Transcript Case Presentation

Case Presentation
Ted D. Williams, PharmD, RPH
Syracuse VAMC
Demographics
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SM
57 years old male
Date of Birth: OCT 6,1951
Sex: MALE
Wt. unavailable
Ht.74
Chief Complaint
• An NF for rosiglitazone was submitted to
pharmacy 8/27/09
• Patient had a recent ER visits with a diagnosis
of renal impairment , BUN of 28 and a
creatinine of 1.6.
• Patient was discharged from St. Joseph’s with
a new Avandia (rosiglitazone) prescription.
• “Patient cannot take glyburide as it causes
hypoglycemia episodes”
Laboratory
• CrClCG: 59ml/min
• eGFR 58ml/min
Past Medical History
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Diabetes Mellitus
Hypertension, Essential
Hyperlipidemia
Coronary Artery Disease
Allergic rhinitis
Osteoarthritis
• Diagnosis dates are not available locally or
through remote VISTA data
Past Rx History
• Active
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Albuterol MDI PRN (no dx)
Aspirin 81 mg EC PO daily
Cetirizine 10mg PO daily
HCTZ/Lisinopril 25mg/20mg daily
Ibuprofen 800mg PO TID PRN
Simvastatin 20mg PO QHS
• Inactive
– Metformin 1000mg PO BID (D/C 8/27/09)
– Glipizide 5mg PO daily (D/C 8/27/09)
Additional Information
• Very little information is available on this
patient
– Eight progress notes locally
– No scanned documents from hospitalization
• A progress note on 5/14/2009 indicated that
the patient has been taking metformin and
glipizide since 2005
• ADR
– Codeine N/V, Syncope
Treatment Options
Rosiglitazone
• MOA
– PPAR- Agonist
• Increase peripheral tissue insulin uptake
• Reduce plaque formation(?)
• Side effects
– Edema (15%)
• Contraindicated in heart failure
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Weight Gain (ADOPT Trial 3.5kg)
Bone Fractures in women
Increased cardiovascular risk
Case reports of macular edema
• Non-Formulary
Meformin
• Why Metformin
– Morbidity & Mortality
– Weight Loss
– Cost
– PO administration
– No hypoglycemia
• Why Not Metformin
– GI Upset
– Lactic Acidosis (LA)…
Lactate Metabolism
• Lactic Acid Production
– Anaerobic Metabolism
– Without oxygen, we
ferment
• Lactate is cleared
primarily by the liver
• Lactic Acid Levels1
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Normal healthy <1mmol/L
Chronic Illness 1-2mmol/L
Hyperlactaemia 2-4mmol/L
Lactic Acidosis >4mmol/L
Diagram from Acar, S. Downloaded from
http://www.fde.metu.edu.tr/personal_sites/haluk/seyda_acar_files/Seyda%201.gif
Lactic Acidosis Risk Factors – Hypoxic
• Promoting Lactic Acid Production
– Resulting in Type A Lactic Acidosis
– Ischemia & reduced tissue perfusion
• Shock
• ACS
• Reduced Cardiac Output (HF)
– Respiratory Failure
• COPD
• Asthma
Nicks, BA, McGinnis, HD, Borron, SW, Megarbane, B. Lactic Acidosis. eMedicine Updated 05/08/2009.
Downloaded from http://emedicine.medscape.com/article/768159-overview
Lactic Acidosis Risk Factors – Non-Hypoxic
• Impaired Clearance
– Resulting in Type B Lactic Acidosis
• Renal Dysfunction
• Acid Base Disturbance
• Liver Dysfunction
– Inadequate lactate clearance
• Malignancies
• Drug Induced
Nicks, BA, McGinnis, HD, Borron, SW, Megarbane, B. Lactic Acidosis. eMedicine Updated 05/08/2009.
Downloaded from http://emedicine.medscape.com/article/768159-overview
KDOQI Stages and Acid Base Balance
• Stage 3, Chronic
Kidney Disease
(CKD) usually
begins to show
bicarbonate
disturbances &
acidosis
Stage
GFR
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>90
2
60-90
3
30-59
4
15-29
5
<15
Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney
Disease. AJKD 2007(49):2 Suppliment 2
Prevalence of LA
• Estimates vary between 1-9 cases per 100,000
patient years in treated diabetics (metformin
and non-metformin)1
1.
Salpeter, SR, Greyber, E, Pasternak, GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with
metformin use in type 2 diabetes mellitus (Review). Cochrane Collaboration 2006 (updated September
2007, re-published 2009)
Metformin Package Insert
Contraindications
1)
Renal disease or renal dysfunction e.g.,
a)
b)
2)
3)
Known hypersensitivity to metformin hydrochloride.
Acute or chronic metabolic acidosis,
a)
4)
Primary as indicated by
I)
serum creatinine levels ≥1.5 mg/dL[males], ≥1.4 mg/dL [females]
II)
abnormal creatinine clearance
Secondary to
I)
cardiovascular collapse (shock)
II)
acute myocardial infarction
III)
septicemia
including diabetic ketoacidosis, with or without coma.
Withheld for iodinated contrast materials
Metformin Package Insert
Black Box
• LA fatal in 50% of cases
• Unstable HF at risk of LA
• Elderly
– Careful monitoring of renal function
– Over 80, do not initiated UNLESS measured CrCl indicates nonreduced renal function
• i.e. don’t assume adequate renal function
• Withhold for
– hypoxia
– dehydration
– sepsis
• Avoided in hepatic disease
• Avoid excessive drinking, potentiate metformin's lactate
production
Phenformin vs Metformin
• Biguanides inhibit gluconeogenesis from
lactate
– Phenformin more potent, affects hepatic and
peripheral lactate production
– Metformin is not believed to affect peripheral
lactate production
• Phenformin was withdrawn due to 40-64
cases of LA per 100,000 patient years
Metformin Kinetics
Elderly subjects, mean age 71 years (range 65-81 years)
ADA/ EASD Consensus
Recommendations
• Reference
– Nathan, DM, Buse, JB, Davidson, MB, Ferrannini, E, Holman, RR,
Sherwin, R, Zinman, B. Medical management of hyperglycaemia in
type 2 diabetes mellitus: a consensus algorithm for the initiation and
adjustment of therapy: A consensus statement from the American
Diabetes Association and the European Association for the Study of
Diabetes Diabetologia (2009) 52:17–30
• “Renal dysfunction is considered a contraindication to
metformin use because it may increase the risk of lactic
acidosis… However, recent studies have suggested that
metformin is safe unless the estimated glomerular filtration
rate falls to <30 ml/min [52].”
Area 52
• Reference
– Shaw, JS, Wilmot, RL, Kilpatrick, ES. Establishing pragmatic estimated
GFR thresholds to guide metformin prescribing. Diabetic Medicine
2007:24;1160–1163.
• Study Objective
– establish “pragmatic” eGFR cut-offs for metformin based on
recommended serum creatinine (SCr)
• Design
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Retrospective chart review
n=12,482 patients (6,712 males, 5,770 females)
Median age 67 years
Compare serum creatinine (SCr) cutoffs with eGFR
• 130μmol/L females (1.47mg/dL)
• 150 μmol/L males (1.7mg/dL)
Area 52
• For males
recommended SCr
150mcmol/L eGFR
~55-45
• For females, eGFR
~50-40
• No patients had a
eGFR less than 30
(CKD Stage 4)
• Most had an eGFR 6030 (CKD Stage 3)
Exit 52
• Author’s Conclusions
– Stage 4 CKD Absolute Contraindication
– Stage 3 CKD Relative Contraindication, based on other risk
factors
• Safety
– No intervention was performed in this study to validate
the safety
– The authors did not report if there were any documented
cases of LA in their patient population
– Authors cited Cochrane review (2006) for safety data
Cochrane Review
• Salpeter, SR, Greyber, E, Pasternak, GA,
Salpeter EE. Risk of fatal and nonfatal lactic
acidosis with metformin use in type 2 diabetes
mellitus (Review). Cochrane Collaboration
2006 (updated September 2007, re-published
2009)
• Pooled data from 274 trials of metformin
– 59,321 patient years for metformin
– 51,627 patient years for non-metformin
Cochrane Review
• No reported incidence of lactic acidosis in either group
– Poisson statistics determined upper limit of the incidence
of lactic acidosis 5.1 in metformin, 5.9 in non-metformin
• Exclusions to studies
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SCr >1.5mg/dL (55%)
Cardiovascular disease (45%)
Liver disease (52%)
Pulmonary disease (15%)
Age >65 (14%)
• No significant change in lactate levels between
metformin and non-metformin groups in the studies
which reported lactate levels
Safety Above 1.5mg/dL
• Rachmani, R, Slavachevski, I, Zohar, L, Bat-Sheva, Z, Kedar, Y, Mordachai, R.
Metformin in patients with type 2 diabetes mellitus: reconsideration of
traditional contraindications. European Journal of Internal Medicine
2002;13:428-433)
• Prospective study of patients admitted to a single facility already on
metformin
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n=393
Randomized, non-blinded
Follow up for 4 years
Mean SCr 1.8
Meanu Albumin to Creatinine Ration (ACR) 46+/-10
• All patients had at least one additional risk factor for LA
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CAD 68%
HF 24%
COPD 23%
Liver Disease 13% (Excluding Cirrhosis)
• No incidence of LA in either group
Prediction of Metformin-Induced LA
• Seidowsky, A, Saad, N, Houdret, N, Fourrier, F.
Metformin-associated lactic acidosis: A
prognostic and therapeutic study. Critical Care
Medicine 2009;30:2191-2196
• Ten year retrospective study
– ICU patients for metformin-associated LA
– n=42
• Group 1 (Intentional overdose) n=13
• Group 2 (All others) n=29
Prediction of Metformin-Induced LA
• Patient Characteristics
– 50% Shock
– 45% Mechanical Ventilation
– 75% Acute Renal Failure (ARF)
• Group 2
– Admission reason circulatory or respiratory failure
with multi-organ dysfunction
– Mortality rate 48%
• Predictors of survival
– Age, Lactate, pH, organ dysfunction, PT activity
– Metformin levels not associated with mortality
Evaluation of LA Case Reports
• Stades, AME, Heikens, JT, Erkelens, SW, Holleman,
F, Hoekstra, JBL. Metformin and lactic acidosis:
Cause or coincidence? A review of case reports.
• Literature search from 1959-1999 identified 80
published case reports
• 47 cases met inclusion criteria for review
– One case had no additional risk factors
– Three cases had two or more additional risk factors
– 44 cases had one additional risk factor
Evaluation of LA Case Reports
• Metformin concentration above 5mcg/mL
NOT associated with LA
• Not associated with mortality
– Serum Metformin concentrations (p=0.19)
– Lactic Acid concentrations(p=0.16)
• Risk factors for mortality
Risk Factor
Odds Ratio
95% CI
Acute Cardiovascular Event
67
1.4-3148
Liver Cirrhosis
41
1.2-1445
Sepsis
23
2.4-216
Metformin & Lactic Acidosis Summary
1.
2.
Although renal impairment can increase metformin serum
concentrations, there has been no evidence to show an
association between metformin use or serum concentrations and
the incidence of lactic acidosis
Kinetic and epidemiological data suggests that metformin can be
used safely in patients with diminished renal function
– eGFR is preferred over serum creatinine
– eGFR 30-60 (KDOQI Stage 3) is a relative contraindication
• suggest dose NTE 500mg BID
• This is more aggressive than FDA contraindications allows
– eGFR <30 absolute contraindication (KDOQI Stage 3)
3.
Patients with multiple risk factors for lactic acidosis should be
evaluated carefully, even if their renal function is acceptable
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Sepsis
Congestive Heart Failure
Severe Respiratory Disease
Hepatic Disease
Back to our case…
Case Assessment
• Patient had metformin held due to elevated creatinine
during hospitalization, which is in accordance with the
package insert, guidelines, and accepted practice
• Diabetes has been well controlled on metformin and
glyburide with A1C at goal (6.4%)
• Patient’s SCr of 1.6mg/dL is a contraindication
according to the package insert
• eGFR of 58 is a relative contraindication according to
ADA Consensus Guidelines
– No diagnosis of hypoxic LA risk factors
– Stage 3 KD with eGFR 58 is a risk factor for acidosis, but
normal bicarbonate levels of 23 and 25
Case Plan
• Medications
– Recommend resume metformin at a reduced dose of
500mg BID
• Titrate dose based on response and any future renal
function changes
– Recommend resume glipizide 5mg PO daily
• If A1C not a goal, consider increasing glipizide to 5mg PO BID
• Monitoring
– Reassess A1C in 3 months
– Renal function: SCr, BUN, eGFR, bicarbonate
• NF for rosiglitazone not approved
Post Hoc Notes
• In November 2009, AJHP published a similar
review of the literature
– Philbrick, et al. Metformin use in renal
dysfunction: Is a serum creatinine threshold
appropriate? AJHP 2009:66:2017-2022