Lactic acidosis in metformin therapy: searching for a link with metformin in reports of 'metformin-associated lactic acidosis'.

OBJECTIVE: The link between metformin and lactic acidosis in metformin therapy may be causal, associated or coincidental. Our objective was to investigate this link by studying and analysing published reports of so-called 'metformin-associated lactic acidosis'. RESEARCH DESIGN AND METHODS: systematically searched in the BIOSIS, DERWENT, EMBASE, MEDLINE, and PASCAL databases of the English language and non-English language literature for all reports of so-called 'metformin-associated lactic acidosis' published from May 1995 through January 2000. We did not include reports related to metformin overdose or contrast media-induced renal failure. Metformin accumulation and concurrent pathologies were critically reviewed as precipitating factors for metformin-associated lactic acidosis. Metformin accumulation was assessed in terms of the recorded measurement of metformin concentration in plasma or, if not available, by the presence of primary renal failure, i.e. renal failure that was not secondary to a shock syndrome. RESULTS: We found 21 reports describing a total of 26 patients. Criteria of lactic acidosis (lactate > 5 mmol/l, pH

Metformin retention independent of renal failure in intestinal occlusion.

Metformin is eliminated by the kidneys, and metformin accumulation has always been noticed in oligo-anuric patients. We have reported an exception to the rule with the case of a metformin-treated patient having metformin accumulation contrasting with a mild increase in serum creatinine in the context of a volvulus of the sigmoid colon. This case prompted us to examine the association between intestinal occlusion and plasma metformin concentrations. For this purpose, we developed an experimental animal model of mechanical obstruction of the intestine. Rats were pre-treated during 3 weeks via drinking solution at a dose of approximately 100 mg/kg/day of metformin. They underwent at day 0 either sham-operation (n=7) or operation (n=8) to place a plastic tube around the ileum near the ileocaecal valve. Metformin administration was pursued on days 1, 2, and 3 giving a single dose of 100 mg/kg by intragastric gavage. Four days after the surgery, i.e. 24 h after the last metformin administration, the surviving intestinal obstructed rats (n=8) developed overt intestinal dilation but no biochemical abnormality compared to sham-operated animals (n=7; arterial lactate concentrations respectively 4.87 +/- 0.63 mmol/l and 3.97 +/- 0.30 mmol/l, NS, and serum creatinine concentrations 69.0 +/- 1.7 micromol/l and 68.7 +/- 1.9 micromol/l, NS). By contrast, there was a striking difference with regard to metformin concentrations, decreasing from 2.95 +/- 0.94 mg/l at day 0 to 0.12 +/- 0.03 mg/l at day 4 (p<0.001) in the sham-operated group but remaining unchanged (1.65 +/- 0.76 mg/l and 1.61 +/- 0.51 mg/l) in the operation group. In conclusion, this is the first experiment showing that intestinal occlusion may be responsible for metformin retention in the absence of renal failure. Whether this observation may be relevant to other drugs remains to be established.

Lactic acidosis in metformin therapy.

The biguanide drugs metformin and phenformin have been linked in the past to lactic acidosis, a metabolic condition associated with high rates of mortality. Although concern over the hyperlactataemic effect of phenformin led to the withdrawal of this drug from clinical practice in the 1970s, the situation with metformin has been less clear. Retrospective data indicate that, in metformin-treated patients with lactic acidosis, neither the degree of hyperlactataemia nor accumulation of metformin is of prognostic significance. Furthermore, the lowest rates of mortality were seen in patients with high plasma concentrations of metformin, which has led to the hypothesis that the drug may confer some benefit, linked to an increase in vasomotility, in such cases. Overall, it appears that mortality in patients receiving metformin who develop lactic acidosis is linked to underlying disease rather than to metformin accumulation, and that metformin can no longer be considered a toxic drug in this respect. These findings are likely to be of considerable relevance to the management of patients with type 2 (non-insulin-dependent) diabetes mellitus, especially where such patients are elderly.

Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations.

OBJECTIVE: The antidiabetic drug metformin has been associated in a small number of patients with lactic acidosis, a serious condition with a poor prognosis. However, because of lack of data, the prognostic significance of hyperlactataemia in metformin-treated patients is not known. METHODS: Data were collected from 49 metformin-treated patients with lactic acidosis (arterial lactate level > or = 5 mmol/L and blood pH < or = 7.35) and available plasma metformin concentration data to investigate the association of arterial lactate levels and plasma metformin concentrations with mortality. RESULTS: The overall mortality rate in this patients sample was 45% and the median arterial lactate level was 13.1 mmol/L. Median lactate levels were similar in patients who survived (13 mmol/L) and those who died (14.3 mmol/L), whereas the median plasma metformin concentration was 3 times higher in patients who survived (20.6 mg/L versus 6.3 mg/L). CONCLUSION: In this, the largest series of metformin-treated patients with lactic acidosis yet reported, 55% of patients survived and these patients had a median arterial lactate level of 13.1 mmol/L. Neither arterial lactate levels nor plasma metformin concentrations were of prognostic significance in relation to mortality in this sample of metformin-treated patients with lactic acidosis. Death in these patients appeared instead to be associated with other hypoxic disease or underlying ill health. These observations suggest that accumulation of metformin may not be as significant with respect to high arterial levels of lactate and their effects as has been traditionally thought.

Vascular and insulinotropic effects of YC 170, a calcium agonist, on isolated perfused rat pancreas.

To explore simultaneously the effects on insulin secretion and on vascular tone of YC 170, a new dihydropyridine derivative calcium agonist, isolated perfused rat pancreases were studied for insulin output and for duodenopancreatic resistances before, during and after exposure to YC 170 10(-4) M (n = 15) or its solvent (n = 10). Although insulin was stimulated transiently during the five first minutes following addition of YC 170 (p less than 0.01) the integrated insulin output measured during the whole experiments was not different with YC 170 from that observed with solvent. Conversely, the initial duodenopancreatic resistances (22 +/- 4 mmHg.ml-1.min-1) rose progressively with YC 170 up to maximal values at the end of experiments (104 +/- 28 mmHg.ml-1.min-1; p less than 0.01); no significant variation occurred with solvent. Vascular and insulinotropic effects of YC 170 can be dissociated, suggesting variable abilities to promote calcium transport across membranes of smooth muscle cells and of pancreatic B-cells.

Microvascularization of the intracranial dura mater.

The authors have studied the microvascularization of the intracranial dura mater by microradiographic and histologic examination of 73 injected anatomic specimens. There exists a very abundant superficial arterial plexus which also serves to supply the inner table of the cranial vault. This plexus is continuous, even at the walls of the venous sinuses and the dural septa. The arteries are for the most part tortuous. The veins may be satellites of the arteries or, on the contrary, from a plexiform network passing through crevices in the interior of the dural layer. The walls of these veins consist only of an endothelium to be seen within the fibrous layer of the dura. Often, the arteries compress the venous lumen; this dangerous situation probably explains the frequent occurrence of arteriovenous fistulae of the dura mater, known by the name of dural fistulae.