Addressing Addressing Challenges in Type 2 Challenges in Type 2 Diabetes Diabetes Speaker:

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1 Addressing Challenges in Type 2 Diabetes Geneva Briggs, PharmD,, BCPS Addressing Challenges in Type 2 Diabetes Speaker: Dr. Geneva Clark Briggs, a board-certified Pharmacotherapy Specialist, received her Doctor of Pharmacy and Bachelor of Science in Pharmacy degrees from Virginia Commonwealth University, Medical College of Virginia. Dr. Briggs is a clinical associate with MedOutcomes, Inc. where she develops and presents educational programs for pharmacists. Speaker Disclosure: Dr. Briggs has no actual or potential conflicts of interest in relation to this program This program has been supported by an educational grant from Merck Pharmaceuticals This program has been supported by an educational grant from Merck Pharmaceuticals PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education Legal Disclaimer: The material presented here does not necessarily reflect the views of Pharmaceutical Education Consultants (PharmCon) or the companies that support educational programming. A qualified healthcare professional Medoutcomes, should Inc always 2009 be consulted before using any therapeutic product discussed. Participants should verify all information and data before treating patients or employing any therapies described in this educational activity. Addressing Challenges in Type 2 Diabetes Accreditation: Pharmacists: L01-P Pharmacy Technicians: L01-T Target Audience: Pharmacists and Pharmacy Technicians Medoutcomes, Inc 2009 CE Credits: 1.0 Credit hour or 0.1 CEU for pharmacists/technicians Expiration Date: 7/29/2011 Program Overview: This program will provide pharmacists with an overview of recent studies of diabetes medications and the impact on the care of diabetic patients. The program will also emphasize the role of the pharmacist in educating patients to on the importance of understanding, reaching and maintaining blood glucose levels. Objectives: Explain how the results of recent studies of diabetes medications can impact the care of your diabetic patients. Communicate to patients the importance of reaching blood glucose goals and maintaining adherence and persistence. Assist patients in interpreting and understanding A1C and average glucose values. This program has been supported by an educational grant from Merck Pharmaceuticals Overview Impact of recent studies of diabetes medications on the care of your patients with diabetes Importance of reaching blood glucose goals. Interpreting and understanding A1C values The Diabetes Epidemic 23.6 million US children and adults have diabetes. 57 million have pre- diabetes Prevalence 13.5% from million undiagnosed 17.9 million diagnosed Prevalence of Overweight in the U.S., % 95% Type 2 National Diabetes Statistics Fact Sheet CDC/NCHS, Health, United States,

2 Prevalence of Diabetes in the U.S., 2005 National Diabetes Surveillance System Case 1 (Arnie) A 46-year-old Caucasian male with a family history of type 2 diabetes, who presented requesting a screening test to see if he had diabetes. no symptoms of diabetes but had gained approximately 30 lbs over the past 10 years. no formal exercise regimen height = 6 1, weight= 228 lbs, BMI = 30.1 kg/m 2 BP = 138/84 mm Hg Natural History of Type 2 Diabetes Glucose 126 mg/dl Relative Function 100% Prediabetes/IGT/IFG Postprandial glucose Fasting glucose Insulin level T2DM Beta-cell function Insulin resistance hepatic and peripheral Years from Diabetes Diagnosis IGT=impaired glucose tolerance; IFG=impaired fasting glucose. Diabetes Care 1992;15: Screening for Type 2 Diabetes Overweight (BMI 25 kg/m 2 ) and additional risk factors: Physical inactivity First-degree relative with diabetes Hypertension HDL cholesterol level <35 mg/dl Triglyceride level >250 mg/dl Women with PCOS History of IGT or IFG History of CVD PCOS, polycystic ovarian syndrome IGT, impaired glucose tolerance IFG, impaired fasting glucose CVD, cardiovascular disease Screening for Type 2 Diabetes Overweight (BMI 25 kg/m 2 ) and additional risk factors: Members of a high-risk ethnic population (e.g., African American, Latino, Native American, Asian American, Pacific Islander) Women who delivered a baby weighing >9 lb or were diagnosed with gestational DM Clinical conditions associated with insulin resistance (severe obesity, acanthosis nigricans) 2

3 Acanthosis Nigricans Screening for Type 2 Diabetes in Children Overweight (BMI >85th percentile for age and gender or weight >120% of ideal for height) Plus any two of the following risk factors: Family history of type 2 diabetes in first or second- degree relative Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander) Signs of insulin resistance or conditions associated with insulin resistance Maternal history of diabetes or GDM Case Study - Should Arnie be screened? Family history (? 1st degree relative) Overweight Types of Screening Programs Self done - Will depend on state regulations Outside screening company Off site - Health fairs, wellness centers, senior centers, workplace Referral to community screening (copromotion?) Interpreting Screening Results IFG = fasting plasma glucose mg/dl IGT = 2-h 2 h plasma glucose mg/dl Diabetes FPG 126 mg/dl 2-h h plasma glucose 200 mg/dl + symptoms Oral glucose tolerance test 200 mg/dl Refer anyone with abnormal values for follow-up Why It Is Important To Screen Large number of people are thought to be undiagnosed Damage occurs before symptoms Increasing weight of US population is increasing DM prevalence 3

4 Case 2 (Bernice) A 75 yr old, recently widowed and lives alone in high rise senior apartment complex History of HTN, osteoporosis (hip fracture 1 yr ago), DM (diagnosed 1 yr ago) Metformin 850 mg bid A1C = 8% Drives to social activities and for activities of daily living What is A1C and Why is it Important? Glycated or glycosylated hemoglobin HbA1C, A1C Normal range: 4.0% to 6.7% Reflects mean glucose levels over preceding 120 days Elevated in: Uncontrolled diabetes mellitus, lead toxicity, alcoholism, iron deficiency anemia, hypertriglyceridemia Difficult for patients to understand It s s Not Just Confusing for Newly Diagnosed Patients High levels of testing of HbA1c for patients with known diabetes (> 90%) Of patients with test in past 6 months: 66% did not know result 25% accurately reported within 1% range (< 7%, 7-8%, 7 8-9%) 8 9% inaccurately reported within 1% range Diabetes Care 2005;28: The A1C-Derived Average Glucose (ADAG) Study Carefully look at relationship between HbA1c and average glucose Determine the mathematical relationship between the two for reliable conversion Establish that the relationship is valid across: Diabetes types A wide range of HbA1c levels and age Different races/ethnicities Diabetes Care 2008;31: ADAG Study: Correlation of AG With HbA1c Estimated Average Glucose (eag( eag) AG (mg/dl) AG (mg/dl) = 28.7 x HbA1c 46.7 R2 = 0.84 P < Linear relationship between A1C and average blood glucose levels ADA now recommends reporting A1C to patients as eag (but call it Average glucose) Online calculator - professional.diabetes.org/glucosecalculator.aspx HbA1c (%) AG (mg/dl) = (28.7 x HbA1c) 46.7 Diabetes Care 2008;31:

5 Mean Plasma Glucose ( Average Glucose ) Average Glucose Blood pressure Cholesterol to help make the A understandable! A1C (%) Mean plasma glucose mg/dl mmol/l Current Treatment Guidelines Biochemical Index Fasting/preprandial plasma glucose (mg/dl) Normal ADA Goal ACE/AACE Goal < < 110 Postprandial <120 <180 < 140 plasma glucose (mg/dl) A1C (%) <6 < Average Glucose (mg/dl) < 126 < ADA = American Diabetes Association ACE/AACE = American College of Endocrinology/American Association of Clinical Endocrinologists Endocr Pract 2002;8(Suppl 1): GOOD GLYCEMIC CONTROL: A CRITICAL GOAL Each 1% reduction in mean A1C Reduces risk of death from diabetes by 21% Reduces risk of microvascular complications by 37% Reduces risk of heart attack by 14% UKPDS 35 BMJ 2000:321: GOOD GLYCEMIC CONTROL: A CRITICAL BUT ELUSIVE GOAL A1C Goal Achievement GOOD GLYCEMIC CONTROL: A CRITICAL BUT ELUSIVE GOAL Multiple factors continue to challenge goal achievement: 36% 64% > 7% < 7% Natural progression of beta-cell dysfunction with increasing hyperglycemia Lack of long term adherence with lifestyle issues (medical nutrition therapy & exercise) and medications Diabetes Care 2004;27: Provider beliefs 5

6 Recent Trials in Type 2 DM - ACCORD 10,251 subjects, median 8 yrs of disease, target A1C <6%, 3.4 yr trial Median A1C 6.4% (intensive) vs 7.5%(standard) 90% in intensive treatment group received rosiglitazone vs 58% of standard group 50% had documented macrovascular disease (35% prior CV event), rest had multiple CV risk factors N Engl J Med 2008;358: Recent Trials in Type 2 DM - ACCORD Only 75% on aspirin Higher incidence of hypoglycemia, heart failure, weight gain, and fluid retention in intensive group -- 28% gained more than 22 lbs N Engl J Med 2008;358: ACCORD Results Intensive Therapy (n=5,128) Standard Therapy (n=5,123) HR P value Primary Outcome 352 (6.9%) 371 (7.2%) 0.90 P=0.16 Death from any cause 257 (5.0%) 203 (4.0%) 1.22 P=0.04 CV mortality 135 (2.6%) 94 (1.8%) 1.35 P=0.02 Primary outcome - composite nonfatal MI, nonfatal stroke, or death from CV cause HR, hazard ratio N Engl J Med 2008;358: Recent Trials in Type 2 DM - ADVANCE Effects of intensive glucose control on vascular outcomes 11,140 patients, mean 8 yrs of disease Intensive (A1C 6.5%) vs standard therapy over 5 years Median A1C 6.4 vs 7.0 Gliclazide (modified release) and other meds as required N Engl J Med 2008;358: Advance Results Recent Trials in Type 2 DM - VDAT Effects of intensive glucose control on cardiovascular events in patients with long- standing type 2 diabetes mellitus 1791 veterans not at goal Intensive Standard better better N Engl J Med 2008;358: mean age = 60.4 years mean number of years since the diagnosis of diabetes = % of the patients had already had a cardiovascular event N Engl J Med 2009;360:

7 VDAT Median follow-up = 5.6 years Median HgA1C = 8.4% (standard-therapy) therapy) vs 6.9% (intensive-therapy). therapy). Major CV event = 264 (standard) vs 235 (intensive) [95% confidence interval [CI], 0.74 to 1.05; P=0.14] Hypoglycemia = 17.6% (standard) vs 24.1% intensive) N Engl J Med 2009;360: United Kingdom Prospective Diabetes Study 10 yr followup data from UKPDS 4209 newly diagnosed Type 2 received conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) No attempt to maintain assigned treatment in long term followup N Engl J Med 2008;359: United Kingdom Prospective Diabetes Study Treatment Group Sulfonylurea -insulin group Metformin group Any diabetesrelated end point 9%, P= %, P=0.01 Relative Risk Reduction Microvascular disease 24%, P=0.001 Myocardial infarction 15%, P=0.01 NR 33%, P=0.005 Death from any cause 13%, P= %, P=0.002 Bottom Line A1C goal should be adjusted based on patient characteristics/risks of hypoglycemia Aggressive goals are probably better for younger patients Once disease has been present for many years, aggressive lowering is not going to reverse macrovascular disease and may increase risk of adverse effects N Engl J Med 2008;359: Case Study - Should Bernice s A1C be lower? At 8% Risks from hypoglycemia No evidence of macrovascular disease Case 3 (Hector) A 42 year old construction worker DM, hyperlipidemia, HTN, obesity A1C = 7.5%, fasting glucose (ADA ) Recently started checking 2 hr post-prandial glucose - averaging 200 mg/dl after breakfast and dinner, lunch 180 mg/dl (ADA < 180 mg/dl) 7

8 Which of the following can be caused by postprandial hyperglycemia? Why Care about Postprandial Hyperglycemia? Microvascular disease Increased triglycerides Prothrombiotic state Coagulation Oxidative Stress CVD PPHG Hyper TG Microvascular disease Cardiovascular disease All of the above Increased Inflammatory Markers risk of death Oxidized LDL Patients With Type 2 Diabetes May Spend 12 Hours per Day in the Postprandial State Duration of Postprandial State Postprandial Postabsorptive Fasting Breakfast Lunch Dinner Midnight 4 AM Breakfast 8 AM 11 AM 2 PM 5 PM Lancet 1999;354: Times of blood sampling to obtain a diurnal blood glucose profile Eur J Clin Invest. 2000;30(suppl 2):3-11. Increasing Contribution of PPG as A1C Improves % Contribution > <7.3 A1C Range (%) FPG PPG FPG = fasting plasma glucose PPG = post prandial glucose Diabetes Care 2003;26: Importance of Postprandial Hyperglycemia IGT is a risk factor for cardiovascular disease Contributes more to A1C than FPG at A1Cs < 7.3% Can be rate limiting factor for achieving adequate glycemic control Diabetolgia 2002;45: Diabetes Care 1999;22:

9 Agents that Target Postprandial Glucose Alpha-glucosidase inhibitors Miglitol (Glyset ) Acarbose (Precose ) Meglitinides Repaglinide (Prandin ) Nateglinide (Starlix ) Rapid-acting insulin Insulin lispro (Humalog ) Insulin aspart (NovoLog ) Insulin glulisine (Apidra ) Incretin agents Exenatide (Byetta ) Pramlintide (Symlin ) DDP4 inhibitors Sitagliptin (Januvia ) Sitagliptin/Metformin (Janumet ) Case Study - Does Hector need an increase in his diabetes medications? A1C = 7.5% (AG = 168 mg/dl) 2 hr postprandial - averaging 200 mg/dl after breakfast and dinner, lunch 180 mg/dl Conclusions Important to screen likely candidates for diabetes and get them into treatment Patients need average glucose or A1C goals and need to understand the importance of reaching these goals How aggressive to be will depend on patient factors Translate A1C to average glucose Target elevated postprandial glucose 9