Raja Hanania, R.Ph, CDM, CDE, BCPS Update on Diabetes Medications and Guidelines in Cardiopulmonary Rehab Setting Raja Hanania, R.Ph, CDM, CDE, BCPS Clinical Pharmacy Specialist Critical Care/Diabetes Care IU-Health- Bloomington Hospital Bloomington-Indiana

Objectives Learn about the impact of diabetes in the United States Review oral and injectable diabetes medications and their role in diabetes management Review the 2013 ADA general recommendations with special emphasis on physical activity and exercise in the cardiopulmonary rehab setting

National Diabetes Estimates 25.8 million Americans (8.3% of the US population) 7 million undiagnosed 79 million American adults aged 20 years or older qualify as being at high risk to develop diabetes (fasting glucose between 100 and 125) If the trend continues, 1-in-3 American adults will have diabetes by 2050 The 7th leading cause of death in the US The leading cause of blindness, renal failure and nontraumatic amputations between the age of 20-74 Cost: U.S. national economic burden of pre-diabetes and diabetes reached $245 billion in 2012, $218 billion in 2007 , $132 billion in 2002 vs. $44 billion in 1997 CDC National Diabetes Fact Sheet 2011. ADA diabetes Statistics 2013

Making the Diagnosis Fasting Plasma Glucose Test 99 or below = Normal 100 to 125 = Pre-diabetes (impaired fasting glucose (IFG)) ≥ 126 = Diabetes Oral Glucose Tolerance Test (OGTT) 2 hr plasma glucose result: 139 and below =Normal 140-199 = Pre-diabetes (impaired glucose tolerance (IGT)) 200 and above = Diabetes Random Plasma Glucose Test 200 or more plus presence of symptoms (polydypsia/polyuria/polyphagia) = Diabetes Results should be confirmed by repeating the test on another day prior to diagnosis A1c ≥ 6.5% (new 2010 criteria for diagnosis)

Classification of Diabetes Insulin-Dependent Diabetes Mellitus (Type I) High anti-beta cell antibodies Low plasma insulin concentration (determined by C-peptide levels) Usually lean and young patients but this trend in changing Non-Insulin-Dependent Diabetes Mellitus (Type II) Serum insulin levels normal or elevated but still have relative insulin deficiency Metabolism does not respond properly to insulin= insulin resistance Usually obese (60-90%) and older but thins trend is changing Losing weight frequently brings glucose levels and insulin sensitivity back under control Strong genetic linkage

Classification of Diabetes (Cont.) Type 1.5 Diabetes (also known as slow onset type I or latent autoimmune diabetes in adults) Patients do not immediately require insulin for treatment Little or no resistance to insulin Antibodies present (especially GAD65) Can be easily misdiagnosed as Type II since patients are older and respond to oral medications except glitazones (since little or no insulin resistance) & usually have good C-peptide levels Gestational Diabetes (GD) In most cases, slender and physically fit patients Approximately 4% of all pregnancies according to ADA 5-10% of women with GD are found to have type 2 diabetes Women with GD have 20-50% chance to develop diabetes in the next 5-10 years

Type 3 Diabetes?? Alzheimer’s can be associated with low levels of insulin in the brain is the reason why increasing numbers of researchers have taken to calling it Type 3 diabetes, or "Diabetes of the Brain“ In Alzheimer’s, the brain, especially parts that deal with memory and personality, become resistant to insulin.  Research is ongoing and there will be more to come on the link between diabetes and the brain.

Risk Factors Family History Obesity: 20% over IBW or BMI > 27 Age: over 45 years old History of impaired glucose tolerance or impaired fasting glucose Hypertension HDL < 35 and/or TG > 200 Smoking Race/Ethnicity Pregnancy

Clinical Practice Recommendations ADA Begin screening at age 45 Preprandial BG 70-130 2 hr postprandial <180 Average bedtime BG 100-140 A1c goal <7% for patients in general, EAG= (28.7x A1c) - 46.7 (6%= 126 mg/dl, 7%= 154, 8%= 183, 9%= 212, etc.) AACE Begin screening at age 30 Preprandial BG 110 2 hr postprandial <140 A1c goal <6.5% ADA= American Diabetes Association AACE= American Association of Clinical Endocrinologists

Benefits of Reducing A1c by 1% Type I diabetes (DCCT) -32% decrease in risk for retinopathy -20% -27% decrease in risk for nephropathy -30% decrease in risk for neuropathy Type II diabetes (UKPDS) -10% decrease in risk in diabetes related death - 6% decrease in all-cause mortality -16% decrease in risk for MI -25% decrease in microvascular complications DCCT= Diabetes Control and Complications Trial UKPDS= United Kingdom Prospective Diabetes Study

A1C Goals Unmet in Majority of Patients With Diabetes 20.2% have A1C >9%3 12.4% have A1C >10%1 10.0 9.5 9.0 A1C (%) 8.5 37.2% have A1C >8% 8.0 7.5 64.2% of patients with type 2 diabetes have A1C 7%2 7.0 6.5 ACE recommended target (<6.5%)4 6.0 Upper limit of normal range (6%) 5.5 1. Data from Saydah SH, et al. JAMA. 2004; 291:335-342 2. Calculated from Koro CE, et al. Diabetes Care. 2004; 27:17-20 3. Data from ADA. Diabetes Care. 2003; 26(suppl 1):S33-S50 4. Data from ACE. Endocrine Practice. 2002

Diabetes Management Control of A1c, fasting glucose(FG) and postprandial glucose levels (PPG) (DECODE study showed that PPG is more predictive than AIC and FG for CV risk*) Hypertension-goal is <140/80 mmHg Dyslipidemia (General Guidelines): *LDL<100 mg/dl *HDL men >40 mg/dl, women >50 mg/dl *Triglycerides<150 mg/dl *Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE)

Review of Oral Hypoglycemic Meds Sulfonylureas Meglitinides Thiazolidinediones Biguanides Alpha-Glucosidase Inhibitors Dipeptidyl Peptidase IV inhibitors (DPP 4 inhibitors) Sodium Glucose Co-transporter 2 Inhibitor (SGLT-2 inhibitor) Combination Products Others: Welchol and Cycloset

Sulfonylureas Stimulate insulin production from pancreas Glyburide (Diabeta®, Micronase®, Glynase®), max. dose 20 mg/day Glipizide (Glucotrol®)-taken 30 min before eating, max. dose 40 mg/day, (Glucotrol XL®)-may be taken with food, max. dose 20 mg/day Glimipiride (Amaryl)-taken with food, max dose 8 mg/day Watch for renal dysfunction: -Glyburide not recommended for CrCl<50 ml/min, contraindicated for patients with severe renal failure -Glimipiride < 30ml/min, start with 1 mg daily and adjust -Glipizide < 10ml/min use a conservative dose & adjust Side effects-hypoglycemia, GI effects and sun sensitivity

Meglitinides Stimulate insulin production from pancreas Repaglinide (Prandin®)-Max. dose 4 mg tid-qid Nateglinide (Starlix®)-Max. dose 120 mg tid To be taken 15-30 min before meals Skip doses for skipped meals Side effects: hypoglycemia and GI effects

Thiazolidinediones (TZDs) Decrease insulin resistance, promote skeletal muscle glucose uptake Rosiglitazone (Avandia®)-taken with meals once or twice daily. Max. dose 8 mg/day Pioglitazone (Actos®)-taken once daily. Max. dose 45 mg/day Monitor LFTs every 2 months for the first year of therapy then periodically. Not recommended if LFTs >2.5 times upper limit or for NYHA class III or IV CHF patients Side effects: Edema (secondary to plasma volume expansion), GI effects, weight gain and back pain

Biguanides Decrease production of glucose in the liver, decrease glucose absorption & improve insulin sensitivity Metformin (Glucophage®, Glucophage XR®, Fortamet®, Riomet® (liquid metformin))- Max dose 2550 mg/day Used first line for obese diabetics May also be used for polycystic ovary syndrome (PCOS) (Not FDA approved for that indication) Should be taken with food Contraindicated in symptomatic CHF patients and renal patients (SCr >1.5 men, SCr>1.4 women) Must be discontinued for 48 hrs after any IV dye procedure due to risk of lactic acidosis Side effects: Nausea, diarrhea and gas that tend to improve with continued use

Alpha-Glucosidase Inhibitors Slow the digestion and absorption of carbohydrates Acarbose (Precose®), Miglitol (Glyset®) Good for lowering post-prandial glucose Contraindicated in patients with cirrhosis ,colon ulcerations, DKA, inflammatory bowel disease and patients with bowel obstruction Usual dose 25,50 or 100 mg tid To be taken with first bite of meal Side effects: gas, diarrhea and abdominal pain (tend to improve with continued use)

DPP- IV inhibitors : Januvia (sitagliptin), Onglyza (saxagliptin), Tradjenta (linagliptin) A relatively new class of oral antidiabetic drugs known as dipeptidyl peptidase-IV (DPP-IV) inhibitors The DPP-IV enzyme normally rapidly inactivates the gut hormone (GLP-1) so that additional insulin secretion is not prolonged more than necessary. Slow the inactivation of that gut hormone, therefore increase insulin release and decrease glucose release by the liver-prolong homeostasis May be taken with or without food Low sugar reactions are rare since they work in a glucose dependent fashion

Invokana® (canagliflozin) Drug Class: Sodium Glucose Cotransporter 2 Inhibitor (SGLT-2 inhibitor) Works by blocking the body’s reuptake of filtered glucose in the kidneys leading to an increased amount of urinary excretion of glucose A typical starting dose of canagliflozin is 100mg orally once a day taken before the first meal

More on Canagliflozin… Doses can be increased to a maximum daily dose of 300mg/day Most common side effects: increased urination, and increased urinary tract infections/genital yeast infections in females May cause increased thirst, constipation and nausea Report symptoms of low blood pressure to Physician

Bile Acid Sequestrants: Welchol® (colesevelam) Decreases blood sugar in Type II diabetics by an unknown mechanism. Originally used for high LDL cholesterol Main side effect is constipation. May cause increased triglycerides May interfere with absorption of other medications and must be separated from them by at least 1 hour

Cycloset® (Bromocriptine) The first drug for type 2 diabetics that targets the body’s dopamine activity Mechanism of Action: Generally unknown , but preclinical studies have shown brain dopamine activity to be low in metabolic disease states which may contribute to insulin resistance Indication: Treatment of type 2 diabetes most likely in combination with all other existing agent Dosage : Initial dose 0.8 mg (one tablet) taken within 2 hours of waking with food. Dose titration weekly by 0.8 mg until clinical effectiveness or a maximum dose of 4.8 mg is reached Contraindications: Patients with syncopal migraines, pregnant and nursing women, use with other dopamine receptor agonists and pediatric patients

Bile Acid Sequestrants: Welchol® (colesevelam) Decreases blood sugar in Type II diabetics by an unknown mechanism. Originally used for high LDL cholesterol Main side effect is constipation. May cause increased triglycerides May interfere with absorption of other medications and must be separated from them by at least 1 hour

Combination Products Glucovance® = Glyburide + Metformin Metaglip® = Metformin+ Glucotrol Avandamet® = Avandia + Metformin Actoplus Met® = Actos + Metformin Avandaryl® = Avandia+ Amaryl Duetact® = Actos + Amaryl Janumet® = Januvia+ Metformin Prandimet ® = Prandin + Metformin Kombiglyze ® = Onglyza + Metformin Juvisync ® = Januvia + Zocor

Symlin® (Pramlintide) Symlin (pramlintide) is an injectable synthetic analog of human amylin, a hormone that is not present in diabetics. It slows gastric emptying, lessens after meals glucagon secretion and suppress appetite May be given as a subcutaneous injection in Type I and Type II diabetics as an add on therapy to meal time insulin May cause Nausea/vomiting and add to risk of hypoglycemia especially in type I diabetics

GLP-1 agonists: Byetta® (exenatide) , Victoza® (liraglutide) and Bydureon® (exenatide LA) Stimulate insulin secretion in a glucose-dependent fashion Slows the movement of food in the stomach (gastric emptying). Slows sugar (glucagon hormone) secretion during hyperglycemia May have some potential in stimulating regeneration of the cells that make insulin (beta cells)

Over The counter Medications of Concern with Diabetes Vitamins & Minerals Calcium 1000 - 1500 mg + Vitamin D daily Approximately 3 glasses of milk Multivitamin or additional supplements as needed to balance diet Decongestants (pseudoephedrine) - prolonged use can increase blood pressure and decrease circulation Watch for sugar and alcohol content (especially in cough syrups) Many products are available sugar free and alcohol free- Diabetic Tussin & Codimal DM

Herbals and Nutraceuticals Consult doctor prior to use Check glucose before and after you take, routinely for first few weeks, then periodically Use caution with all herbals, especially: Ginseng Ma Huang or Ephedra Glucosamine Ginger Nettle Garlic

Cholesterol Medications Total cholesterol goal is < 200, LDL<100, HDL for men>45, for women>55 and triglycerides <150 Have been shown to cut down on the incidence of heart attacks and strokes in diabetics May delay the initiation of insulin in Type II diabetics Take at bedtime and avoid grapefruit and grapefruit Juice Monitor liver function tests Side effects to tell the doctor about include: muscle weakness, skin rash, nausea, vomiting, diarrhea and loss of appetite

Cholesterol Medications (Cont.) Statins (Crestor, Zocor, Lipitor, etc.): raise HDL; lower LDL Niacin: lowers LDL: increases HDL Bile Acid Resins (Questran, Welchol): lower LDL Fibrates (Lopid, Tricor): lower triglycerides; increase HDL Ezetimibe (Zetia): lowers LDL

Blood Pressure Medications Blood pressure goal is 140/80 for diabetics (New 2013 goal ! (lower for some) Blood pressure control has shown to decrease cardiovascular disease, stroke, and kidney damage in diabetics Lifestyle changes may be adequate for some Some diabetics are started on blood pressure medications called ACE Inhibitors or Angiotensin Receptor Blockers which offer kidney protection as well There are many different classes of blood pressures medications for your doctor to choose from

2012 ADA/EASD Guidelines for T2DM Management Algorithm

AACE/ACE Consensus Statement Endocrine Practice 2009; 15 (No. 6)

What to do when OADs fail to maintain control in Type 2 diabetes Reemphasize that diet and exercise can produce at most a 1% reduction from baseline; maximum effect is at 3 months If on 2 first-line oral therapies, a third oral agent will result in a further reduction of A1c levels of only 1% or less Do not add a third oral agent if A1c> 9 % since most patients will not reach target level. It is time to consider insulin!

Basal insulin : what you need when not eating(between meals) Insulin Fundamentals Think about insulin therapy as having three components: Basal insulin : what you need when not eating(between meals) Prandial insulin: to cover food Correction insulin: to fix abnormal glucose levels

Characteristics of Insulin Rapid acting Insulin such as Novolog, Humalog or Apidra Onset: 10-15 min Peak: 30-90 min Duration: 6-8 hrs Fast acting Insulin such as Novolin R or Humulin R Onset : 30 min Peak : 2-4 hrs Duration 8-12 hrs Intermediate Acting Insulin such as Novolin N or Humulin N Onset :1-2 hrs Peak: 4-12 hrs Duration 18-24 hrs Basal (long acting Insulin) such as Lantus or Levemir Onset: 1-2 hrs No Peak Duration: Up to 24 hrs Mixed Insulin such as Humulin or Novolin 70/30, Novolog Mix 70/30, Humalog 75/25, Humalog 50/50

Treatment of Hypoglycemia Things to inform patients: What is an insulin reaction (hypoglycemia) and how is it treated?? Blood glucose becomes too low (below 70 mg/dl for most people) Signs - cold sweat, dizziness, fatigue, nausea, hunger, vision changes, rapid heart rate Treatments - glucose tablets (3-4), glass of milk, juice (1/2 cup), soft drink (1/2 can) Test your glucose again after 15 minutes, and repeat treatment if still below 70 mg/dl Notify your physician!!

Recommendations: Medical Nutrition Therapy (MNT) Individuals who have prediabetes or diabetes should receive individualized MNT as needed to achieve treatment goals, preferably provided by a registered dietitian familiar with the components of diabetes MNT In general, Carbs 45-65%of total daily calories Fats 25-35% of total daily calories (<7% saturated) Protein 12-20 % (kidney disease <10%) Lose weight if body mass index (BMI)>25 The general recommendations for medical nutrition therapy (MNT)1 are included on this slide Individuals who have prediabetes or diabetes should receive individualized MNT as needed to achieve treatment goals, preferably provided by a registered dietitian familiar with the components of diabetes MNT (A) Because it can result in cost savings and improved outcomes (B), MNT should be covered by insurance and other payers (E) Although numerous studies have attempted to identify the optimal mix of macronutrients for meal plans of people with diabetes, it is unlikely that one such combination of macronutrients exists; the best mix of carbohydrates, protein, and fat appears to vary depending on individual circumstances MNT is an integral component of diabetes prevention, management, and self-management education In addition to its role in preventing and controlling diabetes, ADA recognizes the importance of nutrition as an essential component of an overall healthy lifestyle A full review of the evidence regarding nutrition in preventing and controlling diabetes and its complications and additional nutrition related recommendations can be found in the ADA position statement “Nutrition Recommendations and Interventions for Diabetes,” published in 2007 and updated in 20082 ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S21.

ADA Recommendations: Physical Activity Advise people with diabetes to perform at least 150 min/week of moderate-intensity aerobic physical activity (50–70% of maximum heart rate), spread over at least 3 days per week with no more than 2 consecutive days without exercise In absence of contraindications, people with type 2 diabetes should be encouraged to perform resistance training at least twice per week Exercise is an important part of the diabetes management plan Regular exercise has been shown to improve blood glucose control, reduce cardiovascular risk factors, contribute to weight loss, and improve well being1 Regular exercise may also prevent type 2 diabetes in high-risk individuals2-4 A joint position statement by ADA and the American College of Sports Medicine summarizes the evidence for the benefits of exercise in people with type 2 diabetes5 Recommendations for physical activity for people with diabetes1 are summarized on this slide People with diabetes should be advised to perform at least 150 minutes per week of moderate-intensity aerobic physical activity (50-70% of maximum heart rate) (A) In the absence of contraindications, people with type 2 diabetes should be encouraged to perform resistance training three times per week (A) ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S25.

Why Exercise? Benefits Counteracts osteoporosis Counteracts obesity ↑ maximal O2 uptake Benefits ↑ cardiac output ↓ resting heart rate Counteracts osteoporosis ↓ blood pressure Counteracts obesity ↑ metabolism ↑ muscle mass Improved structure & function of ligaments, tendons & joints ↑ capillary density of muscle ↑ mitochondrial density of muscle ↑ HDL cholesterol ↑ muscle strength Improved blood glucose control ↑ endorphins ↑ self esteem Improve endurance ↓ shortness of Breath ↓ risk of heart disease & stroke ↑ insulin sensitivity ↑ glucose uptake

Challenges!! HEALTH CARE LOGIC!!

Process and Assessment Cardiac Rehab Diabetes Self Management Education (DSME) Patient enters certified facility via physician referral Patient enters certified facility via provider referral Graded Exercise Test (optional) Assessment: Cardiovascular anatomy, physiology, physiology Family history - diabetes, complications Physical examination Duration of diabetes, current complications (short & long term) Risk factor profile / risk reduction options Current knowledge, skills, understanding, beliefs of diabetes Learning preferences, barriers, individual goals

Interventions Cardiac Rehab DSME AADE 7 self care behaviors • Monitored exercise training/ DSME physical activity AADE 7 self care behaviors • Self management skills: Blood pressure Eating Healthy Lipids Being Active Tobacco cessation Taking medications Weight control Monitoring Diabetes Problem solving Psychological – social issues Reducing risks • Counseling: Health Coping Psychosocial Nutrition

Diabetes Complications…. and Cardiac Rehab People with DM are 2-4 times more likely to have CV disease, hypertension and dyslipidemia People with DM are susceptible to autonomic neuropathy so may be less likely to have symptoms during exercise (such as angina to reflect myocardial ischemia) People with DM may have developed long-term complications that may make rehab more challenging such as peripheral vascular disease and significant claudication

Glucose Monitoring in Cardiac Rehab • No evidence-based guideline on a specific number of times blood glucose should be measured in the CPR setting • Glucose monitoring establishes patterns for glucose response and potentially prevent hypoglycemia • Glucose monitoring determines how often a individual should tests BG based on his/her medications, co-morbid conditions, medical history, meal plan, time of exercise, and history of hyperglycemia and hypoglycemia • Glucose monitoring assess patient’s knowledge and ability to perform accurate blood glucose checks

Pre Exercise Hypoglycemia Care Journal of Cardiopulmonary Rehabilitation and Prevention 2011;32:101-112

Post Exercise Hypoglycemia Care Journal of Cardiopulmonary Rehabilitation and Prevention 2011;32:101-112

Pre Exercise Hyperglycemia for Patients with Type 1 Diabetes Journal of Cardiopulmonary Rehabilitation and Prevention 2011;32:101-112

Pre Exercise Hyperglycemia for Patients with Type 2 Diabetes Journal of Cardiopulmonary Rehabilitation and Prevention 2011;32:101-112

Post Exercise Hyperglycemia Care Journal of Cardiopulmonary Rehabilitation and Prevention 2011;32:101-112

In Summary… Regular exercise helps maintain appropriate BG levels and is a primary indication in the management of DM The cardiopulmonary rehab setting represents an excellent opportunity for health care providers to monitor and manage DM Aerobic and strength training exercise may trigger hypoglycemia in people with DM Collaboration between health care providers is key for success!!

QUESTIONS??? Rhanania1@iuhealth.org THANK YOU! QUESTIONS??? Rhanania1@iuhealth.org