Transcript Diabetes treatment 2007

Diabetic Medication Update
Gil C. Grimes, MD
April 2007
Disclaimer
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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
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Targets for therapy
Medication Options
New choices
Best initial choices
Best add on therapy
Contraindications for select meds
Treatment Goals
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American Diabetes Association Recommendations
Control of glycemia is important
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Goal is HgA1c less than7%Grade B
Pre-meal glucose 90-130mg/dL
Post-meal glucose <180mg/dL
Blood pressure <130/80
Lipid control
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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
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CDC cost-analysis
Hypothetical cohort patients >25 yo new
diabetes
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Antihypertensive Therapy
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Intensive Glycemic Control
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Improved quality of life and cost savings age 25-84
Very cost-effective 85-94
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
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Dietary changes and exercise works
20-50% of patients can control their
diabetes with diet, exercise and weight
reduction
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Current trial lookAHEAD is recruiting
patients for lifestyle management study
Exercise
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Exercise training reduces the HgA1c
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Metanalysis of 14 trials duration 8 weeks
HgA1 c 7.65% vs. 8.31% 1
Increased activity reduces risk of MI,
Stroke
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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
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Systematic review of 18 RCT lasting 6
months where dietary advice main
intervention
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Diets examined: low-fat/high –carb, highfat/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:CD004097 [Level 1a]
High Fiber Diet
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13 patients with DM-2 randomized in
crossover fashion 6 week each arm
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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
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8 men with DM-2 at VA facility randomized in
crossover trial
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Low-biologically-available-glucose diet
HbA1c 9.8% vs. 7.6%
Took place in research center 1
Low glycemic meals may reduce
hyperinsulinism
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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
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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
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Initial Monotherapy
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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):2005 1a
Monotherapy
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Glycemic control is more difficult over time
Monotherapy vs. diet over 10 years
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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
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When monotherapy fails
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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
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Less expensive than triple oral therapy
No difference in diabetic control compared
1- Diab Care 2004;27:141 [Level 1b]
2- Diab Care 2003;26:2238 [Level 1c]
2
Medications
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Systematic Review of 63 RCTs duration 3
months reporting HbA1c
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Studied sulfonylureas, metformin, alphaglucosidase inhibitors, thiazolidinediones, nonsulfonylurea secreatagogues
Medications at maximal doses were equally
effective (except nateglinide and alphaglucosidase 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
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Increase insulin secretion by pancreas
Take before meals
Contraindicated in sulfa allergic patients
Second generation safer in renal
disease
Multiple drug interactions
Sulfonylureas
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First generation have more interactions
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Acetoheaxmide
Chlorpropamide
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Tolazamide
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Disulfram reaction more likely
May aggravate CHF or fluid retention
May Cause SIADH
Caution in renal dysfunction
Tolbutamide
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BID dosing decreases GI side effects
Sulfonylureas
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Second-generation agents have fewer
interactions
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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
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52 sulfonylurea-treated subjects with DM
mean age 65 RCT glyburide or glipizide 1
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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
1- JAMA 1998;279(2):1442-3 [Level 1b]
2- JAMA 1999;281(12):1084-5 [Level 1b]
2
Sulfonylureas and hypoglycemia
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Glyburide and TMP-Sulfa associated
with increased risk of hypoglycemia
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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
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Retrospective cohort study 5,795 patients on
first ever oral hypoglycemic
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Mean age 66.3 years followed 4.6 years
4,138 on glyburide
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120 on 1st generation sulfonylureas
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Higher glyburide doses associated with higher mortality
HR 1.3 [CI 1.2-1.4]
Higher doses associated with higher mortality HR 2.1 [14.7]
Unclear if this represents patients who had worse
DM control
CMAJ 2006 Jan 17;174(2):169 LOE 1b
Metformin
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Mechanism
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1
Improves response to insulin
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Decreased endogenous glucose production
Decreased hepatic gluconeogenesis (10-30%)
Increased glucose disposal 13%
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
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Side effects
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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
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Risk factors for lactic acidosis
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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
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Preventive measures
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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
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Dissent on contraindications exists
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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 5
2- BMJ 2003;326(7379):4 Level 5
3- Diabetes Care 2005;28(10):2345 Level 2b
Metformin and B12 deficiency
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About 10% of patients taking
metformin develop low B12 levels
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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 3b
2- Am Fam Physician 2004 Jan 15;69(2):264
Metformin and pregnancy
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No increase in risk for major congenital
malformation
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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
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No difference in efficacy of extended release
vs. immediate release both are available as
generic
Monotherapy
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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
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Systematic review 29 RCT 5,259
patients mean follow-up 3 years
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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
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Trade names
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Rosiglitazone: Avandia
Pioglitazone: Actos
Mechanism of action
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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
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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
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Rosiglitazone monotherapy vs. metformin or
glyburide
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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)
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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
Glitazones
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Pioglitazone may increase risk of heart failure
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Secondary outcome of RCT of 5,238 patients 3565 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)
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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
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Adverse Effects
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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
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Adverse Effects
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Hepatotoxicity
Extracted to some degree from data on
troglitazone and case reports
Review 22 studies >6,000 patients
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LFT measured q4weeks x3 months then q6-12
weeks
ALT Levels >3x ULN
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0.32% rosiglitazone
0.17% placebo
0.4% sulfonylurea, metformin, insulin
Diabetes Care 2002;25(5):815-21 LOE 2b
Glitazones and macular edema
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Adverse Effects
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Macular Edema case reports usually in
patients with peripheral edema 1
Drug Interactions
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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):1319-23 LOE 2b
Glitazones and fractures
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2 post hoc outcomes in separate randomized
trials
Pioglitazone from FDA report 1
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>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
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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
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Trade names
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Acarbose: Precose
Works by inhibiting post-prandial absorption of
glucose
Side effects
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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- Cochrane Library 2005 Issue 2:CD003639 LOE 1c
2- The Medical Letter 1996;38(967):9
1
Pramlintide
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Trade name Symlim
Synthetic analog of human amylin
Use with insulin therapy
Injected prior to major meals
Mechanism of action
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Modulates gastric emptying
Increases feeling of satiety
Injection medication
Adverse effects
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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
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Drug Interactions
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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
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Repaglinide trade name Prandin
Nateglinide trade name Starlix
Repaglinide
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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
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0.5 mg prior to meal
Titrate up to maximum of 4 mg/meal four meals a day
Repaglinide
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May cause fewer symptomatic hypoglycemic
events in the elderly
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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
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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
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Byetta
Used with metformin or sulfonylurea or both
Injected prior to morning and evening meal
Mechanism of action
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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
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Improves glycemic control seen in phase III
trials
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336 patients with DM-2 suboptimal control on
metformin randomized to exenatide vs. placebo
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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
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1
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
2
Exenatide vs. Insulin glargine
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Randomized trial to demonstrate no-inferiority
of exenatide vs. insulin glargine
26 week trial of 551 patients
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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):559-69 LOE 2b
Exenatide
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Adverse Effects
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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
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Increase incretin levels
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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
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521 patients with DM-2 in 18 week trial
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Sitagliptan 100 mg once daily
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HbA1c reduction 1.2%
Sitagliptan 200 mg once daily
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1
2
HbA1c reduction 1.04%
741 patients with DM-2 randomized to
one of two doses of sitagliptan 3
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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
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Bedtime NPH with sulfonylurea
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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:CD003418 LOE1a
3- J Fam Pract 2004;53:393 LOE 2a
Insulin Therapy
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Long acting glargine insulin
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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
Inhaled Insulin
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Trade name Exubera
Inhaled 10 minutes prior to meal dosed in
milligrams
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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
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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 220308
Inhaled Insulin
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Adverse Effects
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Hypoglycemia
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Cough
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Related to rate of absorption and duration of action
Similar rate to injection insulin
Mild and non-productive
Occurs within second to minutes
Decreases with continued use
Dry Mouth
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Mild to moderate severity
Prescriber’s Letter 2006 Detail Document 220308
Inhaled Insulin
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Contraindications
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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
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More HbA1c reduction
More hypoglycemia
1- Prescriber’s Letter 2006 Detail Document 220308
2- Diabetes Care 2006 Aug;29(8):1818
3- Diabetes Care 2006 Jun;29(6):1282
Texas Resources
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Texas Diabetes Council
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http://www.dshs.state.tx.us/diabetes/
Minimum standards flow sheets
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http://www.dshs.state.tx.us/diabetes/hcsta
nd.shtm