Diabetes 2013: Achieving Goals Through Comprehensive Treatment Session 2: Individualizing Therapy Joshua L. Cohen, M.D., F.A.C.P. Professor of Medicine Interim Director, Division of Endocrinology & Metabolism The George Washington University School of Medicine
Session 2 Agenda Diabetes treatment guidelines» Standardized evaluation and treatment recommendations» Establishing individualized treatment goals» Review of major classes of oral agents» Initial pharmacologic therapy and stepwise intensification Incretin-based therapy» Incretin physiology» GLP-1 analogues» DPP-4 inhibitors Intensifying insulin therapy» Implementation of basal bolus therapy» Combined insulin GLP-1 therapy
STANDARDS OF MEDICAL CARE IN DIABETES 2013 Supplement 1 January 2013
Treatment of Type 2 Diabetes: Lifestyle Intervention Diabetes education Knowledge about: disease process, potential risks, treatments, glucose monitoring, self-care Weight loss Nutrition Exercise Stop smoking
Patients on multiple-dose insulin (MDI) or insulin pump therapy should do SMBG At least prior to meals and snacks Occasionally post-prandially At bedtime Prior to exercise Recommendations: Glucose Monitoring (1) When they suspect low blood glucose After treating low blood glucose until they are normoglycemic Prior to critical tasks such as driving Diabetes Care 2013;36(suppl 1):S17.
Recommendations: Glucose Monitoring (2) When prescribed as part of a broader educational context, SMBG results may be helpful to guide treatment decisions and/or patient selfmanagement for patients using less frequent insulin injections or noninsulin therapies When prescribing SMBG, ensure that patients receive ongoing instruction and regular evaluation of SMBG technique and SMBG results, as well as their ability to use SMBG data to adjust therapy
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, adults with type 2 diabetes should be encouraged to perform resistance training at least twice per week
Blood Pressure Recommendations: Measure at each visit Dilated eye exam At diagnosis. Initially annually, then every 2-3 years after normal exam Foot exam Examination Annually Laboratory Evaluation A1C Lipids Creatinine Urine albumin Twice yearly for patients meeting treatment goals on stable therapy Yearly Yearly Yearly (spot urine albumin:creatinine ratio)
Guidelines for Blood Pressure & Lipid Control Blood pressure Lipids < 130/80 mmhg LDL: < 100 mg/dl (2.59 mmol/l) < 70 mg/dl (1.81 mmol/l) (with overt CVD) HDL: > 40 mg/dl (1.04 mmol/l) Men > 50 mg/dl (1.30 mmol/l)women TG: < 150 mg/dl (1.69 mmol/l) Statin therapy regardless of baseline lipids for patients with overt CVD or multiple risk factors ADA. Diabetes Care. 2013;36 (Suppl 1):S11-66
CHD Screening and Treatment Routine CAD screening not recommended in asymptomatic patients If CVD risk factors are treated, CAD screening does not improve outcomes Diabetes Care 2013;36(suppl 1):S17.
Recommendations: Antiplatelet Agents (1) Consider aspirin therapy (75 162 mg/day) As a primary prevention strategy in those with type 1 or type 2 diabetes at increased cardiovascular risk (10-year risk >10%) Includes most men >50 years of age or women >60 years of age who have at least one additional major risk factor Family history of CVD Hypertension Smoking Dyslipidemia Albuminuria Diabetes Care 2013;36(suppl 1):S17.
Recommendations: Antiplatelet Agents (2) Aspirin should not be recommended for CVD prevention for adults with diabetes at low CVD risk, since potential adverse effects from bleeding likely offset potential benefits 10-year CVD risk <5%: men <50 and women <60 years of age with no major additional CVD risk factors In patients in these age groups with multiple other risk factors (10-year risk 5 10%), clinical judgment is required Diabetes Care 2013;36(suppl 1):S17.
Recommendations: Immunization (1) Provide influenza vaccine annually to all diabetic patients 6 months of age Administer pneumococcal polysaccharide vaccine to all diabetic patients 2 years One-time revaccination recommended for those >64 years previously immunized at <65 years if administered >5 years ago Other indications for repeat vaccination: nephrotic syndrome, chronic renal disease, immunocompromised states Diabetes Care 2013;36(suppl 1):S17.
Recommendations: Immunization (2) Administer hepatitis B vaccination to unvaccinated adults with diabetes who are aged 19 through 59 years Consider administering hepatitis B vaccination to unvaccinated adults with diabetes who are aged 60 years
Recommendations: Glycemic Goals in Adults (1) Lowering A1C to below or around 7% has been shown to reduce microvascular complications and, if implemented soon after the diagnosis of diabetes, is associated with long-term reduction in macrovascular disease Therefore, a reasonable A1C goal for many nonpregnant adults is <7% Plasma glucose: Pre-prandial PG <130 mg/dl (7.2 mmol/l) Post-prandial PG <180 mg/dl (10.0 mmol/l) ADA. V. Diabetes Care. Diabetes Care 2013;36(suppl 1):S19.
Correlation of A1C with Average Glucose Mean plasma glucose A1C (%) mg/dl mmol/l 6 126 7.0 7 154 8.6 8 183 10.2 9 212 11.8 10 240 13.4 11 269 14.9 12 298 16.5 These estimates are based on ADAG data of ~2,700 glucose measurements over 3 months per A1C measurement in 507 adults with type 1, type 2, and no diabetes. The correlation between A1C and average glucose was 0.92. A calculator for converting A1C results into estimated average glucose (eag), in either mg/dl or mmol/l, is available at http://professional.diabetes.org/eag.
Recommendations: Glycemic Goals in Adults (2) Providers might reasonably suggest more stringent A1C goals (such as <6.5%) for selected individual patients, if this can be achieved without significant hypoglycemia or other adverse effects of treatment Appropriate patients might include those with short duration of diabetes, long life expectancy, and no significant CVD ADA. V. Diabetes Care. Diabetes Care 2013;36(suppl 1):S19.
Recommendations: Glycemic Goals in Adults (3) Less stringent A1C goals (such as <8%) may be appropriate for patients with History of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions Those with longstanding diabetes in whom the general goal is difficult to attain despite diabetes selfmanagement education, appropriate glucose monitoring, and effective doses of multiple glucose lowering agents including insulin
Cardiovascular Outcomes in Recent Prospective Trials n Known diabetes duration (y) Length of treatment intervention (y) A1c difference between groups Reduction of CV Events (CV composite) ADVANCE 11,140 8 5.0 0.7% (7.3 vs 6.5) 6% (NS) ACCORD 10,251 10 3.7 1.1% (7.5 vs 6.4) 10% (NS) Nonfatal MI: 24% (p =.004) VADT 1,791 11.5 5.6 1.5% (8.4 vs 6.9) 12% (NS) Subsequent meta-analysis of these studies and the UKPDS showed no significant effect of intensive glycemic control on overall cardiovascular events or mortality, but did show a significant 15% decrease in fatal or non-fatal MI
Glycemic Control Decision Making Target HbA1C Lower Higher Inzucchi S et al. 2012; Diabetes Care. 35:1364-1379
Selecting Anti-Hyperglycemic Medications Major Distinguishing Features Efficacy Risk of hypoglycemia Weight gain Side effects Costs Safety concerns and contraindications
Antihyperglycemic Agents: Glycosuria Major Sites of Action Kidney Plasma glucose -Glucosidase inhibitors ( ) Carbohydrate Absorption GI tract Glucose Uptake Glucose Production SGLT2 (+) inhibitor Glitazones (+) Muscle/Fat (+) ( ) Metformin ( ) GLP-1 agonist DPP-4 inhibitor Sulfonylureas Meglitinides Nateglinide Liver ( ) Insulin + Insulin Secretion Pancreas Insulin Secretion
Glucose-Lowering Therapy in Type 2 Diabetes (1) Inzucchi S et al. 2012; Diabetes Care. 35:1364-1379
Sulfonylurea Efficacy High Hypoglycemia Moderate risk Weight Gain Major side effects Hypoglycemia Costs Low Advantages Disadvantages Good initial efficacy Risk of hypoglycemia Extensive experience, widely available Weight gain Well tolerated Possible cardiovascular risk compared to metformin Inexpensive
Thiazolidinedione Pioglitazone Efficacy High Hypoglycemia Low risk Weight Gain Major side effects Fluid retention Costs High (However, soon will be generic) Advantages Disadvantages Decrease manifestations of insulin resistance Weight gain Durable activity, may diminish rate of deterioration of beta cell function Fluid retention and increased risk of CHF? Decrease in cardiovascular events Increased osteoporotic fractures in women Safety concerns
Thiazolidinediones Safety Concerns Increased risk of MI (rosiglitazone)» Initial concerns not supported by further studies Fluid retention and CHF» Not associated with increased risk of death, MI or stroke Increased risk of bone fracture in older women Possible association between pioglitazone and bladder cancer
Clinical Inertia in the Treatment of Type 2 Diabetes For patients on one oral agent with HbA1C 7% the median time until addition of another oral agent was 1.6 2.9 years For patients on two oral agents with HbA1C 7% the median time until addition of another oral agent was >6.9 years For patients on two or three oral agents with HbA1C 7.5% the median time until initiation of insulin therapy was >6 years Khunti K, et al. Diabetes Care. 2013; 36:3411-3417
Main Pathophysiological Defects in T2DM pancreatic insulin secretion incretin effect gut carbohydrate delivery & absorption pancreatic glucagon secretion HYPERGLYCEMIA hepatic glucose production peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
Incretin-Based Therapy: GLP-1 Analogs & DPP-4 Inhibitors
Oral glucose (50g) or isoglycemic infusion IV glucose Oral glucose 2.0 * 200 C-Peptide (nmol/l) Plasma Glucose (mg/dl) The Incretin Effect: Difference in Response to Oral vs IV Glucose 100 0 1.5 * * * * 1.0 * * 0.5 0.0 0 60 120 Time (min) 180 0 60 120 180 Time (min) Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.32
Glucagon-Like Peptide 1 (GLP-1) Linker region (15 17) N-terminal region Helical region (7 14) Helical region (18 29) Cleaved from proglucagon in intestinal L-cells and neurons in hindbrain/hypothalamus2 Rapid release from intestinal L cells in response to meals Potentiates insulin release Multiple biologic actions2 Rapidly degraded by protease dipeptidyl peptidase IV (DPP-4) 1. Image courtesy of Cyril Sarrauste de Menthière, PhD, Institute of Human Genetics, Montpellier, France (www.igh.cnrs.fr). 2. Vilsbøll T, Holst JJ. Diabetologia. 2004;47:357-366.
The Insulinotropic Effects of Infusion of GLP-1 and GIP in Healthy Subjects N=8, healthy males Insulin Concentration 250 Meal test Glucose clamp GLP-1 clamp Insulin, pmol/l 200 GIP clamp 150 100 50 0 Time, min 20 30 80 130 180 230 GLP-1 and GIP infusion 6mmol/L Fasting level 7mmol/L Plasma glucose levels during the 3 stepwise glucose clamps Time, min 0 60 90 120 150 210 240 Adapted from Vilsbøll T et al. Regul Pept. 2003;114:115 121. 35
Incretins Improve Multiple Aspects of Islet-Cell Function GLP-1 (produced by L cells in the small intestine) alpha cells beta cells GIP (produced by K cells in the small intestine) Stimulates glucose-dependent insulin release Suppresses glucose-dependent glucagon release Increases insulin gene transcription and insulin biosynthesis Improves beta-cell responsiveness to glucose Increases expression of glucose transporter-2 (GLUT 2) and glucokinase Decreases proinsulin to insulin ratio Promotes differentiation of duct progenitor cells to beta cells, inhibits apotosis of beta cells Stimulates glucose-dependent insulin release Drucker DJ. Molecular Endocrinology. 2003;17:161 171. Farilla L et al. Endocrinology. 2002;143;4397 4408. Holst JJ. Diabetes Metab Res Rev. 2002;18:430 441. Orskov C et al. Endocrinology. 1988;123:2009 2013 Quddusi S et al. Diabetes Care. 2003;26:791 798 Stumvoll M et al. J Clin Endocrinol Metab. 2001;86:1235 1239. 37
The Incretin Effect in Subjects Without and With Type 2 Diabetes Control Subjects (n=8) 0.6 Incretin Effect 80 60 0.4 20 0.1 0 0 0 60 120 180 Time, min 60 0.5 0.4 0.3 40 nmol/l 0.2 nmol / L 0.3 40 0.6 The incretin effect is diminished in type 2 diabetes. 0.5 IR Insulin, mu/l 80 IR Insulin, mu/l Patients With Type 2 Diabetes (n=14) 0.2 20 0.1 0 0 0 60 120 180 Time, min Oral glucose load Intravenous (IV) glucose infusion Adapted with permission from Nauck M et al. Diabetologia. 1986;29:46 52. Copyright 1986 Springer-Verlag. 39
Continuous GLP-1 Infusion in Patients with Diabetes Rachman J, et al. Diabetologia 1997; 40:205-211
GLP-1 and GIP Secretion and Mixed Inactivation meal Intestinal GLP-1 release t½ = 1 to 2 min GLP-1 (7-36) active DPP-4 DPP-4: Dipeptidyl peptidase 4 GLP-1 (9-36) inactive (>80% of pool) Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.
Incretin Pharmacotherapy GLP-1 has a very short half-life and therefore is not suitable for pharmacologic therapy Approaches to therapeutic use of incretins: GLP-1 agonists resistant to DPP-4 DPP-4 inhibition to extend the half-life of endogenous GLP-1
Effect of Exenatide on Fasting Plasma Glucose and Insulin in Type 2 Diabetes Glucose Insulin Placebo Placebo 0.05 µg/kg exenatide 0.1 µg/kg exenatide 15 Mean (SE) Serum Insulin (pmol/l) Mean (SE) Plasma Glucose (mmol/l) 0.05 µg/kg exenatide 0.2 µg/kg exenatide 12.5 10 7.5 5 0.1 µg/kg exenatide 300 0.2 µg/kg exenatide 250 200 150 100 50 0-1 0 1 2 3 4 Time (h) 5 6 7 8-1 0 1 2 3 4 5 6 7 Time (h) Kolterman OG, et al. J Clin Endocrinol Metab 2003; 88:3082-3089 8