Emerging Challenges in Primary Care: Evolving Strategies of Care in Diabetes: The Role and Rationale of Glucoretic Therapy

Transcription

1 Emerging Challenges in Primary Care: 2016 Evolving Strategies of Care in Diabetes: The Role and Rationale of Glucoretic Therapy

2 Faculty Richard S. Beaser, MD Senior Staff Physician Chair, Continuing Medical Education Committee Joslin Diabetes Center Associate Clinical Professor of Medicine Harvard Medical School Boston, MA Mark Stolar, MD Associate Professor of Medicine Feinberg School of Medicine Northwestern University Chicago, IL Louis Kuritzky, MD Clinical Faculty Family Medicine Residency Program Palms Medical Group North Florida Regional Medical Center Clinical Assistant Professor Emeritus Department of Community Health and Family Medicine University of Florida Gainesville, FL Jeff Unger, MD, ABFM, FACE Director, Unger Primary Care Medical Group Rancho Cucamonga, CA 2

3 Disclosures Richard S. Beaser, MD has no relationships to disclose. Louis Kuritzky, MD serves as a speaker and/or advisor and/ or consultant for Boehringer Ingelheim, Sanofi Aventis, Salix, AbbVie, Allergan, Lilly, Lundbeck, Novo Nordisk and Janssen. Mark Stolar, MD serves as a speaker for and/or on the advisory board for Takeda, Sanofi, and Astra Zeneca. Jeff Unger, MD, ABFM, FACE serves as a speaker for Novo Nordisk, Teva and Janssen. Dr. Unger also serves as a stock owner, consultant and researcher for Novo Nordisk. 3

4 Learning Objectives Describe the role of the kidney in glycemic control. Review emerging data surrounding the effects of SGLT2 inhibitor therapy. Recognize the incidence and risk of hypoglycemia in managing patients with diabetes. Discuss approaches to individualizing the treatment of T2DM. 4

5 PRE-TEST QUESTIONS 5

6 Pre-test ARS Question 1 In normal physiologic situations, approximately how many grams of glucose are excreted in the urine each day? 1. 0 g g g g 6

7 Pre-test ARS Question 2 Which of the following adverse events has not been seen with SGLT-2 inhibitors? 1. Increased fracture risk 2. Acute reduction in egfr 3. Normoglycemic ketoacidosis 4. Congestive Heart Failure 7

8 Pre-test ARS Question 3 The patient is a 52-year-old obese African American man with a 7 year history of type 2 diabetes mellitus (HbA1c 8%) and CKD. The decision is made to add an SGLT-2 inhibitor and reinforce lifestyle modifications to control his blood glucose. How should you counsel the patient about his new medication? 1. Explain that his HbA1c will likely decrease 1.5 to 2 percentage points from his current value after beginning the SGLT-2 inhibitor 2. Advise the patient that the new medication may cause a small increase in his blood pressure 3. Warn the patient that the SGLT-2 inhibitor may cause weight gain 4. Counsel patient about the signs and symptoms of orthostatic hypotension which may occur secondary to volume depletion with SGLT-2 inhibitors 8

9 Pre-test ARS Question 4 According to studies using continuous glucose monitoring, approximately what proportion of patients with type 2 diabetes on treatment have unrecognized hypoglycemic episodes? 1. >15% 2. >30% 3. >45% 4. >70% 9

10 Pre-test ARS Question 5 Please rate your confidence in your ability to appropriately use SLGT-2 inhibitors in patients with type 2 diabetes: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 10

11 Diabetes Reduces Years of Life Years Lost Women 10 5 Men 0 < Morgan CL, et al. Diabetes Care. 2000;23: Age at Diagnosis 11

12 Patient Case 1: Edward B. Edward B.: 54-year-old obese black man Ø Works as a long-haul truck driver Ø Diagnosed with T2D 10 years ago Strong family history of T2D (maternal and paternal sides of his family and 2 siblings) Despite counseling for intensive lifestyle modification (including nutritional counseling and physical activity), continues to gain weight Ø 15 lb this year Poor compliance with current drug therapy regimen because of his job Ø Fears experiencing hypoglycemia while driving Finds it difficult to adhere to a dietary regimen because he frequently eats on the go 14

13 Patient Case 1: Edward B. (cont.) HbA1c is 9.2% Fasting plasma glucose (FPG) level is 165 mg/dl Has several additional risk factors for cardiovascular disease including obesity, hypertension, and elevated cholesterol level High blood pressure (140/95 mm Hg; medically managed) Elevated lipid levels (medically managed) Body mass index (BMI) is 36 kg/m 2 Reports episodes of low blood glucose levels Most recent documented blood glucose level via finger stick was 58 mg/dl 15

14 Patient Case 1: Edward B. (cont.) Current medications Metformin 1000 mg twice daily Glimepiride 8 mg once daily Basal insulin glargine Enalapril/HCTZ 10 mg/25 mg once daily Rosuvastatin 20 mg once daily 16

15 Edward B.: Clinical Data Physical Exam: Pertinent positives Acanthosis nigricans on neck R carotid bruit Decreased vibratory sense in feet Labs: Abnormalities: egfr 52 Albumin/creat ratio 60mcg/mg (N <30) 17

16 Patient Case Edward B.: Question #1 How might his medication be changed to address his elevated HbA1c, continued weight gain and fear of hypoglycemia? 1. Discontinue glimepiride and add a GLP-1 receptor agonist 2. Discontinue glimepiride and add an SGLT-2 inhibitor 3. Discontinue metformin and increase the dose of glimepiride 4. Discontinue glimepiride and add a thiazolidinedione 5. Options 1 and 2 18

17 Clinical Rationale for changes Severe insulin resistance not adequately addressed by metformin Hypoglycemia from sulfonylurea despite lack of postprandial efficacy Increased CV/CVA risk (see IRIS study/ EMPA-REG study) Microalbuminuria 19

18 Ominous Octet DeFronzo RA. Diabetes. 2009;58:

19 Normal Glucose Homeostasis Reflects a Balance of Glucose Production, Absorption, and Excretion Ø Multiple pathways maintain constant glucose +/ mg/dl Ø Insulin Ø Glucagon Ø Hepatic: gluconeogenesis, glycogenolysis Ø Renal: gluconeogenesis, glucose reabsorption, glucose excretion Chao E, et al. Nature Rev Drug Discov. 2010;9:

20 The Kidney Plays Key Roles in Maintaining Glucose Homeostasis: Production and Reabsorption of Glucose Gluconeogenesis (Production) Estimated to be responsible for up to 20% of total glucose release Glucose filtration Filters up to 180 g/day of glucose through the renal glomerulus Glucose reabsorption Expedites reabsorption of filtered glucose into plasma and excretion of excess glucose in urine At plasma glucose concentrations up to 180 to 200 mg/dl, essentially all glucose is reabsorbed At levels ~200 to 250 mg/dl or when the filtered glucose load exceeds 375 mg/min, excess glucose is excreted in urine: transport maximum (Tmax) Renal absorption from the kidneys is via SGLT-1 and and SGLT-2 sodium cotransporters Chao E, et al. Nature Rev Drug Discov. 2010;9: ; DeFronzo RA, et al. Diabetes Obes Metab. 2012;14:5-14; Gerich JE. Diabet Med. 2010;27:

21 Normal Glucose Homeostasis Net balance ~0 g/day + Glucose input ~250 g/day: Dietary intake ~180 g/day Glucose production ~70 g/day Gluconeogenesis Glycogenolysis The kidney filters circulating glucose Glucose uptake ~250 g/day: Brain ~125 g/day Rest of the body ~125 g/day The kidney reabsorbs and recirculates glucose Glucose filtered ~180 g/day Glucose reabsorbed ~180 g/day Wright EM. Am J Physiol Renal Physiol. 2001;280:F10-F18. Gerich JE. Diabetes Obes Metab. 2000;2:

22 Renal Cortex Renal Cortex: Releases Glucose Renal Medulla: Reabsorbs Glucose In fasting state in healthy subjects, kidneys contribute 20% to 25% of the glucose released into the circulation via gluconeogenesis (15 to 55 g/d). Gluconeogenesis occurs in proximal tubule cells of renal cortex Insulin directly REDUCES renal gluconeogenesis. In T2DM gluconeogenesis is increased 3 times Insulin REDUCES the substrates of gluconeogenesis, thus controlling renal glucose production Renal gluconeogenesis INCREASES 2 times in postabsorptive state in order to replenish hepatic glycogen stores. PP glucose renal release in T2DM is 100 g vs 70 g in euglycemic subjects Wilding JPH. Metabolism. 2014;63(10):

23 Increased Glucose Transporter Activity in T2DM SGLT-2 and GLUT-2 Protein Expression in Healthy Controls and Patients with T2DM 7.0 Normalized Glucose Transporter Levels Control T2DM P<.05 P< SGLT2 GLUT2 Rahmoune H, et al. Diabetes. 2005;54:

24 Renal Glucose Absorption Takes Place in the Proximal Convoluted Tubules of the Kidneys Filtered Glucose: (180 L/day) X (900 mg/l) = 162 g/day Glucose SGLT 2 S1 Segment Proximal Convoluted Tubules 90% Lumen 10% S3 Segment SGLT-1 No glucose is excreted 27

25 SGLT2 Inhibition Lowers T max, Allowing Elimination of Excess Glucose Overexpression of SGLT2 shifts T max to the right, allowing excess glucose to be reabsorbed SGLT2 inhibition shifts T max to the left, eliminating excess glucose Urinary Glucose Excretion (g/day) Blockade of SGLT2 Normal T2DM SGLT2 inhibition T2DM 240 mg/dl T max Plasma Glucose (mg/dl) Chao E, et al. Nature Rev Drug Discov. 2010;9: ; Bays H. Curr Med Res Opin. 2009;25: ; DeFronzo RA, et al. Diabetes Obes Metab. 2012;14:5-14; Gerich JE. Diabet Med. 2010;27: ; Kim Y, et al. Diabetes Metab Syndr Obes. 2012;5:

26 Is Pharmacologic Blockade of SGLT2 Safe? Familial Renal Glycosuria (FRG) An inherited renal tubular disorder characterized by persistent isolated glucosuria in the absence of hyperglycemia Patients excrete >100 grams of glucose/day (normal glucose excretion = 0 g/d) Caused by mutations in the SGLT2 coding gene, SLC5A2 Patients have normal renal function, are not overweight, and do not develop diabetes Asymptomatic Family members of FRG may show glycosuria when given a 50 grams of glucose tolerance test after 2 and 4 hours Prie D. Diabetes Metab. 2014;40(6 Suppl 1):S Santer N, et al. Clin J Am Soc Nephrol. 2010;5:

27 The Benefits of SGLT2 Inhibitors Unique Mechanism of Action Inhibition of SGLT2 results in: Daily urinary excretion of excess glucose ~70 g, providing: 1 Significant HbA 1c reductions (-0.34% to -1.03%) 2,3 Additional benefits of weight reduction (-2.0 to -3.4 kg) and a reduction in blood pressure (cardioprotective) 2 Reduction of fasting and PPG levels SGLT2 Inhibitors act independently of insulin mechanisms 2 Works regardless of β-cell function Complements insulin-dependent mechanisms Low propensity for hypoglycemia 1. List JF, et al. Diabetes Care 2009;32: Bailey CJ, et al. Lancet 2010;375: Bailey CJ, et al. Diabetes. 2011;60(Suppl. 1):71st ADA Scientific Sessions; San Diego, CA. June 24-28, 2011.Poster #988-P. 31

28 Clinical Attributes of SGLT2 Inhibitors: Glycemic End Points Reduce A1C by approximately 0.5% to 1.0% as monotherapy 1-4 Provide additional A1C reductions when added to: 3,5-11 Metformin (~0.7%) Glimepiride (~0.63%) Pioglitazone (~0.82%-0.97%) DPP-4 inhibitor (~0.5%) Basal insulin (~0.6%-1.0%) 1. Stenlöf K, et al. Diabetes Obes Metab. 2013;15: ; 2. Ferrannini E, et al. Diabetes Care. 2010;33: ; 3. Henry RR, et al. Int J Clin Pract. 2012;66: ; 4. List JF, et al. Diabetes Care. 2009;32: ; 5. Cefalu WT, et al. Lancet. 2013;382: ; 6. Bailey CJ, et al. Lancet. 2010;375: ; 7. Bailey CJ, et al. BMC Med. 2013;11:43; 8. Nauck MA, et al. Diabetes Care. 2011;34: ; 9. Rosenstock J, et al. Diabetes Care. 2012;35: ; 10. Jabbour SA, et al. Diabetes Care. 2014;37: ; 11. Strojek K, et al. Diabetes Obes Metab. 2011;13:

29 Clinical Attributes of SGLT2 Inhibitors: Low Hypoglycemia Risk and Weight Loss Low risk of hypoglycemia 1-8 SGLT2 inhibitors are not associated with hypoglycemia as monotherapy or in combination with metformin or DPP-4 inhibitors May increase hypoglycemia when combined with insulin or insulin secretagogues; dose adjustments of those agents may be necessary SGLT2 inhibitors promote clinically relevant weight loss 1-4,6,9,10 Approximately 2.0 to 2.5 kg in clinical trial settings Significant weight loss versus placebo when added to metformin 4,10 1. Bailey CJ, et al. BMC Med. 2013;11:43; 2. Bolinder J, et al. J Clin Endocrinol Metab. 2012;97: ; 3. Nauck MA, et al. Diabetes Care. 2011;34: ; 4. Rosenstock J, et al. Diabetes Care. 2012;35: ; 5. Schernthaner G, et al. Diabetes Care. 2013;36: ; 6. Stenlöf K, et al. Diabetes Obes Metab. 2013;15: ; 7. Strojek K, et al. Diabetes Obes Metab. 2011;13: ; 8. Wilding JP, et al. Diabetes Care. 2009;32: ; 9. Ferrannini E, et al. Diabetes Care. 2010;33: ; 10. Bailey CJ, et al. Lancet. 2010;375:

30 ADVANCE Severe Hypoglycemia vs Adverse End Points Percent of patients with >1 severe hypoglycemic event Severe Hypoglycemia (n=231) No Severe Hypoglycemia (n=10,909) HR (95% CI): 3.27 ( ) a HR (95% CI): 3.53 ( ) a 19.5 HR (95% CI): ( ) a HR (95% CI): HR (95% CI): 3.79 ( ) a 2.80 ( ) a Major Macrovascular b Event Major Microvascular b Event 9.0 Death From Any Cause CV Disease Non-CV Disease a Adjusted for multiple baseline covariates; b Primary end points. Major macrovascular event=cv death, nonfatal myocardial infarction, or nonfatal stroke Major microvascular event=new or worsening nephropathy or retinopathy. Zoungas S et al. N Engl J Med. 2010;363:

31 Unreported Asymptomatic Episodes of Hypoglycemia Patients With 1 Unrecognized Hypoglycemic Events, % N=70 n=40 n=30 All Patients With Diabetes Type 1 Diabetes Type 2 Diabetes >45% of patients with T2DM had asymptomatic (unrecognized) hypoglycemia, identified via continuous glucose monitoring Similar findings in other studies Chico A, et al. Diabetes Care. 2003;26(4): ; Weber KK, et al. Exp Clin Endocrinol Diabetes. 2007;115(8): ; Zick R, et al. Diab Technol Ther. 2007;9(6):

32 Antihyperglycemic therapy in type 2 diabetes: general recommendations (15) by American Diabetes Association American Diabetes Association Dia Care 2015;38:S41-S48 37

33 Weight Changes and Hypoglycemia Events in Monotherapy Trials of FDA-Approved Agents Endpoint 1 Canagliflozin 100 mg Canagliflozin 300 mg Placebo Change in weight, kg 2.5* 3.4* 0.5 Hypoglycemia, % of patients Endpoint 2 Dapagliflozin 5 mg Dapagliflozin 10 mg Placebo Change in weight, kg Hypoglycemia, % of patients *P<.001 versus placebo No major hypoglycemic events were reported in either trial. 1 kg=2.2 pounds. 1. Stenlöf K, et al. Diabetes Obes Metab. 2013;15: Ferrannini E, et al. Diabetes Care. 2010; 33:

34 Clinical Attributes of SGLT2 Inhibitors: Metabolic Effects Blood pressure: both SBP and DBP 1-3 Lipids Small, generally non clinically relevant LDL-C 4,5 Small TRG 3 Small HDL 3,5 Renal Small transient (1-4 weeks) egfr returns to baseline. 1. Clar C, et al. BMJ Open. 2012;2:e Stenlöf K, et al. Diabetes Obes Metab. 2013;15: Bailey CJ, et al. Lancet. 2010;375: Farxiga (dapagliflozin). Package insert. Princeton, NJ: Bristol-Myers Squibb; Invokana (canagliflozin). Package insert. Titusville, NJ: Janssen Pharmaceuticals; Warner C, et al. NEJM. DOI: / NEJMoa

35 Clinical Attributes of SGLT2 Inhibitors: Cardiovascular Outcome Trial With Empagliflozin EMPA-REG OUTCOME Trial Study Design Multicenter, randomized, double blind, placebo controlled trial comparing the effect of CV outcomes between empagliflozin 10 & 25 mg with placebo Background therapy was continued, but pts were randomized following a 2 week placebo run-in phase Drug naiive pts had A1C > 7.0 to < 9.0 at screening Subjects on background meds had A1C > 7.0 to < 10.0 at screening Pts had to be high risk for CV events Primary endpoint was first occurrence of CV death, non-fatal MI, or nonfatal stroke Zinman B, et al. Cardiovasc Diabetol ;13:102. Zinman B, et al. N Engl J Med Sep 17. [Epub ahead of print] 40

36 Empa 10, 25 mg or standard of care Patients With Event, % Patients With Event, % EMPA-REG Trial Cumulative Incidence of the Primary Outcome a P=0.04 for superiority Hazard ratio, 0.86 (95.02% CI, ) Placebo Empagliflozin Cumulative Incidence of Death From CV Causes P<0.001 Hazard ratio, 0.62 (95% CI, ) Death from a CV event, non-fatal MI, or stroke 14% risk reduction 38% risk reduction Placebo Empagliflozin Patients With Event, % P=0.002 Hazard ratio, 0.65 (95% CI, ) Hospitalization for Heart Failure 35% risk reduction Placebo a Cumulative incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. N=7020 patients with T2DM at high risk of cardiovascular events. Zinman B, et al. N Engl J Med. 2015;373(22): Empagliflozin Month 41

37 Empa-Reg Renal Data ê Incidence of nephropathy by 39 % Warner C, et al. NEJM. DOI: /NEJMoa

38 SGLT-2 Inhibitors Cardiovascular Outcome Trials in Progress Drug Trial Expected Conclusion Canagliflozin CANVAS Mar 2017 Dapagliflozin DECLARE TIMI- 58 Apr

39 LEADER CV Outcomes Trial Double-blind, placebo controlled randomized trial evaluating the safety and efficacy of liraglutide vs. placebo (1:1) in pts with T2DM A1C > 7 % Inclusion criteria: > Age 50, at least 1 CV precondition (PVD, CKD stage 3 or greater, NYHA class II-III, microalbuminuria, LVH, ABI < 0.9, no prior usage of a GLP-1 RA randomized patients. Retention rate over 5 years was 99 % Primary outcome was time to1st occurrence of death from CV causes, nonfatal MI, nonfatal stroke, coronary revascularization, unstable angina, new onset macroalbumiuria Marso SP, et al. NEJM. 6/13/16. DOI NEJ Moa

40 LEADER Results 13% Reduction in Primary Outcome (Death from CV event) 22 % reduction in non-fatal MI and stroke vs PBO Rate of all cause mortality lower in lira vs PBO Time to 1 st occurrence of death from CV event was < with Lira than PBO Marso SP, et al. NEJM. 6/13/16. DOI NEJ Moa

41 Patient Case 2: Felicia - A Challenging Patient Felicia is a 56 yo African American woman with a 5 year history of type 2 diabetes. She was initially well controlled on metformin alone, but since a hospitalization 3 years ago for acute systolic CHF (HFrEF) due to hypertensive urgency, her diabetes is difficult to control. She is currently on metformin 1000 mg BID and detemir 70 units am 46

42 Felicia: A Challenging Patient PMH : Fracture of left femur 2012 Hypertension Idiopathic microhematuria Pancreatitis 1998 felt due to cholelithiasis Meds: Metformin 1000 mg bid, detemir 70u qam, metoprolol tartrate 100mg bid, losartan 100mg qam, furosemide 40mg BID, amlodipine 5mg qd, atorvastatin 20mg 47

43 Felicia: The Challenging Patient PE: Height 5ft 6 in, wt 210lb BMI 33.9 BP 126/86 P 72 Physical exam is normal except for an S4 and trace peripheral edema. Labs : HGB A1c 7.7% Creatinine 1.45 egfr48 Albumin/creatinine 68 mcg/mg 48

44 ARS QUESTION Which of the following statements are false? 1. SGLT-2 inhibitors should not be used in a patient with history of fractures 2. Incretin based therapy would be a good option for postprandial control in this patient 3. Pioglitazone would be an effective add-on therapy in this patient 4. All of the above 49

45 ARS QUESTION Which of the following complications of SGLT-2 therapy is the patient most at risk for? 1. Recurrent fracture 2. Ketoacidosis 3. Bladder Cancer 4. Orthostatic Hypotension 5. AKI (Acute kidney injury) 50

46 Safety and Tolerability Common adverse events include slight increase versus placebo in rate of: Urinary tract infections (~5% to 10%) 1-8 Genital tract infections (~8% to 10%) 1-8 Generally not serious and easily managed Renal dosing considerations 9,10,11 Dapagliflozin contraindicated for patients with egfr <60 ml/min/1.73 m 2 Canagliflozin: Limit dose to 100 mg in patients with egfr 45 to <60 ml/min/1.73 m 2 contraindicated at egfr <45 ml/min/1.73 m 2. Potential for hypovolemic events, particularly in elderly patients or patients with renal impairment Empagliflozin should be discontinued in patients with a persistent egfr less than 45 ml/min/1.73 m 2 Should not be used for patients with active bladder cancer 9 Safe/well-tolerated when added to existing therapy for patients aged >55 years Bailey CJ, et al. Lancet. 2010;375: ; 2. Bolinder J, et al. J Clin Endocrinol Metab. 2012;97: ; 3. Clar C, et al. BMJ Open. 2012;2:e001007; 4. List JF, et al. Diabetes Care. 2009;32: ; 5. Rosenstock J, et al. Diabetes Care. 2012;35: ; 6. Schernthaner G, et al. Diabetes Care. 2013;36: ; 7. Stenlöf K, et al. Diabetes Obes Metab. 2013;15: ; 8. Wilding JP, et al. Diabetes Care. 2009;32: ; 9. Farxiga (dapagliflozin) [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2014; 10. Invokana (canagliflozin) [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2013; 11. Jardiance (empagliflozin) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2014; 12. Bode B, et al. Hosp Pract (1995). 2013;41:

47 SGLT2 Label Comparisons Topic Canagliflozin Dapagliflozin Empagliflozin Dose and timing 100 mg/300 mg prior to 1 st meal of the day 5 mg/10 mg independent of meals 10/25 mg in AM independent of meals Dosing regarding GFR 100 mg/d if GFR >60 ml/min; titrate to 300 mg/d 100 mg.day if GFR 45 to 60 ml/min Warnings/precautions Hypotension with ACE and ARBS Hypo with SUs and insulin Hyperkalemia Increased LDL-C DKA Increased risk of bone fractures Reduced bone density 5 mg if GFR >60 ml/ min with titration to 10 mg Do NOT use if GFR <60 ml/min Hypotension Hypoglycemia with SUs and insulin Bladder cancer Category C pregnancy rating Assess renal function 1 st Do NOT initiate if egfr is <45 ml/ min Initial dose is 10 mg Can increase to 25 mg if tolerated Hypotension Risk of impaired renal function is higher in elderly Hypo with SUs and insulin Increased LDL-C

48 SGLT 2 Inhibitors and DKA Concerns &? Mechanisms Concerns 20 cases of DKA in T2DM reported to the FDA Adverse Events Reporting System 3/13-6/ published case of eudka in patients with T1DM and T2DM Most were women 9 cases in T1DM, 4 in T2DM Most cases linked to reduced insulin doses Possible link to increased activity, recent illness, alcohol use, decreased food intake Some patients had no identifying cause All patients responded to IV rehydration and insulin All patients with T1DM should be counseled regarding off label use of SGLT2s Taylor SI, et al. J Clini Enocrinol Metab. 2015;100 (8): Peters A, et al. Diabetes Care doi: 10:2337/dc

49 SGLT2 Inhibition SGLT 2 Inhibitors and DKA Concerns &? Mechanisms Ø Increases glucose renal clearance Potential Mechanisms Ø Decreases renal clearance of ketone bodies Ø Endogenous/exogenous insulin levels reduced + dehydration or increased activity level + Increased in alpha cell secretion of glucagon (mediated by SGLT2) Ø Increase in lipolysis Ø EuDiabetic Ketoacidosis Taylor SI, et al. J Clini Enocrinol Metab. 2015;100 (8): Peters A, et al. Diabetes Care doi: 10:2337/dc

50 Patient Case 4: Christine M A lean type 2 diabetic Christine M is a 42 yo yoga instructor who developed developed diabetes 9 months after her last pregnancy - 15 years ago. Her mother and grandmother all have diabetes with onset in their early 40s, and both started on insulin in their late 50 s. She was started on metformin 1000mg bid and sitagliptin 100mg qam but most recent A1c was 7.8% 56

51 Christine M: Clinical data Height 5ft 7 Weight 142 lb BMI 22.2 BP 110/62 Laboratory data all normal Physical exam normal HGM shows average fasting of 120mg/dl. 57

52 ARS QUESTION What is next best step for Christine? 1. Add basal insulin 2. Add an SGLT-2 inhibitor 3. Change DPP-4 to a once weekly GLP-1 analogue 4. Discontinue metformin and add sulfonylurea for postprandial control 5. 2 and 3 and stop metformin 58

53 Rationale for changes in treatment 1) Patient is not insulin resistant. The need/ mechanism for metformin isn t essential 2) The patient s hyperglycemia is mostly postprandial. Basal insulin may be useful in a relatively insulin deficient patient but not postprandially 3) GLP-1 more potent in beta cell effects than DPP-4 and glucagon suppression (may address NDKA risk) 59

54 Summary: SGLT2 Inhibitors Approved for use in patients with T2DM Benefits Glucose control (FPG, PPG, and A1c) Weight reduction BP reduction Adverse effects: predominantly mild and transient Thirst, increase in urination frequency, UTI, mycotic infections Hypoglycemia risk heightened when used with SUFs or insulin Seniors: be vigilant for volume depletion and subsequent orthostasis Monitor Renal Fx (no toxicity with CKD, but lack of efficacy) Fx risk increased 60

55 POST-TEST QUESTIONS 61

56 Post-test ARS Question 1 In normal physiologic situations, approximately how many grams of glucose are excreted in the urine each day? 1. 0 g g g g 62

57 Post-test ARS Question 2 Which of the following adverse events has not been seen with SGLT-2 inhibitors? 1. Increased fracture risk 2. Acute reduction in egfr 3. Normoglycemic ketoacidosis 4. Congestive Heart Failure 63

58 Post-test ARS Question 3 The patient is a 52-year-old obese African American man with a 7 year history of type 2 diabetes mellitus (HbA1c 8%) and CKD. The decision is made to add an SGLT-2 inhibitor and reinforce lifestyle modifications to control his blood glucose. How should you counsel the patient about his new medication? 1. Explain that his HbA1c will likely decrease 1.5 to 2 percentage points from his current value after beginning the SGLT-2 inhibitor 2. Advise the patient that the new medication may cause a small increase in his blood pressure 3. Warn the patient that the SGLT-2 inhibitor may cause weight gain 4. Counsel patient about the signs and symptoms of orthostatic hypotension which may occur secondary to volume depletion with SGLT-2 inhibitors 64

59 Post-test ARS Question 4 According to studies using continuous glucose monitoring, approximately what proportion of patients with type 2 diabetes on treatment have unrecognized hypoglycemic episodes? 1. >15% 2. >30% 3. >45% 4. >70% 65

60 Post-test ARS Question 5 Please rate your confidence in your ability to appropriately use SLGT-2 inhibitors in patients with type 2 diabetes: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 66

61 Post-test ARS Question 6 Which of the statements below describes your approach to the assessment and management of patients with Diabetes? 1. I do not participate in the assessment and management of patients with Diabetes, nor do I plan to this year. 2. I did not participate in the assessment and management of patients with Diabetes before this course, but as a result of attending this course I m thinking of doing this now. 3. I do participate in the assessment and management of patients with Diabetes and I now plan to change my treatment methods based on completing this course. 4. I do participate in the assessment and management of patients with Diabetes and this course confirmed that I don t need to change my methods. 67