Phenethyldiguanide: A Dangerous Sideeffect

Walker, Robert; Linton, A. L.

doi:10.1136/bmj.2.5158.1005

Cited by 39 publications

(12 citation statements)

References 11 publications

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“…Between 1959 and 1977 at least 429 cases were reported which fit the criteria previously mentioned [6,. In 99 cases the clinical, laboratory, and treatment data could not be associated with specific patients, so that these had to be excluded, leaving a total of 330.…”

Section: Resultsmentioning

confidence: 98%

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Lactic acidosis in biguanide-treated diabetics

1978

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The paper presents an analysis of clinical symptoms, signs and laboratory data of 330 diabetic patients who developed lactic acidosis after having been treated with biguanides (phenformin, buformin, metformin). From the review of the literature an attempt is made to find special features that predisposed patients to develop lactic acidosis such as accompanying illnesses and additional medications, to describe the course of illness and also the factors that influenced the prognosis. Of the patients that developed lactic acidosis 50.3% died. These patients were older, they suffered more frequently from cardiovascular shock, their acidosis was more severe, the whole blood lactate concentration was higher, and the degree of renal insufficiency was more advanced. From our observations we conclude the the treatment of diabetes mellitus with biguanides should be reserved for specially selected patients.

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Section: Resultsmentioning

confidence: 98%

“…Metformin (1,1-dimethyl-biguanide). Walker and Linton [6] in 1959 described the clinical picture of severe metabolic acidosis without ketosis in biguanide-treated diabetics. The accumulation of lactic acid soon became recognized as the cause of the acidosis.…”

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confidence: 98%

Lactic acidosis in biguanide-treated diabetics

1978

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“…A significant increase in ketone body concentra-tions was found in our patients on biguanide therapy. This has received scant attention previously although isolated reports of increased ketonaemia have appeared [32,33] and a small increase in 3-hydroxybutyrate concentration was noted in patients taking buformin [34]. This could be explained by the more reduced state within the cell.…”

Section: Discussionmentioning

confidence: 99%

Comparative effects of phenformin, metformin and glibenclamide on metabolic rhythms in maturity-onset diabetics

et al. 1977

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Twelve hour metabolic rhythms have been performed on six maturity-onset diabetic subjects during successive periods of therapy with phenformin, metformin, and glibenclamide. Moderate control of blood glucose concentration was achieved with phenformin and metformin, the lowest concentrations being found with glibenclamide. Mean blood lactate concentration was grossly elevated during phenformin therapy, moderately elevated with metformin and normal during glibenclamide treatment. Similar patterns were found for the lactate/pyruvate ratio, alanine, glycerol and ketone bodies. Serum triglyceride concentrations were significantly higher during phenformin treatment than with the other two regimes. Serum insulin concentration was higher on glibenclamide than with either biguanide. Most of these effects of the biguanides could be accounted for by an inhibitory effect on hepatic gluconeogenesis. It is concluded that the use of biguanides as hypoglycaemic agents in diabetes is associated with the production of multiple metabolic abnormalities.

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“…The risk of lactic acidosis, especially with phenformin and buformin, was evident from the outset, and the controversy was fuelled when phenformin was withdrawn from the University Group Diabetes Program (UGDP) trial in the USA in 1971 [46][47][48]. Phenformin was removed from the market in the USA in 1978, and phenformin and buformin were discontinued in much of Europe around this time, although both agents can still be obtained in some countries [49].…”

Section: Lactic Acidosismentioning

confidence: 99%

Metformin: historical overview

2017

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Metformin (dimethylbiguanide) has become the preferred first-line oral blood glucose-lowering agent to manage type 2 diabetes. Its history is linked to Galega officinalis (also known as goat's rue), a traditional herbal medicine in Europe, found to be rich in guanidine, which, in 1918, was shown to lower blood glucose. Guanidine derivatives, including metformin, were synthesised and some (not metformin) were used to treat diabetes in the 1920s and 1930s but were discontinued due to toxicity and the increased availability of insulin. Metformin was rediscovered in the search for antimalarial agents in the 1940s and, during clinical tests, proved useful to treat influenza when it sometimes lowered blood glucose. This property was pursued by the French physician Jean Sterne, who first reported the use of metformin to treat diabetes in 1957. However, metformin received limited attention as it was less potent than other glucose-lowering biguanides (phenformin and buformin), which were generally discontinued in the late 1970s due to high risk of lactic acidosis. Metformin's future was precarious, its reputation tarnished by association with other biguanides despite evident differences. The ability of metformin to counter insulin resistance and address adult-onset hyperglycaemia without weight gain or increased risk of hypoglycaemia gradually gathered credence in Europe, and after intensive scrutiny metformin was introduced into the USA in 1995. Long-term cardiovascular benefits of metformin were identified by the UK Prospective Diabetes Study (UKPDS) in 1998, providing a new rationale to adopt metformin as initial therapy to manage hyperglycaemia in type 2 diabetes. Sixty years after its introduction in diabetes treatment, metformin has become the most prescribed glucose-lowering medicine worldwide with the potential for further therapeutic applications.

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Phenethyldiguanide: A Dangerous Sideeffect

Cited by 39 publications

References 11 publications

Lactic acidosis in biguanide-treated diabetics

Lactic acidosis in biguanide-treated diabetics

Comparative effects of phenformin, metformin and glibenclamide on metabolic rhythms in maturity-onset diabetics

Metformin: historical overview

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