OBJECTIVES 4/7/2014. Diabetes Update Overview of the Diabetes Epidemic in the United States. ISHP Annual Spring Meeting

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1 Diabetes Update 2014 ISHP Annual Spring Meeting Hayley Miller MD April 13, 2014 OBJECTIVES Review diabetes guidelines. Understand diabetes management targets. Discuss current therapeutic strategies. Overview of the Diabetes Epidemic in the United States 25.8 million people (8.3% of the population) have diabetes million people are undiagnosed 11.3% of adults aged 20 years have diabetes 1 ~1.9 million people aged 20 years were newly diagnosed in million or 26.9% of U.S. residents aged 65 years and older had diabetes in th leading cause of death in the U.S total estimated cost was $245 billion 2 Including $176 billion in direct medical expenditures Average medical expenditures among people with diabetes are 2.3x higher than in the absence of diabetes 2. ADA. Diabetes Care. 2013;36: CDC. National Diabetes Fact Sheet, Atlanta, GA: US Dept of Health and Human Services, Centers for Disease Control and Prevention. 1

2 Characteristics of Type 2 Diabetes T2DM is a chronic illness that results from a progressive insulin secretory defect on the background of insulin resistance 1,2 Increased risk for serious complications 1,2 CVD Retinopathy Neuropathy Nephropathy CVD = cardiovascular disease. 1. ADA. Diabetes Care. 2013;36(suppl 1):S11-S ADA. Diabetes Care. 2013;36(suppl 1):S67-S74. Criteria for the Diagnosis of Diabetes: ADA Clinical Practice Recommendations 1. A1C < 6.5%. The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay. a OR 2. FPG < 126 mg/dl. Fasting is defined as no calori intake for at least 8 hours. a OR 3. 2-hour plasma glucose ε 200 mg/dl during an OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water a OR 4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ε 200 mg/dl a. In the absence of unequivocal hyperglycemia, criteria 1-3 should be confirmed by repeat testing on a different day. ADA = American Diabetes Association; DCCT = Diabetes Control and Complications Trial; FPG = fasting plasma glucose; NGSP = National Glycohemoglobin Standardization Program; OGTT = oral glucose tolerance test; WHO = World Health Organization. ADA. Diabetes Care. 2013;36(suppl 1):S13. Main Pathophysiological Defects in T2DM GLA-4125-P Approved for Distribution Expires incretin effect gut carbohydrate delivery & absorption pancreatic glucagon secretion pancreatic insulin secretion HYPERGLYCEMIA satiety AM dopamine receptor activity? hepatic glucose production + Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine; Meece J. Curr Med Res Opin. 2007;23(4): DeFronzo RA. Diabetes Care. 2011;34(4): peripheral glucose uptake Sanofi US 2

3 Natural History of T2DM Glucose, mg/dl Relative -Cell Function, % PPG β-cell failure Fasting glucose Insulin resistance Insulin level Diabetes, y PPG = postprandial plasma glucose. Adapted with permission from Bergenstal R et al. Endocrinology. Philadelphia, PA: WB Saunders Co; 2001: Progressive β-cell Failure in T2DM β-cell Function,% β Diagnosis Years Based on data of UKPDS 16: conventional (diet) treatment group UKPDS = UK Prospective Diabetes Study. UKPDS Group. Diabetes. 1995;44: Results From the UKPDS: Correlation Between a 1.0% A1C Decrease and Reduced Risk of Complications Risk Reduction, % Microvascular Complications -37% Diabetes Related Death -21% Myocardial Infarction All-Cause Mortality -14% -14% P< for microvascular complications, diabetes-related death, myocardial infarction, and all-cause mortality UKPDS = UK Prospective Diabetes Study. Stratton IM et al. BMJ. 2000;321:

4 Management of Hyperglycemia in Type 2 Diabetes Mellitus Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) Inzucchi SE, et al. Diabetes Care 2012;35: Overview Patient-centered care o Include patients in decision making for treatment selection Targets are based on important link between glycemic control and morbidity/mortality o Intensive therapy reduces microvascular, cardiovascular, and mortality outcomes o Comprehensive CV risk reduction must be a major focus of therapy Individualize glycemic targets o Lower glucose targets for younger patients o er targets for older patients or patients with significant comorbidities to reduce hypoglycemia Glycemic Targets for T2DM 2012 ADA/EASD recommendations are less prescriptive than previous guidelines Focus on general recommendation strategies instead of algorithms Targets should be individualized Not all patients benefit from aggressive glucose management A1C < 7.0% is not ideal for all patients Less stringent target may be preferred if achievable through less complex therapy with minimal side effects utilizing the percentage of diabetic patients who are achieving an HbA1c 7.0% as a quality indicator, as promulgated by various health care organizations, is inconsistent with the emphasis on individualization of treatment goals. 4

5 Approach to Management of Hyperglycemia 15 Glycemic Targets 09 recommendations 12 recommendations More stringent Less stringent Patient characteristics Most patients Younger patients Short disease duration No significant cardiovascular disease Older patients History of severe hypoglycemia Significant comorbidity Target is difficult to achieve despite non-drug and drug intervention, including insulin A1C range <7.0% % (Preprandial If achievable < 130 mg/dl and without significant postprandial hypoglycemia < or 180 mg/dl) adverse effects %+ Nathan DM et al. Diabetes Care. 2009;32: Inzucchi SE et al. Diabetes Care 2012;35: General Recommendations for Type 2 Diabetes 17 5

6 Goals of Non-Insulin Drug Treatment Avoid acute osmotic symptoms of hyperglycemia. Avoid blood glucose instability. Prevent/delay development of diabetes complications. Maintain quality of life. GLA-3973-R DO NOT DISTRIBUTE Primary Sites of Action of Expires 7/17/14 Therapeutic Options for T2DM Liver: Glucose production Metformin TZDs Insulin Muscle and adipose tissue: Peripheral glucose uptake Metformin TZDs Insulin Pancreas: Insulin secretion Sulfonylureas Meglitinides DPP-IV Inhibitors GLP-1 Analogs Intestine: Digestion and absorption of carbohydrates α-glucosidase Inhibitors Amylin Analogs DPP-IV Inhibitors GLP-1 Analogs Fonseca V. The CADRE Handbook of Diabetes Management. 2004; Lantus [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2007; Byetta [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc.; 2007; Januvia [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2007; Symlin [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc.; Sanofi US Properties of Anti-Hyperglycemic Agents Class Mechanism Advantages Disadvantages Cost Biguanides Activates AMP-kinase Extensive experience Gastrointestinal side No hypoglycemia effects Hepatic glucose production No weight gain Likely CVD events (UKPDS) Lactic acidosis risk (rare) B-12 deficiency Contraindications Low Sulfonylureas Closes KATPchannels on ß-cell plasma membranes Insulin secretion Extensive experience Microvascular risk (UKPDS) Hypoglycemia Weight gain Low durability? Blunts ischemic preconditioning Low TZDs PPAR- activator No hypoglycemia Durability insulin sensitivity TGs (pio) HDL-C? CVD events (ProACTIVE, pio) Weight gain Edema/heart failure Bone fractures LDL-C (rosi)? MI (rosi)? Bladder ca (pio) Meglitinides (glinides) Closes KATP channels on ß-cell plasma membranes Insulin secretion Postprandial glucose excursions Dosing flexibility Hypoglycemia Weight gain?blunts ischemic preconditioning Frequent dosing schedule 6

7 Properties of Anti-Hyperglycemic Agents Class Mechanism Advantages Disadvantages Cost DPP-4 inhibitors Inhibits DPP-4 activity postprandial GLP-1, GIP concentrations Insulin secretion (glucose-dependent) Glucagon secretion (glucose-dependent) No hypoglycemia Well tolerated Generally modest A1c? Pancreatitis Urticaria/angioedema GLP-1 receptor agonists Amylin mimetics Activates GLP-1 R Insulin secretion (glucose-dependent) Glucagon secretion (glucose-dependent) Slows gastric emptying Satiety Activates amylin receptor Glucagon secretion Slows gastric emptying Satiety Weight reduction No hypoglycemia? Improved ß-cell mass/function? CV protective actions Weight reduction PPG excursions GI side effects? Acute pancreatitis C-cell hyperplasia/ medullary thyroid tumors in animals Injectable Training requirements GI side effects (N/V) Generally modest A1c Injectable Hypoglycemia w/ insulin Dosing frequency Properties of Anti-Hyperglycemic Agents Class α-gis Bile acid sequestrants Mechanism Advantages Disadvantages Cost Inhibits intestinal α glucosidase Slows intestinal carbohydrate digestion/absorption Binds bile acids in intestinal tract, increasing hepatic bile acid production? Hepatic glucose production No hypoglycemia Non-systemic Post-prandial glucose excursions? CVD events (STOP-NIDDM) No hypoglycemia LDL-C Gastrointestinal side effects (flatulence, diarrhea) Dosing frequency Generally modest A1c Constipation Generally modest A1c Triglycerides May absorption of other medications Mod Dopamine-2 agonists Activates dopaminergic No hypoglycemia receptor? CVD events Modulates hypothalamic (Cycloset Safety control of metabolism Trial) insulin sensitivity Generally modest A1c Dizziness/syncope Nausea Fatigue Rhinitis Note: α-glucosidase inhibitors, bile acid sequestrants, dopamine-2 agonists and amylin mimetics have limited use in the U.S./Europe Properties of Anti-Hyperglycemic Agents Class Mechanism Advantages Disadvantages Cost Insulin Activates insulin receptor Glucose disposal Hepatic glucose production Universally effective Theoretically unlimited efficacy Microvascular risk (UKPDS) Hypoglycemia Weight gain? Mitogenic effects Injectable Variable Training requirements Stigma (for patients) 7

8 Initial Drug Therapy Most patients A1C (e.g., 9.0%) Metformin initiated with low dose due to gastrointestinal side effects Generally require combination therapy with two noninsulin therapies or initial treatment with insulin Significant hyperglycemic symptoms or very high glucose* Insulin (mandatory if catabolic features or ketonuria are present) *Plasma glucose > mg/dl or A1C % Selecting Second Agent Consider likely occurrence of problematic adverse events when selecting individual drug Weight gain Hypoglycemia risk Gastrointestinal side effects Fluid retention Fracture risk Cost should also be considered in resource limited settings 8

9 Failure with Combination Therapy Triple combination therapy (adding a 3 rd noninsulin agent) Some studies have shown benefit from adding a third oral agent, but a more robust response is usually seen with adding insulin If using 3 noninsulin agents, select agents with complementary mechanisms Monitor closely and promptly reconsider if unsuccessful Months of uncontrolled hyperglycemia should be avoided Most patients with long-standing T2DM will eventually require insulin due to β-cell loss Insulin is preferred to triple combination therapy in patients with high hyperglycemia (e.g., 8.5%) Strategies for Combination Therapy 24 Insulin Management in T2DM Typically initiated as basal insulin Unless marked hyperglycemia or patient is symptomatic Usually intermediate- or long-acting insulin Less overnight hypoglycemia with glargine and detemir Slightly less weight gain with detemir Dosing may differ, with most comparative trials showing a higher average unit requirement with insulin detemir NPH insulin is less costly than long acting analogs Prandial short-acting insulin may need to be added for some patients 9

10 More Complex Insulin Strategies Inzucchi SE et al. Diabetes Care 2012;35: Transition to Insulin: Prandial Dosing Adding prandial dosing may be necessary when: Postprandial glucose excursions are high (e.g., > 180 mg/dl) Fasting glucose is at target but A1C remains above goal for 3 6 months with basal insulin Increasing basal insulin results in large drops in overnight or between-meal glucose Basal dose > 0.5 U/kg/d, especially as it approaches 1 U/kg/d Overall Results of Comparative Insulin Trials in Type 2 Diabetes Any insulin reduces glucose and A1C All insulin increase risk for weight gain and hypoglycemia Larger insulin doses and aggressive titration result in lower A1C, however, adverse events are more likely Insulin effects differ by formulation duration Long-acting insulin reduces overnight hypoglycemia Rapid-acting insulin reduces postprandial glucose but generally does not result in clinically significant lower A1C 10

11 Strategies for Improving Care Care should be aligned with components of the Chronic Care Model to ensure productive interactions between a prepared proactive practice team and an informed active patient. Care systems should support team-based care, community involvement, patient registries, and embedded decision support tools to meet patient needs. Treatment decisions should be timely and based on evidence-based guidelines that are tailored to individual patient preferences, prognoses, and comorbidities. A patient centered communication style should be employed that incorporates patient preferences, assesses literacy and numeracy, and addresses cultural barriers to care. ADA. Diabetes Care. 2013;36(suppl 1):S11-S66. Overall Conclusions Lifestyle intervention and metformin are recommended as initial therapy for most patients with T2DM. When lifestyle intervention and metformin are not sufficient to achieve and sustain glycemic goals, option include combination non-insulin therapy or basal insulin. Most patients ultimately require insulin because of the progressive nature of T2DM. The ADA offers Clinical Practice Recommendations and Standards of Medical Care in Diabetes for various aspects of treatment that are updated every January in Diabetes Care /Supplement 1 Overall Conclusions The increasing incidence and prevalence of T2DM in the United States represents a growing burden. Intensive glycemic control may help reduce the risk of microvascular complications in patients with T2DM. The ADA/EASD has developed a position statement to guide health care providers in choosing the most appropriate patient-centered therapies for T2DM. ADA = American Diabetes Association; EASD = European Association for the Study of Diabetes. 11

12 Thank you! 12