Emerging Challenges in Primary Care: The Progression of Type 2 Diabetes: A Rational Approach for Long-term Disease Management

Transcription

1 Emerging Challenges in Primary Care: 2018 The Progression of Type 2 Diabetes: A Rational Approach for Long-term Disease Management 1

2 Faculty Rodolfo J. Galindo, MD Assistant Professor of Medicine Emory University School of Medicine Principal Investigator, Center for Diabetes and Metabolism Research Division of Endocrinology, Diabetes and Metabolism Emory University Hospital Midtown Medical Chair, Hospital Diabetes Taskforce Emory Healthcare System Atlanta, GA Javier Morales, MD, FACP, FACE Clinical Associate Professor of Medicine Donald and Barbara Zucker School of Medicine at Hofstra/Northwell University Vice President, Advanced Internal Medicine Group, P.C. East Hills, NY 2

3 Faculty Leann Olansky, MD, FACP, FACE Department of Endocrinology, Diabetes and Metabolism Endocrinology & Metabolism Institute Cleveland Clinic Cleveland, OH Mark Stolar, MD Associate Professor of Clinical Medicine Feinberg School of Medicine Northwestern University Chicago, IL Jeff Unger, MD, FAAFP, FACE Assistant Clinical Professor of Family Medicine UC Riverside School of Medicine Director, Unger Concierge Primary Care Medical Group Rancho Cucamonga, CA 3

4 Disclosures Rodolfo J. Galindo, MD has no relevant financial relationships to disclose. Javier Morales, MD, FACP, FACE serves on the speakers bureau and as a consultant for Lilly, Novo Nordisk, Janssen, and Abbott. Leann Olansky, MD, FACP, FACE has no relevant financial relationships to disclose. Mark Stolar, MD serves on the speakers bureau for Astra Zeneca. Jeff Unger, MD, FAAFP, FACE serves as a consultant, researcher and advisory board member for Novo Nordisk, Janssen, and Abbott Diabetes. 4

5 Learning Objectives Recognize the pathogenesis of type 2 diabetes (T2D) as a progressive, multi-defect disorder Discuss the strengths and limitations of current guidelines for diabetes management Successfully use strategies for adherence to multiple medications to improve outcomes in diabetes Examine data on current combination strategies to choose therapies that most effectively address a patient s underlying pathophysiologic needs 5

6 PRE-TEST QUESTIONS

7 Pre-test ARS Question 1 Please rate your confidence in your ability to manage T2D as a multi-defect disorder with individualized combination therapy: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 7

8 Pre-test ARS Question 2 How often do you select antidiabetic therapy based on its mechanism of action? 1. Never 2. Rarely 3. Sometimes 4. Often 5. Always 8

9 Pre-test ARS Question 3 Approximately how many patients with Diabetes do you see on a weekly basis, in any clinical setting? 1. None >25 9

10 Progressive β-cell Dysfunction Is a Key Driver of Progressive Dysglycemia in T2D By diabetes onset, up to 80% of β-cell function may be lost 1,2 Insulin Resistance Decreasing β-cell function partially driven by incretin defect PPG FPG Normal Glucose Tolerance Impaired Glucose Tolerance Insulin Secretion β-cell Function Diagnosis Severity of Glucose Intolerance Time in Years PPG=postprandial plasma glucose; FPG=fasting plasma glucose. 1. Defronzo RA. Diabetes. 2009;58: Fehse F, et al. J Clin Endocrinol Metab. 2005;90: Figure adapted from Kendall DM, et al. Am J Med. 2009;122(6 Supp):S37-S50. 10

11 ARS Question 4 All of the following are pathophysiologic mechanisms of T2D, EXCEPT: 1. Increased lipolysis 2. Decreased incretin effect 3. Decreased glucagon secretion 4. Increased glucose reabsorption 11

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

13 ARS Question 5 According to current AACE and ADA guidelines, which therapy should be considered for a patient with symptoms of hyperglycemia at diagnosis of T2D? 1. Metformin monotherapy 2. Metformin plus 1 other antidiabetic drug 3. Metformin plus 2 other antidiabetic drugs 4. Basal insulin +/- other antidiabetic drugs 13

14 2018 ADA Standards of Care in Diabetes DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT2i, sodium-glucose cotransporter 2 inhibitor; GLP-1 RA, glucagonlike peptide-1 receptor agonist; SU, sulfonylurea; TZD, thiazolidinedione. ADA. Diabetes Care. 2018;41(Suppl. 1):S1 S

15 AACE: Glycemic Control Algorithm 15

16 Biguanides: Metformin Mechanism Decreased hepatic glucose production. May not be sensitizer. Decreased intestinal glucose absorption Advantages No weight gain or hypoglycemia Disadvantages Gastrointestinal side effects Renal function monitoring GFR<45ml/min/1.73m2è1000mg/day GFR<30ml/min/1.73m2èdiscontinue Vitamin B12 deficiency accessed July

17 Discussion Points When Intensifying Pharmacotherapy Tx intensification needed because diabetes is progressive, not because of patient non-compliance. Maintaining A1C 6%-6.5% for 4-6 years after diagnosis induces metabolic memory and the legacy effect. Complications are reduced. Tx options are based on disease duration. Longer duration = lower beta-cell mass and function. Frequency, timing and route of administration should be clearly defined. Discuss risks and benefits of all meds prescribed. Excellent composite endpoint would be to achieve target A1C without weight gain or hypoglycemia. Unger J. Diabetes Management In Primary Care. Lippincott

18 Age Factors to Guide Therapeutic Choices When A1C Not at Goal Comorbidity Mechanism of action Clinical clues If younger, durability of therapy/beta-cell impact important If older, safety essential Risks of hypoglycemia Absolute risk of known side effect profile vs reported risk What isn t being treated currently? What is ineffective? Acanthosis, low HDL, hypertriglyceridemia markers of insulin resistance Leaner body weight = likelihood of beta cell dysfunction SMBG PBG better guide than FBG when A1C <8.0% 18

19 Consequences of Delayed Intervention A1C % Patients with A1C 7% not receiving IT within 1 year Patients with A1C <7% who received IT before 1 year of diagnosis At 5.3 years, increased risks: - MI 67% (95% CI: 39%,101%) - Stroke 51% (95% CI: 25%, 83%) - HF 64% (95% CI: 40%, 91%) - Composite CVE 62% (95% CI: 46%, 80%) Bad glycemic legacy Drives risk for complications Months CVE = cardiovascular endpoint; HF = heart failure; IT = treatment intensification; MI = myocardial infarction Paul S et al. Cardiovasc Diabetol 2015;14:100 doi: /s x 19

20 Add-on Therapy: What Comes After Metformin? Joe was diagnosed with diabetes 1 year ago He was started on metformin when his A1C was 8.0% Despite trying his hardest at weight loss and physical activity, his weight is the same and A1C remains 7.5% What factors guide you as to next steps for therapy? Should Joe have started combination therapy at diagnosis? If so, what combination? 20

21 Questions to Consider 21

22 Sulfonylureas and Glitinides Cheap Oral Advantages Effective for patients with MODY (Monogenetic Diabetes) Disadvantages Hypoglycemia risk Elderly and CKD Weight gain Myocardial ischemic preconditioning, increases MI risk after PCI (glyburide) Unger J. Diabetes Management In Primary Care. Lippincott Loss of durability in every clinical trial Glitinides must be taken ½ hour before meals 22

23 Thiazolidinediones (TZD):Pioglitazone Advantages No hypoglycemia Cheap Can prevent progression of prediabetes to clinical diabetes Durability of effect Favorable beta cell function Only muscle and adipocyte insulin sensitizer May reduce NASH Favorable TG and HDL effects Disadvantages Weight gain Edema Cannot use in patients with HF Bone fractures? Bladder cancer 23

24 DPP-4 Inhibitors Advantages Enhance glucosedependent insulin secretion Decrease inappropriate glucagon secretion** Oral, once daily Very low side effect profile Weight neutral No apparent CV risk (saxagliptin, alogliptin, sitagliptin) Cost Efficacy Disadvantages Pancreatitis warning Durability?? Heart failure (saxagliptin,alogliptin) Same mechanism but significantly less efficacy than GLP-1 RA 24

25 GLP-1 Receptor Agonists Advantages Enhance glucose dependent insulin secretion Decrease inappropriate glucagon secretion Low risk of hypoglycemia Single dose effect on beta cell function Superior efficacy compared to orals Weight loss Cost Disadvantages Injection/injection site issues Nausea Pancreatitis warning (no longer for liraglutide and dulaglutide) MTC warning CVD safety / benefit 25

26 2-Hour Postprandial Plasma GLP-1 Concentration (pm) GLP-1 RA Pharmacologic Activity Higher with GLP-1 RAs than DPP N=61 metformin-treated, evaluable patients 0 Baseline 7 Sitagliptin once daily 15 Endogenous GLP-1 Activity Plasma GLP-1 Exenatide twice daily 64 Added GLP-1 RA Activity Plasma Exenatide Hour Plasma Exenatide Concentration (pm) DeFronzo RA, et al. Curr Med Res Opin. 2008;24(10):

27 Incretin Therapies to Treat T2DM Incretin effect is impaired in T2D Natural GLP-1/GIP have extremely short half-lives Oral agents Add GLP-1 analogues with longer half-life: Exendin-4 Based: Exenatide Exenatide QW Lixisenatide Injectables Human GLP-1: Liraglutide Semaglutide Dulagutide Block DPP-4, the enzyme that degrades GLP-1: Sitagliptin Saxagliptin Linagliptin Alogliptin Drucker. Curr Pharm Des. 2001;7(14): Drucker. Mol Endocrinol. 2003;17(2):

28 Only About One-third of Patients Are Adherent to GLP-1 RAs POORLY ADHERENT ADHERENT 34% Adherent with GLP-1 RA QD over 1 year of treatment Claims database study of 1321 patients with T2D treated with liraglutide qd Adherence defined as PDC 0.8 Buysman EK, et al. Adv Ther. 2015;32:

29 Glucoretic Based Therapies SGLT 2 Inhibitors Agents Advantages Disadvantages Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin Effectiveness independent of insulin Low risk for hypoglycemia Small amount of weight loss Modest reduction in blood pressure Possible favorable CV/renal outcomes Adequate renal function/monitoring required Amputation risk increased Euglycemic DKA Cost Diabetes Care 2014;37: S

30 Normal Glucose Homeostasis Net balance ~ 0 g/day Glucose input ~250 g/day: Dietary intake ~180 g/d Glucose production ~70 g/d Gluconeogenesis Glycogenolysis Glucose uptake ~250 g/day: Brain ~125 g/d Rest of the body ~125 g/d + Kidney filters circulating glucose Kidney reabsorbs and recirculates glucose Glucose filtered ~180 g/day Glucose reabsorbed ~180 g/day 30

31 SGLT-2 Inhibitors: Mechanism of Action (cont) Free Filtration of Solute Active Reabsorption Glucose SGLT-2 SGLT-1 Glucose Juxtoglomerular Complex Proximal Convoluted Tubules Loop of Henle Type 2 Diabetes 31

32 Empa 10, 25 mg or standard of care EMPA-REG Trial Death from a CV event, non-fatal MI, or stroke Patients With Event, % Patients With Event, % Patients With Event, % 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, ) Placebo Empagliflozin P=0.002 Hazard ratio, 0.65 (95% CI, ) 14% risk reduction 38% risk reduction Hospitalization for Heart Failure 35% risk reduction Placebo Empagliflozin Month 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):

33 Empa-Reg Renal Data Warner C, et al. NEJM. DOI: /NEJMoa

34 Why Not Use Insulin as Add-on Therapy? Effective means of insulin-providing therapy Most potent A1C reductions Indicated as add-on to monotherapy when A1C above 8.5% Hypoglycemia and weight gain are barriers but insulin itself does not cause weight gain metabolically Bedtime NPH, basal insulin or ultralong-acting basal insulins provide varying cost options as add-on therapy, with differences in hypoglycemia and weight gain 34

35 Barriers to Multimolecular Therapy Adherence Hypoglycemia Underutilization of combination meds 35

36 Medication Adherence in T2D Medication adherence rates are ~45% among diabetics ~1/3 of all initial prescriptions for glucose-lowering agents go unfilled Non-adherence increases likelihood of long-term complications / negative glycemic legacy and risk of hospitalization Hospitalization risk is 30% at the lowest quintile of adherence vs. 13% in highest quintile 36

37 Improving Patient Adherence Discussion between patients and clinicians related to risk:benefit ratio is critical Choose therapies that reduce risk of hypoglycemia and weight gain Hypoglycemia risk increases with duration of disease and age Hypoglycemia increases risk of mortality Consider use of drugs that may improve CV outcomes (death from MI, nonfatal MI, stroke, CHF) and/or renal disease progression Decisions that are patient-centered are likely to improve clinical outcomes Garcia-Perez et al. Diabetes Ther. 2013;4:

38 Meet Edward: A 45 y/o Man with T2D 45 y/o Hispanic male with 2-year history of T2D Currently on metformin 1000 mg BID A1C 7.3% 1 year ago, 7.6% 3 months ago, and 8.0% today Obese (BMI 33.7 kg/m 2 ), sedentary, diet very high in carbohydrates Says he is unlikely to modify his lifestyle soon PE: Normal except for acanthosis nigricans SMBG shows average FBG 140mg/d but PBG >200mg/dL 38

39 ARS Question What Is Happening Physiologically with Edward? 1. Beta-cell function is declining 2. Metformin is not providing adequate insulin sensitivity 3. Lifestyle nonadherence is main reason for his increasing blood glucose 4. Impact on weight is more important than durability of action in choosing next therapy for this patient 5. 1 and 2 39

40 ARS Question: What Would You Add Next? 1. Basal insulin 2. Combination oral agent 3. DPP-4 inhibitor 4. GLP-1 RA 5. Pioglitazone 6. Secretagogue 7. SGLT-2 inhibitor 40

41 Andy: 54 y/o with CAD and T2D 54 y/o man with 3-year history of T2D Controlled on metformin 850 bid and glimepiride 1 mg A1C has ranged from 7.1% to 7.3% Last year, hospitalized for NSTEMI; found to have grade 1 diastolic dysfunction and grade 1 right carotid bruit that did not require intervention At a recent office visit, A1C had risen to 7.8% with no changes in diet, activity, or weight Reports 2 episodes of hypoglycemia while on the golf course but attributed them to missing lunch 41

42 Considerations in Intensifying Therapy in Patients with CAD Impact of hypoglycemia risk on CV risk Impact on cardiometabolic risk factors Impact on CV outcomes (liraglutide, empagliflozin) Impact on CNS/Stroke outcomes (semaglutide, pioglitazone) What s the best change in therapy for Andy? 42

43 Hypoglycemia and Cardiovascular Risk Desouza CV et al. Diabetes Care. 2010;33:

44 CV Outcomes Trials for GLP-1 RAs Trial Agent Complete FREEDOM- CVO REWIND NCT EXSCEL NCT LEADER 1 NCT ELIXA 2 NCT SUSTAIN-6 3 NCT Exenatide ICTA Dulaglutide 2019 Exenatide QW 2017 Liraglutide 2016 Lixisenatide 2014 Semaglutide Marso SP. N Engl J Med Sep 16; 375: Pfeffer M. N Engl J Med Dec 3;373(23): Phase 3 safety trial meets primary & secondary endpoints demonstrating non-inferiority for cardiovascular (CV) safety with exenatide qw / micropump 13% reduction in first occurrence of death from CV causes, death from any causes, nonfatal MI, or nonfatal stroke with liraglutide No increased risk for CV death, heart attack, stroke, unstable angina, or heart failure in people with T2DM and recent acute coronary syndrome with lixisenatide 26% reduction in CV death, nonfatal MI, or nonfatal stroke was significantly lower among patients (at high CV risk) with semaglutide versus placebo 44

45 Shavante: 39 y/o on Multiple Meds 39 y/o with 4-year history T2D Had gestational diabetes with last 2 pregnancies but was diabetes-free for 4 years Initially treated with metformin 1000 mg bid, then added glimepiride 4 mg, and finally sitagliptin 100 mg Only has time to exercise 1 day/week; diet is affected by what her kids will eat At last 2 visits, A1C 8.4% and weight stable at 238 lbs Average FBG 130 mg/dl Doesn t check later in the day because those numbers were too high when she did check 45

46 ARS Question 6 What might be an appropriate next step for Shavante? 1. Add pioglitazone and/or SGLT-2 inhibitor 2. Discontinue all oral agents and initiate basal-bolus insulin 3. Discontinue glimepiride and sitagliptin and start 2 alternative oral antidiabetic agents 4. Enhance adherence by initiating once weekly GLP-1 RA or daily combined basal insulin/glp-1 RA 46

47 GLP-1 RA + Basal Insulin Basal insulin analogs GLP-1 RAs Simple to initiate Control nocturnal hyperglycemia Control FPG Less hypoglycemia risk vs NPH Can cause weight gain Achieve A1C target in ~50% a Simple to initiate Can control FPG and PPG Do not impair α-cell response to hypoglycemia (reduce severe hypoglycemia) Reduce weight Achieve A1C target in ~60% a Insulin degludec/liraglutide (DEG-LIRA), insulin glargine/lixisenatide (GLAR-LIXI) combinations FDA-approved 1. Buse JB, et al. Diabetes Obes Metab. 2015;17(2): Holst JJ, Vilsbøll T. Diabetes Obes Metab. 2013;15(1): Vora J, et al. Diabetes Metab. 2013;39(1):

48 Recommendations for GLP-1 RA with Basal Insulin GLP-1 RA may be used in combination with basal insulin in patients who do not reach glycemic target with 2-3 glucose-lowering medications 1-4 If taking a sulfonylurea (SU), consider discontinuing or reducing the dose of SU If adding GLP-1RA to basal insulin, consider reducing basal insulin dose 20% if A1C 8.0% Thereafter, adjust basal insulin dose based on selfmonitoring of blood glucose especially in first six weeks post insulin dose reduction Monitor for hypoglycemia 1. Inzucchi SE, et al. Diabetes Care. 2015;38: American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S Handelsman Y, et al. Endocr Pract. 2015;21(suppl 1): Garber AJ, et al. Endocr Pract. 2015;21:e1-e10. 48

49 Change in A1C, % DEG-LIRA Basal Insulin/GLP-1 RA Fixed-ratio Coformulations DEG LIRA GLAR-LIXI A1C < 7%, % * 65 * Change in Body Weight, kg DEG-LIRA noninferior to DEG and superior to LIRA (26-week open-label, treat-to-target RCT; N=1663 [insulin naïve]) * -0.5 * severe hypoglycemic episodes per group -1.6 GLAR GLAR-LIXI superior to GLAR (24-week open-label, treat-to-target RCT; N=323 [insulin naïve]). 2 Lower rate of hypoglycemia for LIRA vs DEG or DEG-LIRA (overall and nocturnal) 1 Lower rate of hypoglycemia for GLAR-LIXI than for GLAR (overall) 2,e 0.5 Individual GLP-1 RAs should not be mixed with or injected adjacent to insulin 3 *P<0.001 vs DEG-LIRA; P<0.001 vs GLAR-LIXI. RCT=randomized controlled trial. 1. Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2: Rosenstock J, et al. Diabetologia. 2014;57(suppl 1) [abstract 241]. 3. US FDA. Drugs@FDA. Accessed August 23, e P <.001 vs GLAR-LIXI 49

50 Principles of Multimolecular Therapy Metformin remains foundation of therapy but is not universally effective in all patients, especially those who are insulin deficient Look for untreated mechanistic targets and add accordingly Remove any medications that are not providing expected therapeutic benefit Reconsider pioglitazone for the insulin-resistant patient Metformin is NOT the sensitizer we once thought, though very effective in lowering glucose overall Look to GLP-1 RA and SGLT-2 in insulin-deficient patients and always look to add insulin earlier instead of additional oral agents 50

51 POST-TEST QUESTIONS 51 51

52 Post-test ARS Question 1 After completing this activity, please rate your confidence now in your ability to manage T2D as a multi-defect disorder with individualized combination therapy: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 52

53 Post-test ARS Question 2 After completing this activity, how often do you intend to select antidiabetic therapy based on its mechanism of action? 1. Never 2. Rarely 3. Sometimes 4. Often 5. Always 53

54 Post-test ARS Question 3 All of the following are pathophysiologic mechanisms of T2D, EXCEPT: 1. Increased lipolysis 2. Decreased incretin effect 3. Decreased glucagon secretion 4. Increased glucose reabsorption 54

55 Post-test ARS Question 4 According to current AACE and ADA guidelines, which therapy should be considered for a patient with symptoms of hyperglycemia at diagnosis of T2D? 1. Metformin monotherapy 2. Metformin plus 1 other antidiabetic drug 3. Metformin plus 2 other antidiabetic drugs 4. Basal insulin +/- other antidiabetic drugs 55

56 Post-test ARS Question 5: Shavante 39 y/o with 4-year history T2D Had gestational diabetes with last 2 pregnancies but was diabetes-free for 4 years Initially treated with metformin 1000 mg bid, then added glimepiride 4 mg, and finally sitagliptin 100 mg Only has time to exercise 1 day/week; diet is affected by what her kids will eat At last 2 visits, A1C 8.4% and weight stable at 238 lbs Average FBG 130 mg/dl Doesn t check later in the day because those numbers were too high when she did check 56

57 Post-test ARS Question 5 Cont d What might be an appropriate next step for Shavante? 1. Add pioglitazone and/or SGLT-2 inhibitor 2. Discontinue all oral agents and initiate basalbolus insulin 3. Discontinue glimepiride and sitagliptin and start 2 alternative oral antidiabetic agents 4. Enhance adherence by initiating once weekly GLP-1 RA or daily combined basal insulin/glp-1 RA 57

58 Questions? 58