Diabetic Medication Update

Gil C. Grimes, MDApril 2007

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

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

Treatment Goals American Diabetes Association

Recommendations Control of glycemia is important

Goal is HgA1c less than7%Grade B Pre-meal glucose 90-130mg/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

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):2542-51 [Level 2b]

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

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]

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 controlCochrane Library 2004 Issue2:CD004097 [Level 1a]

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):1392-8 [Level 1b]

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):2375-82 [Level 1b]2- JAMA 2002;287(18):2414-23 [Level 3a]

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

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 toleratedMedical Letter 2002;1:1JAMA 1999 Jun 2;281(21):2005 1a

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

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]

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

Sulfonylureas Increase insulin secretion by

pancreas Take before meals Contraindicated in sulfa allergic

patients Second generation safer in renal

disease Multiple drug interactions

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

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

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):1442-3 [Level 1b]2- JAMA 1999;281(12):1084-5 [Level 1b]

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):1652-8 LOE 3b

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 1.2-1.4]

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 controlCMAJ 2006 Jan 17;174(2):169 LOE 1b

Metformin Mechanism

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):867-72 Level 1c

Metformin side effects 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:CD002967 LOE 1a

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

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

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 2005 30:173(5):502-05 Level 52- BMJ 2003;326(7379):4 Level 53- Diabetes Care 2005;28(10):2345 Level 2b

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 [2.15-3.87] Duration >3yrs OR 2.39 [1.46-3.91]

Other small studies and case report suggest range is 6-30% 2

1- Arch Intern Med. 2006 166(18):1975-9 LOE 3b2- Am Fam Physician 2004 Jan 15;69(2):264

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 [0.15-1.6]Fertil Steril 2006 Sep;86(3):658 LOE 1b

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):759-64 LOE 1b

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:CD002966 Level 1c

Glitazones Trade names

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:CD006060 LOE 1b

Glitazones Rosiglitazone monotherapy vs. metformin

or glyburide 4,360 patients 30-75 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% glyburideN Engl J Med 2006 Dec 7;355(23):2427 LOE 2b

Glitazones Pioglitazone may increase risk of heart

failure Secondary outcome of RCT of 5,238 patients

35-65 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

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

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):815-21 LOE 2b

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 42- Diabetologia 2003;46(10):1319-23 LOE 2b

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

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 11- Cochrane Library 2005 Issue 2:CD003639 LOE 1c2- The Medical Letter 1996;38(967):9

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

Pramlintide Drug Interactions

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):816-22 Level 2b

Meglitinide analogs Repaglinide trade name Prandin Nateglinide trade name Starlix

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

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

Nateglinide Dosing 120 mg three times daily

with meals Lower dose in patients with better

control Onset of action 15-30 minutes

duration 2 hours No long term data on patient

oriented outcomes

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 210603

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 2b2- Diabetes Care 2004 Nov;27(11):2628 LOE 2b

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 hypoglycemiaAnn Intern Med 2005;143(8):559-69 LOE 2b

Exenatide Adverse Effects

Hypoglycemia seen in patients on sulfonylurea (14.4-35.7% dose dependent)

Nausea, vomiting, diarrhea, dizziness, headache, dyspepsia

Withdrawal due to adverse effects 7% vs. 3%

May alter absorption of oral medications Cost $147-172 per moth

Prescriber’s Letter 2005 Detail Document 210603

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

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

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 1c2- Cochrane 2004:CD003418 LOE1a3- J Fam Pract 2004;53:393 LOE 2a

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 32- Diabetes Care 2005;28:260 LOE 3

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

circulationPrescriber’s Letter 2006 Detail Document 220308

Inhaled Insulin Adverse Effects

Hypoglycemia 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 220308

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 2203082- Diabetes Care 2006 Aug;29(8):18183- Diabetes Care 2006 Jun;29(6):1282

Texas Resources Texas Diabetes Council

http://www.dshs.state.tx.us/diabetes/ Minimum standards flow sheets

http://www.dshs.state.tx.us/diabetes/hcstand.shtm