Case Study: Metformin-Associated Lactic Acidosis - Caus...

Case Study: Metformin-Associated Lactic Acidosis

Case Study: Metformin-Associated Lactic Acidosis
Could orlistat be relevant?
Dana Dawson, MBBS, MRCP1 and Christopher Conlon, MD, FRCP2

1 Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, U.K.
2 Nuffield Department of Medicine, University of Oxford, Oxford, U.K

Address correspondence to Dana Dawson, MBBS, MRCP, Cardiovascular Department, Rm 5810, Level 5, John Radcliffe Hospital, Oxford, OX3 9DU, U.K. E-mail: dana.dawson@cardiov.ox.ac.uk and dana.dawson@doctors.org.uk

Lactic acidosis is a rare (1) but serious complication of metformin therapy with a high fatality rate (2). In the majority of reported cases there is a preexisting disease, most often a degree of renal impairment. We present a case of metformin-associated lactic acidosis (MALA) where drug interactions (orlistat in the long term and cimetidine over a short period of time) may have potentiated the condition.

A 59-year-old woman with type 2 diabetes for 14 years presented with a history of 3 months of vague abdominal pain and four to five loose bowel movements daily, which worsened over the 4 days before admission to hospital. On the day of admission she reported weakness, dizziness, and blurred vision. Her husband had noticed slurred speech and a reduced level of consciousness.

There was a past history of a healed duodenal ulcer and obesity. She had documented normal renal function 4 months before this admission (urea 5.7 mmol/l and creatinine 105 µmol/l). Her diabetes was well controlled on metformin at 500 mg t.i.d. for the past 8 years. Three months before admission she started orlistat at 120 mg t.i.d., which coincided with the onset of the abdominal pain and chronic diarrhea. During the 4 days before admission, as her abdominal pain worsened, cimetidine (400 mg b.i.d.) was prescribed on the presumption of reactivation of her duodenal ulcer.

Clinical examination showed an obese woman who was agitated and confused, with a Glasgow Coma Scale of 10/15. She was apyrexial, with a pulse of 70 bpm in sinus rhythm, blood pressure 85/40 mmHg, and O2 saturation 97% on air. General examination was otherwise unremarkable; in particular there was no evidence of diabetic retinopathy or neuropathy.

Preliminary laboratory investigations showed a life-threatening metabolic acidosis with a pH of 6.5, bicarbonate of 2 mmol/l, and base excess of -38 mmol/l. The blood glucose was 5.6 and serum lactate 23.1 mmol/l. Her renal function was markedly impaired with a urea of 48.8 mmol/l and a creatinine of 753 µmol/l. Electrolytes, liver function, amylase, and inflammatory markers were normal. A blood metformin level measured 30 mg/l (therapeutic levels <2 mg/l).

The chest radiograph was normal, as was the electrocardiogram. A urinary catheter yielded a small amount of urine, which showed a trace of protein on dipstick testing. Central venous pressure was 1 cm H2O. Renal ultrasound ruled out obstruction.

A diagnosis of metformin-associated lactic acidosis with cardiovascular collapse and acute prerenal renal failure was made.

She required vigorous rehydration, sodium bicarbonate infusion, inotropic support, and renal replacement therapy. All cultures of blood, urine, and feces were sterile. Three years after this episode she is dialysis independent and her renal function has stabilized with a creatinine of 250 µmol/l.

So, what could have triggered MALA in a patient with previously normal renal function? As the mechanism of this condition is not known, treatment options are supportive and usually aim to stop the drug, correct the acidosis, and treat contibutory underlying conditions, most often renal impairment (3). Renal replacement therapy not only removes lactate but also removes metformin from the blood. Metformin is absorbed relatively quickly at the intestinal level, is not metabolized, and 90% of the drug is eliminated by glomerulofiltration and tubular secretion (1). Its half-life is between 1.5 and 5 h. Compared with phenformin, it produces a minimal increase in lactate productionÛthis appears to be via the extrahepatic splanchnic bed, with animal studies favoring the small intestine as site of origin (4). Metformin interacts with few other drugs, but a relevant interaction is its competitive inhibition for renal tubular secretion by cimetidine, resulting in decreased metformin renal clearance (5). Most cases of MALA occur in the setting of impaired renal function when plasma levels of metformin would be expected to rise (6). Intuitively, most studies relate the level of metformin to the degree of acidosis and to the outcome; recent work suggests that this is not necessarily the case (1,7).

The pharmacokinetic interactions of orlistat, a pancreatic lipase inhibitor that reduces intestinal absorbtion of dietary fat by up to 37% (8), have only recently been explored (9). With the exception of cyclosporine, there were no reported drug interactions. By far the most frequent adverse event during orlistat therapy is gastrointestinal upset (8,10). To date, there is one randomized-controlled study that compared orlistat with placebo in patients with type 2 diabetes on concurrent metformin therapy (11); the value of orlistat in achieving weight loss, alongside better glycemic control, lower cholesterol levels, and systolic blood pressure, is indisputable in both diabetic (11,12) and nondiabetic (8) patients. Of note are consistent gastrointestinal side effects reported by the orlistat group; however, no cases as extreme as our patient are reported.

We postulate two possible ways that orlistat could have played a role in the development of lactic acidosis in our patient:

1) It is possible that chronic diarrhea caused by orlistat may have led to a degree of renal impairment. Rising metformin levels may have increased the probability of intestinal upset of metformin itself (which also causes nausea, epigasrtic discomfort, and diarrhea), continuing a vicious circle of increasing renal failure. The final addition of cimetidine in an attempt to treat the gastrointestinal symptoms might have further impaired metformin excretion, precipitating the onset of lactic acidosis.

2) An alternative, though not exclusive, possibility is that orlistat affected intestinal handling of metformin and/or lactate. Metformin is concentrated more in the intestine than in the plasma, and it is known that there is a metformin-induced conversion of glucose to lactate in the intestinal mucosa (13,14). It is possible that orlistat, by affecting the fat absorption in the small intestine, may alter intestinal metformin levels, leading to either increased metformin absorption or driving the conversion of glucose to lactate. This process may have been exacerbated by cimetidine reducing the excretion of metformin.

In conclusion, the combination of metformin and orlistat (although safe in all studies reported so far) should be closely monitored, especially if the patient is also taking cimetidine.

References

1. Davidson MB, Peters AL: An overview of metformin in the treatment of type 2 diabetes mellitus (Review Article). Am J Med 102:99Ò110, 1997[Medline]
2. Chan NN, Brain HP, Feher MD: Metformin-associated lactic acidosis: a rare or very rare clinical entity (Review Article) Diabet Med16:273Ò281, 1999
3. Lalau JD, Race JM: Lactic acidosis in metformin therapy. Drugs 58(Suppl. 1):55Ò60, 1999
4. Bailey CJ, Wilcock C, Day C: Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol 105:1009Ò1013, 1992[Medline]
5. Somogyi A, Stockley C, Keal J, Rolan P, Bochner F: Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol 23:545Ò551, 1987[Medline]
6. Sulkin TV, Bosman D, Krentz AJ: Contraindications to metformin therapy in patients with NIDDM. Diabetes Care 20:925Ò928, 1997[Abstract]
7. Lalau JD, Lacroix C, Compagnon P, de Cagny B, Rigaud JP, Bleichner G, Chauveau P, Dulbecco P, Guerin C, Haegy JM: Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care 18:779Ò784, 1995[Abstract]
8. Sjostrom L, Rissanen A, Andersen T, Boldrin M, Golay A, Koppeschaar HP, Krempf M: Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients: European Multicentre Orlistat Study Group. Lancet 352:167Ò172, 1998[Medline]
9. Zhi J, Moore R, Kanitra L, Mulligan TE: Pharmacokinetic evaluation of the possible interaction between selected concomitant medications and orlistat at steady state in healthy subjects. J Clin Pharmacol 42:1011Ò1019, 2002[Abstract]
10. Torgerson JS, Arlinger K, Kappi M, Sjostrom L: Principles for enhanced recruitment of subjects in a large clinical trial: the XENDOS (XENical in the prevention of Diabetes in Obese Subjects) study experience. Control Clin Trials 22:515Ò525, 2001[Medline]
11. Miles JM, Leiter L, Hollander P, Wadden T, Anderson JW, Doyle M, Foreyt J, Aronne L, Klein S: Effect of orlistat in overweight and obese patients with type 2 diabetes treated with metformin. Diabetes Care 25:1123Ò1128, 2002[Abstract/Free Full Text]
12. Kelley DE, Bray GA, Pi-Sunyer FX, Klein S, Hill J, Miles J, Hollander P: Clinical efficacy of orlistat therapy in overweight and obese patients with insulin-treated type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care 25:1033Ò1041, 2002[Abstract/Free Full Text]
13. Lalau JD, Race JM, Brinquin L: Lactic acidosis in metformin therapy: relationship between plasma metformin concentration and renal function (Letter). Diabetes Care 21:1366Ò1367, 1998[Medline]
14. Lalau JD, Race JM, Andreelli F, Lacroix C, Canarelli JP: Metformin retention independent of renal failure in intestinal occlusion. Diabetes Metab 27:24Ò28, 2001[Medline]