HeartWise 2014 April 11, 2014 Matthew A. Sauder, MD LG Health Physicians Diabetes and Endocrinology Diabetes It s not just sugar Objectives Review the link between diabetes and cardiovascular disease Discuss diabetic dyslipidemia Explore the pharmacologic strategies to obtain glycemic control. 1
Diabetes and Risk of Heart Disease Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, Ingelsson E, Lawlor DA, Selvin E, Stampfer M, Stehouwer CD, Lewington S, Pennells L, Thompson A, Sattar N, White IR, Ray KK, Danesh J. Lancet. 2010;375(9733):2215 Women > Men Women: HR 2.59 (95% CI 2.29-2.93) Men: HR 1.89 (95% CI 1.73 2.06) Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, Ingelsson E, Lawlor DA, Selvin E, Stampfer M, Stehouwer CD, Lewington S, Pennells L, Thompson A, Sattar N, White IR, Ray KK, Danesh J. Lancet. 2010;375(9733):2215 Effects of Various Interventions Sattar. Revisiting the links between glycemia, diabetes, and cardiovascular risks. Diabetologia. (2013) 56:686-695. 2
Glycemic Control and CV disease Several recent trials (ACCORD, ADVANCE, VADT) did not show a cardiovascular benefit for intensive control No single diabetic drug has definitively been shown to reduced CV events Legacy effect Metformin?? Cycloset?? Steno-2 8 year study 160 diabetic patients with microalbuminuria Intensive vs. Conventional treatment Treated intensely with A1c targets, lipid targets, BP targets, and Aspirin vs standard of care Gaede, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. NEJM. 2003 Jan 30;348(5):383-93. Gaede, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. NEJM. 2003 Jan 30;348(5):383-93. 3
Steno - 2 Primary endpoint: Cardiovascular events Gaede, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. NEJM. 2003 Jan 30;348(5):383-93. Steno - 2 Gaede, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. NEJM. 2003 Jan 30;348(5):383-93. Interventions to Reduce CAD Diet Exercise ASA (when indicated) Blood pressure control Lipid management Smoking cessation 4
Microalbuminuria It is not just nephropathy It is strongly associated with coronary artery disease (even if there is no diabetes) Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, HalléJP, Young J, Rashkow A, Joyce C, Nawaz S, Yusuf S, HOPE Study Investigators. JAMA. 2001;286(4):421 Diabetic Dyslipidemia Hypoglycemia begets hypoglycemia Hyperglycemia begets hyperglycemia Hyperglycemia begets dyslipidemia Case 1 52 yo with a history of obesity, diabetes, hypertension, fatty liver disease PE: BMI 43. BP 138/88 Meds: Metformin, Lisinopril, HCTZ, Glyburide, Labs: AST 47, ALT 42, A1c 9.3. Cholesterol: Total cholesterol 210, HDL 34, Triglycerides are 390, Calculated LDL 98 5
What is the best medication for his dyslipidemia? A.) Niacin B.) Fenofibrate C.) Statin D.) Fix the glucose first E.) Fish oil Tenenbaum and Fisman Cardiovascular Diabetology 2012, 11:125 Supremacy of Statins 20% risk reduction for every 40 points of LDL lowering in diabetics, no matter what the baseline lipid levels NNT to avoid a vascular event 25 Cholesterol Treatment Trailist Collaborators. Efficacy of Cholesterol lowering in 18686 people with diabetes in 14 randomised trials of statins: a meta-analysis Lancet 2008: 371: 117-125. 6
But don t statins cause diabetes? Statins and Diabetes Sattar et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet 2010: 375: 735-742. Statins and Diabetes Incident diabetes: 1:255 New vascular events: 5.4 events per 255 patients 7
Case 2 60 yo male with uncontrolled DM2, dyslipidemia, and hypertension Meds: Lisinopril, Atorvastatin, Glyburide A1c 10.1 Total cholesterol: 200 HDL: 48 LDL: 70 Triglycerides: 410 What is the next step in management? 1.) Fenofibrate 2.) Niacin 3.) Lower glucose 4.) Colesevalem Hypertriglyceridemia Marker of ectopic fat Glycemic control can have a huge effect Diet: (depends on the level) Less data to suggest specific therapy aimed at lowering triglycerides (caveat: low HDL group) 8
Benefits of Glycemic Control Improved lipid control Prevention of Nephropathy Prevention of Retinopathy Prevention of Neuropathy Slows the rate of complications Diet is the heart and soul of this thing Bariatric surgery The intervention that is most likely to put diabetes in remission 9
9:22 Metformin Sulfonylureas Meglitinides Alpha-glucosidase inhibitors Thiazolidinediones GLP-1 agonists SGLT-2 inhibitors Cabergoline Bile acid sequestrants Symlin Insulin Holy Grail of Diabetes Meds Helps to preserve beta cells Prevents heart disease Robustly lowers glucose and A1c No hypoglycemia Promotes weight loss No side effects Cheap Antihyperglycemic therapy in type 2 diabetes: general recommendations. Inzucchi S E et al. Dia Care 2012;35:1364-1379 Copyright 2011 American Diabetes Association, Inc. 10
Drugs and Hypoglycemia 100,000 Emergency Room visits secondary to drug adverse effects every year for people over 65 ½ of these are in persons over 80 4 medications composed 67% of these admissions Warfarin 33% Insulin 14% Anti-platelet 13% Oral hypoglycemics 11% Budnitz et al. Emergency Hospitalizations for Adverse Drug Events in Older Americans. New England Journal of Medicine 2011; 365:2002-2012 Metformin 11
Case 3 47 yo male presents for diabetes. He is frustrated by his weight and inability to control glucoses. He tries to limit carbs but says his appetite is voracious. Current meds: Metformin BMI 43 A1c 8.6, Cr 1.0, ALT 14 What s the best med? 1.) Insulin 2.) Sulfonylurea 3.) DPP-IV 4.) GLP-1 agonist 5.) TZD How to decide? Efficacy Weight Side effects Hypoglycemia Cheap Insulin High Gain Hypo High risk +/- Sulfonylurea High Gain Hypo Interm risk Very cheap DPP-IV Intermed Neutral Rare Minimal Expensive GLP-1 Agonist High Loss GI Minimal Expensive TZD s High Gain Edema, CHF, osteoporosis Minimal Now generic 12
Insulin Efficacy: Highest Hypoglycemia: The most Weight: Weight gain is common Adverse effects: Hypoglycemia. No risk of cancer. Cost: Variable/expensive Avoid clinical inertia. Sulfonylureas Glipizide, Glimiperide, and Glyburide Efficacy: About 1% Hypoglycemia: Common Weight: Weight loss is common Adverse effects: Hypoglycemia. Increased cardiovascular events?? Cost: Inexpensive Do not use Glyburide with impaired renal function DPP-IV s Sitagliptin, Saxagliptin, Linagliptin, Alogliptin Efficacy: Intermediate (0.5-1.0%) Hypoglycemia: Very little Weight: Neutral Adverse effects: Pretty rare. Cost: Expensive Ideal situation: Elderly patient with an A1c of 8.3 and multiple comorbidities 13
TZD s Pioglitazone (Actos) and Rosiglitzone (Avandia) Efficacy: Very good (1 1.5%) Hypoglycemia: Very little Weight: Weight gain is common Adverse effects: Edema, HF, weight gain, fractures, cardiac???, bladder ca? Cost: $10 a month at Costco (generic) One of the only insulin sensitizers GLP-1 in DM2 Adapted from Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986 Jan; 29(1): 46-52 GLP-1 Agonists Once weekly exenatide (Bydureon) Once daily liraglutide (Victoza) Twice daily exenatide (Byetta) ~ 1% reduction in A1c (0.5-1.5%) Head to head: Greater A1c reduction than DPP-IV, TZD, sulfonylurea, and insulin Weight loss ( 2.8 kg, 3.4 to 2.3;18 trials) - - Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A Glucagon- like pep>de analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011 - - Visboll et al. Effects of glucagon- like pep3de- 1 receptor agonists on weight loss: systema3c review and meta- analyses of randomised controlled trials. BMJ 2012;344:7771 14
Effects of GLP-1 Stimulates glucose-dependent insulin secretion Suppresses glucagon Slows gastric emptying Increases satiety (and/or nausea) Increases Beta-cell proliferation?? GLP-1 Agonists Adverse Effects GI side effects (8-40%): Less common for the longer acting preparations Hypoglycemia: rare but increased when combined with sulfonylureas or insulin Exenatide-once weekly and injection site reactions Long-acting formulations and C-cell tumor (species-specific) Renal disease Pancreatitis GLP-1 and Pancreatic Safety February 27, 2014 FDA and EMA (European Medicines Agency) Casual relationship with pancreatitis is not supported by the evidence Research will continue Egan, et al. Pancrea>c Safety of Incre>n Based Drugs- FDA and EMA assessment. N Engl J Med 2014; 370:794-797 15
Case 4 48 yo white female presents with uncontrolled diabetes. A1c is 7.8. She is tolerating Metformin. She is very concerned about weight and absolutely refuses any medication that will cause weight gain. She has a history of recurrent pancreatitis. She has a family history of MEN 2A. What medication would you choose? A. Glimeperide (Amaryl) B. Pioglitazone (Actos) C. Canagliflozin (Invokana) D. Nateglinide (Starlix) E. Bromocriptine (Cycloset) 16
Meglitinides Repaglinide (Prandin) and Nateglinide (Starlix) Efficacy: 1% Hypoglycemia: Common Weight: Weight gain is common Adverse effects: Hypoglycemia. Cost: Now generic Can be used with other agents SGLT Inhibitors Canagliflozin (Invokana), Dapagliflozin (Forxiga) Efficacy: Intermediate 0.5 1.0 Hypoglycemia: Very limited Weight: Weight loss is common Adverse effects: UTI s. Yeast infections. Cost: Expensive SGLT-2 Physiology 17
SGLT-2 Inhibitor A1c reduction of about 0.5% - 1.0% Weight loss of about 2-3 kg Blood pressure reduction of 2-5 mmhg Rosenwasser et al. SGLT-2 inhibitors and their potential in the treatment of diabetes. Diabetes Metabolic Syndrome Obesity 2013 Nov 27;6:453-467 Adverse Effects Do not use if GFR>45 Genital mycotic infections (7% in females, 2.5% in males) Slight increase in UTI s (2-13%) Very low rate of hypoglycemia (unless used with a sulfonylurea) Low rate of orthostatic hypotension Rosenwasser et al. SGLT-2 inhibitors and their potential in the treatment of diabetes. Diabetes Metabolic Syndrome Obesity 2013 Nov 27;6:453-467 Others Colesevelem (Welchol): A1c reduction of about 0.5% Bromocriptine (Cycloset): A1c reductin of about 0.4-0.5%. Some GI side effects 18
Case 5 43 yo white male presents with a 6 month history of weight loss, polyuria, and fatigue. Glucose in the office is 346. A1c = 11.4 What is the preferred treatment? 1.) Metformin 2.) Glipizide 3.) Liraglutide (Victoza) 4.) Insulin 5.) Canagliflozin (Invokana) Summary Good diabetes care involves targeting all cardiovascular risk factors Management of diabetic dyslipidemia is at the core of cardiac prevention There is an expanding array of options for diabetes and therapy should be individualized 19