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DIABETES COMPLICATIONS AND THERAPEUTICS Robert Zimmerman, MD A 19 yo f has a 1 year hx of type 1 DM. Which of the following statements is true regarding her evaluation? A. She should be referred to an ophthalmologist to screen for diabetic retinopathy B. She should have a urine screen for albumin. C. She should have screening lipids. D. She should have a creatinine clearance. E. All of the above Screening Guidelines for Diabetes Mellitus Type 1 DM Type 2 DM Retinopathy 5 years baseline Nephropathy 5 years baseline HgbA1c baseline baseline Lipids baseline baseline Foot exam baseline baseline A 50 y/o male presents with chest pain – Pt. developed chest pain walking to his seat at at the Cleveland Dew Tour. – Pain was substernal, radiating to the left arm. – The pain resolved after sitting in his seat. The pain returned after a biker nearly fell off his bike while soaring over Terminal Tower. The pain resolved 2 minutes later. – During the Dew Tour the patient drank 8 large cokes and missed much of the acrobatics due to frequent stops in the bathroom. 50 y/o family history/PE – Patient’s father had type 2 diabetes and died of a heart attack at age 57. Patient’s brother has hypertension, diabetes, hyperlipidemia Physical Exam – – – WD/WN WM NAD BP 156/92 P84 R12 – Abd benign No edema Head NC/AT Eyes No retinopathy Lungs clear Heart sounds normal LAB – – – EKG NS ST-TW changes Glucose 250, Na 130, K 4.0, CBC normal – – – – – A. Insulin B. Sulfonylurea C Metformin D Thiozolidinedione E Nateglanide UKPDS: Glycemic Control Study in Type 2 Diabetes Effect of Metformin 0 Any DiabetesRelated Endpoint DiabetesRelated Death All-Cause Mortality Myocardial Infarction Fatal MI -10 -20 Risk Reduction-30 (%) -40 -50 -32 -36 -42 -39 -50 -60 UKPDS Report 34. Lancet 1998. 50 y/o – Patient treated with metformin 1000 bid initially with good response – Also treated with atenolol 50 q am for chest pain and hypertension – After 1 year he gained 10 pounds and was having blood sugars in the 200’s – Patient developed chest pain during rib burn-off at the lakefront. – Patient to be admitted for cath and possible angioplasty – The patient was found to have a 90 % occlusion in the LAD, and underwent angioplasty after being treated with glimeperide for his elevated blood sugar and atorvastatin 10 mg for LDL cholesterol of 130 mg/dl. – Prior to his next office visit he was found to have the following labs – – – – – TG 160 Cholesterol 190 LDL Cholesterol 98 HbA1c 7.2 FBS 130 Which of the following would be the most appropriate management for this patient? A Increase atorvastatin to 80 mg/d B Improve glycemic control to a goal HbA1c of 6.0 C Add fenofibrate D Add ezetimibe ACCORD – A comprehensive, customized, therapeutic strategy targeting glycated hemoglobin levels below 6.0% increased the rate of death from any cause after a mean of 3.5 years, as compared with a strategy targeting levels of 7.0 to 7.9% in patients with a median glycated hemoglobin level of 8.1% and either previous cardiovascular events or multiple cardiovascular risk factors. – As compared with the standard-therapy group, the intensive-therapy group had a relative increase in mortality of 22% and an absolute increase of 1.0% during this follow-up period, with similar differences in death from cardiovascular causes Gerstein HC et al N Engl J Med 2008; 358: 2545-2559 Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus ACCORD n engl j med 362;17, 2010 Effect of Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia on carotid intimal thickness Simvastatin LDL cholesterol 192.7±60.3 mg/dl Combined-therapy group 141.3±52.6 mg/dl n engl j med 358, 1431, 2008 Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease La Rosa et al n engl j med 352, 1426, 2005 – PROVE IT–TIMI 22 - Randomized, double-blind - N=4162; ACS <10 d - Atorvastatin 80 mg/d, pravastatin 40 mg/d - Design: equivalence – Primary endpoint: composite CV events – LDL-C - Baseline: 106 mg/dL - Study: 95 mg/dL vs 62 mg/dL Death or Major Cardiovascular Event (%) Is Very Low LDL-C the Answer? 30 40 mg of pravastatin 25 20 80 mg of atorvastatin 15 10 5 0 P = 0.005 0 No. at Risk Prav 2063 Atorv 2099 3 6 9 12 15 18 21 24 27 30 Months of Follow-up 1688 1736 – 25% relative risk reduction of outcomes Cannon CP et al. N Engl J Med 2004;350:1495-1504. Copyright 2004 Massachusetts Medical Society. All rights reserved. 1536 1591 1423 1485 810 842 138 133 52 y/o B/M with diabetes following a kidney transplant – Patient developed end stage renal disease secondary to hypertension – Doing well after transplant but now has increased urination due to prednisone 10 mg/d – Found to have high blood sugar on random afternoon check of 300. – – – – Patient has Cr of 1.6 Patient treated with glipizide 10 mg q AM Blood sugars AM 100, L118, D 110 HS 300 How would you treat this patient at this time? – A Add metformin – B Add a second dose of glipizide at supper – C Add a dose of repaglinide at supper – D Stop prednisone – E Start glucovance Insulin Response to Repaglinide 100 80 Insulin 60 (U/mL) 40 Repaglinide 20 Placebo 0 100 80 Repaglinide Doses Repaglinide 60 Blood Levels (mg/mL) 40 20 0 0 2 4 6 1 1 1 1 8 0 2 4 6 Hours After First Dose 1 8 2 0 2 2 2 4 Strange P, Diabetes Technol Ther 1999. 40 y/o W/F who presents with acanthosis nigracans, hirsutism, and diabetes – – – – She has been having irregular periods since age 12 She has been struggling with facial hair since age 14 Physical Exam is notable for BP 150/93 Ht 5’2”, weight 130 lbs, acanthosis nigricans around her neck, hair above her lip – Labs notable for glucose 250, Testosterone 95 (2080), Hb A1c 9.0, Cr 1.6 Which of the following agents would be most appropriate to start in this patient? – – – – – A. Insulin B. Glyburide C Repaglinide D Thiazolidinedione E Metformin 52 y/o obese male c/o nocturia 2 x/night, 10 lb weight loss, and blurred vision. You screen the patient for diabetes. Which of the following is diagnostic of diabetes A. 3+ glucose on urine dip stick B. HbA1c 6.5 C. FBS 125 D. 2 Hr post prandial blood sugar 199 E. Evidence of proliferative diabetic retinopathy New Diabetes Classifications Increased Risk for Diabetes – IFG FPG >100 <126 – IGT 2 hour p 75 g glucose dissolved in water PG > 140 <200 – HbA1c 5.7-6.4% Diabetes – Diabetes FPG >126 , 2 hour p 75 g glucose load PG> 200, casual glucose > 200 with symptoms – HbA1c > 6.5% 23 y/o w/f with Type 1 Diabetes presents with difficult to control blood sugars , frequent nightmares, and a wet pillow case. She is currently taking 20 N 10 R AM , 10N 10 R PM Breakfast Lunch Dinner Bedtime 254 95 115 178 300 120 98 110 285 110 89 95 You check a 3 am blood sugar and it is 30. The most apporpriate action is to A Decrease the PM NPH insulin due to the Dawn phenomenon B Decrease the PM NPH due to the Somogyi effect C Increase the PM NPH due to high blood sugars in the AM D Decrease the bedtime snack due to high blood sugars in the AM Which of the following has been shown to be the most effective treatment to prevent diabetes in a patient with IFG or IGT? – A Exenatide – B Insulin – C Exercise – D Metformin 3234 subjects with IFG or IGT Which of the following is not a criteria for the metabolic syndrome? – A Waist circumference > 102 cm in men – B Evidence of Coronary Artery Disease – C Triglyceride level greater than 150 – D BP > 130/85 – E Fasting glucose > 110 Which of the following is associated with the greatest weight reduction? – – – – – A Metformin B Exenatide/Liraglutide C Acarbose D Pramlintide E Nateglanide Mechanism of Incretins Incretin Incretin Mimetic Mimetic Ingestion of food GI tract DPP-4 inhibitor Glucose dependent Insulin (GLP-1and GIP) Pancreas Release of active incretins GLP-1 and GIP X Inactive GLP-1 DPP-4 enzyme Beta cells Blood glucose in fasting and postprandial states Alpha cells Glucosedependent Glucagon (GLP-1) Inactive GIP Glucose uptake by peripheral tissue Hepatic glucose production Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels in response to a meal. Incretin Mimetics are resistant to DPP-4 inactivation Concentrations of the active intact hormones are increased by DPP-4 inhibition, thereby increasing and prolonging the actions of these hormones. GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide. Matching Pharmacology to Pathophysiology Glucose Influx Glucagon Secretion -Glucosidase Inhibitors Hepatic Glucose Output Metformin (Glitazones) Plasma Glucose Insulin SU Meglitinides Nateglinide Glitazones (Metformin) Peripheral Glucose Uptake Source: DeFronzo R, Ann Intern Med 1999;131:281-303 Insulin Secretion Which of the following is not approved for treating diabetes in the United States? –A –B –C –D –E Rosiglitizone Bromocriptine Colesevelam Pramlintide Carbergoline Pramlintide Reduces Postprandial Glucose Excursions – Suppresses postprandial glucagon secretion – Slows gastric emptying – Reduces food intake – Decreases weight – Reduces HbA1c up to 0.7% – Requires 3 injections/day Bromocriptine: Proposed mechanism of action Morning administration (within 2 hours of waking) of CYCLOSET Corrects Low dopaminergic tone in hypothalamus in early morning in diabetes Restoration of morning peak in dopaminergic activity (via D2 receptormediated activity) Sympathetic tone HPA axis tone Hepatic gluconeogenesis FFA and TG Insulin resistance Inflammation/hypercoagulation Impaired glucose metabolism, hyperglycemia and insulin resistance Adverse cardiovascular pathology Sympathetic tone HPA axis tone Hepatic gluconeogenesis FFA and TG Insulin resistance Inflammation/hypercoagulation Decreased postprandial glucose levels Reduction in insulin resistance Day-long reduction in plasma glucose, TGs and FFAs Fonseca. Use of Dopamine agonists in Type-2-Diabetes. Oxford American Pocket Cards. OUP, 2010 Cincotta. Hypothalamic role in Insulin Resistance and insulin Resistance Syndrome. Frontiers in Animal39 Diabetes Research Series. Taylor and Francis, Eds Hansen, B Shafrir, E London, pp 271-312, 2002 39 CYCLOSET® (bromocriptine mesylate) Tablets A unique formulation of bromocriptine CYCLOSET® 4.8 mg tablets • Traditional formulations of bromocriptine were not designed to provide the same pharmacokinetic/ pharmacodynamic profile as CYCLOSET at equivalent dosing • CYCLOSET is a novel quick-release formulation of bromocriptine that increases CNS dopaminergic activity • CYCLOSET has no AB-rated equivalent Novartis Parlodel® 5 mg tablets Mylan bromocriptine 5 mg tablets *AB is the FDA therapeutic equivalence rating that indicates bioequivalence has been studied and demonstrated 40 confidential Data on file, Santarus, Inc Cycloset® Safety Trial: Evaluation of A1c Reduction of Cycloset in a 24-week Efficacy Period 0.6% to 0.9% HbA1c reductions vs. placebo when CYCLOSET added to other oral antidiabetics (OAD) 0.4 Failing Any OAD (n=412) Failing Metformin ± OAD (n=282) Failing Metformin + Sulfonylurea (n=192) Failing TZD ± OAD (n=81) Placebo 0.2 CYCLOSET 0 Average baseline HbA1c 8.3% -0.2 -0.4 -0.6 - 0.57 P<.0001 -0.8 - 0.69 P<.0001 - 0.69 P=.0002 - 0.91 P=.0026 HbA1c changes from baseline vs. placebo in patients completing 24 weeks of treatment (per protocol population) (%) Efficacy data in combination with thiazolidinediones are limited. Efficacy has not been confirmed in combination with insulin. Data on file, Santarus, Inc Scranton et al, Diabetologia 2008; 51 (Suppl. 1): S372-373. Poster, EASD 2008. Rome, Italy Cincotta et al, Diabetologia 2008; 51 (Suppl. 1): S22. Poster, EASD 2008. Rome, Italy KM Curve – Cycloset® Safety Trial Cumulative Percent Composite CVD Endpoint HR 0.58; 95% CI, 0.35-0.96 RRR=42 % *MI, Stroke, hospitalization unstable angina, hospitalization CHF, or coronary revasc. KM Curve: the separation in favor of Cycloset begins 3 months and persists through the end of the study 42 Gaziano M. Diabetes Care 2010, March 23 online Colesevelam N=141 N=166 Fonseca, DIABETES CARE, VOLUME 31, NUMBER 8, AUGUST 2008 – 70-year-old man who has type 2 diabetes mellitus and severe chronic broncho-pulmonary disease – Admitted to the intensive care unit (ICU) for treatment of TB. He is mechanically ventilated. – On the second hospital day, the patient begins receiving enteral feeding (Ensure 50cc/hr) through a nasogastric catheter. – He has had 3 recent hospitalizations for respiratory failure with ICU stays of greater than 2 weeks. – His usual diabetes medications are insulin levemir, 30 units at bedtime, and pioglitizone, 30 mg orally daily. – A recent hemoglobin A1C is 7.5% [4.0–6.1]. Which of the following is the best treatment plan to manage this patient’s plasma glucose levels and reduce mortality risk? – (A) Regular Insulin infusion with a plasma glucose goal of 80 to 110 mg/dL – (B) Lispro Insulin infusion with a plasma glucose goal of 80 to 220 mg/dL – (C) Regular Insulin infusion with a plasma glucose goal of 140 to 180 mg/dL – (D) Insulin glargine, 20 units daily, and supplemental insulin lispro every six hours with a plasma glucose goal of 100-150 mg/dL – (E) Insulin Levemir, 20 units daily, and supplemental insulin Novolog every six hours with a plasma glucose goal of 140 to 180 mg/dL Intensive Insulin Therapy in Critically Ill Patients Conventional Intensive Mean AM BG (mg/dL) 153 103 % Receiving insulin 39% 100% 6 39 BG <40 mg/dL Conventional insulin treatment Rx insulin when blood glucose >215 mg/dL Intensive insulin treatment Rx insulin when glucose >110 mg/dL; target range = 80–110 mg/dL N=1548 van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367. Leuven Study: Intensive Insulin Therapy in Critically Ill Patients Improves Survival Survival in ICU (%) 100 Intensive treatment 96 4.6% mortality 92 Conventional treatment 8% mortality 88 84 Risk reduction = 40% 80 0 0 20 40 60 80 100 120 140 160 Days After Admission 20 mg/dL BG associated with 30% risk of death van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367. NICE - SUGAR Intensive Control 90 day mortality 27.5% 24.9% Severe hypoglycemia 6.8% 0.5% Glucose control (median) 107 141 mg/dL Insulin infusion 97% 69% No difference – 30 day mortality, ICU days, hospital days, days of mechanical ventilation, days of renal replacement, organ failures Critically Ill Patients • Insulin therapy should be initiated for treatment of persistent hyperglycemia, starting at a threshold of no greater than 180 mg/dL (10.0 mmol/L). • Once insulin therapy has been started, a glucose range of 140 to 180 mg/dL (7.8 to 10.0 mmol/L) is recommended for the majority of critically ill patients. • Intravenous insulin infusions are the preferred method for achieving and maintaining glycemic control in critically ill patients. • Validated insulin infusion protocols with 49 demonstrated safety and efficacy, and with l t f fh l i Severe Diabetic Complications Overview Microvascular Complications Macrovascular Complications Diabetic Retinopathy Stroke Diabetic Nephropathy Heart Disease Diabetic Neuropathy Peripheral Vascular Disease Harris MI. Clin Invest Med 1995;18:231-239 Nelson RG et al. Adv Nephrol Necker Hosp 1995;24:145-156 World Health Organization, 2002;Fact Sheet N° 138 50 Which of the following is not true regarding diabetic retinopathy? A. Glycemic control predicts the risk for onset of diabetic retinopathy B. Glycemic control predicts the risk for progression of diabetic retinopathy C. Laser therapy reduces risk of visual loss D. Office ophthalmoscopy is adequate for detection of significant retinopathy E. PKC inhibitor trials show regression of proliferative retinopathy 51 Retinopathy 52 DCCT: Glycemic Control Study in Type 1 Diabetes Effect on Cumulative Incidence of Complications 60.0 50.0 40.0 55.0 64% Risk Reduction Cumulative Incidence 30.0 (%) 20.0 59% Risk Reduction 29.8 Conventional Intensive 39% Risk Reduction 64% 23.9 16.4 13.0 10.0 7.9 0.0 Retinopathy Progression 54% Risk Reduction 5.1 2.5 Laser Rx Microalbuminuria Albuminuria Risk Reduction 13.4 5.0 Clinical Neuropathy DCCT. Ann Intern Med 1995. DCCT. Kidney Int 1995. DCCT. Ophthalmology 1995. A 65 yo m has new onset type 2 DM. Which of the following statements is/are likely true? A. His WHR ratio is <0.65 B. His HDL cholesterol is low. C. His LDL-C particle size is larger than his non diabetic counterpart D. His HgbA1c is normal at diagnosis E. He will not develop renal disease Which of the following is not true of 55 yo f with a 20 yr hx of DM? A. Her CHD risk is 5x her non DM female counterpart B. An ulcer on her metatarsal is more likely secondary to neuropathy than PVD. C. Her risk for PVD is increased by smoking D. Ischemic CHD symptoms are similar to her male counterpart with DM Cardiovascular Events in DCCT/EDIC Cumulative Incidence Cumulative Incidence of First of Any Event 0.12 0.10 Risk reduction 42% 95% CI: 19, 63 Log-rank P = 0.016 0.08 0.06 Conventional 0.04 Intensive 0.02 0.00 0 1 2 3 4 5 Number at Risk Intensive: 705 Conventional: 714 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years from Study Entry 683 688 629 618 113 92 Lipid Lowering Trials in DM – Summary of Lipid lowering trials with diabetic patients shows favorable effects of LDL cholesterol lowering (Snow, Ann Int Med, 2004;140:650) – Large subset of diabetic subjects in Heart Protection Study (simva) got RR that was the same as nondiabetic subjects – CARDs trial (atorva) had a RR 37% – ASPEN trial (atorva) had a RR 10% (P = NS) Use of Fibrates in Diabetes Mellitus – Diabetic patients with/without CHD: focus on LDL strategies – Fibrate use or Niacin should be considered in pts with ↑ triglycerides (↑ non-HDL cholesterol) Complications of Type 1 DM Neuropathy - Peripheral Altered Sensation (Numbness, Pain, Dysesthesias) - Autonomic Gastroparesis Impaired bladder emptying Orthostatic Resting hypotension tachycardia Hypoglycemic unawareness A 55 yo m with 30 yr hx of type 1 DM presents with diarrhea and fecal incontinence. Which one of the following is not likely to be associated? A. Resting tachycardia B. Orthostatic hypotension C. Impotence D. Heme positive stools E. Gustatory sweating Which of the following statements is not true about complications of diabetes mellitus? A. ACE-inhibitor and ARB therapy have both shown favorable reduction in nephropathy risk B. Vitamin B12 deficiency may be associated with glucophage use C. Onset and progression of peripheral neuropathy are related to duration of diabetes mellitus, but not to glycemic control D Coronary heart disease risk in diabetic patients is 25 higher than in non-diabetic patients E Onset and progression of diabetic retinopathy are favorably affected by intensive glycemic control – Treatment of Diabetes now has more therapeutic options – Choice of Agents is often determined by pathophysiology and side effects – Improved control can prevent or delay the long term complications of diabetes – Preservation of Beta Cell Function is emerging as a potential target of therapy