diabetic medication update gil c. grimes, md april 2007
TRANSCRIPT
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