1.1) 32 (1.6) EMDAC Background For discussion document. purposes only. Available Not intended at: for promotional use. Any promotional claims will need to be supported by label and clinical data and dependent upon global

80 Risks vs Benefits Benefits Risks HbA1C Body Weight Blood Pressure Low Risk of Hypoglycemia? Reno-Protective GTIs UTIs Hypovolemia Risk of DKA/EKA LDL Cholesterol HDL and TGs