1. Inpatient Management of Diabetes Mellitus William Harper, MD, FRCPC Endocrinology & Metabolism Assistant Professor of Medicine, McMaster University

2. BS > 11.1 mmol/L Renal threshold for glycosuria (normal GFR) Decreased WBC function Chemotaxsis Phagocytosis Decreased Wound Healing

3. Evidence to support Inpatient BS control? DIGAMI 620 patients AMI, prior dx DM or BS > 11 mM IV insulin gtt started @ 5 U/h Titrated to keep BS 7-10.9 mM Insulin IV > 24h  MDI > 3 months No in-hospital mortality benefit. Rx Increased hospitalization by 1.8d 0.5% reduction HbA1c @ 3 months @ 1 year % on Insulin: 72% Rx Group 49% Cntrl Group 1 year mort: ARR 7.5% NNT 13 3.4 y mort: ARR 11% NNT 9

4. Evidence to support Inpatient BS control? Leuven, Belgium Study 1548 ICU patients (63% CV Sx) If BS > 6.1 mM: Rx with IV insulin gtt & TPN +/- tube feeds Start IV insulin @ 2-4 U/h, titrated to BS 4.4-6.1 mM Ave insulin dose: Rx group 3.0 U/h Cntrl group 1.4 U/h Once out of ICU relaxed treatment goal to < 11.1 mM Mortality in ICU: ARR 3.4% NNT 29 Mortality in-hospital: ARR 3.7% NNT 27 Greatest reduction in mortality was sepsis-related. Insulin Rx reduced: bacteremia, ARF needing HD, need for PRBC, critical illness polyneuropathy, duration of ventilation and length of stay in ICU To what extent were benefits nutrition related as opposed to insulin related?

5. Goals of Inpatient DM Management “Avoid hypoglycemia and marked hyperglycemia” Target BS: 7.0 - 11.0 mM (5.0 – 10.0 mM) Avoid Hypoglycemia Precipitating arrhythmia or other cardiac events Inducing seizure, focal or cognitive defects periop Avoid Marked Hyperglycemia (BS > 11.1 mM) Treat (and avoid) DKA, HONC

6. DM Inpatient Management 1.Eating 2.NPO: temporary (for a test or surgery) 3.NPO: prolonged

7. DM Inpatient Management 1.Eating Diet (T2DM) OHA (T2DM) Insulin (T2DM and T1DM) 2.NPO: temporary (for a test or surgery) 3.NPO: prolonged

8. Pathophysiology of T2DM Blood glucose diet Hepatic glucose output INSULIN Peripheral Tissue Uptake + _

9. GLUCOSE ABSORPTION GLUCOSE PRODUCTION Metformin Thiazolidinediones MUSCLE PERIPHERAL GLUCOSE UPTAKE Thiazolidinediones Metformin PANCREAS INSULIN SECRETION Sulfonylureas: Glyburide, Gliclazide, Glimepiride Non-SU Secretagogues: Repaglinide, Nateglinide ADIPOSE TISSUE LIVER Alpha-glucosidase inhibitors INTESTINE Sites of Action of Currently Available Therapeutic Options

11. OHAs: Drug  BG  HbA1c Side-effects Sulfonylurea FBG 20% 1.0-2.0%Hypoglycemia Weight gain Biguanide FBG 2.8-3.9 mM 1.0-2.0%Lactic acidosis GI intolerance TZD FBG 2.2-3.6 mM 1.0-1.5%Edema Weight gain Liver monitoring Meglitinide FPG 4 mM PPG 5.6 mM 1.0-2.0%Hypoglycemia (50% < SU) α-glucosidase Inhibitor FPG 14% PPG 25% 0.5-1.0%GI intolerance

12. DrugTradeDoseCostODB Glyburide Diabeta Start 1.25-5 mg od Spit dose bid > 10mg/d Max 10 mg bid $14/mosYes Gliclazide Diamicron Start 80 mg bid Max 160 mg bid $90/mosNo Gliclazide MR Diamicron MR Start 30 mg od Max 120 mg od $30/mosExp Sect 8 Glimepiride Amaryl Start 1-2 mg od Max 8 mg od $30-40/mosNo Repaglinide Gluconorm Start 0.5 mg tid-qid Max 4 mg qid $45/mosExp Sect 8 Nateglinide Starlix Start 60-120 mg tid Max 180 mg tid $45/mosExp Sect 8 Metformin Glucophage Start 500 mg od-bid Max 1000 mg bid $14/mosYes Pioglitazone Actos Start 15 mg od Max 45 mg od $115/mos Exp Sect 8 Rosiglitazone Avandia Start 4 mg od Max 4 mg bid $ 60/mos $ 120/mos Exp Sect 8

13. TZD adverse effects Edema 4-5% of patients get mild-moderate edema 15% if TZD used in combo with insulin Mild anemia (dilutional) Weight gain Increase in subcutaneous not visceral fat Myalgia (pioglitazone only) Myalgia 5.4% pioglitaz. versus 2.7% placebo Few patients with unexplained CK > 10x ULN Contraindicated in class II, III and IV CHF Contraindicated if ALT > 2.5x ULN or active liver disease

14. Metformin Contraindications: Creatinine >133 uM (men), >124 uM (women), CrCl < 1.17 mL/s CHF symptomatic (> NYHA class III, E.F. < 35-40%) Liver failure Alcoholism Hypoxic respiratory condition Active moderate to severe infection Radiocontrast or Surgery with GA: –Hold metformin for 24-48h –Restart after documented preservation of renal function

15. Metformin Side effects: Lactic acidosis (metformin 0.03 cases/1000 patient years) –Phenformin 10-20X higher rates of lactic acidosis GI: diarrhea, flatulence, abdominal discomfort –Usually disappear within 2 weeks –Dose dependent: avoided by slow titration & in some cases dose reduction –5% of patients can’t tolerate metformin due to GI S/E’s Starting dose: 500 mg with largest meal (prevent GI S/E’s) Increase by 500 mg increments q1-2 wk Maximal hypoglycemic affect: 1000 mg bid

16. Insulin TypeStartsPeaksDuration Humalog NovoRapid 5-10 min0.5-1hrs3.5 hrs Regular30 min2-4 hrs6-8 hrs NPH Lente 1-2 hrs6-10 hrs16-24 hrs Ultralente4-6 hrs8-24 hrs24-36 hrs Glargine1.5hNoneUp to 24 hrs

17. BIDS Therapy T2DM: “Introduction to insulin” Keep on OHAs Start NPH 0.2 U/kg SC qhs Increase by 2-4 U q4d until FBS 4-7 If dose > 30-40U or if BS high late in day despite OK FBS than split into 2 injections with 2/3 acB and 1/3 qhs

18. Starting Insulin Regimen TDD = 0.5-0.7 U/kg “2/3, 1/3” Regimens 2/3 of TDD acB, 1/3 acD 2/3 of TDD as Long-acting, 1/3 as short acting Pre-mix: acB 30/70 acD 30/70 MDI Regimens 2/3, 1/3 Regimen: move acD long acting to qhs i.e. acB N, H acD H qhs N ac meals H qhs N (bolus 60%, basal 40%) ac meals H UL q12h (bolus 50%, basal 50%)

19. Insulin Regimens acB acL acD qhs Bedtime NPH (+/-bids) N NPH bid N N 30/70 bid 30/70 30/70 MDI (3 injections) H + N H N MDI (>4 injections) H (+/-N) H H N MDI (>4 injections) H + UL H H UL CSII (Insulin Pump)

20. NEJM 347:1342-9

21. acBacLacDqhsRx 22 (5R) 93.1 (O.J.) 15 acB N20 R10 acD R5 qhs N10 201578 acB N20 R10 acD R5 qhs N10 2217 (RN calls) acB N20 R10 Surgeon:? Internal Medicine:? Endocrinologist:?

22. acBacLacDqhsRx 22 (5R) 93.1 (O.J.) 15 acB N20 R10 acD R5 qhs N10 201578 acB N20 R10 acD R5 qhs N10 2217 (RN calls) acB N20 R10 Surgeon:Give 5 U Regular SC now Internist:? Endocrine:?

23. acBacLacDqhsRx 22 (5R) 93.1 (O.J.) 15 acB N20 R10 acD R5 qhs N10 201578 acB N20 R10 acD R5 qhs N10 2217 (RN calls) acB N20 R10 Surgeon:Give 5 U Regular SC now Internist:Increase qhs N to 12 tonight and acB R to 12 tomorrow Endocrine:?

24. acBacLacDqhsRx 22 (5R) 93.1 (O.J.) 15 acB N20 R10 acD R5 qhs N10 201578 acB N20 R10 acD R5 qhs N10 2217 (RN calls) acB N20 R10 Surgeon:Give 5 U Regular SC now Internist:Increase qhs N to 12 tonight and acB R to 12 tomorrow Endocrine:Increase qhs N to 12 start tonight Decrease acB N15 R7 starting tomorrow AM Check 3AM BS tonight

25. Guideline for Insulin Adjustments 1.Adjust the insulin that accounts for the high or low reading. 2.Always compare an abnormal BS reading with the one previous. 3.If insulin dose is: Less than 8U, adjust by 1U 8-20U, adjust by 2U > 20 U, adjust by 10% (increase), 20% (decrease) 4.Don’t forget to compensate for a successful adjustment

26. SC Insulin Supplemental Scale CBGAction < 4.0Call MD 4.1-10.0nil 10.1-12.0Humalog 2 U SC 12.1-14.0Humalog 4 U SC 14.1-16.0Humalog 6 U SC 16.1-18.0Humalog 8 U SC 18.1-20.0Humalog 10 U SC > 20.0Call MD

27. DM Inpatient Management 1.Eating 2.NPO: temporary (for a test) 3.NPO: prolonged

28. NPO for a test: T2DM on Diet Rx or OHA Schedule test for the AM Hold OHAs on AM of test CBG @ 7AM: < 3.0Consider postpone test 3.1-4.0IV D5W gtt @ 75-100 cc/h 4.1-11.0Proceed with test, no Rx necessary > 11.1Insulin R or analogue SC supplemental or IV insulin gtt & IV D5W gtt @ 75-100 cc/h > 20.0Check urine ketones, consider postpone test

29. Insulin IV gtt Add 50 U of Human regular insulin (Humulin R or Novolin Toronto) to 500cc D5W (1U/10cc). Flush & discard first 50cc. Infuse insulin solution by IVAC (intravenous infusion pump), piggybacked into D5W running at 100cc/h. Start insulin @ 0.9 U/h (9cc/h) or start at a rate dependent on patient’s insulin dose: IV insulin gtt rate = ( ½ TDD ) / 24

30. Insulin IV gtt CPG q1h x 2, then q2h: Adjust Insulin IV infusion rate as per scale below: < 4.0 Call MD 4.1-6.0 0.5 U/h (5cc/h) 6.1-8.0 1.0 U/h (10cc/h) 8.1-10.0 1.5 U/h (15cc/h) 10.1-12.0 2.0 U/h (20cc/h) 12.1-15.0 2.5 U/h (25cc/h) 15.1-18.1 3.0 U/h (30cc/h) 18.1-22.0 3.5 U/h (35cc/h) > 22.1 Call MD

31. NPO for a test: T1/T2DM on Insulin Schedule the test for the AM Hold AM Insulin on day of test CBG @ 7AM: < 3.0Consider postpone test 3.1-11.0Give ½ of total AM insulin dose as NPH SC IV D5W gtt @ 75-100 cc/h > 11.1IV insulin gtt & IV D5W gtt @ 75-100 cc/h > 20.0Check urine ketones, consider postpone test

32. DM Inpatient Management 1.Eating 2.NPO: temporary (for a test) 3.NPO: prolonged Patient put on D5W if not on feeds or TPN IV insulin gtt SC NPH or UL q12h (+/- supplemental scale) »Starting dose 0.2 U/Kg q12h