Case Presentation

1. Case Presentation Ted D. Williams, PharmD, RPH Syracuse VAMC

2. Demographics • SM • 57 years old male • Date of Birth: OCT 6,1951 • Sex: MALE • Wt. unavailable • Ht.74

3. 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”

4. Laboratory • CrClCG: 59ml/min • eGFR 58ml/min

5. 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

6. 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)

7. 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

8. Treatment Options

9. 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

10. Meformin • Why Metformin • Morbidity & Mortality • Weight Loss • Cost • PO administration • No hypoglycemia • Why Not Metformin • GI Upset • Lactic Acidosis (LA)…

11. 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

12. 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

13. 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

14. KDOQI Stages and Acid Base Balance • Stage 3, Chronic Kidney Disease (CKD) usually begins to show bicarbonate disturbances & acidosis Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. AJKD 2007(49):2 Suppliment 2

15. Prevalence of LA • Estimates vary between 1-9 cases per 100,000 patient years in treated diabetics (metformin and non-metformin)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)

16. Metformin Package Insert Contraindications • Renal disease or renal dysfunction e.g., • Primary as indicated by • serum creatinine levels ≥1.5 mg/dL[males], ≥1.4 mg/dL [females] • abnormal creatinine clearance • Secondary to • cardiovascular collapse (shock) • acute myocardial infarction • septicemia • Known hypersensitivity to metformin hydrochloride. • Acute or chronic metabolic acidosis, • including diabetic ketoacidosis, with or without coma. • Withheld for iodinated contrast materials

17. 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

18. 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

19. Metformin Kinetics Elderly subjects, mean age 71 years (range 65-81 years)

20. 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 AmericanDiabetes 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 studieshave suggested that metformin is safe unless the estimated glomerular filtration rate falls to <30 ml/min [52].”

21. 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)

22. 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)

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. Metformin & Lactic Acidosis Summary • 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) • 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

32. Back to our case…

33. 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

34. 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

35. 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