Practical Considerations in Clinical Management

Guideline-recommended glycemic targets in diabetes A1C (%) FPG (mg/dL) Postprandial glucose (mg/dL) ADA< <180* ACE≤6.5<110<140 † *Plasma; † Blood ADA = American Diabetes Association ACE = American College of Endocrinology ADA. Diabetes Care. 2007;30(suppl 1):S4-41. ACE. Endocr Pract. 2002;8(suppl 1):5-11.

Glucose dynamics: Basal and prandial Riddle MC. Am J Med. 2004;116(suppl):3S-9. Plasma glucose (mg/dL) Time of day Type 2 diabetes 2400 Normal Basal hyperglycemia Postprandial hyperglycemia

Relative contributions of postprandial glucose and FPG to A1C Fasting plasma glucose Postprandial plasma glucose Monnier L et al. Diabetes Care. 2003;26: A1C quintiles (%) 0 > – –9.27.3–8.4<7.3 Contribution (%)

Glycemic control deteriorates with standard therapies Cook MN et al. Diabetes Care. 2005;28: N = 2220 with T2DM treated with SU + MET ≥ ~85% of patients had A1C ≥8% after 4 years Patients with A1C ≥8% (%) SU = sulfonylurea, MET = metformin Pre-SU A1C levels (%) Time from sulfonylurea initiation (years)

A1C reduction with glucose-lowering medications Nathan DM. N Engl J Med. 2007;356: Oral agents  A1C (%)* Sulfonylureas1.5 Biguanides (metformin)1.5 Glinides1.0–1.5 Thiazolidinediones0.8–1.0 DPP-IV inhibitors0.5–0.9 α-Glucosidase inhibitors0.5–0.8 Parenteral/inhaled agents Insulin≥2.5 Inhaled insulin1.5 GLP analogues0.6 Amylin analogues0.6 *Monotherapy DPP = dipeptidyl peptidase; GLP = glucagon-like peptide

Oral diabetes agents Drug classAgent(s)Mechanism(s) of action α-Glucosidase inhibitors Acarbose, miglitolDelay carbohydrate absorption BiguanidesMetformin  Hepatic glucose production  Insulin sensitivity in liver + muscle SulfonylureasGlimepiride, glipizide, glyburide  Insulin secretion from pancreatic  cells MeglitinidesNateglinide, repaglinide  Insulin secretion from pancreatic  cells ThiazolidinedionesPioglitazone, rosiglitazone  Insulin sensitivity in fat cells + muscle DPP-IV inhibitorsSitagliptin, vildagliptin (Phase III)  GLP-1 degradation;  Glucose- dependent insulin secretion Trujillo J. Formulary Luna B, Feinglos MN. Am Fam Physician Smyth S, Heron A. Nat Med

Incretin agents in glucose control DPP-IV inhibitorsIncretin mimetics Significant  A1C Weight neutral Oral administration Almost no GI side effects Very low rate of hypoglycemia Multiple targets (GLP-1 and GIP) Significant  A1C Weight loss Injection Higher rate of GI side effects Low rate of hypoglycemia Single target (GLP-1) Trujillo J. Formulary. 2006;41: GIP = gastric inhibitory peptide

ADA: Managing hyperglycemia in T2DM Adapted from ADA. Diabetes Care. 2007;30(Suppl 1):S4-41. Lifestyle intervention + metformin If A1C > goal Add sulfonylurea (least expensive) Add basal insulin (most effective) Add glitazone (no hypoglycemia) Add basal or intensify insulin Intensive insulin + metformin +/- glitazone If A1C > goal Intensify insulinAdd glitazoneAdd basal insulinAdd sulfonylurea If A1C > goal ADA goal: A1C <7%

ACE road map to glycemic goals in T2DM: Treated patients Maximize OAD combinations Maximize insulin therapy A1C (%) Mono- or combination therapy Current therapyIntervention Monitor every 2–3 months Adjust treatment to meet ACE glycemic goals Monotherapy Combination therapy ACE/AACE. Initiate insulin therapy (basal-bolus) Initiate combination therapy* Continue therapy or adjust as needed to meet ACE glycemic targets *Add rapid-acting insulin analogs at any time to address persistent postprandial hyperglycemia Continue lifestyle modification 6.0– –8.5 >8.5

Treat-to-Target study: Basal insulin lowers FPG and A1C Riddle MC et al. Diabetes Care. 2003;26:3080−6. N = 756 previously treated with 1–2 OADs; Mean A1C 8.6% ~60% reached A1C ≤7% FPG, mean (mg/dL) NPHInsulin glargine A1C, mean (%) Weeks of treatment NPH = neutral protamine Hagedorn insulin

Treat-to-Target: Nocturnal hypoglycemia vs glycemic control Riddle MC et al. Diabetes Care. 2003;26:3080―6. Insulin glargine (n = 367) NPH (n = 389)P A1C ≤7% (%)5857 Without nocturnal hypoglycemia (%)3327<0.05 FPG ≤100 mg/dL (%)3634 Without nocturnal hypoglycemia (%)2216<0.03 Dose, mean (units/day) <0.005

Fewer hypoglycemic episodes with insulin analogue N = 371 with poorly controlled T2DM on SU + MET Janka HU et al. Diabetes Care. 2005;28: Insulin glargine + OADPremixed insulin* Hypoglycemic events, mean (per patient-years) P < P = P = *30% regular/70% NPH insulin

Insulin glargine + OAD effect on weight, A1C N = 12,216 with poorly controlled T2DM on OAD; 9-month outcomes Schrieber SA, Haak T. Diabetes Obes Metab. 2007;9:31-8. <2525 to <3030 to <35≥35 BMI subgroup analysis  BMI (kg/m 2 ) BMI (kg/m 2 )  A1C (%) All -1.6  = change from baseline at 9 months

Glycemic control and weight change with detemir vs NPH insulin Hermansen K et al. Diabetes Care. 2006;29: N = 475 with poorly controlled T2DM on OAD; add-on detemir or NPH >70% achieved A1C ≤7%Mean weight gain (lbs) Detemir: 2.6; NPH: 6.2 (P < 0.001) A1C (%) Study week Body weight (lbs) Study week NPHDetemir

Add-on treatment with glargine vs rosiglitazone + SU/MET: A1C and FPG N = 217 with T2DM Rosenstock J et al. Diabetes Care. 2006;29: *P < 0.05, † P = between groups A1C,  from baseline (%) FPG, mean (mg/dL) Time (weeks) RosiglitazoneInsulin glargine † † † † * * * *

Glargine vs rosiglitazone added to SU + MET: Lipid effects Rosenstock J et al. Diabetes Care. 2006;29: Change from baseline (%) Total-CLDL-CTG HDL-C * *P = , † P = , ‡ P = 0.001, § P = 0.04 between groups † ‡ § Insulin glargineRosiglitazone N = 217 with T2DM

Add-on Rx with glargine vs rosiglitazone + SU/MET: Comparative adverse effects Insulin glargine (n = 105) Rosiglitazone (n = 112)P Nocturnal hypoglycemia* (%) Weight gain (lb) Peripheral edema (%) Adverse events (%) < Rosenstock J et al. Diabetes Care. 2006;29: *Plasma glucose <70 mg/dL N = 217 with T2DM

Basal and bolus insulin pharmacodynamics FormulationCoverageDuration (hr)Dosing GlargineBasal24Once daily DetemirBasal14Once or twice daily NPHBasal13Twice daily LisproPrandial3–4≤15 min premeal to immediately postmeal AspartPrandial3–4≤15 min premeal to immediately postmeal GlulisinePrandial3–4≤15 min premeal to ≤20 min postmeal RHIPrandial6–830 min premeal Flood TM. J Fam Practice. 2007;56(suppl):S1-12. RHI = regular human insulin Basal Bolus

Dispelling misconceptions about insulin Traditional thinking Atherogenic Fear of hypoglycemia Fear of weight gain Frequent injections Newer concepts Anti-atherogenic Less nocturnal hypoglycemia with steady-state once-daily basal insulins Weight neutral Long-acting basal insulins require fewer injections Dandona P et al. Am J Cardiol. 2007;99(suppl):15B-26. Stotland NL. Insulin. 2006;1:38-45.

IIIaIIbIII B B C Aggressively modify other CV risk factors (physical activity, weight, BP, cholesterol) Coordinate care with endocrinologist or PCP ACC/AHA secondary prevention guidelines: Diabetes management Smith SC et al. Circulation. 2006;113: Initiate lifestyle and pharmacotherapy to achieve A1C <7% Class and level of evidence

Discharge strategies for patients with hyperglycemia ACE/ADA. Diabetes Care. 2006;29: Lifestyle modification (nutrition and exercise) Insulin vs OAD for long-term management Patient education eg, self-monitoring of glucose Continuity of care PCP ± Endocrinologist

Managing glucose in T2DM Diabetes is a progressive disease Most patients will require multiple therapies to achieve A1C goals Utilize lifestyle intervention and metformin as initial treatment Add medications rapidly and transition to new agents when A1C target is not achieved/sustained Add insulin early in patients who do not meet A1C targets Nathan DM et al. Diabetologia. 2006;49:

Continuity of care for diabetes: It takes a health care team ADA. Patient Physician Dietician Podiatrist Social worker or psychologist Exercise physiologist Eye doctor Diabetes educator