A Case-based Approach to Treating Diabetes Workshop WF02. D.C. Dugdale MD University of Washington Dawn DeWitt MD University of Melbourne

Transcription

1 A Case-based Approach to Treating Diabetes Workshop WF02 D.C. Dugdale MD University of Washington Dawn DeWitt MD University of Melbourne

2 Conflicts of Interest Neither Dr. DeWitt nor Dr. Dugdale do paid lectureships or accept gifts from the pharmaceutical industry. Parts of this talk and a scientific review were published in JAMA 2003;289: and

3 Overview Use of and complications related to newer oral agents Use of new insulin regimens Use of insulin pump Treating steroid-induced hyperglycemia 3-Day glucose sensors Real Life Streamlined inpatient diabetes management

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5 Case 1 A 58 y.o. man presented for care in 1994 on glyburide 2.5 mg BID with an A1C of 7.8%. Over the subsequent 6 years, his glyburide was increased to 10 mg BID. In 2000 his A1C was 10%. He had no known complications or comorbidities. Weight 161 lbs. BMI 24.

6 Case 1 treatment issues Augmenting oral therapy is unlikely to achieve goals Oral agents lower A1c 1-2% or 3% in combination Thus patients with an A1c > 9 will not reach target More pills may be toxic and expensive However, patients are often reluctant or refuse to take insulin If patients are willing to take insulin: bedtime NPH or glargine are preferred

7 UKPDS Extrapolated ß-cell Function 100 IGT PPH T2 ß -Cell Function (% ß) Years UKPDS Lancet 1997, Lebovitz, 1999.

8 Case 1-cost comparison Current regimen: metformin was added and glyburide was decreased glyburide 5 mg bid + metformin 1000 mg bid tests 1/day cost/month ~ $67 for pills, $25 for 1 test/day Proposed starting regimen insulin glargine 15 Units/day (0.2 Units/kg) tests 2/day cost/month ~$66 for insulin + syringes, $44 for 2 tests/day Pill cost/month: glyburide ~$11; metformin ~$56; repaglinide ~$103; rosiglitazone (Avandia) ~$144

9 Take Home Messages B-cell function is < 50%, and often at 10-20%, at presentation in many patients with T2DM Once A1C is >9%, additional oral agents are unlikely to adequately control glucose Insulin at bedtime with or without oral agents is the preferred strategy, especially if B-cell function is relatively preserved Cost is heavily dependent on testing frequency, but insulin is often less expensive than multiple oral medications

10 Case 2 A 54 year-old woman with type 2 diabetes treated with glyburide and rosiglitazone presents with an asthma attack. She has gained 30 lbs since her visit 3 months ago; BMI 35. Exam reveals wheezing and basilar crackles, elevated JVP, an S3, and edema. She has no cardiac history and is ruled out for an MI.

11 Thiazolidinediones and CHF Increase peripheral/muscle uptake of glucose mean 4-8 kg gain; kg is possible Adipose tissue and fluid retention Increasing recognition of CHF requiring hospitalization precipitated by TZDs but data are conflicting and PRCTs are needed Delea (Diabetes Care 2003) found an adjusted incidence of 8.2% HF in TZDs vs 5.3% in controls (N=5441) Masoud (Circulation 2005) analysed diabetes patients admitted with HF and found Hazard Ratios of 0.87 for TZDs and Metformin for death compared with insulin but the HR for HF readmission for TZDs was 1.06

12 Take home messages Safe use of TZDs Use with insulin risks large weight gain, only pioglitazone FDA approved in combination Not recommended in NYHA III-IV CHF Use caution in NYHA I-II CHF Liver monitoring: before initiation and every 2 months x 12 months; monitor closely if >1.5x ULN; stop if > 3x ULN or jaundice See: Consensus statement on TZDs and HF. Nesto et al, Diabetes Care, 2004.

13 Case 3 A 68 year-old woman with T2DM and CHF has been on 70/30 (N/R) insulin for 4 years. She takes 16 Units in the morning and 12 Units in the evening. Her diet is high in rice and carbohydrates. FBG runs and she has hypoglycemic events if her lunch is late. Her pre-dinner BG runs Her A1C is 8.5%

14 Non-physiologic Insulin Replacement JAMA. 2003;289: American Medical Association

15 Insulin options NPH/Regular or UL/Regular Premeal and nocturnal hypoglycemia common 70N/30R pre-mixed Same as above; convenient 75/25 pre-mixed protamine lispro/lispro 70/30 pre-mixed protamine aspart/aspart May be better convenience insulins, may need supplemental insulin at lunch Good for patients with high carbohydrate diets or premeal (e.g., lunch or dinner) hypoglycemia Basal-prandial combinations, insulin glargine, or CSII

16 Premix intermediate/rapid insulin JAMA. 2003;289: American Medical Association

17 Using bedtime insulin Give at 9 PM ( bedtime ); check FBG Increase by 2 Units every 3 days if FBG > 110 mg/dl Many T2DM patients need large doses Overlap when switching to glargine in T1 because of lag to onset of action (4-5 hours)

18 Why use glargine? Glargine has a 24-hour duration without peak Clear, must be given separately Better basal insulin than NPH, which has a hour duration with a peak Lower FPG and better post-dinner control Equivalent daytime control 25% less hypoglycemia at night Less weight gain (1 kg less at 28 weeks) Significantly higher patient satisfaction and convenience Witthaus, Diabet Med, 2001.Rosenstock, Diabetes Care, Rosenstock, Diabetes Care, 2000.

19 NPH vs. Glargine The Treat to Target Trial Randomized open-label parallel trial x 24 weeks in 756 overweight T2DM patients with A1C > 7.5% Duration of DM > 2 years Already on 1 or 2 oral agents Bedtime NPH vs Glargine 60% attained A1C < 7% 25% fewer patients on glargine had nocturnal hypoglycemia (33% vs 26%) Symptomatic hypoglycemia was 21-48% lower with glargine» Riddle, Diabetes Care, 2003;26:

20 Treat to Target Trial Protocol If CBG is above target for 3 consecutive days, increase insulin glargine as follows: >139 mg/dl increase glargine 4-6 units mg/dl increase glargine 2-4 units mg/dl increase glargine by 2 units < 99 mg/dl no change If CBG < 63 mg/dl on more than one occasion decrease dose by 2 units Riddle, Diabetes Care, 2003;26:

21 Starting insulin in T2DM: INITIATE trial RCT for 28 weeks A1C >8% on > 1000 mg/day of metformin + other oral agents optimized Randomized to Insulin Regimens 70/30 aspart 5-6 units before BF and D HS glargine units (higher doses FCBG >180 mg/dl) Dose titration weekly for 12 weeks, then q 2 wk 70/30 aspart : based on premeal CBG <80, decrease 2; , no change; , increase 2; , increase 4; >180, increase 6 Glargine: based on FCBG <80, decrease 2; , no change; , increase 2-4; , increase 4-6; >180, increase 6-8) Max increase 10 units or 10% of current total daily dose

22 T2DM Insulin INITIATE trial results Mean diabetes duration 9 yr Mean baseline A1C 9.7%; FCBG 250 mg/dl At study conclusion 70/30 Aspart Glargine Mean A1C: 6.9% 7.4% Mean wt gain: 5.4 kg 3.5 kg Hypo: minor 3.4/pt yr 0.7/pt yr Hypo: major 0 events 1 event» Raskin Diabetes Care 2005;28:

23 Case 4 A 76 y.o. woman with T2DM and recent nephropathy (Cr 1.6) is on 70/30 (NPH/R) BID with an A1c between 7.2% and 8.6%. She is very intelligent and values independence and flexibility. She prefers to get up after 10 a.m. some days and her meal schedule is very erratic, but usually she eats an early dinner. She frequently becomes hypoglycemic in the evening.

24 Insulin Stacking JAMA. 2003;289: American Medical Association

25 Basal-Prandial Insulin JAMA. 2003;289: American Medical Association

26 Starting basal-prandial insulin Major considerations: weight and insulin resistance; e.g. use more in type 2 Traditionally: 2/3 long-acting and 1/3 short-acting Basal-prandial regimens=½ basal and ½ prandial Usual starting dose for basal component is Units/kg (physiologic regimens) In a patient already on NPH/UL use ~80% of NPH/UL dose as glargine For prandial insulin use carb counting or diet history with % of carbohydrates at each meal as a guide

27 Prandial therapy with insulin analogs: why and how Better post-prandial control with decreased glucose excursions and less late hypoglycemia However, most will need lunchtime insulin, especially if glargine used as basal insulin No need for bedtime snack (bedtime snack needed if regular insulin used at dinner to cover tail of insulin action)

28 Prandial therapy with rapid insulin analogs is convenient Insulin lispro and aspart are equivalent Meal-time injection: onset 15 min, peak min, duration 3-5 hours Lag time can be much shorter: 0-10 min vs min ac for regular If hyperglycemic, use lag time: 10 min if CBG in 100s; 20 min if CBG in 200s; 30 min if CBG >300» Rassam, Diabetes Care 1999;22:

29 Take home messages The concept of basal-prandial physiologic insulin dosing often helps improve patients understanding Prandial rapid-acting insulins cause less hypoglycemia than regular insulin Bedtime NPH or Glargine Bedtime dosing gives better control of FBG and easier dose adjustment Glargine: less weight gain and 25% less hypoglycemia with glargine vs NPH Glargine is $58/vial vs NPH $30/vial

30 Case 5 58 y/o man, type 2 DM, HbA1c 7.5% Glucose Concentration (mg/dl) N, 10R 6N, 12H :00 AM 4:00 AM 8:00 AM 12:00 PM 4:00 PM 8:00 PM 12:00 AM

31 Take home messages 3-Day Glucose Sensors Indications: Uncontrolled diabetes Life-threatening hypoglycemia Need to educate patient Current cost at UW is $400 Equivalent data from frequent CBGs possible But hard to obtain representative data and highest incidence of severe hypoglycemia at night Common finding is unexpectedly large glucose excursions

32 Real Life with Alex

33 Carbs Juice 2 carbs Croissant 4 carbs Hot choc 2 carbs Rapid insulin at 1Unit/carb =8 Units rapid

34 Prandial therapy: carbohydrate counting Carbohydrate counting: two techniques: count grams of carbohydrate from label or portion size and calculate insulin using a ratio, OR, plan portion sizes around carbs, the term used for each 15 gram increment of carbohydrate Most basic physiologic insulin regimens call for a dose or supplement of 1-2 units per carb Involve diabetes educator for patient training

35 Prandial therapy with insulin analogs Adapting to meal content and preprandial CBG Carbohydrate counting: 1 Unit/10-15 gm carbohydrate, is typical starting point, but requires individual adjustment Use supplement (in addition to usual prandial insulin) based on premeal glucose: 1-2 Unit/50 mg/dl over 150 mg/dl is a typical starting point, but again requires individual adjustment Adjust supplement based on anticipated activity

36 Prandial therapy: carb counting, cont d Carbohydrate counting examples (each are 15 g): Apple, ¾ medium Apple juice, ½ cup Bagel, ¼ (e.g., half of a half) Bread, sandwich, 2/3 slice Cereal, ½ - ¾ cup French fries, 1/3 of a small bag (depends on store) Hamburger, ½ (including bun) Milk, 10 ounces Orange juice, ½ cup Pasta, cooked, ½ cup Rice, cooked, 1/3 cup Free foods: most vegetables, most nuts, cheese, most meats or fish

37 Prandial therapy: carb counting, cont d Sources of information for patients General reference: Reference for fast foods:

38 Exercise: Reduce prandial insulin by 1 Unit per 15 min OR Give 1 carb snack before exercise per 15 min Requires individualization!

39 Take home real life issues Basal prandial insulin strategy and carbohydrate counting give maximum flexibility but for T2DM this may be more complex than necessary Self monitoring enhances the patient s understanding and sense of control over diabetes Treatment plans evolve at different rates Total insulin dose goal higher than often realized 1 unit per kg for type 1 (after honeymoon phase) units often needed for bedtime basal insulin for T2

40 Case 6 A 32 year-old man with type 1 DM presents with severe throat pain, unable to eat. He uses an insulin pump, basal rate 1 Unit/hour lispro. He uses 1 Unit lispro per 10 gm of carbohydrate for meals. Initially he is NPO. How should he be managed? After 36 hours, EGD shows HSV esophagitis. Acyclovir and TPN are started. How would you manage him now?

41 Take home messages Pumps in the hospital Probably the easiest way to manage patients Use only basal rates for fasting patients Adjust based on usual CBG monitoring Factors that affect insulin needs for inpatients Insulin resistance from endogenous stress hormones or medications (steroids) Often more caloric control with meals Decreased physical activity Give lispro supplements with intake (using pump!)

42 Case 7 A 62 y.o. woman with T2DM managed with metformin and glyburide presents with altered mental status. Glucose is 40 mg/dl; Cr is 5.0 (baseline 1.2 mg/dl). Glucose infusion was begun. She required 10 Units NPH and 10 Units regular SC BID. Renal biopsy showed interstitial nephritis and methylprednisolone was begun. Two hours later her CBG was 500 mg/dl. A supplemental scale was used for the next 24 hours with fingersticks remaining at 500 mg/dl despite 60 Units regular insulin SC.

43 Issues in patients on steroids In the hospital, insulin drip may be best Physiologic effects of steroids Increased gluconeogenesis Suppress insulin secretion Decreased peripheral uptake Increased insulin resistance (esp. with wt gain) Often normal FBG but high post-prandial glucose measurements Consider prandial insulin, repaglinide (limited)

44 Hospitalized patients Myths of diabetes care Just use a sliding scale. Sliding scale attempts to retrospectively lower elevated BG levels by giving predetermined insulin doses on a predetermined schedule Does not consider patient s prehospital regimen Does not consider meal time or status, or differing target BG based on time relative to meals

45 Hospitalized patients Myths of diabetes care Just use a sliding scale. Associated with cycles of hypo- and hyperglycemia Clinical trials find either no benefit or worse control Ann Fam Med 2003;1: Arch Int Med 1997;157:

46 Hospitalized patients Myths of diabetes care No food, no insulin. Patients with type 1 always need insulin. DKA is an insulin deficiency state, not merely a high glucose state Many patients with type 2 diabetes need insulin to maintain metabolic control

47 Hospitalized patients Myths of diabetes care Just keep their glucose under 400. In general medical and surgical patients, adverse outcomes associated with fasting BG > 126 mg/dl or random BG > 198 mg/dl Umpierrez, J Clin Endo Metab 2002;87:

48 Morbidity/Mortality and Hyperglycemia in Inpatients Hyperglycemia present in 38% of admissions 26% known DM, 12% had no history of diabetes Normoglycemia Known DM New hyperglycemia Length of Stay 4.5 days 5.5 days 9 days Risk of death due to infection 4% 4% 12% In hospital mortality 1.7% 3% (ARR 3) 16% (ARR 18) Umpierrez, J Clin Endo Metab 2002;87:

49 Better glucose control results in: Shorter stays Fewer surgical wound infections Fewer infectious complications in medical patients Better outcomes patients with MI (DIGAMI) Better outcomes in patients with stroke Reduced mortality in SICU patients on insulin drips with glucose < 110 mg/dl» Umpierrez, J Clin Endoc Metab, Capes, Lancet, Capes, Stroke, Latham, Infection Cont and Hosp Epi, Zerr, Ann Thor Surg, Malmberg, J Am Coll Cardio, Van der Berghe, NEJM, 2001.

50 Practical application Keeping the glucose below the renal threshold (~180 mg/dl) simplifies fluid and electrolyte management Recommended goal for CBG is mg/dl Consider insulin glargine or IV insulin with pre-meal rapid-acting supplements Preprinted order sheet simplifies care. UW protocol published: Trence, et al. J Clin Endo Metab 2003:88(6):2430.

51 Subcutaneous Insulin Orders: Blood Glucose (BG) Monitoring: Before meals and at bedtime. hrs after meals. 2-3 am Prandial Insulin Orders Breakfast Lunch Dinner Bedtime Give units of: Lispro (Humalog ) Give units of: Lispro (Humalog ) Give units of: Lispro (Humalog ) Aspart (Novolog ) Aspart (Novolog ) Aspart (Novolog ) U-100 Regular U-100 Regular U-100 Regular Basal Insulin Orders Give units of: NPH Lente Ultralente Glargine Give units of: NPH Lente Ultralente Glargine Give units of: NPH Lente Ultralente Glargine Give units of: NPH Lente Ultralente Glargine

52 Premeal algorithm for Hyperglycemia: To be administered in addition to scheduled insulin dose to correct premeal hyperglycemia. Lispro Aspart Low Dose Algorithm (for patients requiring 40 units of insulin per day) Premeal Blood Glucose Additional Insulin unit units units units >349 5 units

53 Oh Drs. DeWitt and Dugdale, May I be excused? My brain is full.

54 Cost of oral agents Glipizide 10 mg, #60 $10.99 Glipizide 24 hr 10 mg, #60 $39.98 Metformin 1000 mg, #60 $55.99 Glucophage 500 mg, #120 $93.98 Metformin 24 hr tab 500 mg, #120 $79.98 Avandia (rosiglitazone) 8 mg, #30 $ Precose (acarbose) 100 mg, #90 $80.97 Prandin (repaglinide) 2 mg, #90 $ Generic glipizide and glyburide ~ same cost Drugstore.com prices

55 Cost of insulin 100 Units/ml, 10 ml Humulin 70/30 $31.00 Humulin N $29.85 Humulin R $29.85 Humulin U $29.85 Lantus (glargine) $57.76 Humalog (lispro) $58.99 Humalog 75/25 $64.62 Insulin should be discarded after one month Drugstore.com prices

56 Cost of supplies Accu-chek Advantage monitoring kit $65.79 Accu-chek test strips, #100 $84.99 B-D Ultra-fine II short 30G 1cc, #100 $25.99 Insulin pens Insulin pump Pump supplies (tubing/infusion sets) free but increase cost of insulin ~30% ~$5000 ~$1500/yr Drugstore.com prices

57 American Diabetes Association: Clinical Practice Recommendations ADA practice guidelines available as full text at or via ADA website Includes guidelines for treatment of type 1 and type 2 diabetes, as well as multiple practical topics Updated annually in January

58 Insulin Pearls on the ADA website Don t mix glargine with other products When mixing rapid insulin and intermediate insulin, inject within 15 minutes Syringe reuse acceptable with meticulous cleanliness; small needles (30 ga) develop barbed tips easily Insulin pens improve dose accuracy Injection site should be clean, alcohol wipe unnecessary Injection site rotation reduces lipoatrophy but increases variability of absorption fastest: abdomen > arm > leg exercise increases rate of absorption

59 Insulin Infusion Protocol General Surgical patients who have received an oral diabetes medication within 24 hrs should start when CBG > 120. Other patients start when BG > 70. Discontinue insulin infusion when a patient is eating and has received first dose of subcutaneous insulin. Choosing an algorithm Algorithm 1: Start here for most patients. Algorithm 2: If algorithm fails, S/P CABG, S/P transplant, or glucocorticoids or in patient on > 80U insulin/day as outpatient Algorithm 3 or 4: No patients start here. Use for failure of #1 or 2 Changing algorithms Moving up: Algorithm failure if CBG > 180 mg/dl, and the CBG does not change by at least 60 mg/dl in 1 hour. Moving down: When CBG is less than 70 mg/dl x 2 hours

60 UWMC Insulin Drip Protocol Algorithm 1 Algorithm 2 Algorithm 3 Algorithm 4 Units / Units / Units / Units / BG BG hr BG BG hr hr hr <60 = Hypoglycemia (See below for treatment) <70 Off <70 Off <70 Off <70 Off

61 Annotated Bibliography Papers of interest to generalists

62 DeWitt DE, Dugdale DC. Clinical Correlations: Using New Insulin Strategies in the Outpatient Treatment of Diabetes. JAMA, May 7, Contains more detailed discussion of principles discussed in this workshop Accompanying scientific review: DeWitt DE, Hirsch IB. Outpatient Insulin Therapy in Type 1 and Type 2 Diabetes: Scientific Review.

63 ADA Guidelines: Implications of the Diabetes Control and Complications Trial. Diabetes Care 2003;26:S25- S27. Also at and UpToDate 11.1 Compared intensive therapy (pump or 3+ daily injections) to conventional therapy (1-2 daily injections) in T1DM. Intensive group mean A1c of 7.2%, mean glu 155 mg/dl; conventional group mean A1c 9.0%. In primary prevention cohort, 6 yr. mean follow-up: retinopathy risk 76%, microalbuminuria risk 34%, neuropathy risk 69%. In secondary prevention cohort, 6 yr. mean follow-up, retinopathy risk 54%, microalbuminuria risk 43%, neuropathy risk 57%. Intensive insulin therapy slows decline of B cell function (Ann Intern Med 1998;128: )

64 ADA Guidelines: Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care 2003;26:S28-S32. Also at and UpToDate Study Design RCT new onset T2 DM; randomized to sulfonylurea, metformin, or insulin, with different glucose goals. Conventional Rx goal: fasting glu <270 mg/dl and no sx. Intensive Rx goal: fasting glu <108 mg/dl; premeal glu <126 mg/dl. Insulin regimens: q day NPH or UL, with premeal R added if more than 14 U per day of basal insulin used, OR premeal or bedtime glu <126 mg/dl.

65 ADA Guidelines: Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care 2003;26:S28-S32. Also at and UpToDate Original reports: Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 DM. Lancet 1998;352: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 DM. Lancet 1998;352:

66 ADA Guidelines: Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care 2003;26:S28-S32. Also at and UpToDate Conclusions. Baseline median A1c 9.1%; conventional Rx group achieved median A1c 7.9%, intensive Rx group 7.0%. Risk of microvascular complications continuously related to glucose control as assessed by HBA1c. For every 1% decrease in A1c, there was 35% reduction of complication risk, with no threshold level.

67 ADA Guidelines: Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care 2003;26:S28-S32. Also at and UpToDate Conclusions Risk of cardiovascular complications continuously related to glucose control as assessed by HBA1c. For every 1% decrease in A1c, there was 25% reduction in diabetes-related deaths, 7% reduction in all-cause mortality, and 18% reduction in MI, again with no threshold level In subgroup of obese patients (ideal body weight >120%; corresponds to BMI >26), metformin used in the intensive treatment group showed 42% reduction in diabetes-related deaths, 36% reduction in allcause mortality, and 39% reduction in MI compared to conventional group; SU and insulin arms had no benefit on these endpoints.

68 Wright et al. Sulfonylurea inadequacy. Efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the UKPDS. Diabetes Care 2002;25: Design Substudy of UKPDS in which patients who were in intensive therapy group with sulfonylurea had ultralente insulin added if fasting plasma glucose (FPG) > 6 mmol/l (to convert mmol/l to mg/dl, multiply by 18). Initial dose was 2 x (fasting plasma glu [mmol/l] - 3), for a person at 100% ideal body weight (IBW). For each 20% above IBW, initial dose was increased by 50% of the dose for 100% IBW. Regular insulin was added for premeal glu > 126 mg/dl. Comparison group was that who received insulin only.

69 Wright et al. Sulfonylurea inadequacy. Efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the UKPDS. Diabetes Care 2002;25: Results. Over 6 yrs, 53% had insulin added Median HBA1c 6.6% in combination group, 7.1% in insulin only group Of combination group, 47% had HBA1c < 7%; 35% in insulin only group Annual rate of major hypoglycemia 1.6% in combination group, 3.2% in insulin only group

70 Malmberg et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): Effects on mortality at one year. J Am Coll Card 1995;26: patients with diabetes and acute MI. 306 randomized to insulin-glucose infusion followed by multiple injection insulin therapy (MIT) for > 3 mos Vs. 314 conventional treatment. 1-year mortality 18.6% mortality in infusion group Vs. 26.1% in the control group. ARR 7.5%; RRR 29%. Conclusion: Insulin-glucose infusion and MIT improves 1 year mortality in patients with diabetes (this was particularly notable in low risk patients who had not previously been treated with insulin).

71 Inzucchi. Oral antihyperglycemic therapy for type 2 diabetes, scientific review. JAMA 2002;287: Companion article, Holmboe ES. Oral antihyperglycemic therapy for type 2 diabetes, clinical applications. JAMA 2002;287: , contains illustrative cases. Compared with placebo, monotherapy lowers A1C levels 1-2%; combination therapy lowers them 2-3%. Sulfonylureas decrease microvascular risk Metformin decreases microvascular and macrovascular risk Thazolidinediones not proven to reduce vascular risk Alpha glucosidase inhibitors target postprandial glycemia and are nonsystemic Non-sulfonylurea secretagogues target postprandial glycemia

72 Comparison of Bedtime Insulin Regimens in Patients with Type 2 Diabetes Mellitus. A Randomized Controlled Trial. Yki-Jarvinen et al. Ann Intern Med 1999;130: Methods. Enrolled pts with fasting glu > 144 mg/dl, and > 3 yrs sulfonylurea therapy Randomized to bedtime NPH plus glyburide, metformin, or AM NPH

73 Comparison of Bedtime Insulin Regimens in Patients with Type 2 Diabetes Mellitus. A Randomized Controlled Trial. Yki-Jarvinen et al. Ann Intern Med 1999;130: Results. Best control in combination metformin and bedtime NPH group (9.7% A1c baseline, 7.2% A1c at 1 yr) No weight gain in metformin and bedtime NPH group; 4 kg at 1 yr. in other groups Less symptomatic and biochemical hypoglycemia in metformin and bedtime NPH group; 1.8 Vs episodes per pt per yr. in other groups

74 Yki-Jarvinen, et al. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care 2000;23: Type2 DM patients; age ~59 yrs, BMI Randomized to bedtime glargine Vs. bedtime NPH. Control and weight gain were the same at 1 year. Glargine lowered post-dinner glucose 9.9 Vs mmol/l (p < 0.02). Glargine induced less hypoglycemia 9.9% Vs. 24% (p < 0.02).

75 Rosenstock et al. Basal insulin therapy in type 2 diabetes. Diabetes Care 2001;24: patients randomized to qhs glargine Vs.. NPH qhs or qam and qhs for 28 weeks, open label. Similar A1C improvements. 1 kg less wt gain (0.4 G Vs. 1.4 NPH ). Overall symptomatic hypoglycemia ~same (61% of pts receiving G Vs. 67% of pts receiving NPH ). Severe hypoglycemia (glu < 36 mg/dl) in 7% of pts receiving G Vs. 10% of pts receiving NPH (p=0.06). Nocturnal hypoglycemia reduced 25% (26.5% Vs. 35.5%; p = 0.01).

76 Riddle et al. The Treat to Target Trial: Randomized addition of glargine of human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003;26: patients randomized to qhs glargine Vs.. NPH qhs or qam and qhs for 28 weeks, open label. Similar A1C improvements. 1 kg less wt gain (0.4 G Vs. 1.4 NPH ). Overall symptomatic hypoglycemia ~same (61% of pts receiving G Vs. 67% of pts receiving NPH ). Severe hypoglycemia (glu < 36 mg/dl) in 7% of pts receiving G Vs. 10% of pts receiving NPH (p=0.06). Nocturnal hypoglycemia reduced 25% (26.5% Vs. 35.5%; p = 0.01).

77 Fritsche et al. Glimepride combined with morning insulin glargine, bedtime NPH insulin, or bedtime insulin glargine in patient with type 2 diabetes. Ann Int Med 2003;138: patients with T2DM receiving oral agents, mean A1C 9.1% (range 7.5% to 10.5%) Patients given glimepride 3 mg plus 1 of 3 insulin regimens for 24 weeks, open label. Initial dose = (FBG-50)/10 (in mg/dl) dose titrated upward based on FBG.

78 American Diabetes Association: Clinical Practice Recommendations Diabetes Care 2005;28:S1-S79. Contains ADA practice guidelines. Available as full text at or via ADA website Includes guidelines for treatment of type 1 and type 2 diabetes, as well as multiple practical topics

79 American Diabetes Association. Insulin Administration. Diabetes Care 2003;26:S121-S124. Contains multiple tips about insulin: Don t mix glargine with other products When mixing rapid acting insulin and intermediate acting insulin, inject within 15 minutes Syringe reuse acceptable but needs meticulous attention to cleanliness; small needles (30 ga) develop barbed tips easily