Management of new type II diabetes diagnosis

Management of new type II diabetes diagnosis

Case 31yr old healthy black man who presents to clinic with polyuria and polydipsia, small amount of weight loss. Family history: DM in grandmothers Social history: loves fried chicken, macaroni and cheese, and sweet tea. Works in the receiving dock at UNC. PE: BMI: 31, BP: 142/82, P: 102, FSBG: 437 Obese black man, otherwise normal exam.

Case Labs: Chem profile normal except glucose 430. Hgb A1C: 16.2 Plan Diet modification! Oral therapy vs insulin? How many agents?

Overview Oral diabetes medications Injectible diabetes medications Average Hgb A1C reduction with monotherapy Study discussion: rosiglitazone o vs glyburide vs metformin monotherapy. New diabetes diagnosis algorithms

Diabetes medications Class Drug name Effects Side effects Contraindications Biguanides Metformin (glucophage) Decreased hepatic glucose output GI nausea, diarrhea Renal failure, CHF, hypoxia, sepsis, acidosis, IV contrast Sulfonylureas Glyburide (diabeta, micronase, glynase), glipizide (glucotrol/xl), glimepiride (amaryl), y), chlorpropamide (diabenese) Insulin secretagogue Weight gain and hypoglycemia (chlorpropamide worse than others) Coronary artery disease. Meglitinides Nateglinide (starlix), repaglinide (prandin) Insulin secretagogue Hypoglycemia Nateglinide can not be used with renal failure.

Diabetes Medications Class Drug name Effects Side effects Contraindications TZD s Rosiglitazone (avandia), pioglitazone (actos), troglitazone Increase insulin sensitivity, preserve beta cell function Weight gain CHF Alpha-glucosidase inhibitors Acarbose, miglitol Delay carb absorption in the small intestine Flatulance, GI discomfort, weight gain Malabsorption, chronic diarrhea, IBD Incretin mimetics Exenatide (byeta) (injection only) slows gastric emptying, regulates postprandial glucagon, decreases appetite, enhances glucose dependent insulin secretion Nausea Amayln mimetics Pramlintide (injection only) slows gastric emptying, regulates postprandial glucagon, and decreases appetite Nausea Only approved for use with insulin

New class DPP-4 4i inhibitors: sitagliptin ti (Januvia). DPP-4 is the enzyme which breaks down incretins. Drug results in increased insulin release and decreased glucagon release.

Insulin therapy Type of insulin Name Onset of action Time to peak effect Duration of action Long-acting peakless analog Glargine Detemir About 2 hours No peak Glargine 20 to >24hours Detemir 6 to 24hours Intermediate acting NPH About 2 hours 6 to 10 hours 18 to 28 hours Rapid acting Regular About 30 minutes 2 to 4 hours 5 to 8 hours Very rapid acting analog Aspart Lispro Glusiline 5 to 15 minutes 45 to 75 minutes 2 to 4 hours

Hgb A1C reduction at Sulfonylureas: 1.0-2.0% 0% Meglitinides: 1.1% Metformin: 1.4% Rosiglitazone: 0.1-0.7% Pioglitazone: 0.3-0.9% Alpha-glucosidase l inhibitors: 0.5-1.0% 10% maximum dose *AACE Diabetes Guidelines, 2002

Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy NEJM Dec 7, 2006

Study set-up 4360 patients followed over a median of 4.0 years. Double-blind, randomized trial 3 groups: rosiglitazone, metformin, and glyburide gy monotherapy Primary outcome: Time to monotherapy failure (i.e. fasting plasma glucose of more than 180mg/dl after 6weeks on maximum dose.)

Study population Mostly middle aged: 50 s (range 30-75) Over half patients were men (55-60%) Almost all white (~88%) Fasting glucose at initiation: 126-180mg/dl Average Hgb A1C: 7.36% Average BMI: 32 Excluded: liver disease, renal failure, hx lactic acidosis, unstable/severe angina, CHF (any stage), uncontrolled hypertension.

Primary outcome: monotherapy failure Rosiglitazone: 143 patients = 15% at 5yrs Metformin: 207 patients = 21% at 5yrs Glyburide: 311 patients = 34% at 5yrs RRR rosiglitazone:metformin = 32% (? Bias?) RRR rosiglitazone:glyburide = 63% At time of treatment failure, ~99% patients on maximum dosage of drug.

Secondary outcomes Hgb A1C < 7%: Rosiglitazone group: 40% Metformin: 36% Glyburide: 26% Beta cell function (as measured by HOMA): Increased in glyburide group in the 1st 6 months (but then declined). Declined least overall in the rosiglitazone group: only 2%

Weight changes Increased in rosiglitazone group: 4.8kg Decreased in metformin group: -2.9kg Increased initially i i in glyburide, then remained stable: 1.6kg

Adverse outcomes Rosiglitazone: more edema, decreased d hematocrit, higher LDL,?fracture Metformin: more GI side effects Glyburide: more hypoglycemia, increases in ALT, weight gain

Problems with the study Primary endpoint: fasting blood glucose measurement High drop-out rate without intention to treat analysis 63% finished in the rosiglitazone group 62% in the metformin group 56% in the glyburide group Bias could not be excluded in the comparison of rosiglitazone to metformin. Sponsorship by GlaxoSmithKline

Summary Consider rosiglitazone as initial iti monotherapy for patients with new diabetes. Consider side effect profiles when choosing initial therapy. Even with low starting Hgb A1C levels, monotherapy failure is frequent.

Questions that remain to be answered At what point do you add insulin? Is there a best initial i i monotherapy? Is there a best initial combination therapy?

Diabetes Algorithms UNC New Diabetes Diagnosis i algorithm: http://www.med.unc.edu/medicine/generalm/enh ancedcare.html American Diabetes Association algorithm: http://care.diabetesjournals.org/cgi/content/full/3 0/suppl_1/S4/F1

References American Diabetes Association website: www.diabetes.org. American Association of Clinical Endocrinologists website: www.aace.com. Kahn, S, et.al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355: 2427-43. Sicat, BL, LA Morgan. New therapeutic options for the management of diabetes. Consult Pharm. 2007 Jan; 22(1): 45-56. AACE Diabetes Guidelines, Endocr Pract. 2002; 8(suppl 1).