3/30/2012

The use of metformin in diabetic patients with chronic kidney disease.

Marissa Quinones, Pharm.D. Clinical Pharmacy Specialist Parkland Health and Hospital Southeast Dallas Health Center

Conflicts of Interest

None

Objectives
Review the history and contraindications of metformin in patients with chronic kidney disease. Evaluate the current literature regarding the use of metformin in patients with chronic kidney disease. Provide recommendations for the use of metformin in chronic kidney disease.

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Patient Case
65 year old obese AAF presents for diabetes PMH: DM type 2, HTN, HLD, h/o CAD, Stage 1 CKD Medications
Metformin 1000mg BID Glyburide 10mg BID Rosuvastatin 10mg daily Lisinopril/HCTZ 20/12.5mg daily Metoprolol 100mg BID

Patient Case, Cont.

Labs:
BP 133/81 HR 67, Wt 90kg HbA1c = 7.5% Increased to SCr = 1.3 LDL 72, TG 188, TC 183, HDL 41

Doctor calls you and wants to know if Metformin should be continued?

History of Metformin
In 1977s, phenformin removed due to cases of lactic acidosis (not safe) Metformin released for use in the U.S. in 1995

Metformin used widely as a 1st line agent in treatment of Type 2 diabetes

Figure. Pharmacological Approaches to the Major Metabolic Defects of Type 2 Diabetes Mellitus.

JAMA 2002;287:360-372. Int Urol Nephrol 2008;40:411-417

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Advantages and Disadvantages of Metformin

Advantages
Great & Old Drug No hypoglycemia Weight loss Reduces mortality and morbidity in Type 2 Decreases microvascular and macrovascular risk Other benefits A1c lowering 1.5-2% Used in PCOS/Prevention of DM

Disadvantages
Adverse events
GI upset (N/V/D)

Elimination unchanged in the kidney Contraindications

SCr 1.4 mg/dL (females); 1.5 mg/dL (males)

Cases of lactic acidosis (rare)

Risk is minimal per recent Cochrane review

JAMA 2002;287:360-372. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD002967. Diabetes Care 2011;34(6):1431-1437.

Metformin and Renal Impairment

Subjects (n) Adults with Type 2 DM 850mg single dose (23) 850mg TID for 19 doses (9) Mild (CrCl 61-90 ml/min) (5) Moderate (CrCl 31-60 ml/min) (4) Severe (CrCl 10-30 ml/min) (6) 1.48 ( 0.5) 1.90 ( 0.62) 1.86 ( 0.52) 4.12 ( 1.83) 3.93 ( 0.92) 3.32 ( 1.08) 2.01 ( 1.22) 3.20 ( 0.45) 3.75 ( 0.50) 4.01 ( 1.10) 491 ( 138) 550 ( 160) 384 ( 122) 108 ( 57) 130 ( 90) Cmax* (mcg/ml) Tmax (hrs) Renal Clearance (ml/min)

Adults with Renal impairment- 850mg single dose

*peak plasma concentration, time to peak concentration, CrCl = creatinine clearance normalized to body surface area of 1.73 m2

Glucophage Package Insert. Available at: http://packageinserts.bms.com/pi/pi_glucophage.pdf J Clin Pharmacol 1995; 35(11): 1094-1102. Abstract

Metformin and Kidney Disease

The Problem
decreased renal impairment / CrCl decreases = = decreased renal clearance / longer half-life (t ) = metformin accumulation = potential concerns for lactic acidosis (again rare) We want good control of diabetes in CKD

What do we do?

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Deaths related to complications

Predicted absolute number of deaths caused by life-threatening complications of metformin, sulfonylurea's, and insulin Metformin associated lactic acidosis
Incidence of lactic acidosis or severe hypoglycemia in Type 2 DM (number per 100,000 patient yrs) Mortality (%, most pessimistic available figure)

Sulfonylurea induced hypoglycemia 1,000 [2]

InsulinInduced hypoglycemia 1,800 [2]

6.3 [4]

50% [22]

4.3% [21]

4.3% [21]

Predicted absolute no. of deaths (number per 100,000 pt years)

43

77.4

Taken from Table 1: Int Urol Nephrol 2008;40:411-417

Metformin Prescribing in Renal Impairment

Episodes Total number of subjects Continued metformin after event Started metformin at time of event Stopped Metformin after event 148 88 59 (67%) 7 (8%) 22 (25%)

Of notes, only 1 episode of lactic acidosis was identified in the study. A 72 year old patient on metformin with normal renal clearance who had an MI and developed acute renal failure and died

Package insert vs. FDA recommendations

Guideline Glucophage Package Insert Recommendation -Renal disease or renal dysfunction - SCr 1.4 (females); 1.5 (males) or abnormal CrCl. Need to monitor closely in those with renal disease and elderly -No real guide regarding CrCl cut off FDA -Stop if serum creatinine 1.4 mg/dL in women and 1.5 mg/dL in men Or -Decreased clearance in people over age 80

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What do the guidelines say?

Guideline ADA Guidelines KDOQI Guidelines Recommendation Contraindicated in renal dysfunction. Safe unless GFR falls to <30ml/min Serum creatinine of 1.5 mg/dL or greater in men and 1.4 mg/dL or greater in women it is cleared by the kidney and may build up with even modest impairment of kidney function, putting patients at risk of lactic acidosis -Stage 1-2 (>89ml/min) as long as stable renal function in last 3 months -Stage 3 (30-59ml/min) continue in stable CKD -Stop if acute changes in renal function or illness (GI upset, dehydration) or hypoxia (cardiac or respiratory failure)
AJKD 2007; 49(2)S1-S180. CMAJ 2008; 179(11): 1154-1162. Diabetes Care 2009; 31(1): 193-203.

Canadian Clinical Guidelines

Review by Herrington and Levy 2008 Metformin: effective and safe in renal disease?
Guideline/Paper British National Formulary (BNF) Jones, et. al. Canadian Pharmacists Association McCormack, et. al. Recommendation Warning not to use metformin in mild renal impairment (GFR 20-50ml/min) SCr absolute cut off point of 1.7mg/dL; use caution in elderly SCr 1.5 in males and 1.4 females; caution in advanced age (>80) unless CrCl not reduced Acknowledged problem with use of SCr alone; use CrCl based on PK principles reduce the max dose of metformin by 50% when CrCl decreases < 60ml/min Use Cockcroft Gault; absolute cut off GFR of 30ml/min (discontinue metformin); GFR 30-50ml/min extreme caution Int Urol Nephrol 2008;40:411-417. JAMC 2005; 173(5): 502-504.

Nisbet, et.al.

MJA 2004; 180(2): 53-54.

Patient Case, Cont

Although pts SCr is 1.3 Lets calculate her CrCl
Using MDRD = 49 ml/min Using Cockcroft Gault = 61.3 ml/min

What do we do? Her SCr is not at the cut off but her clearance has decreased.

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Herrington and Levy 2008

Recommend
Stage 1 2 (GFR 60 90 ml/min): continue but may reduce starting dose of metformin by 50% Stage 3 (GFR 30 60 ml/min): use with caution, then further reduce metformin dose by another 50%
Weight risk versus benefit

Stage 5 (GFR < 30 ml/min): do not use Stop in acute or chronic hypoxia, acute renal function (MI, sepsis, shock, surgery), contrast imaging
Int Urol Nephrol 2008;40:411-417.

Lipska, et. al.

Proposed recommendations for use of Metformin based on eGFR
eGFR level
60 (stage 1-2) <60 and 45 (stage 3) <45 and 30 (stage 3-4) <30 (stage 5)

Action
-No renal contraindication to metformin -Monitor renal function annually -Increase monitoring of renal function (every 3-6 months) -Prescribe metformin with caution -Use lower doses (e.g., 50% or half-maximal dose) -Closely monitor renal function (every 3 months) -Do not start new patients on metformin -Stop Metformin

Diabetes Care 2011;34(6):1431-1437.

Conclusion
Lack of studies using metformin with renal impairment
Pharmacokinetic studies were small patients usually healthy on single doses of metformin Little is known about prolonged therapy in renal disease

No good evidence base Use of SCr versus CrCL?

What do we use Cockcroft Gault versus MDRD

Must consider risk versus benefit

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Patient Case, Cont.

Once pt reaches Stage 3 we must consider the risk versus the benefit
Can decrease dose by 50% to 500mg BID

AND NEED TO CAREFULLY MONTIOR SCr Will need insulin therapy

Questions
Marissa E. Quinones, Pharm.D. Clinical Pharmacy Specialist Southeast Dallas Health Center Community Oriented Primary Care Clinic 9202 Elam Road Dallas, TX 75217 E-mail: marissa.quinones@phhs.org Office: 214-266-1738 Pager: 214-786-4875