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Diabetic Medication Update

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Presentation on theme: "Diabetic Medication Update"— Presentation transcript:

1 Diabetic Medication Update
Gil C. Grimes, MD April 2007

2 Disclaimer Not on the company dole
Rarely the first to try something new Rarely the last to try something new Like therapeutic decisions to have good evidence

3 Goals and Objectives Targets for therapy Medication Options
New choices Best initial choices Best add on therapy Contraindications for select meds

4 Treatment Goals American Diabetes Association Recommendations
Control of glycemia is important Goal is HgA1c less than7%Grade B Pre-meal glucose mg/dL Post-meal glucose <180mg/dL Blood pressure <130/80 Lipid control LDL <100 mg/dL Triglycerides <150 mg/dL HDL >40 mg/dL men or >50 mg/dL women Diabetes Care 2006 Jan;29(suppl 1):S4-S42

5 Cost-effectiveness CDC cost-analysis
Hypothetical cohort patients >25 yo new diabetes Antihypertensive Therapy Improved quality of life and cost savings age 25-84 Very cost-effective 85-94 Intensive Glycemic Control Increase cost and improved outcome Decreasing effect on quality of life Decreasing cost effectiveness with increasing age Lipid management improved quality of life at increased cost JAMA 2002;287(19): [Level 2b]

6 Lifestyle Changes Dietary changes and exercise works
20-50% of patients can control their diabetes with diet, exercise and weight reduction Current trial lookAHEAD is recruiting patients for lifestyle management study

7 Exercise Exercise training reduces the HgA1c
Metanalysis of 14 trials duration 8 weeks HgA1 c 7.65% vs. 8.31% 1 Increased activity reduces risk of MI, Stroke Walking 2 hours/week lower mortality NNT 61 for one year 2 1- JAMA 2001;286:1218 [Level 1a] 2- Circ 2003;163:1440 [Level 1c]

8 Dietary Advice Systematic review of 18 RCT lasting 6 months where dietary advice main intervention Diets examined: low-fat/high –carb, high-fat/low-carb, low-cal (1,000 kcal/day), very-low-calorie (500 kcal/day) Data did no provide robust conclusions on effectiveness of dietary advice Exercise improves glycemic control Cochrane Library 2004 Issue2:CD [Level 1a]

9 High Fiber Diet 13 patients with DM-2 randomized in crossover fashion 6 week each arm ADA diet 8gm soluble fiber 16 gm insoluble fiber High-fiber 25 gm soluble fiber and 25 gm insoluble fiber Mean pre-prandial glucose 142 vs. 130 (p=0.04) Mean HbA1c 7.2% vs. 6.9% (p=0.09) Mean LDL 142 mg/dL vs. 133 mg/dL (p=0.11) May not be generalizable due to meals etc. NEJM 2000;342(19): [Level 1b]

10 Glycemic Index 8 men with DM-2 at VA facility randomized in crossover trial Low-biologically-available-glucose diet HbA1c 9.8% vs. 7.6% Took place in research center 1 Low glycemic meals may reduce hyperinsulinism Evidence limited Small studies with methodological problems 1- Diabetes 2004;53(9): [Level 1b] 2- JAMA 2002;287(18): [Level 3a]

11 Protein Restriction ADA recommendation for patients with any chronic kidney disease Limit protein intake 0.8g/kg/day Grade B Diabetes Care 2006;29(suppl 1):S4-S42

12 Medications Initial Monotherapy Sulfonylureas inexpensive
Metformin inexpensive Rosiglitazone and pioglitazone are expensive and lacking long-term data Nateglinide less effective than repaglinide Acarobose and miglitol less effective poorly tolerated Medical Letter 2002;1:1 JAMA 1999 Jun 2;281(21): a

13 Monotherapy Glycemic control is more difficult over time
Monotherapy vs. diet over 10 years Medication 2-3 associated with better control (HbA1c <7%) Insulin 28% vs. 9 % (NNT 6) Sulfonylurea 24% vs. 8% (NNT 7) Metformin in obese patients 13% vs. 11% (NNT 50) Only 50% attained at 3yrs Only 25% maintained at 9 years JAMA 1999 Jun 2;281(21):2005 LOE 1b

14 Medications When monotherapy fails
Add second drug with different mechanism of action Metformin (vs. pioglitazone) probably better choice for 2nd agent 1 Dual therapy fails add insulin with metformin Less expensive than triple oral therapy No difference in diabetic control compared 2 1- Diab Care 2004;27:141 [Level 1b] 2- Diab Care 2003;26:2238 [Level 1c]

15 Medications Systematic Review of 63 RCTs duration 3 months reporting HbA1c Studied sulfonylureas, metformin, alpha-glucosidase inhibitors, thiazolidinediones, non-sulfonylurea secreatagogues Medications at maximal doses were equally effective (except nateglinide and alpha-glucosidase inhibitors) Only Sulfonylureas and metformin demonstrate long term vascular risk reduction Metformin has advantage of lack of weight gain and lack of hypoglycemia JAMA 1999 Jun 2;281(21):2005 LOE 1a

16 Sulfonylureas Increase insulin secretion by pancreas Take before meals
Contraindicated in sulfa allergic patients Second generation safer in renal disease Multiple drug interactions

17 Sulfonylureas First generation have more interactions Acetoheaxmide
Chlorpropamide Disulfram reaction more likely May aggravate CHF or fluid retention May Cause SIADH Tolazamide Caution in renal dysfunction Tolbutamide BID dosing decreases GI side effects

18 Sulfonylureas Second-generation agents have fewer interactions
Glipizide and Glyburide are less likely to have disulfram reaction Glyburide is renally eliminated watch in renal disease Glipizide little benefit to doses >20mg/day Glimepiride watch in hepatic and renal disease Only sustained release glipizide and glimepiride really work as once daily dosing

19 Sulfonylureas and hypoglycemia
52 sulfonylurea-treated subjects with DM mean age 65 RCT glyburide or glipizide 1 Participated in 23 hour fasting study 1 week placebo vs. 10mg/day or 20 mg/day of active drug No hypoglycemia observed in 156 fasting studies Second study glipizide similar results 2 1- JAMA 1998;279(2): [Level 1b] 2- JAMA 1999;281(12): [Level 1b]

20 Sulfonylureas and hypoglycemia
Glyburide and TMP-Sulfa associated with increased risk of hypoglycemia Case-control study 909 glyburide recipients with hypoglycemia requiring hospital stay vs. patients on glyburide but nor hypoglycemic TMP-Sulfa in prior week OR 6.6 JAMA 2003 Apr 2;289(13): LOE 3b

21 Sulfonylureas and cardiovascular mortality
Retrospective cohort study 5,795 patients on first ever oral hypoglycemic Mean age 66.3 years followed 4.6 years 4,138 on glyburide Higher glyburide doses associated with higher mortality HR 1.3 [CI ] 120 on 1st generation sulfonylureas Higher doses associated with higher mortality HR 2.1 [1-4.7] Unclear if this represents patients who had worse DM control CMAJ 2006 Jan 17;174(2):169 LOE 1b

22 Metformin Mechanism Improves response to insulin
Decreased endogenous glucose production Decreased hepatic gluconeogenesis (10-30%) 1 Increased glucose disposal 13% Improves response to insulin Enhanced insulin-mediated glucose uptake Increased use of glucose in intestine and adipose Reduced GI glucose absorption Does not stimulate insulin secretion Requires insulin to be effective 1- NEJM 1998;338(13): Level 1c

23 Metformin side effects
Gastrointestinal upset (up to 30%) Nausea, anorexia, diarrhea, abdominal discomfort, metallic taste Dose-related Minimized by taking with meals and gradually increasing the dose 0.003% lactic acidosis Cochrane Library 2006 Issue 1:CD LOE 1a

24 Metformin and potential lactic acidosis
Risk factors for lactic acidosis Renal impairment (Creat> 1.5 mg/dL men >1.4 mg/dL women) CHF on medications Hepatic insufficiency Hypoxia Perioperative from major surgery Binge drinking Iodinated contrast agents

25 Metformin and acute tubular necrosis
Preventive measures Hold prior to procedure Restart after 48 hours if renal function is normal Check creatinine if renal function abnormal prior and do not restart metformin until creatinine has returned to baseline

26 Metformin and heart failure
Dissent on contraindications exists 1-3 Use in pt with CHF associated with decreased mortality 1,883 patients with DM and CHF HR 0.66 for metformin vs. sulfonylurea and metformin 0.54 1- CMAJ :173(5): Level 5 2- BMJ 2003;326(7379):4 Level 5 3- Diabetes Care 2005;28(10):2345 Level 2b

27 Metformin and B12 deficiency
About 10% of patients taking metformin develop low B12 levels Case control study of 155 cased of B12 deficiency vs. 310 controls 1 For each 1gm/day OR 2.88 [ ] Duration >3yrs OR 2.39 [ ] Other small studies and case report suggest range is 6-30% 2 1- Arch Intern Med (18): LOE 3b 2- Am Fam Physician 2004 Jan 15;69(2):264

28 Metformin and pregnancy
No increase in risk for major congenital malformation Meta-analysis of 8 studies in women with polycystic ovarian syndrome or diabetes and metformin use in the first trimester May be protective against major malformations OR 0.5 [ ] Fertil Steril 2006 Sep;86(3):658 LOE 1b

29 Metformin dosing No difference in efficacy of extended release vs. immediate release both are available as generic Monotherapy Initial dosing 500 mg twice daily with meals Initial dose 1000 mg with supper for ER Increase by 500mg/day each week Maximum dose 2,550mg daily (850mg TID) Extended release less GI side effects with initial dosing period Diabetes Care 2006 Apr;29(4): LOE 1b

30 Metformin Systematic review 29 RCT 5,259 patients mean follow-up 3 years Reduction of mortality from MI in obese or overweight patients Improves glycemic control, weight, lipids, insulinemia, and diastolic pressure Cochrane Library 2005 Issue 3:CD Level 1c

31 Glitazones Trade names Mechanism of action Rosiglitazone: Avandia
Pioglitazone: Actos Mechanism of action Decrease insulin resistance at peripheral sites and liver Decrease hepatic glucose production Effective as add on therapy but not as monotherapy Systematic review of 22 RCT of pioglitazone monotherapy Not effective for patient oriented outcomes (morbidity, mortality, cost, health related quality of life) Associated with increased risk of edema (NNH 13) Cochrane Library 2006 Issue 4:CD LOE 1b

32 Glitazones Rosiglitazone monotherapy vs. metformin or glyburide
4,360 patients years old newly diagnosed randomized to one agent for median of 4 years Dropout rates high (only 20% completed study) 37% rosiglitazone, 38% metformin, 44% glyburide Treatment failure 15% rosiglitazone, 21% metformin, 26% glyburide Weight change +4.8 kg rosiglitazone, -2.9kg metformin, +1.6 kg glyburide CHF events 1.5% rosiglitazone, 1.3% metformin, 0.6% glyburide N Engl J Med 2006 Dec 7;355(23):2427 LOE 2b

33 Glitazones Pioglitazone may increase risk of heart failure
Secondary outcome of RCT of 5,238 patients with DM-2 and evidence of coronary artery disease or peripheral vascular disease Pioglitazone vs. placebo plus additional glucose lowering therapy as needed Follow-up was great (only 2 patients lost) 10.8% vs. 7.5% for any HF (NNH 30) 5.7% vs. 4.1% for HF requiring hospitalization (NNH 62) Lancet 2005 Oct 8;366(9493):1279 LOE 2b

34 Glitazones and heart failure
Adverse Effects Fluid retention and heart failure Retrospective study 5,441 patients DM-2 on glitazones vs. 28,103 controls Mean follow-up 9 months CHF 2.3% treatment group vs. 1.4% controls NNH 111 Diabetes Care 2003 Nov;26(11):2983 LOE 3b

35 Glitazones and hepatotoxicity
Adverse Effects Hepatotoxicity Extracted to some degree from data on troglitazone and case reports Review 22 studies >6,000 patients LFT measured q4weeks x3 months then q6-12 weeks ALT Levels >3x ULN 0.32% rosiglitazone 0.17% placebo 0.4% sulfonylurea, metformin, insulin Diabetes Care 2002;25(5): LOE 2b

36 Glitazones and macular edema
Adverse Effects Macular Edema case reports usually in patients with peripheral edema 1 Drug Interactions Gemfibrozil inhibits metabolism or rosiglitazone and possibly pioglitazone Randomized crossover trial 10 health volunteer 2 1- FDA MedWatch 2006 Jan5 LOE 4 2- Diabetologia 2003;46(10): LOE 2b

37 Glitazones and fractures
2 post hoc outcomes in separate randomized trials Pioglitazone from FDA report 1 >8,100 pioglitazone patients vs. >7,400 comparator treated patients 1.9 per 100 patient years vs. 1.1 in women mainly upper arm Rosiglitazone had similar results for women 2 9.3% with rosiglitazone, 5.09% metformin, 3.47% glyburide 1- FDA MedWatch 2007 Mar 9 2- FDA MedWatch 2007 Feb 20

38 Alpha-glucosidase inhibitors
Trade names Acarbose: Precose Works by inhibiting post-prandial absorption of glucose Side effects Flatulence, cramps, abdominal distention, borborygmus, diarrhea May interfere with glucose therapy for hypoglycemia 2 Improved glycemic control and insulin levels No effect on lipids or body weight Unknown effectiveness on morbidity and mortality 1 1- Cochrane Library 2005 Issue 2:CD LOE 1c 2- The Medical Letter 1996;38(967):9

39 Pramlintide Trade name Symlim Synthetic analog of human amylin
Use with insulin therapy Injected prior to major meals Mechanism of action Modulates gastric emptying Increases feeling of satiety Injection medication Adverse effects Hypoglycemia especially in DM-1 or gastroparesis Should not be used in pt unable to determine when blood sugar is low Nausea, vomiting, abdominal pain, headache, fatigue, dizziness FDA Talk Paper 2005 March 17

40 Pramlintide Drug Interactions Cost AWP $79.50 per month
May decrease absorption of oral drugs Not recommended with anticholinergics, acarbose, or miglitol Cost AWP $79.50 per month Am J Health Syst Pharm 2005;62(8): Level 2b

41 Meglitinide analogs Repaglinide trade name Prandin
Nateglinide trade name Starlix

42 Repaglinide Short acting hypoglycemic with mechanism similar to sulfonylureas Long term safety unknown Stimulate release of insulin Rapid onset of action and short duration(4 hour) Taken within 30 minutes of a meal Dosing 0.5 mg prior to meal Titrate up to maximum of 4 mg/meal four meals a day

43 Repaglinide May cause fewer symptomatic hypoglycemic events in the elderly Open label randomized crossover trial 90 patients (mean age 75) with 88 completing trial 33 vs. 70 for symptomatic hypoglycemia <72 mg/dl 10 vs. 23 for symptomatic hypoglycemia <48 mg/dl 26% vs. 42% for at least one hypoglycemic event (NNT 6) Diabetes Care 2006 Aug;29(8):1918 LOE 2c

44 Nateglinide Dosing 120 mg three times daily with meals
Lower dose in patients with better control Onset of action minutes duration 2 hours No long term data on patient oriented outcomes

45 Exenatide Byetta Used with metformin or sulfonylurea or both
Injected prior to morning and evening meal Mechanism of action Incretin mimetic, stimulates glucagon-like peptide-1 receptor Stimulates production of insulin in the presence of high blood glucose Inhibits release of glucagon Slows gastric emptying Associated appetite suppression and weight loss Avoid if creatinine clearance <30 ml/minute Prescriber’s Letter 2005 Detail Document

46 Exenatide phase III data
Improves glycemic control seen in phase III trials 336 patients with DM-2 suboptimal control on metformin randomized to exenatide vs. placebo 1 HbA1c levels decreased 0.4% with 5mcg and 0.8% with 10 mcg Weight loss 1.6kg for 5mcg and 2.8 kg for 10 mcg Similar study design for patients on sulfonylurea 2 HbA1c levels decreased 0.46% with 5 mcg and 0.86% with 10 mcg 1- Diabetes Care 2005 May;28(5):1092 LOE 2b 2- Diabetes Care 2004 Nov;27(11):2628 LOE 2b

47 Exenatide vs. Insulin glargine
Randomized trial to demonstrate no-inferiority of exenatide vs. insulin glargine 26 week trial of 551 patients Body weight decreased 2.3 kg in exenatide group Body weight increased 1.8 kg in glargine group No difference in HbA1c reductions No difference in hypoglycemia Ann Intern Med 2005;143(8): LOE 2b

48 Exenatide Adverse Effects Cost $147-172 per moth
Hypoglycemia seen in patients on sulfonylurea ( % dose dependent) Nausea, vomiting, diarrhea, dizziness, headache, dyspepsia Withdrawal due to adverse effects 7% vs. 3% May alter absorption of oral medications Cost $ per moth Prescriber’s Letter 2005 Detail Document

49 Dipeptidyl peptidase IV inhibitors
Increase incretin levels Suppress the degradation of glucagon-like peptide 1 and other peptides Extends their bioactivity Sitagliptin trade name Januvia Vildagliptin trade name Galvus (not yet FDA approved) Phase III trials are all that is available Long term data is lacking on these agents

50 Sitagliptan 521 patients with DM-2 in 18 week trial
Sitagliptan 100 mg once daily 1 HbA1c reduction 1.2% Sitagliptan 200 mg once daily 2 HbA1c reduction 1.04% 741 patients with DM-2 randomized to one of two doses of sitagliptan 3 Reduction of HbA1c 0.79% at 100 mg daily Reduction of HbA1c 0.94% at 200 mg daily 1- Diabetologia 2005; 48(Suppl 1): A287 2- Diabetologia 2005; 48(Suppl 1): A287 3- Diabetes Care 2006 Dec;29(12):2632

51 Insulin Therapy Bedtime NPH with sulfonylurea
Better than NPH alone for control Allows for lower insulin dose Based on metanalysis of 16 studies 1 Metformin as well reduces weight gain 2 Addition of PNH vs.. 70/30 reduces hypogylcemia, reduces weight gain, not as effective 3 1- Arch Intern Med 1996;156:259 LOE 1c 2- Cochrane 2004:CD LOE1a 3- J Fam Pract 2004;53:393 LOE 2a

52 Insulin Therapy Long acting glargine insulin
With sulfonylurea/metformin may be better than NPH for glycemic control 1 Second study 70/30 associated with improved control vs. glargine but more hypoglycemic episodes 2 1- Diabetes Care 2005;28:254 LOE 3 2- Diabetes Care 2005;28:260 LOE 3

53 Inhaled Insulin Trade name Exubera
Inhaled 10 minutes prior to meal dosed in milligrams 0.05 mg/kg rounding down 1mg ≈ 3 units regular & 3mg ≈ 8 units Three 1mg doses is not equal to one 3mg dose Mechanism of action Small particle size 1-3 microns dry powder Deposited in alveoli Absorbed into capillary bloodstream 6-10% of inhaled insulin reached systemic circulation Prescriber’s Letter 2006 Detail Document

54 Inhaled Insulin Adverse Effects Hypoglycemia Cough Dry Mouth
Related to rate of absorption and duration of action Similar rate to injection insulin Cough Mild and non-productive Occurs within second to minutes Decreases with continued use Dry Mouth Mild to moderate severity Prescriber’s Letter 2006 Detail Document

55 Inhaled Insulin Contraindications
Hypersensitivity to human insulin Smoking within the last 6 months Unstable or poorly controlled lung disease Speed of onset similar to rapid acting insulin Inhaled insulin vs. either sulfonylurea or metformin 2,3 More HbA1c reduction More hypoglycemia 1- Prescriber’s Letter 2006 Detail Document 2- Diabetes Care 2006 Aug;29(8):1818 3- Diabetes Care 2006 Jun;29(6):1282

56 Texas Resources Texas Diabetes Council Minimum standards flow sheets
Minimum standards flow sheets



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