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Please Help Us with the Following Prior to the start of the program, check your syllabus to ensure you have the following printed program materials: • Baseline Survey – In the front of your syllabus – Remove from your packet – Fill out the demographic information on page 2 – Throughout the program, please take a moment to fill in your answers to the corresponding Polling Questions on this form (slides will be marked as “Polling Questions” throughout the deck) Disclosures All relevant financial relationships with commercial interests reported by faculty speakers, steering committee members, non-faculty content contributors and/or reviewers, or their spouses/partners have been listed in your program syllabus. Off-label Discussion Disclosure This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: • Apply diagnostic criteria and recent clinical experience to improve the recognition of hyperglycemic emergencies, specifically DKA and HHS • Evaluate the impact of the results from recent randomized control trials on the prevalence, risk factors, and consequences of antidiabetic therapy-induced hypoglycemia for the care of T2DM patients • Utilize guidelines and expert recommendations to manage patients with diabetes who present with hypoglycemic and hyperglycemic complication Polling Question Baseline Survey Please rate your confidence in managing T2DM in patients who present with a hypoglycemic emergency: A. Expert B. Very confident C. Confident D. Slightly confident E. Not confident Polling Question Baseline Survey Please rate your confidence in recognizing and managing a hyperglycemic emergency such as DKA in your T2DM patients: A. Expert B. Very confident C. Confident D. Slightly confident E. Not confident Polling Question Baseline Survey An 82-year-old man with a 33-year history of T2DM presents to the emergency department with increasing agitation and slurred speech, which began about 2 hours ago. He also says he has had a stomach virus for about a week. Medications include metformin, along with meal-time and a once-daily insulin to manage his T2DM, and an antihypertensive. The patient states he is compliant with his medications. What do you consider? A. TIA or stroke, quickly test for confirmation, and initiate tissue plasminogen activator immediately since still within window for neurologic correction B. Hypoglycemia since the patient’s oral intake has been greatly reduced, but the patient continues to take antihyperglycemic medications as prescribed; measure the patient’s glucose level C. HHS due to dehydration from ongoing vomiting D. Acute pancreatitis Polling Question Baseline Survey A 56-year-old overweight woman presents with sudden-onset severe lethargy. Other symptoms include nausea and vomiting and complaints of pain on urination. She was diagnosed with pneumonia 2 weeks prior. The patient is also an alcoholic, but says she has not had a drink in the past week. Medications include an SGLT-2 inhibitor, beta-blocker and statin therapy, and aspirin. Her most recent HbA1c level was 7.4%, blood pressure 135/78 mm/Hg. and cholesterol 188 mg/dL. What do you consider? A. Her breath smells sweet; measure the patient’s blood-alcohol level B. Test for DKA because of the patient’s symptoms, infection status, and medical history C. Hydrate the patient and prescribe antibiotics for a UTI prior to discharge D. Work-up the patient for an MI due to her medical history Hyperglycemic Emergencies: DKA and Hyperglycemic Hyperosmolar Hyperglycemic Crises • DKA – Most common hyperglycemic emergency in patients with type 1 and type 2 diabetes – DKA accounts for 4%-9% of all hospital discharge summaries among patients with diabetes – Annual average of ~135,000 hospitalizations for DKA in the United States – Most common mortality rate <2% • HHS – Hospitalization rate lower than DKA, approximately <1% of all primary diabetic admissions – Mortality rates ~15% Kitabchi AE et al. Diabetes Care 2009;32:1335-1343. DKA Incidence from NHDS Number (in Thousands) Growth in incidence since 1980 (primary diagnosis) Year 2006 Incidence: 134,663 episodes CDC/NCHS, National Hospital Discharge Survey (NHDS). www.cdc.gov/nchs/about/major/hdasd/nhds.htm. Accessed: 12/2011. Type 1 Diabetes Accounts for the Majority of Primary* DKA Episodes Primary DKA Episodes • 34% of episodes are T2D ~46,000 cases 134,633 (2006 T1D - Children 18% T1D - Adults 48% T2D 34% 66% • Longer hospital stays with T2D 4.2 days with T2D vs average of 3.5 days with T1D 34% T2D accounts for 34% of primary DKA cases and more than 50% of secondary causes *Primary DKA: DKA with no known precipitating cause vs secondary DKA: DKA caused by a precipitating cause (infection, heart attack, etc.) National Hospital Discharge Survey (NHDS); 2006. DKA-related Mortality Rates Have Been in Decline Since the 90s Mortality due to DKA (per annum) DKA Death Rates per 100,000 pop Crude Overall 2006 mortality rate for DKA: 0.41% Centers for Disease Control and Prevention. www.cdc.gov/diabetes/statistics/complications_national.htm. Age Adjusted Pathogenesis of Hyperglycemic Crises Hyperglycemia osmotic diuresis Dehydration LipolysisIncreased FFA Increased glucose production Insulin Deficiency Counterregulatory Hormones Decreased glucose uptake Increased ketogenesis Metabolic acidosis Electrolyte abnormalities Hypertonicity Pasquel FJ, Umpierrez GE. DKA & HHS Pathogenesis; In: DeGroot Endocrinology Textbook. 2014. Diagnostic Criteria for DKA and HHS DKA Plasma glucose (mg/dl) pH Bicarbonate (mEq/l) Urine ketones* Serum ketones* Effective serum Osmol (mOsm/kg)† Alteration in sensoria or mental obtundation Mild Moderate Severe HHS >250 7.25-7.3 15-18 positive positive variable >250 7.0-<7.24 10- <15 positive positive variable >250 <7.0 <10 positive positive variable > 600 >7.30 > 15 small small >320 alert alert/ drowsy stupor/ coma stupor/ coma * Nitroprusside reaction method † Calculation: 2[measured Na (mEq/L)] + glucose (mg/dL)/18 Kitabchi AE et al. Diabetes Care. 2001;24:131-153. Useful Formulas for the Evaluation of DKA 1. Calculation of anion gap (AG): AG = [Na+] – [Cl- + HCO3-] (normal <12 mEq/L) 2. Total and effective serum osmolality: Total = 2[Na+] + glucose (mg/dL) + BUN (mg/dL) 18 2.8 (normal 275-295 mmol/L) Effective = 2[Na+] + glucose (mg/dL) 18 Case Study 18-year-old African American male admitted with a 3 week hx. of polyuria, polydipsia, and 20-lb weight loss. One day prior to admission, developed nausea, vomiting, and diffuse abdominal pain. Physical exam: 100/80 mmHg, HR: 112/min, RR: 24/min Weight: 160 lb, BMI: 22 kg/m2 Lethargic with Kussmaul breathing; otherwise, PE was WNL; no endorgan complications of DM 14.4 12.4 315k 44% 130 92 22 636 5.4 12 1.1 Venous pH: 7.18 B-OH-B: 8.7 MM U/A: + ketones HbA1c: 13.2% Precipitating Causes for DKA and HHS Umpierrez GE et al. Arch Intern Med. 1997;157:669-675. Euglycemic Diabetic Ketoacidosis A Potential Complication of Treatment with Sodium-Glucose Co-transporter 2 Inhibition Peters AL et al. Diabetes Care. 2015;38:1687-1693. SGLT2-I and Risk of Ketoacidosis in T1D Potential Mechanisms Taylor SI et al. J Clin Endocrinol Metab. 2015;100:2849-2852. Polling Question Baseline Survey Which of the following is not a sign/symptom of DKA? A. Nausea and/or vomiting B. Decreased urine output C. Tachycardia D. Acetone breath Clinical Presentation of DKA Symptoms Signs • Polydipsia • Hypothermia • Polyuria • Tachycardia • Weakness • Tachypnea • Weight loss • Kussmaul breathing • Nausea • Ileus • Vomiting • Acetone breath • Abdominal pain • Altered sensorium The onset of DKA is usually relative short, ranging from hours to a day or two. Mental Status at Presentation in DKA Mental Status and Osmolality Serum Osmolality (mOsm/L) Level of Consciousness Alert: <300 mOsm/L Stupor or coma: ≥320 mOsm/L Umpierrez GE et al. Arch Intern Med. 1997;157:669-675. Polling Question Baseline Survey Laboratory studies to confirm a diagnosis of DKA include: A. CMP, urinalysis, serum ketones B. Venous or arterial pH C. MRI in patients with altered mental status D. A and B E. A and C CMP = comprehensive metabolic panel Initial Laboratory Studies • Immediate determination of blood glucose by finger stick and serum ketones (B-OH-B) or urinary ketones • Laboratory studies: – Venous or arterial pH (ABG’ss) – CBC with differential – CMP (glucose, electrolytes, bicarbonate, PO4, Mg, BUN, creatinine) – Serum ketones – Urinalysis – Bacterial cultures* – Cardiac enzymes* * If clinically indicated Kitabchi AE et al. Diabetes Care. 2009;32:1335-1343. Blood -OHB Levels in DKA Detection and Treatment • -OHB concentrations >0.5 mmol/L are considered “abnormal” • Patients presenting with DKA can range between 3-12 mmol/L -OHB – -OHB ≤1.0 mmol/L — treat blood glucose level appropriately – -OHB 1.1 to 3.0 mmol/L — insulin and fluids; retest in 1 hour and, if no improvement, contact physician – -OHB >3.0 mmol/L — insulin, fluids, urgent medical attention Wallace TM et al. Q J Med. 2004;97:773-780. Guerci B et al. Diabetes Metab. 2005;31:401-406. Managing Hyperglycemic Emergencies Management of DKA • Replacement of fluid losses • Correction of hyperglycemia/metabolic acidosis • Replacement of electrolyte losses • Detection and treatment of precipitating causes • Conversion to a maintenance diabetes regimen (prevention of recurrence) Kitabchi AE et al. Diabetes Care. 2009;32:1335-1343. Fluid Therapy in DKA Normal saline, 1-2 L over 1-2 h Calculate corrected serum sodium Normal or high serum sodium Low serum sodium ½ NS at 250-500 mL/h NS at 250-500 mL/h Glucose <250 mg/dL Change to D5% NS or 1/2NS Kitabchi AE et al. Diabetes Care. 2009;32:1335-1343. Intravenous Insulin Therapy in DKA I.V. Bolus: 0.1 U/kg body Wgt I.V. drip: 0.1 U/kg/h body Wgt Glucose <250 mg/dL IV drip: 0.05 – 0.1 U/kg/h Until resolution of ketoacidosis Studies Comparing SC Injections of Lispro vs Continuous Infusion of Regular insulin in DKA Vincent M, Nobécourt E. Diabetes Metab. 2013;39:299-305. Potassium Replacement and Bicarbonate Therapy in DKA K+ = >5.5 mEq/L; no supplemental is required K+ = 4-5 mEq/L; 20 mEq/L of replacement fluid K+ = 3-4 mEq/L; 40 mEq/L of replacement fluid If admission K+ = <3 mEq/L give 10-20 mEq/h until K+ >3 mEq/L, then add 40 mEq/L to replacement fluid Bicarbonate Therapy pH ≥7.0 no bicarbonate pH <7.0 and bicarbonate <5 mEq/l 44.6 mEq in 500 mL 0.45% saline over 1 h until pH ≥7.0 Kitabchi AE et al. Diabetes Care. 2009;32:1335-1343. Management after Resolution of DKA • Patients with DKA should be treated with IV insulin or rapid-acting SC insulin until ketoacidosis is resolved • Criteria for resolution of DKA – BG ≤250 mg/dL – Serum bicarbonate level ≥18 mEq/L – Venous pH ≥7.3 – (B-OH-B, anion gap) Transition to Subcutaneous Insulin after Resolution of DKA After Initial IV or SQ therapy (pH >7.3, HCO3 >18, AG < 14) Give SQ basal insulin 2-4 hours before stopping IV insulin Start multi-dose insulin (basal bolus) regimen • Insulin analogs are preferred over human insulin • Basal: glargine / detemir • Rapid-acting insulin analogs (lispro, aspart, glulisine) • Analogs results in similar BG control, but less hypoglycemia than human insulin (15% vs 41%) Use of ‘early’ glargine insulin during treatment of DKA may prevent rebound hyperglycemia during insulin infusion Draznin et al. JCEM. 2012;97:3132-3137. Umpierrez GE et al. Diabetes Care. 2009;32:1164-1169. Summary • DKA is a common, serious, and expensive complication in patients with type 1 and type 2 diabetes • Prevention of metabolic decompensation through patient education, strict surveillance of glucose homeostasis, and aggressive diabetes management might reduce the high morbidity and mortality • Recent treatment protocols have improved clinical outcomes in patients with DKA Hypoglycemic Emergencies: Hypoglycemia Definitions: Hypoglycemia Hypoglycemia: “all episodes of abnormally low plasma glucose concentration that expose the individual to potential harm” 1. Severe hypoglycemia: An event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions (definitions vary) 2. Documented symptomatic hypoglycemia: An event during which typical symptoms of hypoglycemia are accompanied by a low measured BG concentration International Hypoglycemia Study Group. Diabetes Care. 2015;38:1583-1591. Definitions: Hypoglycemia (cont) 3. Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of hypoglycemia, but with a measured low BG concentration 4. Probable symptomatic hypoglycemia: An event during which symptoms typical of hypoglycemia are not accompanied by a BG determination but that are presumed to be caused by a low plasma glucose concentration 5. Relative (or pseudo-) hypoglycemia: An event during which the person with diabetes reports any of the typical symptoms of hypoglycemia and interprets those as indicative of hypoglycemia with a measured BG concentration that is not low International Hypoglycemia Study Group. Diabetes Care. 2015;38:1583-1591. Rates of Hypoglycemia • 30%-40% of individuals with T1D have 1-3 episodes of severe hypoglycemia/year • Rates in insulin-treated T2D ~1/3rd as common • Rates of mild hypoglycemia ~50 times more common • Use of SUs, a glinide, or insulin and increased duration of diabetes increase the risk for hypoglycemia of any kind International Hypoglycemia Study Group. Diabetes Care. 2015;38:1583-1591. Hypoglycemia: Impact on Healthcare Resources • Analysis of healthcare resource use during severe hypoglycemia events (requiring external assistance) from 15 trials of T1 and T2DM using insulin (degludec; degludec/aspart; glargine, biphasic aspart, detemir) • 536 severe hypoglycemia events – 29.3% involved an ambulance/emergency team – 11.9% led to hospital/emergency room attendance of ≤24 hours – 6.7% required hospital admission (>24 hours) • Those receiving basal-oral therapy had greater risk for hospitalization (47.6%) • Once a severe episode occurred, the tendency to utilize healthcare resources was higher in T2 vs T1DM Heller SR et al. Diabet Med. 2015; doi: 10.1111/dme.12844. [Epub ahead of print]. Economic Impact of Severe and Non-severe Hypoglycemia Episodes • Review of 14 studies on T1 and T2DM • Direct cost associated per hypoglycemia episodes requiring assistance from a healthcare practitioner: $116 Indirect costs associated with: T1DM T2DM severe hypoglycemia requiring non-medical assistance $242 $579 severe hypoglycemia requiring medical assistance $160 $176 non-severe hypoglycemia $11 $11 Foos V et al. J Med Econ. 2015;18:420-432. Case 1: Hypoglycemia • SV is a 58-year-old female with a 30-year history of type 1 diabetes. She has diabetic retinopathy, but no other complications. • She is very physically active working in a preschool. • She also trains for running 10 Ks and runs 5 days per week. • Recently she has been having episodes of severe hypoglycemia, twice overnight when her husband treated her with glucagon and once while at school when paramedics had to be called. • Her target A1c is 6%. Case 1: Hypoglycemia (cont) • On questioning, her insulin dosing has not changed. • However, she no longer senses her lows regularly. • Currently, she is taking 10 units of long-acting insulin at bedtime and gives 1 unit for every 20 grams of carbs and a correction (or sensitivity) factor of 50. • Her CGM tracing follows. • What would you recommend and why? Case 1: Hypoglycemia (cont) Polling Question Baseline Survey Which of the following is true of severe hypoglycemia: A. It is associated with an increased risk for mortality in people with type 2 diabetes B. It is less common in people with type 1 diabetes C. It is strictly defined as hypoglycemia causing a seizure, loss of consciousness, or a coma D. It directly causes an increase in mortality in people with type 1 diabetes Intensive Control Increases the Risk of Severe Hypoglycemia TABLE – Effects of intensive, compared with conventional, glycemic therapy of type 2 diabetes: meta-analysis of 12 randomized controlled trails (20) Effect (no. of randomized controlled trials) Relative risk 95% CI (P) No. of patients All-cause mortality 1.02 0.91-1.13 (0.74) 28,359 Cardiovascular mortality (12) 1.11 0.92-1.35 (0.27) 28,359 Microvascular complications (3) 0.88 0.78-0.97 (0.01) 25,600 Severe hypoglycemia (9) 2.39 1.71-3.34 (0.001) 27,844 International Hypoglycemia Study Group. Diabetes Care. 2015;38:1583-1591. Risk of CV Events and Death in Patients With vs Without Severe Hypoglycemia: (ADVANCE) Study inclusion criteria: T2DM + major vascular disease or ≥1 CV risk factor Macrovascular events 3.45 (2.34-5.08); P<0.001 Death—any cause 3.30 (2.31-4.72); P<0.001 Death—CV cause 3.78 (2.34-6.11); P<0.001 Death—non-CV cause 2.86 (1.67-4.90); P<0.001 Decreased risk Adjusted Hazard Ratio (95% CI) Increased risk Zoungas S et al; ADVANCE Collaborative Group. N Engl J Med. 2010;363:1410-1418. Summary of ACCORD, ADVANCE, VADT Severe Hypoglycemia and Mortality Risk ACCORD ADVANCE VADT Severe Hypo Intensive Standard Intensive Standard Intensive Standard (%/ year) 3.1% 1.1% 0.7% 0.4% 12.0% 4.0% Annual mortality 5.0% 4.9% 4.0% 2.8% 3.0% No hypo 1+ Hypo 2.0% 1.0% 1.3% 1.0% 0.0% Intensive Standard Bonds DE et al. BMJ. 2010;340:b4909. Polling Question Baseline Survey Treatment of hypoglycemia associated autonomic failure (HAAF) involves: A. Reducing the total daily insulin dose B. Hypoglycemia avoidance for 1-2 months C. Hypoglycemia avoidance for 2-3 weeks D. Reducing bolus insulin dose Hypoglycemia Associated Autonomic Failure (HAAF) • Defined as attenuation of the sympathoadrenal response to hypoglycemia that leads to impaired awareness of hypoglycemia, which increases the risk for severe hypoglycemia • It is often induced by antecedent hypoglycemia • The diagnosis is generally made clinically, based on the patient’s subjective sense of a reduction in symptoms of hypoglycemia • This impaired awareness is reversible by 2-3 weeks of hypoglycemia avoidance • Educational programs exist to help patients restore their sense of lows Little SA et al. Diabetes Metab Res Rev. 2014;30:175-190. Hypoglycemia Associated Autonomic Failure (HAAF) Cryer PE. Diabetes. 2005;54:3592-3601. Management of Hypoglycemic Emergencies Recommendations of the International Hypoglycemia Study Group People with diabetes treated with a sulfonylurea, a glinide, or insulin should: • Be educated about hypoglycemia • Treat SMPG levels ≤70 mg/dL (3.9 mmol/L) to avoid progression to clinical iatrogenic hypoglycemia • Regularly be queried about hypoglycemia, including the glucose level at which symptoms develop; those developing symptoms at a glucose level 55 mg/dL (3.0 mmol/L) should be considered at risk SMPG = self-monitored plasma glucose International Hypoglycemia Study Group. Diabetes Care. 2015;38:1583-1591. Recommendations of the International Hypoglycemia Study Group (cont) When hypoglycemia becomes a problem, the diabetes healthcare provider should: • Consider each conventional risk factor and those indicative of compromised glucose counter-regulation • Avoid sulfonylureas (and glinides) if possible, using insulin analogs when insulin is required, and consider using CSII, CGM, and CSII + CGM in selected patients • Provide structured education and, in patients with impaired awareness of hypoglycemia, prescribe short-term scrupulous avoidance of hypoglycemia • Seek to achieve the lowest A1c level that does not cause severe hypoglycemia and preserves awareness of hypoglycemia with an acceptable number of lessthan-severe episodes of hypoglycemia, provided that benefit from glycemic control can be anticipated International Hypoglycemia Study Group. Diabetes Care. 2015;38:1583-1591. Rule of 15 for Treating Hypoglycemia Guide for Patients • If BG is 50-70 mg/dL – take 15 grams of simple sugar, such as 4 oz of juice or 4 glucose tablets. • Then eat a snack with 15 grams of carbohydrates and a protein. You can use a carton of yogurt; an apple with cheese; 6 to 7 crackers with cheese or peanut butter, a KindPlus Bar. You must combine these additional carbohydrates with a protein. It is important to drink lots of water when you are low. • If less than 50 mg/dL – take 30 grams of simple sugar, such as 8 oz of juice or 8 glucose tablets. Then use the same instructions as above for your snack. Drink lots of water. Medline Plus. https://www.nlm.nih.gov/medlineplus/ency/imagepages/19815.htm. Accessed: 12/5/2015. Rule of 15 for Treating Hypoglycemia Guide for Patients • Recheck blood sugar again in 15 minutes. If you are still 70 mg/dL or less, then repeat the above and recheck in 15 minutes. • When you are low, your liver also produces glucose. Your glucose will go up sooner than you will feel better. You must not eat TOO much when you are treating a low. If you prepare some of these snacks ahead of time, so they are handy, you will have better control when you are eating. • If you eat more than the 30-45 grams of carbohydrates, you will need to take insulin aspart/insulin lispro/insulin glulisine to cover these carbs, or your glucose will go very high. Novolog (insulin aspart), Humalog (insulin lispro), Apidra (insulin glulisine) Medline Plus. https://www.nlm.nih.gov/medlineplus/ency/imagepages/19815.htm. Accessed: 12/5/2015. Conclusions • Hypoglycemia is common in people with diabetes treated with sulfonylurea agents, glinides, and insulin • Mild hypoglycemia is much more common than severe hypoglycemia • Severe hypoglycemia is associated with an increased risk of mortality • HAAF increases the risk for severe hypoglycemia • Approaches to prevent and treat hypoglycemia need to be employed CME Credit • Post-activity Survey and Evaluation – Please remove from the back of your syllabus – Take a moment to answer the Post-activity Survey questions on your form – Your answers are important and will help us identify remaining educational gaps and shape future CME activities • CME Evaluation – If you’re seeking credit, ensure you fill in your name and demographic information and complete the entire CME Evaluation form – Return all forms to on-site CME staff Thank you for joining us today!