Type 2 Diabetes Novel Therapies and Difficult Cases Matt Dowell, DO Type 2 Diabetes - An Epidemic Is Here 1
Age-Adjusted Prevalence of Diagnosed Diabetes Among US Adults 2005 Missing data <4.5% 4.5% 5.9% 6.0% 7.4% 7.5% 8.9% 9.0% CDC s Division of Diabetes Translation. United States Surveillance System available at http://www.cdc.gov/diabetes/data Age-Adjusted Prevalence of Diagnosed Diabetes Among US Adults 2010 Missing data <4.5% 4.5% 5.9% 6.0% 7.4% 7.5% 8.9% 9.0% CDC s Division of Diabetes Translation. United States Surveillance System available at http://www.cdc.gov/diabetes/data 2
Age-Adjusted Prevalence of Diagnosed Diabetes Among US Adults 2015 Missing data <4.5% 4.5% 5.9% 6.0% 7.4% 7.5% 8.9% 9.0% CDC s Division of Diabetes Translation. United States Surveillance System available at http://www.cdc.gov/diabetes/data Number and Percentage of U.S. Population with Diagnosed Diabetes, 1958-2015 8 25 Percentage with Diabetes 7 6 5 4 3 2 1 Percentage with Diabetes Number with Diabetes 20 15 10 5 Number with Diabetes (Millions) 0 1958 61 64 67 70 73 76 79 82 85 88 91 94 97 00 03 06 09 12 15 Year 0 CDC s Division of Diabetes Translation. United States Diabetes Surveillance System available at http://www.cdc.gov/diabetes/data 3
Societal Impact of Diabetes 7 th leading cause of death in US in 2013 Leading cause of kidney failure, lower-limb amputations, and adult-onset blindness Over 20% of health care spending is for people with diagnosed diabetes. Source: National Diabetes Surveillance System, 2016. Who Should Care for Diabetics? 90 percent of diabetics receive care from generalist Mortality rates and functional status no better for endocrinologists vs. FPs 1 Specialty clinics better at complying with eye exams and HgbA1C 2 1. JAMA 1995 Nov 8;274(18):1436-44 2. Diabetes Care 1997 Apr;20(4):472-5 4
Control of CV Risk Factors in Diabetic Hypertensive Patients in Academic Medical Centers A1C <7% LDL <100 BP <130/85 mmhg Daily Aspirin (ASA) Use BP, Lipids and A1C BP, Lipids, A1C + ASA 27% 36% 27% 46% 3% 2% McFarlane SI. Diabetes Care 2002;25:718 UKPDS Blood Pressure Study: Tight vs. Less Tight Control 1148 type 2 patients BP lowered to avg. 144/82 (controls-154/87); 9 yr follow-up Endpoint Risk Reduction(%) P Value Any diabetes related endpoint 24 0.0046 Diabetes related deaths 32 0.019 Heart failure 56 0.0043 Stroke 44 0.013 Myocardial infarction 21 NS Microvascular disease 37 0.0092 UKPDS. BMJ. 317: 703-713. 1998. 5
Effect of Tighter Glycemic Control on Progression of Retinopathy DCCT Glycemic Control Reduces Complications DCCT UKPDS HbA1C 9 7.2% 8 7% Retinopathy 63% 17% to 21 % Nephropathy 54% 24% to 33% Neuropathy 60% - Cardiovascular Disease 41% 16% Diabetes Control and Complications Trial (DCCT) Research Group. N Engl J Med 1893:329:977-988 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1993; 352:837-853. 6
ABCs Of Diabetes Management Glycemic control A1C <7.0% Preprandial plasma glucose 90-130 mg/dl Postprandial plasma glucose <180 mg/dl Blood pressure <140/90 mmhg Lipids LDL-cholesterol <100 mm/dl Triglycerides <150 mm/dl HDL >40 mm/dl Antiplatelet therapy Everyone over 50 w risk factors Smoking cessation Universal Diabetes Care 2017;30:S4-41 7
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INSULIN SULPHONYLUREAS METFORMIN ALPHA GLUCOSIDASE INHIBITORS THIAZOLIDINEDIONES MEGLITINIDES GLP 1 RAs SYNTHETIC AMYLIN ANALOG DPP 4 INHIBITORS 1921 1930 s INSULIN 1950 s 1980 S 1 st BIOSYNTHETIC INSULIN 1990 S 2000 2001-10 2010-15 FUTURE? 1 st BASAL INSULIN SGLT 2 INHIBITORS THE DECADES OF DIABETES AFREZZA TOUJEO DEGLUDEC Pathogenesis of T2DM: The Ominous Octet Kruger DF, et al. Diabetes Educ 2010; 36: 44S. 9
What do GLP-1 agonists do? GLP-1 Modulates Numerous Functions in Humans GLP-1: Secreted upon the ingestion of food Promotes satiety and reduces appetite Alpha cells: Glucose-dependent postprandial glucagon secretion Beta cells: Enhances glucose-dependent insulin secretion Liver: Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying Data from Flint A, et al. J Clin Invest 1998;101:515-520. Data from Larsson H, et al. Acta Physiol Scand 1997;160:413-422. Data from Nauck MA, et al. Diabetologia 1996;39:1546-1553. Data from Drucker DJ. Diabetes 1998;47:159-169. 10
Ingestion of food GI tract Release of gut hormones incretins* Active GLP-1 & GIP Inactive GLP-1 DPP-4 enzyme Inactive GIP Pancreas Glucose-dependent Insulin from β cells (GLP-1 and GIP) β cells α cells Glucose dependent Glucagon from α cells (GLP-1) *Incretins are also released throughout the day at basal levels. Glucose uptake by muscles Glucose production by liver Blood glucose in fasting and postprandial states Adapted from Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876 913; Ahrén B. Curr Diab Rep. 2003;2:365 372; Drucker DJ. Diabetes Care. 2003;26:2929 2940; Holst JJ. Diabetes Metab Res Rev. 2002;18:430 441. 10 The Incretin Effect oral glucose load (50 g) iv glucose infusion 15 Plasma glucose 270 80 Plasma insulin 10 mmol/l 5 180 mg/dl 90 60 mu/l 40 20 Incretin effect 0 10 5 60 120 180 Time (min) 0 0 10 5 60 120 180 Time (min) Insulin response is greater following oral glucose than iv glucose, despite similar plasma glucose concentrations Nauck MA et al. Diabetologia 1986;29:46 52. Healthy volunteers n=8 11
Decreased GLP-1 Levels in T2DM Toft-Nielsen et al. J Clin Endocrinol Metab. 2001, 86:3717-23 Benefits of GLP-1 RAs Weight loss Low risk of hypoglycemia A1c Efficacy Weekly Dosing β-cell preservation? 12
GLP-1 Receptor Agonist Drugs Short-Acting Meier JJ. Nat Rev Endocrinol. 2012;8(12):728 742. Lund A, et al. Eur J Intern Med. 2014;25(5):407 414. Long-Acting Liraglutide (Victoza) Exenatide-LAR FDA Approved Drugs Exenatide (Byetta) (Bydureon) Albiglutide (Tanzeum) Dulaglutide (Trulicity) Half-life 2 5 h 12 h several days Fasting BG Modest reduction Strong reduction A1C Modest reduction Strong reduction Postprandial hyperglycemia Strong reduction Modest reduction Gastric emptying rate Deceleration No effect Blood pressure Reduction Reduction Body weight reduction 1 5 kg 2 5 kg DPP-4 Inhibitors (Daily Dosing) Inhibitor Trade Name FDA Approval Sitagliptin Januvia 2006 Saxagliptin Onglyza 2009 Linagliptin Tradjenta 2011 Alogliptin Nesina 2013 13
GLP-1R Agonists vs DPP-4 Inhibitors Property/Effect GLP 1R Agonists DPP 4 Inhibitors Mechanism of action Pharmacologic agonist of GLP 1R Inhibitor of incretin degradation Route of administration Subcutaneous Oral A1C lowering (dose dependent) Up to 1.5% Up to 1% Slows gastric emptying Yes No Promotes satiety Yes No Weight Decreased Neutral Drucker DJ. Cell Metab. 2006 Mar;3(3):153 165. Lund A, et al. Eur J Intern Med. 2014;25(5):407 414. Neumiller JJ. Clin Ther. 2011;33(5):528 576. GLP-1R Agonists vs DPP-4 Inhibitors (continued) Property/Effect GLP 1R Agonists DPP 4 Inhibitors Hypoglycemia Low risk Low risk Side effects Early nausea, vomiting Well tolerated FDA approved drugs Exenatide Liraglutide Exenatide LAR Albiglutide Dulaglutide BID QD QW QW QW Sitagliptin Saxagliptin Linagliptin Alogliptin QD Drucker DJ. Cell Metab. 2006 Mar;3(3):153 165. Lund A, et al. Eur J Intern Med. 2014;25(5):407 414. Neumiller JJ. Clin Ther. 2011;33(5):528 576. 14
LEADER Outcome Study Liraglutide (Victoza) - 9340 patients Average exposure to drug or placebo - 3.5 years Age > 50 with T2DM and CVD Age > 60 with T2DM and 1 CV risk factor Outcomes measured: CV death, CV event, death any cause, serious renal disease, significant retinopathy, neoplasms, pancreatitis Results: CV death 4.7% vs 6.0; Death any cause 8.2% vs 9.6 Nonfatal MI or CVA lower in liraglutide (not statistically significant) Nephropathy 1.5% vs. 1.9 Retinopathy 0.6% vs. 0.5 (not statistically significant) LEADER Outcome Study Liraglutide (Victoza) Adverse effects Pancreatitis - 0.4% vs. 0.5 Malignant neoplasm 6.3% vs. 6.6 (not statistically significant) Pancreatic cancer 0.3% vs 0.1 (p = 0.06) Nausea 1.6% vs 0.4 15
SGLT Inhibitors How Do SGLT2 Inhibitors Work? Glucose in blood Glucosuria Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559. 32 16
SGLT2 Inhibition as a Treatment for Diabetes Efficacy Reduction in A1C of 0.5% to 1.0% Weight reduction of ~3 kg Reduction in systolic BP of 3 to 5 mmhg Effective as monotherapy and in combination Diminished efficacy at GFR < 45 Safety Little or no risk of hypoglycemia Increased risk of mycotic genital infections Uncommon hyperkalemia in select populations Side Effects (typically transient) Increased urination Mild hypotension FDA Warning for SGLT2 Inhibitors 20 cases of diabetic ketoacidosis, ketoacidosis, or ketosis were identified FDA Adverse Event Reporting System March 2013 June 6, 2014 Not statistically different than placebo in EMPA-Reg and Canvas Study FDA will determine whether label changes are needed Increased risk of foot amputation http://www.fda.gov/drugs/drugsafety/ucm446845.htm. Accessed May 2015. 17
EMPA-Reg Outcome Key inclusion and exclusion criteria Key inclusion criteria Adults with type 2 diabetes BMI 45 kg/m 2 HbA1c 7 10%* Established cardiovascular disease Prior myocardial infarction, coronary artery disease, stroke, unstable angina or occlusive peripheral arterial disease Key exclusion criteria egfr <30 ml/min/1.73m 2 (MDRD) 7020 patients randomized to empagliflozin 10 mg, 20 mg, or placebo BMI, body mass index; egfr, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease *No glucose-lowering therapy for 12 weeks prior to randomisation or no change in dose for 12 weeks prior to randomisation or, in the case of insulin, unchanged by >10% compared to the dose at randomisation 35 EMPA-Reg Outcome Empagliflozin - Jardiance Results 38% reduction in CV death 32% reduction in all-cause mortality 35% reduction in hospitalization for CHF 18
All-cause mortality Empagliflozin 10 mg HR 0.70 (95% CI 0.56, 0.87) p=0.0013 Empagliflozin 25 mg HR 0.67 (95% CI 0.54, 0.83) p=0.0003 HR 0.68 (95% CI 0.57, 0.82) p<0.0001 Kaplan-Meier estimate. HR, hazard ratio 37 Hospitalization for heart failure HR 0.65 (95% CI 0.50, 0.85) p=0.0017 Cumulative incidence function. HR, hazard ratio 38 19
CANVAS Study/CANVAS-R canagliflozin (Invokana) 1/3 study participants didn t have CV disease but did have CV risk factors Doubled risk of amputation (6.3 vs 3.4/1000 patient years Reduces major CV risk, hospitalization for CHF and progression of renal disease Didn t reduce CV death risk CANVAS Results canagliflozin reduces the risk of major cardiovascular adverse events (MACE) per 1000 patients over 5 years by 23, risk of hospitalization for heart failure by 17 per 1000, and renal events by 16. amputations will occur in 15 more patients per 1000 over 5 years. 20
Diabetes Questions Making the Diagnosis Type 1 vs. Type 2 Type 1 Vs Type 2: How To Tell Them Apart Type 1 Type 2 Treatment Always insulin; 4+ shots Pills Insulin Age at Onset 10% of adults w/ new dx 50% of children w/ new dx Weight ~20% obese ~10% thin Family History 10% w/ a close relative >50% w/ a close relative DKA Can happen Can happen Blood Glucose More variable; big hypo s More stable; milder hypo s Thyroid Disease Often Sometimes Antibodies Usually (Anti-GAD) Not usually C-peptide Early: low nl; Late: ~0 Early: high nl; Late: low nl 21
Case Study #1 HP is a 67 yo female who presents to the clinic for a followup. She is currently taking Metformin ER 1g 2 tablets once daily, and Glipizide XL 10mg 1 tablet once daily for her diabetes. She reports being rather discouraged today as she has been trying to lose weight and has not been successful. Current weight = 190 lbs, Height = 5 3 PMH: Diabetes x 1 year, HTN, Dyslipidemia, Osteoporosis Point of Care A1c today = 8.6% Which of the following new classes is NOT associated with weight loss: a. Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RA) b. Dipeptydil Peptidase-4 (DPP-4) Inhibitors c. Sodium Glucose Co-Transporter 2 (SGLT-2) Inhibitors Case Study #2 28 year-old Mexican American female was noted to have a random glucose of 125 mg/dl on a chemistry panel obtained as part of an annual health fair by her employer. No symptoms or prior history of abnormal glucose (screening OGTT during pregnancy 4 years ago was negative) PMH Negative Medications None FHx Mother and brother have type 2 diabetes Mother has a history of retinal laser treatments, proteinuria and foot ulcer 22
Case Study #2 Social Hx She has smoked 1ppd since age 19 years She and her husband own a convenience store They have two children, ages 4 and 6 years ROS Frequent yeast infections PE Height 64" Weight 200 lb BP 142/92, 92 Waist 38" Skin tags Trace edema Further exam normal Labs A1C 6.3% (normal 4-6%) 1-hour postprandial glucose 133 mg/dl Questions Diabetic? How would you counsel her? Case Study #3 32 year-old Caucasian female with a history of gestational diabetes presents for confirmation of pregnancy (LMP 10 weeks ago). Recent home pregnancy test was positive. Asymptomatic except for nocturia without dysuria or fatigue PMH She has two children, ages 3 years and 26 months Previous gestational diabetes requiring insulin therapy during both previous pregnancies Glucose tolerance test 6 weeks post-partum normal FHx No diabetes or vascular disease 23
Case Study #3 Social Hx No tobacco or EtOH Power-walks 30 minutes 5-7 days a week Follows standard nutritional guidelines Weight stable for past 4 years PE Height 64" Weight 110 lb BP 110/62, 66 Afebrile Further exam negative Labs Urine beta-hcg positive A1C 9.4% Glucose 277 mg/dl (3 hr pc); yesterday at PCP 295 mg/dl (4h pc) Questions Diabetic? Type 1 or Type 2? Case Study #4 78 year-old nursing home resident presents for evaluation of recurrent episodes of severe hypoglycemia. Diabetes diagnosed at age 65 years during routine insurance exam Current treatment includes insulin 70/30 14 units qam; glargine 10 units qhs and sulfonylurea Fingerstick glucose logs (4-6 readings per day) reveal levels from 30 s to mid 500 s for past two weeks Severe hypoglycemia usually occurs during the afternoon or early morning The average measurement is 196 mg/dl (SD 130 mg/dl) PMH Otherwise unremarkable FHx No vascular disease 24
Case Study #4 Social Hx Denies tobacco or EtOH use PE Height 61" Weight 98 lb BP 138/66, 82 Further exam normal Labs A1C 8.6% Creatinine 1.3 Total Cholesterol 150 mg/dl HDL 70 mg/dl LDL 70 mg/dl Triglycerides 50 mg/dl Questions Diabetic? Type 1 or Type 2? Case Study #5 39 y/o female with h/o T2DM who underwent Roux-en-Y gastric bypass 1 year ago. She lost 100 pounds and stopped metformin and insulin thinking her DM was cured. Recently sx of polydipsia and weight loss and post prandial glucose >400. Her father has T2DM. Vitals: Ht 72 inches Wt 219# BP 112/74 Exam: unremarkable Lab: glucose 290, A1c 9.2% Diagnosis:? Treatment: 25
Case #5 - continued She returns three months later and is taking Tresiba insulin 24 u daily and metformin XR 500 mg daily. Fasting glucose < 130. A1c is 6.6%. She has lost 3 pounds and feels great. Any changes in treatment? Questions? 26