Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

Writing Group American Diabetes Association Richard M. Bergenstal MD Int’l Diabetes Center, Minneapolis, MN John B. Buse MD, PhD University of North Carolina, Chapel Hill, NC Anne L. Peters MD Univ. of Southern California, Los Angeles, CA Richard Wender MD Thomas Jefferson University, Philadelphia, PA Silvio E. Inzucchi MD (co-chair) Yale University, New Haven, CT European Assoc. for the Study of Diabetes Michaela Diamant MD, PhD VU University, Amsterdam, The Netherlands Ele Ferrannini MD University of Pisa, Pisa, Italy Michael Nauck MD Diabeteszentrum, Bad Lauterberg, Germany Apostolos Tsapas MD, PhD Aristotle University, Thessaloniki, Greece David R. Matthews MD, DPhil (co-chair) Oxford University, Oxford, UK

PATIENT-CENTERED APPROACH 2. BACKGROUND ADA-EASD Position Statement: Management of Hyperglycemia in T2DM: A Patient-Centered Approach PATIENT-CENTERED APPROACH 2. BACKGROUND Epidemiology and health care impact Relationship of glycemic control to outcomes Overview of the pathogenesis of Type 2 diabetes 3. ANTI-HYPERGLYCEMIC THERAPY Glycemic targets Therapeutic options - Lifestyle - Oral agents & non-insulin injectables - Insulin Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

3. ANTIHYPERGLYCEMIC THERAPY ADA-EASD Position Statement: Management of Hyperglycemia in T2DM: A Patient-Centered Approach 3. ANTIHYPERGLYCEMIC THERAPY Implementation Strategies - Initial drug therapy - Advancing to dual combination therapy - Advancing to triple combination therapy - Transitions to and titrations of insulin 4. OTHER CONSIDERATIONS Age Weight Sex/racial/ethnic/genetic differences Comorbidities (Coronary artery disease, Heart failure, Chronic kidney disease, Liver dysfunction, Hypoglycemia) 5. FUTURE DIRECTIONS / RESEARCH NEEDS Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM Patient-Centered Approach “...providing care that is respectful of and responsive to individual patient preferences, needs, and values - ensuring that patient values guide all clinical decisions.” Gauge patient’s preferred level of involvement. Explore, where possible, therapeutic choices. Utilize decision aids. Shared decision making – final decisions re: lifestyle choices ultimately lie with the patient. Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 2. BACKGROUND Epidemiology and health care impact Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

Age-adjusted Percentage of U. S Age-adjusted Percentage of U.S. Adults with Obesity or Diagnosed Diabetes Obesity (BMI ≥30 kg/m2) 1994 2000 2009 O B E S I T Y No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0% Diabetes D I A B E T E S 1994 2000 2009 Changes in obesity and diabetes rates in the United States over a 15 year period. No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0% CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics

The Diabetes Epidemic: Global Projections, 2010–2030 Figures given are: number of people with diabetes in 2011 and predicted number of people that will have diabetes in 2030 according to IDF estimates. Percentage is the increase in diabetes from 2011 to 2030. “World” box acts as the legend. The burden of diabetes is one of the greatest challenges of the 21st century, as seen in the global incidence and projections of diabetes epidemic worldwide. 366 million people have diabetes in 2011 and this is predicted to rise to 552 million by 2030. Diabetes caused at least $465 billion in healthcare expenditure in 2011 – 11% of the total expenditure, and is expected to exceed $595 billion by 2030. IDF. Diabetes Atlas 5th Ed. 2011

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 2. BACKGROUND Relationship of glycemic control to outcomes Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials Study Microvasc CVD Mortality UKPDS   DCCT / EDIC* ACCORD  ADVANCE VADT Overview of the microvascular, macrovascular and mortality outcomes from large T2DM and T1DM randomized clinical trials that focused on the relationship between glycemic control and complications. Kendall DM, Bergenstal RM. © International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024) Initial Trial Long Term Follow-up * in T1DM

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 2. BACKGROUND Overview of the pathogenesis of T2DM Insulin secretory dysfunction Insulin resistance (muscle, fat, liver) Increased endogenous glucose production Deranged adipocyte biology Decreased incretin effect Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

Main Pathophysiological Defects in T2DM ? gut carbohydrate delivery & absorption incretin effect pancreatic insulin secretion + - pancreatic glucagon secretion HYPERGLYCEMIA peripheral glucose uptake hepatic glucose production Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Glycemic targets HbA1c < 7.0% (mean PG 150-160 mg/dl [8.3-8.9 mmol/l]) Pre-prandial PG <130 mg/dl (7.2 mmol/l) Post-prandial PG <180 mg/dl (10.0 mmol/l) Individualization is key: Tighter targets (6.0 - 6.5%) - younger, healthier Looser targets (7.5 - 8.0%+) - older, comorbidities, hypoglycemia prone, etc. Avoidance of hypoglycemia PG = plasma glucose Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

Depiction of the elements of decision-making used to determine appropriate efforts to achieve glycaemic targets. Greater concerns about a particular domain are represented by increasing height of the ramp. Thus, characteristics/predicaments towards the left justify more stringent efforts to lower HbA1c, whereas those towards the right are compatible with less stringent efforts. Where possible, such decisions should be made in conjunction with the patient, reflecting his or her preferences, needs and values. This ‘scale’ is not designed to be applied rigidly but to be used as a broad construct to help guide clinical decisions. Adapted with permission from Ismail-Beigi et al [ref 20] Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596 (Adapted with permission from: Ismail-Beigi et al. Ann Intern Med 2011;154:554) Figure 1

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Lifestyle Weight optimization Healthy diet Increased activity level Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Oral agents & non-insulin injectables Metformin Sulfonylureas Thiazolidinediones DPP-4 inhibitors GLP-1 receptor agonists Meglitinides a-glucosidase inhibitors Bile acid sequestrants Dopamine-2 agonists Amylin mimetics Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

Class Mechanism Advantages Disadvantages Cost Biguanides (Metformin) Activates AMP-kinase  Hepatic glucose production Extensive experience No hypoglycemia Weight neutral ?  CVD events Gastrointestinal Lactic acidosis B-12 deficiency Contraindications Low SUs / Meglitinides Closes KATP channels  Insulin secretion  Microvascular risk Hypoglycemia Weight gain Low durability ?  Ischemic preconditioning TZDs Activates PPAR-g  Insulin sensitivity Durability  TGs,  HDL-C ?  CVD events (pio) Edema / heart failure Bone fractures ?  MI (rosi) ? Bladder ca (pio) High a-GIs Inhibits a-glucosidase Slows carbohydrate absorption Nonsystemic  Post-prandial glucose Dosing frequency Modest  A1c Mod. Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596 Table 1. Properties of anti-hyperglycemic agents

Class Mechanism Advantages Disadvantages Cost DPP-4 inhibitors Inhibits DPP-4 Increases GLP-1, GIP No hypoglycemia Well tolerated Modest  A1c ? Pancreatitis Urticaria High GLP-1 receptor agonists Activates GLP-1 receptor  Insulin,  glucagon  gastric emptying  satiety Weight loss ?  Beta cell mass ? CV protection GI Medullary ca Injectable Amylin mimetics Activates amylin receptor  glucagon  Post-prandial glucose Hypo w/ insulin Dosing frequency Bile acid sequestrants Binds bile acids  Hepatic glucose production Nonsystemic  LDL-C  TGs Dopamine-2 agonists Activates DA receptor Modulates hypothalamic control of metabolism  Insulin sensitivity ?  CVD events Dizziness/syncope Nausea Fatigue Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596 Table 1. Properties of anti-hyperglycemic agents

Class Mechanism Advantages Disadvantages Cost Insulin Activates insulin receptor  Glucose disposal  Hepatic glucose production Universally effective Unlimited efficacy  Microvascular risk Hypoglycemia Weight gain ? Mitogenicity Injectable Training requirements “Stigma” Variable Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596 Table 1. Properties of anti-hyperglycemic agents

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Insulin - Human Neutral protamine Hagedorn (NPH) - Human Regular - Basal analogues (glargine, detemir) - Rapid analogues (lispro, aspart, glulisine) - Pre-mixed varieties Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Insulin Rapid (Lispro, Aspart, Glulisine) Short (Regular) Insulin level Intermediate (NPH) Diagrammatic representation of the approximate pharmacokinetic properties of various insulin formulations. Long (Detemir) Long (Glargine) Hours 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours after injection

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Implementation strategies: Initial therapy Advancing to dual combination therapy Advancing to triple combination therapy Transitions to & titrations of insulin Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

Fig. 2. T2DM Antihyperglycemic Therapy: General Recommendations Moving from the top to the bottom of the figure, potential sequences of anti-hyperglycaemic therapy. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis (unless there are explicit contraindications). Fig. 2. T2DM Antihyperglycemic Therapy: General Recommendations Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

Fig. 2. T2DM Antihyperglycemic Therapy: General Recommendations If the A1c target is not achieved after ~3 months, consider one of the 5 treatment options combined with metformin (dual combination): a sulfonylurea, TZD, DPP-4 inhibitor, GLP-1 receptor agonist or basal insulin. Note that the order in the chart is determined by historical introduction andr oute of administration and is not meant to denote any specific preference. Choice is based on patient and drug characteristics, with the over-riding goal of improving glycemic control while minimizing side effects. Shared decision-making with the patient may help in the selection of therapeutic options. Rapid-acting secretagogues (meglitinides) may be used in place of sulfonylureas. Consider in patients with irregular meal schedules or who develop late postprandialhypoglycemia on sulfonylureas. Other drugs not shown (α-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where available in selected patients but have modest efficacy and/or limiting side effects. In patients intolerant of, or with contraindications for, metformin, select initial drug from other classes depicted, and proceed accordingly. Consider starting with 2-drug combinations in patients with very high HbA1c (e.g. ≥9%). Fig. 2. T2DM Antihyperglycemic Therapy: General Recommendations Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

Fig. 2. T2DM Antihyperglycemic Therapy: General Recommendations Further progression to 3-drug combinations are reasonable if 2-drug combinations do not achieve target. If metformin contraindicated or not tolerated, while published trials are generally lacking, it is reasonable to consider 3-drug combinations other than metformin. Insulin is likely to be more effective than most other agents as a third-line therapy, especially when HbA1c is very high (e.g. ≥9.0%). The therapeutic regimen should include some basal insulin before moving to more complex insulin strategies (see Fig. 3) Fig. 2. T2DM Antihyperglycemic Therapy: General Recommendations Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

Ultimately, more intensive insulin regimens may be required (see Figure 3.) Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a 2-drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycaemia (e.g. HbA1c ≥10.0-12.0%). Consider beginning with insulin if patient presents with severe hyperglycemia (≥300-350 mg/dl [≥16.7-19.4 mmol/l]; HbA1c ≥10.0-12.0%) with or without catabolic features (weight loss, ketosis, etc). Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

Fig. 3. Sequential Insulin Strategies in T2DM Basal insulin alone is usually the optimal initial regimen, beginning at 0.1-0.2 U/kg body weight, depending on the degree of hyperglycemia. It is usually prescribed in conjunction with 1-2 non-insulin agents. In patients willing to take >1 injection and who have higher A1c levels (≥9.0%), BID pre-mixed insulin or a more advanced basal plus mealtime insulin regimen could also be considered (curved dashed arrow lines). When basal insulin has been titrated to an acceptable FPG but A1c remains above target, consider proceeding to basal + meal-time insulin, consisting of 1-3 injections of rapid-acting analogues. A less studied alternative—progression from basal insulin to a twice daily pre-mixed insulin—could be also considered (straight dashed arrow line); if this is unsuccessful, move to basal + mealtime insulin. The figure describes the number of injections required at each stage, together with the relative complexity and flexibility. Once a strategy is initiated, titration of the insulin dose is important, with dose adjustments made based on the prevailing BG levels as reported by the patient. Non-insulin agents may be continued, although insulin secretagogues (sulfonylureas, meglitinides) are typically stopped once more complex regimens beyond basal insulin are utilized. Comprehensive education regarding self-monitoring of BG, diet, exercise, and the avoidance of, and response to, hypoglycemia are critical in any patient on insulin therapy. Fig. 3. Sequential Insulin Strategies in T2DM Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Age Weight Sex / racial / ethnic / genetic differences Comorbidities Coronary artery disease Heart Failure Chronic kidney disease Liver dysfunction Hypoglycemia Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Age: Older adults Reduced life expectancy Higher CVD burden Reduced GFR At risk for adverse events from polypharmacy More likely to be compromised from hypoglycemia Less ambitious targets HbA1c <7.5–8.0% if tighter targets not easily achieved Focus on drug safety Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Weight Majority of T2DM patients overweight / obese Intensive lifestyle program Metformin GLP-1 receptor agonists ? Bariatric surgery Consider LADA in lean patients Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

T2DM Anti-hyperglycemic Therapy: General Recommendations Overview of anti-hyperglycemic therapy in T2DM (Figure 2.) What follows are variations of this figure to help guide the clinician in choosing agents which may be most appropriate under certain situations: to avoid weight gain, to avoid hypoglycemia, and to minimize costs. T2DM Anti-hyperglycemic Therapy: General Recommendations Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

Adapted Recommendations: When Goal is to Avoid Weight Gain Fig. 2A should be considered when the goal is to avoid hypoglycemia. Note that "hidden" agents may obviously still be used when required, but additional care is needed to avoid adverse events. Here, the risk of hypoglycemia when using the hidden agents will be, in part, dependent on the baseline degree of hyperglycemia, the treatment target, and the adequacy of patient education. Adapted Recommendations: When Goal is to Avoid Weight Gain Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Sex/ethnic/racial/genetic differences Little is known MODY & other monogenic forms of diabetes Latinos: more insulin resistance East Asians: more beta cell dysfunction Gender may drive concerns about adverse effects (e.g., bone loss from TZDs) Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Metformin: CVD benefit (UKPDS) Avoid hypoglycemia ? SUs & ischemic preconditioning ? Pioglitazone &  CVD events ? Effects of incretin-based therapies Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Metformin: May use unless condition is unstable or severe Avoid TZDs ? Effects of incretin-based therapies Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Increased risk of hypoglycemia Metformin & lactic acidosis US: stop @SCr ≥ 1.5 (1.4 women) UK: half-dose @GFR < 45 & stop @GFR < 30 Caution with SUs (esp. glyburide) DPP-4-i’s – dose adjust for most Avoid exenatide if GFR < 30 Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Most drugs not tested in advanced liver disease Pioglitazone may help steatosis Insulin best option if disease severe Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Emerging concerns regarding association with increased morbidity / mortality Proper drug selection is key in the hypoglycemia prone Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

T2DM Anti-hyperglycemic Therapy: General Recommendations Overview of anti-hyperglycemic therapy in T2DM (Figure 2.) What follows are variations of this figure to help guide the clinician in choosing agents which may be most appropriate under certain situations: to avoid weight gain, to avoid hypoglycemia, and to minimize costs. T2DM Anti-hyperglycemic Therapy: General Recommendations Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

Adapted Recommendations: When Goal is to Avoid Hypoglycemia Fig. 2B should be considered when the goal is to avoid weight gain. Note that "hidden" agents may obviously still be used when required, but additional care is needed to avoid adverse events. Here, the chances of weight gain when using the hidden agents will be mitigated by more rigorous adherence to dietary recommendations and optimal dosing. Adapted Recommendations: When Goal is to Avoid Hypoglycemia Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

Adapted Recommendations: When Goal is to Minimize Costs Fig. 2C should be considered when the goal is to minimize costs. This reflects prevailing costs in the North America and Europe in early 2012; costs of certain drugs may vary considerably from country to country and as generic formulations become available.   Adapted Recommendations: When Goal is to Minimize Costs Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

Guidelines for Glucose, BP, & Lipid Control American Diabetes Assoc. Goals HbA1C < 7.0% (individualization) Preprandial glucose 70-130 mg/dL (3.9-7.2 mmol/l) Postprandial glucose < 180 mg/dL Blood pressure < 130/80 mmHg Lipids 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) > 50 mg/dL (1.30 mmol/l) TG: < 150 mg/dL (1.69 mmol/l) Avoiding ‘glucocentricity’ is key in the comprehensive management of the patient with T2DM. Cardiovascular risk factor reduction must incorporate blood pressure and lipid control, in addition to, where indicated, anti-platelet therapy. HDL = high-density lipoprotein; LDL = low-density lipoprotein; PG = plasma glucose; TG = triglycerides. ADA. Diabetes Care 2012;35:S11–S63

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. FUTURE DIRECTIONS / RESEARCH NEEDS Comparative effectiveness research Focus on important clinical outcomes Contributions of genomic research Perpetual need for clinical judgment! Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM KEY POINTS Glycemic targets & BG-lowering therapies must be individualized. Diet, exercise, & education: foundation of any T2DM therapy program Unless contraindicated, metformin = optimal 1st-line drug. After metformin, data are limited. Combination therapy with 1-2 other oral / injectable agents is reasonable; minimize side effects. Ultimately, many patients will require insulin therapy alone / in combination with other agents to maintain BG control. All treatment decisions should be made in conjunction with the patient (focus on preferences, needs & values.) Comprehensive CV risk reduction - a major focus of therapy. Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM Invited Reviewers James Best, The University of Melbourne, Australia Henk Bilo, Isala Clinics, Zwolle, Netherlands John Boltri, Wayne State University, Detroit, MI Thomas Buchanan, Univ of So California, LA, CA Paul Callaway, University of Kansas,Wichita, KS Bernard Charbonnel, University of Nantes, France Stephen Colagiuri, The University of Sydney, Australia Samuel Dagogo-Jack, Univ of Tenn, Memphis, TN Margo Farber, Detroit Medical Center, Detroit, MI Cynthia Fritschi, University of Illinois, Chicago, IL Rowan Hillson, Hillingdon Hospital, Uxbridge, U.K. Faramarz Ismail-Beigi, CWR Univ, Cleveland, OH Devan Kansagara, Oregon H&S Univ, Portland, OR Ilias Migdalis, NIMTS Hospital, Athens, Greece Donna Miller, Univ of So California, LA, CA Robert Ratner, MedStar/Georgetown Univ, DC Julio Rosenstock, Dallas Diab/Endo Ctr, Dallas, TX Guntram Schernthaner, Rudolfstiftung Hosp, Vienna, Austria Robert Sherwin, Yale University, New Haven, CT Jay Skyler, University of Miami, Miami, FL Geralyn Spollett, Yale University, New Haven, CT Ellie Strock, Int’l Diabetes Center, Minneapolis, MN Agathocles Tsatsoulis, University of Ioannina, Greece Andrew Wolf, Univ of Virginia Charlottesville, VA Bernard Zinman, University of Toronto, Ontario, Canada Professional Practice Committee, American Diabetes Association Panel for Overseeing Guidelines and Statements, European Association for the Study of Diabetes American Association of Diabetes Educators The Endocrine Society American College of Physicians