Case Presentation

Ted D. Williams, PharmD, RPHSyracuse VAMC

Demographics

• 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

• 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– 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– 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

– 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

Nicks, BA, McGinnis, HD, Borron, SW, Megarbane, B. Lactic Acidosis. eMedicine Updated 05/08/2009. Downloaded from http://emedicine.medscape.com/article/768159-overview

• Impaired Clearance– Resulting in Type B Lactic Acidosis

• Renal Dysfunction • Acid Base Disturbance• Liver Dysfunction

– Inadequate lactate clearance• Malignancies• Drug Induced

KDOQI Stages and Acid Base Balance

• Stage 3, Chronic Kidney Disease (CKD) usually begins to show bicarbonate disturbances & acidosis

Stage GFR

1 >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) Primary as indicated by

I) serum creatinine levels ≥1.5 mg/dL[males], ≥1.4 mg/dL [females]II) abnormal creatinine clearance

b) Secondary to I) cardiovascular collapse (shock)II) acute myocardial infarctionIII) septicemia

2) Known hypersensitivity to metformin hydrochloride.3) Acute or chronic metabolic acidosis,

a) including diabetic ketoacidosis, with or without coma.

4) 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 non-

reduced 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

– 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 60-30 (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– 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– 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– 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 mortalityRisk 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 Summary1. 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

2. 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– 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 dysfunctio

n: Is a serum creatinine threshold appropriate? AJHP 2009:66:2017-2022