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All patients admitted with severe lactic acidosis to a university teaching hospital during a 17-month period were taking phenformin hydrochloride. Serum phenformin concentration was measured in one patient and found to be four to nine times the usual therapeutic concentration. Prerenal azotemia was present at the time of admission in all but one of these patients, but renal function was normal at the time of discharge in those patients with phenformin-associated lactic acidosis who survived. Phenformin-associated lactic acidosis accounted for 7% of the episodes of metabolic acidosis and 27% of deaths due to metabolic acidosis in diabetics.

To the Editor:— We acknowledge our error in the interpretation of the work of Wick et al and extend our apologies to those authors. It is unfortunate that the experience of Dr. Freedman and Mr. Blitz with our method for phenformin assay varied so much from our own. Our comparison (before and after dialysis) of the absorption of extracts of 16 sera, two of which represented pooled specimens from approximately 50 hospitalized patients each, reveals a maximum difference of 11% and a mean difference of 6%. Studies of the effect of added creatinine on the phenformin procedure reveal that creatinine is removed from the original serum so inefficiently that serum creatinine levels at or above 10 mg/100 ml are required before any significant contribution to final ultraviolet absorption is seen. Arginine is not present in sufficient concentration in serum to affect the determination. Furthermore, duplicate determinations on 48 serum specimens

The relative effectiveness of combined oral therapy with tolbutamide and phenformin was studied in a group of 80 clinic patients with ketoacidosis-resistant diabetes mellitus who had been imperfectly or inadequately regulated by a single oral drug. The tolbutamide-phenformin regimen was observed to bring about significant improvement in 70 per cent of patients previously imperfectly controlled by tolbutamide alone and in 60 per cent of patients imperfectly controlled by phenformin alone. Many of the gratifying responses to combination therapy occurred in extremely difficult patients in whom prior therapy with chlorpropamide, metahexamide, and insulin had been unsatisfactory. The results indicate that tolbutamide-phenformin combination therapy is the most potent of the oral antihyperglycemic regimens tested and makes adequate control with oral drugs a practical possibility for most ketoacidosis-resistant diabetics in whom single oral agents have been unsuccessful.

A total of 25 ambulatory diabetic patients were treated with a combination of phenformin (DBI) and a sulfonylurea drug (either tolbutamide or chlorpropamide). These patients had failed to respond fully to treatment with a sulfonylurea drug alone. The therapy was successful in reducing blood sugar to satisfactory levels in 19 patients, but 3 discontinued the treatment because of gastrointestinal intolerance. The therapy was unsuccessful in six patients, owing to the severity of the diabetes. The use of a combination of drugs increases the percentage of diabetic patients for whom oral therapy is applicable and decreases the incidence of side effects.

The authors describe three cases of fatal acidosis observed in women aged 69, 74, and 68 yr. The striking feature was the high concentration of lactic acid in the serum (a maximum of 44 mM/liter in Case 2), as compared with concentrations (maximum 13 mM/liter) found in 23 cases of shock and uremia. The three patients were diabetics who had been treated with phenformin hydrochloride; all had histories of renal disease and infection. The authors recommend caution in the use of phenformin hydrochloride in the treatment of diabetes when renal function has been impaired by acute or chronic disease.

Two cases of diabetic patients on phenformin (phenethylbiguanide) hydrochloride therapy in metabolic acidosis due to lactic acidosis are described. Each had hypotension due to myocardial and mesenteric infarction respectively. Significant ketosis was not present. Altered lactate metabolism has been described in diabetic patients treated with phenformin hydrochloride. It is possible that the hyperlactatemia of vascular collapse may have been magnified by a biguanide block in oxidative metabolism. However, it is equally possible that the association was entirely fortuitous, particularly since lactic acidosis is being described with increasing frequency in patients not receiving phenformin hydrochloride.

Chlorpropamide was given to 479 selected patients during a six-year period. Analysis of results in 339 of these showed that 196 or 58% achieved satisfactory control and 143 or 42%, unsatisfactory control. In the latter group were 31 patients with primary and 17 with secondary failure. Noteworthy is the fact that the 339 patients included 95 whose response previously to other sulfonylureas had been unsatisfactory. Untoward effects were noted in 20 patients: gastrointestinal, nine; skin rash, seven; and symptomatic hypoglycemia, four patients. Jaundice considered due to chlorpropamide hypersensitivity occurred in one patient; in a second patient mild, transient jaundice may have occurred. In certain other patients abnormalities were noted in serial liver function tests but a comparison of findings with those in control subjects failed to reveal significant differences.

The University Group Diabetes Program (UGDP), a long-term prospective clinical trial, was designed to evaluate the effects of various hypoglycemic agents on vascular complications in patients with asymptomatic, adult-onset diabetes. This study provided no evidence that phenformin was more efficacious than diet alone or than diet and insulin in prolonging life for the patients studied. In fact, the observed mortality from all causes and from cardiovascular causes for patients in the phenformin treatment group was higher than that observed in any of the other treatment groups. In addition, there was no evidence that phenformin was more effective than any of the other treatments in preventing the occurrence of nonfatal vascular complications associated with diabetes. For these reasons, the use of phenformin has been terminated in the UGDP. Data collection in this study is continuing for all surviving patients. The additional information obtained over a longer period of follow-up on patients in the two insulin groups compared with the patients in the placebo group will provide a more adequate basis for the assessment of the long-term effects of insulin.

To the Editor:— I read with interest the two articles in the Dec. 24 issue ofThe Journalon combined oral therapy for diabetes. Both of the authors clearly presented and documented their experience and opinions. I believe, however, that one rather important item has been omitted from both articles. I grant that a certain percentage of patients can be controlled on two agents when either one alone is unsuccessful. However, it is generally conceded that this particular type of patient can be controlled with a reasonable amount of depot insulin. Our experience with a similar group of cases supports this idea. I know that the combined oral approach is adaptable for an occasional person with diabetes. However, its potential inconvenience and expense outweighs, in my opinion, most of its advantages. For example, Dr. Unger's patients taking 3 gm. of tolbutamide daily and an average of 159 mg. of phenformin

One hundred and four diabetic patients of both sexes, ranging in age from 4 to 83 years, were studied for seven months in a private office practice to evaluate the effect of phenformin therapy. Most of these patients had had difficulty in controlling their diabetes before taking phenformin. Fair to excellent control was achieved by 91 (88%) with or without adjunctive exogenous insulin; failures which occurred in 13 cases were attributable to gastrointestinal, behavioral, or environmental difficulties. Special importance was attached to the value of combined phenformininsulin therapy in reducing the incidence and severity of hypoglycemic episodes and in improving the control of previously labile patients.