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Insulin, glucagon and oral hypoglycemic drugs
H.M.J. Krans
44
Insulin, glucagon and oral hypoglycemic drugs
INSULIN (SED 9, 705; SEDA-4, 298; SEDA-5, 386; SEDA-6, 367) The availability of human insulin may affect the insulin market in the near future. It has not yet been proven that the theoretical advantages o f synthetic human insulin (less allergic reactions and a decrease in insulin resistance) justify the increased cost of prescription; the psychological effect of treatment with a 'natural' insulin, however, will certainly stimulate a substantial use of synthetic human insulin. The major sources of human insulin are recombinant DNAtechniques or a chemical modification of porcine insulin in which the C-terminal amino acid of the B-chain phenylalanine is replaced by threonine (see SEDA-6, 367). A short review paper on the control of drugs produced by recombinant DNA-technology has been published ( 1). Allergic reactions (SED 9, 707; SEDA-4, 299; SEDA-5, 389; SEDA-6, 369) It has become increasingly evident that some allergic reactions are elicited by insulin itself and not by impurities or additions. The type of allergy is variable. In a randomized clinical study 20 diabetic patients were treated with Des-phe-insulin (insulin from which the C-terminal amino acid in the B-chain has been deleted) mixed with cristalline insulin of the same species (bovine or porcine) (2c). In two patients allergic reactions were seen. One patient showed local allergy, the other showed generalized urticaria, Quincke's edema and Arthus phenomenon. Lipohypertrophy was found in 20% of 126 patients using highly purified insulins and in 14% of 96 patients using conventional beef insulin (3c). It was associated with the repeated use of a restricted injection site in a single anatomical area. Lipoatrophy was con-
fined to patients using conventional insulin (16% of the cases). It is not established y e t if and how lipohypertrophy influences insulin absorption. Of 335 patients in another series, 26 showed insulin allergy (7 generalized and 19 localized) (4C). There was no sex preference. All were being treated with Lente insulin, regular insulin or a combination of Lente and Actrapid. After a switch-over to highly purified insulin the allergic symptoms disappeared in all patients. In 22 patients (17 females) treated with Lente, Rapitard, NPH or Ultralente insulin lipodystrophy on the site where insulin was injected was present. Twenty patients were transferred to highly purified insulin, and the lesions subsided in 16 of them within 1 - 1 2 months; injections into the atrophic area seemed to speed up recovery. In the other four cases lipoatrophy was still present after 2 - 4 years. Four patients had lipohypertrophy (combined with lipoatrophy); highly purified insulins had no beneficial effect in these cases. Lipohypertrophy without lipoatrophy was not seen. A patient described by Schernthaner et al. showed an extended, localized allergic reaction (type I reaction) three days after the onset o f treatment with highly purified insulin (5c). It was highly unlikely that she had had earlier contact with insulin. She had relatively high IgE antibody titers and low IgG insulin antibodies. Detailed skin testing with various insulin preparations of different species, including pancreatic, biosynthetic and semisynthetic human insulin, indicated an allergy against the insulin molecule itself. Nine out of 15 diabetics (6 r) with recurrent painful local manifestations were intensively studied by deShazo et al. All patients had been started on beef pork neutral insulin. The dermal insulin reactions failed to resolve when purified insulin was substi-
404 tuted during a number of months. Three types of reactions were seen: (a)A wheal and flare reaction followed by an induration after 5-6 hours. These reactions lasted 24 hours and were transferred with Pransnitz-Ktistner testing. They were histologically 'late phase' reactions with increased IgE levels. (b) A tuberculin type late phase hypersensitivity. These reactions developed 8-12 hours after testing and peaked after 24 hours without a preceding wheal and flare. They were not transferable with Pransnitz-Kilstner testing. (e) A third type emerged after 4-6 hours, peaked after 12 hours, was not transferable with Prausnitz-Kiistner testing and showed histologically the local vasculitis characteristic of the Arthus phenomenon. IgG type antibodies were in none of the patients found to be higher than in comparable diabetic patients without dermal reactions. No specific contribution of zinc to the allergic reactions could be demonstrated. Of 85 patients (7 R ) with allergic reactions during insulin treatment six showed an immediate reaction (type I), 76 a late reaction (type IV) and 3 a combined reaction (type I and IV). Extensive testing to various types of insulin, surfen, solbrol (a preservative) and NaC1 revealed that the immediate and combined allergies were exclusively pure insulin allergies. In the late reactions nine patients had surfen allergy, 34 pure insulin allergy and 11 pure bovine insulin allergy. This means, as pointed out above, that m a n y allergic reactions are induced by insulin itself. This does not support the common belief that additives are the most frequent cause of insulin allergy. The in vitro binding of insulin of various species sources (bovine, porcine and human) and the IgE levels were investigated by Kumar in 10 patients with systemic insulin allergy and five non-allergic insulin-resistant cases (8). A high ratio of IgE/IgG seems to be more typically associated with insulin allergy than does an absolute high titer of IgE. The avidity for porcine insulin was also significantly higher when compared with human or desphenylalanine-porcine insulin. However, a patient has been described (9 c ) with an anaphylactic reaction to highly purified pork insulin, without allergy for beef insulin. The insulin was here the allergen. IgE antibodies were high and IgG antibodies low. The RAST method (10) was used in this paper, but the value of the RAST method is debatable. In 100 con-
H.M.J. Krans secutive patients Melioli et al. (11 c) found that whilst six patients were allergic, only one had a positive (P)RAST-test. The allergic reactions (type IV) caused by surfen (a constituent of various insulin preparations which delays the uptake of insulin) have been investigated (12) in 240 patients with local (infiltration, erythema, necrosis) or systemic (exanthema, urticaria) eruptions. Skin testing with a great variety of insulins (some containing surfen) and various additives to insulin revealed in 30 of the 240 patients tested a tuberculoid granulomatous reaction of the delayed type. Histological examination revealed a granulomatous inflammation without signs of foreign body reaction. This type of reaction was caused only by surfen or surfen-containing insulins. Painful indurations and redness of the skin were traced by questioning in most patients within a few days or weeks after the start of therapy with surfen-containing insulin. A 27-year-old patient with giant urticaria three years after institution of insulin therapy, and who had a history of childhood rheumatic fever, mild asthma and pernicious anemia, benefited only for one month from a transfer to m o n o c o m p o n e n t insulin. Then the urticaria worsened (13 C). Cimetidine 300 mg stopped the reaction within two weeks. After two months all antiurticarial therapy had been stopped. No relapse was seen during the subsequent two years. The authors point to various conflicting studies regarding the effect o f cimetidine in chronic idiopathic urticaria. A strong urticarial reaction 15 days after institution of b e e f insulin (14 C) had to be treated with cortisone and antihistamines. Other beef insulins induced the same reaction. Rapid desensitization with highly purified insulin permitted resumption of insulin therapy with no unwanted side effects. A generalized allergy may induce insulin resistance. A patient reported from Japan (15 c ) developed urticaria nine days after restarting NPH insulin therapy; treatment was continued. On the 13th day ketoacidosis developed, and 450 units of regular insulin and fluid administration did n o t prevent coma. Switch-over to Actrapid ameliorated the situation. Evidence for the presence of anti-insulin IgE antibodies and insulin binding antibodies was not presented.
Insulin, glucagon and oral hypoglycemic drugs A case of transient generalized edema in the initial stage of insulin therapy (16 C ) in a 26-year-old man has been presented. Newer routes o f administration o f insulin
(SEDA-4, 301; SEDA-5, 388; SED-6, 367) Constant s.c. and i.v. infusion by pumps was discussed in SEDA-6 (p. 367). The major goal is to achieve normalization of blood glucose levels. This may prevent or retard the complications of diabetes mellitus. Besides pump failures (breakdown or irregularities), however, infections, allergic reactions and hypoglycemic reactions are reported. Hypoglycemic coma in a highly complient and intelligent patient treated with continuous subcutaneous insulin infusion (CSII) (17 c) was not caused by failure of the pump or wrong handling, but the tight glucose control and the failure to recognize hypoglycemic symptoms were major factors. The recommendation was made that pumps must only be used by experienced physicians and that constant supervision of these patients has to be provided for. This recommendation is supported in the conclusion of a panel of diabetes experts convened by the (American) centers of disease control. Reports of 11 deaths in patients with pumps prompted a review of the cases. Pump malfunction was excluded as cause. The panel concluded that none of the deaths could be attributed to the infusion pumps, but advised that the physicians should be careful when choosing blood target levels of glucose (18). One death could be attributed to hypoglycemia. In others the role of hypoglycemia was uncertain. No data are available yet on deaths in patients in whom very strict diabetic control is sought by means other than CSII. Over a period of 2 years both infections and local allergic reactions were seen (19 c ) in 20 patients on CSII for periods ranging from 2 - 2 2 months. Six patients had on seven occasions evidence of infection at the site of needle insertion. Three patients developed large areas of erythema and induration with subcutaneous abscess formation. Cultures showed Staphylococcus aureus. Four patients had minor infections (erythema and induration). When the need for proper hygiene and care was stressed, when the needle site was changed at least every other day (instead of leaving the
405 infusion needle in place for 4 - 6 days) and when the needle was changed immediately at the first sign of inflammation no further skin infections were seen. Allergic reactions were seen in five patients. They started from one day to three months after starting CSII. The local induration and erythema emerged 4 - 8 hours after the start of the infusion and persisted for 2 4 - 3 6 hours after the infusion site had been changed. Three had no previous history of insulin allergy during subcutaneous administration, but two had a previous history of local skin reaction to beef or pork insulin. All five patients involved had used pork insulin (with a purity of 10 ppm). The three patients with no previous allergic reaction responded well to a changeover to Novo Actrapid; the two other patients showed no change after the switch-over. In three of eight patients (20 c) treated from 9 months to 289 years with CSII infections were seen. The infections precipitated in two patients ketoacidosis, whilst in one patient multiple abscesses were preceded by local allergic reactions. A list of major and minor complications during 289 years of daily use of the Mill Hill perfusor in an unspecified number of patients had been presented (21); it comprises changes in the basal pumping rate or total breakdown of the pump (changes in the sound of the pump or in timing are alerting signals), expiration of the battery (change the battery about every three weeks, or use it after three weeks only in the daytime), problems in delivery system (such as an obstructed butterfly, disconnection of tubing from needle, needle falling out of the skin, insulin leakage), and intradermal (inflammation), or intravenous (hypoglycemia) location of the needle. In addition, subcutaneous nodules or irritation by surgical tape were seen. Nocturnal pump failure may represent a greater danger than failure of the pump during the day. Alternative ways to administer insulin are increasingly being used. Insulin has been administered intranasally (22) in a small number of patients. It may be effective when subcutaneous injections elicit unwanted reactions. No hypoglycemic reactions have as yet been reported. Hypoglycemia (SED 9, 705; SEDA-4, 298;
SEDA-5, 386; SEDA-6, 368) Hypoglycemia remains the most frequent
406 unwanted effect of insulin therapy. In a study of 71 cases of the hypoglycemic syndrome in an emergency unit (23 r) 84% were caused by insulin or oral drugs. In 40% of the patients accompanying diseases were present. Alcoholism was the most frequent one, but chronic renal insufficiency, hepatic cirrhosis, gastrectomy, congestive heart insufficiency and drugs like salieylates, betablockers, or beta-stimulating agents also contributed. Hypoglycemia induced b y oral hypoglycemic drugs more frequently caused hospitalization exceeding 24 hours and relapses during hospitalization. When the cases were further analyzed b y studying two subgroups where blood glucose was above or below 35 mg/100 ml (+2 mmol/1) excessive perspiration was seen in about 50% of the eases in both groups, but neurological manifestations were more prominent in the group with lower blood glucose levels. The danger of hypoglycemic attacks to patients in developing countries is stressed in a publication from Ethiopia (24). Of 25 cases seen in one hospital, 18 were being treated with insulin and seven with oral hypoglycemic agents. Infrequent control and poor education o f diabetics contributed to the hypoglycemic episodes, which otherwise could have been prevented. Hypoglyeemic periods may not only be due to an increased action of hypoglycemic drugs. Deficiency of counterregulatory hormones (glucagon, growth hormone, epinephrine, norepinephrine and cortisol) leading to permanent brain damage has been described as a cause (25c). Frequent home monitoring may then help to prevent the attacks. Other unwanted effects
Abscesses caused by insulin injections are relatively rare. The problem has been discussed in an editorial (26). A moist environm e n t may favor the growth of bacteria in the syringe. Experience with repeated use of dry plastic syringes is encouraging as regards the appearance o f infections. Two reports have been published about (presumed) unnecessary or excessive insulin treatment. In the first report (27 c) seven patients are described with diabetes mellitus who used fairly high amounts of insulin ( 3 6 - 8 8 units daily) and in whom control was difficult to achieve. They had frequent (unrecognized) hypoglycemias. All could be
H.M.J. Krans treated better with diet, though sometimes oral hypoglycemic drugs had to be added. The patients were clearly being overtreated with insulin, and the same effect could probably have been obtained when the amount of insulin was significantly reduced. A second report (28 C) deals with two patients with renal glucosuria who had been diagnosed as having diabetes mellitus and were treated for 33 and 51 years. They had hypoglycemic attacks and showed suppressed C-peptide secretion in the urine. In both patients the antibody titer fell after interruption of the insulin therapy. The glucosuria was still present but no high blood sugars were seen. It is of interest to note that after such a long period of suppression the islets could still function normally. No signs of microangiopathy could be found in the patients. ORAL AGENTS (SED 9, 709; SEDA-4, 303; SEDA-5, 390; SEDA-6, 369) The number of reported side effects of oral drugs used in diabetes therapy is decreasing. No new oral drugs are being marketed and most unexpected effects have been reported already. Even the vigorous discussion about the dangers and benefits of oral therapy in the treatment of diabetes generated by the UGDP-study (SEDA-5, 391) has apparently come to an 8nd. The use of hypoglycemic drugs may be stimulated by reports about an increase in the number of insulin receptors induced by these drugs. Many studies are based upon the concept that changes in the number of insulin binding sites (often in non-diabetic persons or animals) determines insulin action. Receptors are, however, only one step in the transfer of the message of insulin. Affinity changes, post-receptor defects and the very rapid changes which can occur in numbers of receptors tend to be ignored in the discussion on the binding sites. Some recent reviews about the pharmacology of sulfonylureas (29 R, 30 R) discuss the interactions of the various sulfonylureas with other drugs. They do not treat the subject of side effects. Only one review (31 R) includes an extensive treatment of the latter. Bone loss is a common feature of longstanding diabetes mellitus and not an adverse reaction to the drugs used to treat it. Treatment with oral hypoglycemic drugs may be
Insulin, glucagon and oral hypoglycemic drugs less effective in the prevention. A decrease in 25-hydroxycholecalciferol, a rise in the bone fraction o f alkaline phosphatase isoenzymes and of hydroxyproline excretion was found in 22 patients on (not specified) oral hypoglycemics (32) when compared with non-diabetics. The changes in these parameters in insulin-treated patients were intermediate, but the groups were not totally identical.
Chlorpropamide(SED 9, 604, 709, 711; SEDA-4, 305; SEDA-5, 391; SEDA-6, 370) A 64-year-old woman (33 C) developed hemolytic anemia with hematuria within one week after starting treatment with 300 mg of chlorpropamide daily. No haptoglobin was found and a strong direct positive Coombs test was present. An IgG was found in vitro. Lysis of the complement-sensitive cells was seen when the patient's serum, taken during the period of paroxysmal nocturnal hemoglobinuria, was incubated with normal fresh serum and chlorpropamide. In addition a positive Coombs test was found in an incubation mixture of red cells o f the patient, normal serum and chlorpropamide. Withdrawal of chlorpropamide reversed the symptoms. Optic neuropathy was described in a 65-year-old woman who used chlorpropamide 250 mg for one year (34c). She had a bilateral visual loss (20/400) of unknown duration but present for at least six months. Bilateral optic disc drusen were found. The patient was a member of a family with an autosomal dominant syndrome in which the affected women were mildly mentally deficient and the affected men were severely retarded. A daughter affected by the syndrome had normal visual acuity and no disc drusen. Four days before admittance to the hospital the patient stopped chlorpropamide; the visual acuity was 20/40+ in both eyes. During five days on chlorpropamide the visual acuity decreased to 20/70 OD and 20/60 OS. Discontinuation resulted in rapid return to a visual acuity of 20/50 OD and 20/40 OS. The syndrome o f inappropriate antidiuretic hormone secretion (see SEDA-4, 303) was described (35 c ) in two patients in whom the dose of chlorpropamide was doubled after they had been treated for 13 years and 10 years respectively with 250 mg daily.
Hypoglycemic attacks with neurological s y m p t o m s and confusion in a 72-year-old
407 man were reported (36c). He developed watery diarrhea. When he took no oral food no attacks were seen. The reinstitution of a normal diet induced recurrence of the symptoms. Further investigation revealed celiac disease. The reduced resorption of food may have contributed to the hypoglycemic attacks. A crossover study (37 c) of chlorpropamide once daily and glibenclamide once and twice daily was carried out in 12 patients: doses were increased until the fasting blood glucose concentrations were under 6 mmol/l. Six patients on glibenclamide twice daily had postprandial hypoglycemic reactions and four had such reactions when glibenclamide was given, in one reduced dose. One patient on chlorpropamide had a similar reaction. No patient had overnight symptomatic hypoglycemia. Four patients on chlorpropamide complained about flushing when using alcohol. T h e rise a n d f a l l o f t h e chlorpropamide a l c o h o l f l u s h i n g t e s t ( C P A F )
(SEDA-5, 391; SEDA-6, 370) In 1978 Leslie and Pyke reported (38) that small amounts o f alcohol (40 mt o f sherry, containing 18% alcohol) 12 hours after 250 mg o f ehlorpropamide could induce a facial flush reaction. This reaction was seen in 81% o f patients with noninsulindependent diabetes mellitus (NIDDM, type II) with a first degree family history o f diabetes and in only 31% o f NIDDM patients without a family history. The test was only positive in 10% o f normal subjects and in 10% o f patients with insulin-dependent diabetes mellitus (IDDM, type 1). The test was reported to be specific. Only one out o f 193 patients flushed after placebo and alcohol. In some patients the flush was more noticeable i f alcohol was used f o r a second time 36 hours after chlorpropamide. The challenged flushing was also f o u n d in family members o f NIDDM (39} with a positive family history f o r diabetes. Half the offspring o f CPAF-positive diabetics showed CPAF even though carbohydrate tolerance might be normal (40). The CPAF test was therefore propagated as a specific genetic marker for NIDDM. Families with mild diabetes o f early onset (sometimes called "Mason-type') seemed to f i t very well in the flushing pattern (39).
408
Further investigations revealed that the development o f secondary complications was less severe in diabetic patients with a positive CPAF as compared to patients with a negative CPAF. Retinopathy was reported to be less common and less severe (41, 42). Only one o f 191 CPAF-positive patients was blind, compared to eight o f 100 CPAFnegative patients. When nephropathy was studied with reagent strips (albustix) on at least three consecutive visits, 2% o f the CPAF-positive patients showed persistent proteinuria versus 14% in CPAF-negative patients, indicating that nephropathy was less frequent (43}. When insulin-dependent diabetics were investigated only 9% o f the patients with severe microangiopathy were CPAF-positive versus 28% o f the insulin treated patients with no complications (44). In a group o f 22 patients large vessel disease was seen in 45% o f the non-flushers and in 24% o f the flushers (45). In CPAF-positives a less frequent history o f myocardial infarction, angina pectoris, claudicatio intermittens or absent foot pulses were found. All these data were produced by the group o f Pyke, indicating that CPAF could be used as a genetic marker and might be indicative o f reduced secondary complications. Alcohol intolerance as a side effect o f sulfonylureas has been known for a long time (SED 8, 909-911). The disulfiramlike effects are most frequently seen with chlorpropamide, especially if alcohol is also taken (SEDA-6, 370). The pharmacological action o f disulfiram is not identical to the action o f chlorpropamide. Disulfiram blocks the aldehyde degradation, but sulfonylureas block the ethanol degradation itself (SED 9, 710). The symptoms are a vasomotor reaction o f the skin (redness and hot feelings), sometimes accompanied by tachycardia, giddiness, angina pectoris or headache. In early studies chlorpropamide did not induce a rise in acetaldehyde (46). When more sensitive methods were available acetaldehyde levels appeared to be increased (47, 48, 49) and a significant correlation between flush and acetaldehyde levels could be demonstrated (50). There is also a suggestion that the metabolism o f chlorpropamide is related to the CPAF reaction. In CPAFpositive patients the chlorpropamlde concentration in the blood is significantly higher than in chlorpropamide-negative
H.M.J. Krans persons {51, 52}. Prostaglandins may also play a role; sulfonylureas may enhance prostaglandin synthesis in platelets (53}, or inhibit the alcohol-stimulated prostaglandin release in the nervous system (54). The flush can be blocked by aspirin, 300 mg (54), or by indomethacin if major vessel disease is absent (55). Naproxene (a prostaglandin synthesis inhibitor), however, could not abolish the flush and aspirin reduced the flush without reduction o f the rise in aldehyde levels (50). Enkephalin release in the brain may be involved as well. The breathlessness seen in some CPAF-positive patients could be prevented by giving naloxone, as in an asthmatic reaction (56}. It was reported that the CPAF could be blocked by naloxone and could be produced by an enkephalin analogue (57), but this observation has not been confirmed (58). When other groups tried to use the CPAF-test, however, it emerged that the CPAF was less unequivocal than had been stated. The subjective feelings o f the patient were the most important factors for the decision as to whether the patient belonged to the CPAF-positive or -negative group. Measurements o f skin temperature did not always correlate with the subjective feelings o f the patient (59, 60, 61, 62). Nor was the reaction always by any means an all or none reaction. The reaction may improve when chlorpropamide is given for at least one week (52}, but this does not help the investigation in family members with normal GTT's. Nor could the great discrepancy in percentages between flushers and nonflushers be confirmed by other authors. False-positives and false-negatives were found in a frequency that made the test unfit for genetic counseling (63). Numbers reported by other investigators differed substantially from the original ones: Ki~bberling found 69% positive flushers in control subjects, 23.3% in IDDM and 60.5% in NIDDM (61), whilst according to De Silva 24% were positive in NtDDM, but 18% also flushed when a placebo was given (60}. There may be a faster rise in facial temperature in CPAF-positive subjects than in alcohol flushers. The induction o f the flush is not specific for chlorpropamide, all sulfonylureas can elicit the flush. A patient has been described (64 c) who flushed on tolbutamide but not on chlorpropamide. We have to conclude that the CPAF test-
Insulin, glucagon and oral hypoglycemic drugs ing only has clear discriminatory value when used by certain specific workers. In general we have to be cautious in drawing conclusions from CPAF investigations (65). The test appears to be neither specific f o r chlorpropamide, nor capable o f discriminating as well as has been postulated by its proponents.
Glibenclamide (SED 9, 712; SEDA-4, 305; SEDA-5, 387, 391; SEDA-6, 370} A case of fatal severe hypoglycemia after ingestion of an u n k n o w n a m o u n t o f glibenclamide in a suicidal a t t e m p t has been reported (66 c). Blood glucose could be c o r r e c t e d but c o m a persisted. The patient died after f o u r days. H y p o g l y c e m i a with intrahepatic cholestasis and cutaneous bullae (67 C) has been r e p o r t e d in a 61-year-old m a n using 10 mg of glibenclamide. In the course of three weeks he became gradually unwell with loss of appetite and drowsiness. On admittance he was unconscious with a blood glucose of 1.5 mmol/1. He had two clear colorless bullae 3 cm in diameter on the sole of his right foot, resembling those seen in barbiturate poisoning or porphyria cutanea tarda; both diagnoses were, however, excluded. No signs of extrahepatic biliary obstruction were seen and an ultrasound scan of liver and gall bladder revealed no abnormality. After seven days the alkaline phosphatase was normalized from a level of 2420 U/I. The other liver functions were normalized after four days. A liver biopsy on the 1 lth day was normal. The buUae dried up in a month.
Tolazamide (SED 9, 714) Factitious hypoglycemia was described in a nurse who appeared to have been taking t o l a z a m i d e (68 c ) after a history of h y p o glycemic episodes which eventually led to l a p a r o t o m y and removal o f 2/3 o f t h e pancreas and splenectomy. The multiple biopsies were described as showing focal islet hyperplasia. Three months later she was referred to another hospital for the same complaints. Local and general investigations (including a tolbutamide test) gave no signs of insulinoma. The patient was treated with diazoxide and hydroehlorothiazide. When she was admitted on a later occasion a level of 30 vg/1 tolazamide was found when blood was investigated for sulfonylurea levels. The patient declined contact with a psychiatrist. In a later episode she asked for a
409 medical alert, requesting tolazamide levels to be obtained if she was found to be hypoglycemic. Chronic eosinophitic pneumonia was described in a 70-year-old man with a nineyear history of diabetes mellitus treated with tolazamide ( 6 9 c ) . When tolazamide was o m i t t e d the patient b e c a m e afebrile and asymptomatic. When tolazamide was restarted i n t e r m i t t e n t fever, cough and weakness reccurred and after six weeks bilateral upper lobe infiltrates had reappeared. A f t e r discontinuance o f tolazamide the s y m p t o m s disappeared within a week.
Biguanides (SED 9, 714; SEDA-4, 306; SEDA-5, 393; SEDA-6, 3 71) A case of fatal lactic acidosis (70 r ) during metformin therapy has been described in an 84-year-old w o m a n . Years earlier m e t f o r m i n 1.5 g/day had been instit u t e d ; creatinine was then 93.7 /~mol/1. One m o n t h later the creatinine level was 110 #moI/1. During admission to hospital creatinine was high: 234/.tmol/1. She had a plasma m e t f o r m i n level o f 16.3 /lg/1 (normal levels in chronic t r e a t m e n t being 0.06-2.25/~g/1). In a series of 595 diabetic patients treated w i t h biguanides or c o m b i n a t i o n s of biguanides and other h y p o g l y c e m i c agents (71 R) hyperlactemia (although still within the range of normal values) correlated with the dosage and t y p e of biguanides m o r e as regards p h e n f o r m i n than m e t f o r m i n . Hyperlactemia is rarely f o u n d in c o m b i n a t i o n therapy and appears to represent a metabolic effect due to biguanide treatment. Cases of lactic acidosis after phenformin therapy c o n t i n u e to be r e p o r t e d (73 c ) including fatalities (72 c ) . The prevalence of lactic acidosis m a y be related to the rate o f h y d r o x y l a t i o n o f p h e n f o r m i n . The excretion of p h e n f o r m i n has been found n o t to be related to the rate o f renal i m p a i r m e n t (74); the excretion of p-hydroxyphenethylbiguanide, a metabolite of phenformin, was variable. R e d u c t i o n in f o r m a t i o n of this m e t a b o l i t e was c o n c o m i t ant with an increase in the a m o u n t of circulating phenformin. A reduced h y d r o x y l a t i o n of debrisoquine has been found in two patients who had had lactic acidotic c o m a and were o f f p h e n f o r m i n since that time (75). No direct parallel b e t w e e n the rate of i m p a i r m e n t of phenformin metabolism (in seven patients with a history of lactic acidosis) and debriso-
410 quine m e t a b o l i s m (in 138 healthy persons and in seven patients) could be found, but the Study indicated that the changed debrisoquine metabolism m a y be only one among the several factors involved in the d e v e l o p m e n t o f lactic acidosis (76). Genetic factors seem at all events to be involved in the metabolism o f p h e n f o r m i n ; slow metabolizers have an increased risk in developing lactic acidosis. D i c h l o r o a c e t a t e has been propagated for the t r e a t m e n t o f lactic acidosis (SEDA-3, 348). A recent review (77 r) concludes that it is n e u r o t o x i c , can cause cataract and m a y be mutagenic. New d e v e l o p m e n t s A p o t e n t i a l n e w d e v e l o p m e n t in the treatm e n t of diabetes is the use o f specific enz y m e inhibitors, which retard the carbohydrate and fat absorption f r o m the gut. The search for these drugs has been stimulated
H.M.J. Krans w h e n s u p p l e m e n t i n g fibers to the diet appeared to slow d o w n the absorption of carbohydrates. Acarbose, a bacterial aglucoside hydrolase inhibitor, has a retarding effect on glucose and fat absorption and reduces glucose levels in blood (78). The m a j o r side effects are excessive flatulence and meteorism. S o m e patients react with m a l a b s o r p t i o n diarrhea. Until n o w the drug has been used e x p e r i m e n t a l l y only. The effects and side effects are summarized in the proceedings o f a c o n f e r e n c e (79R). An F D A c o m m i t t e e decided in D e c e m b e r 1982 that acarbose should n o t be approved for clinical trials in the US until the q u e s t i o n o f possible carcinogenicity had been satisfactorily dealt with. The manufacturers had r e p o r t e d the occurrence of renal adenomas and h y p e r n e p h r o i d carcinomas in rats during chronic t o x i c i t y testing. These tumors are unusual in that species. T h e c o m p o u n d also appears to raise alkaline phosphatase in animals (80).
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76,479. 3. Young, R.L., Steel, J.M., Frier, B.M. and Duncan, L.J.P. (1981): Insulin injection sites in diabetes - a neglected area? Brit. med. J., 283, 349. 4. Sakamoto, Y., Matsuba, I., Itoh, K. et al. (1981): Therapeutic effects of highly purified insulin on insulin allergy and insulin lipodystrophy induced by conventional insulin treatment. Jikeikai Med. J., 28, 41. 5. Schernthaner, G., Ludwig, H., Jarisch, R. et al. (1981): Immediate-type allergy against insulin itself: clinical and immunologic studies on a diabetic patient with insulin intolerance. Diabetes Care, 4, 196. 6. deShazo, D., Boehm, T.M., Kumar, D. et al. (1982): Dermal hypersensitivity reactions to insulin: correlations of three patterns to their histopathology. J. Allergy clin. lmmunol., 69, 229. 7. Hasche, H., Haslbeck, M., Bachmann, W. et al. (1981): Verteilung aUergischer Hautreaktionen bei Insulintherapie. Dtsch. reed. ~r 106, 1451. 8. Kumar, D. (1981): Insulin allergy: differences in the binding of porcine, bovine, and human insulins with anti-insulin IgE. Diabetes Care, 4, 104.
9. Carini, C., Brostoff, J. and Kurtz, A.B. (1982): An anaphylactic reaction to highly purified pork insulin. Confirmation by RAST and RAST inhibition. Diabetologia, 22, 324. 10. Wide, L., Bennich, H. and Johansson, S.G.O. (1967): Diagnoses of allergy by an in vitro test for allergic antibodies. Lancet, H, 1105. 11. Melioli, G., de Micheli, A., Prando, R. et al. (1981): Lack of evidence of anti-insulin IgE tested by PRAST in insulin allergy. IRCS reed.
ScL, 10,9. 12. Goerz, G., Ruzicka, T., Hofmann, N. et al. (1981): Granulomat6se allergische Reaktion yore verz6gerten Typ auf Surfen. Hautarzt, 32, 187. 13. Chideckel, E.W., Mullin, C.J. and Michael, B.E. (1981): Cimetidine in insulin allergy. Diabetes Care, 4, 503. 14. Furno, F., Gallesio, M.T., Patrito, G. et al. (1981): Di un easo di diabete mellito con allergia all'insulina trattato con uno schema di desensibilizzazione rapida. Folia allergol, immunol. clin., 28, 512. 15. Shinozuka, M., Hirose, K., Guji, M. et al. (1981): Diabetic coma due to insulin resistance associated with insulin allergy: A case report. J. Jap. Diab. Soc., 24, 755. 16. Marthedal, N.J., Larsen, K-E., and Haugsted, P. (1982): Insulin-induced oedema (in Danish). Ugeskr. Laeg., 144, 244. 17. Lock, D.R. and Rigg, L.A. (1981): Hypoglycemic coma associated with subcutaneous insulin infusion by portable pump. Diabetes Care, 4, 389.
Insulin, glucagon and oral hypoglycemic drugs 18. News (1982): Lancet, I, 636. 19. Pietri, A. and Raskin, P. (1981): Cutaneous complications of chronic continuous subcutaneous insulin infusion therapy. Diabetes Care, 4, 624. 20. Shipp, J.C. (1982): Practical problems with insulin pumps. New Engl. J. Med., 306, 1369. 21. Fishman, V. and Fishman, M. (1982): Practical problems with insulin pumps. New Engl. J. Med., 306, 1369. 22. Pontiroli, A.E., Alberetto, M., Secchi, A. et al. (1982): Insulin given intranasaUy induced hypoglycaemia in normal and diabetic subjects. Brit. reed. J., 284, 303. 23. Tortes Marti, A., Font, J., Cano, F. et al. (1981): Epidemiologic study of hypoglycemic syndrome in an emergency unit. Study of 71 cases. Med. Clin. (Barcelona), 77, 405. 24. Lester, F.T. (1982): Severe hypoglycaemic reactions in Ethiopian diabetics. Ethiop. reed. J., 20, 33. 25. Boden, G., Reichard, G.A., Jr., Hoeldtke, R.D. et al. (1981): Severe insulin-induced hypoglycemia associated with deficiencies in the release of counterregulatory hormones. New Engl. J. Med., 305, 1200. 26. Editorial (1981): Insulin injections and infections. Brit. reed. J., 282, 340. 27. Kromann, H., Borch, E. and Gale, E.A.M. (1981): Unnecessary insulin treatment for diabetes. Brit. reed. J., 283, 1386. 28. Asplund, J., Ahlmark, G., Gunnarsson, R. et al. (1981): Long-term insulin treatment in two nondiabetic patients. J. Amer. med. Ass., 246, 870. 29. Skillman, T.G. and Feldman, J.M. (1981): The pharmacology of sulfonylureas. Amer. J. Med., 70, 361. 30. Balant, L. (1981): Clinical pharmacokinetics of sulphonylurea hypoglycaemic drugs. Clin. Pharmacokin., 6, 215. 31. Jackson, J.E. and Bressler, R. (1981): Clinical pharmacology of sulphonylurea hypoglycaemic agents: Part 1. Drugs, 22, 211, and part 2. Drugs, 22, 295. 32. Step,n, J., Wilczek, H., Justov~i, V. et al. (1982): Plasma 25-hydroxycholecalciferol in oral sulfonylurea treated diabetes mellitus. Horm. Metabol. Res., 14, 98. 33. Saffouri, B., Cho., J.H. and Felber, N. (1981): Chlorpropamide-induced haemolytic anaemia. Postgrad. med. J., 5 7, 44. 34. Wymore, J. and Carter, J.E. (1982): .Chlorpropamide-induced optic neuropathy. Arch. intern. Med., 142, 381. 35. Tanay, A., Firemann, Z., Yust, I. et al. (1981): Chlorpropamide-induced syndrome of inappropriate antidiuretic hormone secretion. J. Amer. Geriat. Soc., 29, 334. 36. Rosenbaum, L.H. and Rosenbaum, H. (1982): Chlorpropamide-induced hypoglycemia. A dramatic presentation of celiac disease. Z Amer. med. Ass.. 247, 818.
411 37. Ward, E.A., Lang, D.A., Phillips, M.R. et al. (1981): Comparison of chtorpropamide and glibenclamide treatment of maturity-onset diabetes: Control assessed by fasting plasma glucose concentrations. Diabetes Care, 4, 293. 38. Leslie, R.D.G. and Pyke, D.A. (1978): Chlorpropamide-alcohol flushing: a dominantly inherited trait associated with diabetes. Brit. med. J., 2, 1519. 39. Pyke, D.A. and Leslie, R.D.G. (1978): Chlorpropamide-alcohol flushing: a definition of its relation to non-insulin-dependent diabetes. Brit. reed. J., 2, 1521. 40. Pyke, D.A. (1979): Diabetes: The genetic connections. Diabetologia, 17, 333. 41. Cudworth, A.G. (1979): Type 2 (insulin-independent) diabetes fibres and flushers. Diabet-
ologia, 17, 67. 42. Leslie, R.D.G., Barnett, A.H. and Pyke, D.A. (1979): Chlorpropamide-alcohol flushing and diabetic retinopathy. Lancet, I, 997. 43. Barnett, A.H., Leslie, R.D.G. and Pyke, D.A. (1981): Chlorpropamide-alcohol flushing and proteinuria in non-insulin-dependent diabetics. Brit. reed. J., 282, 522. 44. Barnett, A.H., Mace, P.J.E. and Pyke, D.A. (1981): Chlorpropamide-alcohol flushing and microangiopathy in insulin-dependent diabetes. Brit. reed. J., 282, 523. 45. Barnett, A.H. and Pyke, D.A. (1980): Chlorpropamide-alcohol flushing and large vessel disease in non-insulin-dependent diabetes. Brit. rned. J., 2, 261. 46. Fitzgerald, M.G., Gaddie, R., Malins, J.M. et al. (1962): Alcohol sensitivity in diabetics receiving chlorpropamide. Diabetes, 11, 40. 47. Lyle, W.H. (1981): Chlorpropamide alcohol flushing. Lancet, 1, 336. 48. Lightman, S. (1981): Chlorpropamide alcohol flushing. Lancet, 1, 337. 49. Barnett, A.H. and Pyke, D.A. (1981): Chlorpropamide alcohol flushing. Lancet, 1, 222. 50. Jerntorp, P., Ohlin, H., Bergstr6m, B. et al. (1981): Increase of plasma acetaldehyde. An objective indicator of the chlorpropamide alcohol flush. Diabetes, 30, 788. 51. Jerntorp, P., Alm6r, L-O. and Melander, A. (1981): Is the blood chlorpropamide concentration critical in chlorpropamide alcohol flush? Lancet, I, 165. 52. Jefferys, D.B., Keen, H. and Tang Fui, S.Ng. (1981): Chlorpropamide alcohol flush. Lancet, 1, 440. 53. Horrobin, D.F. and Manku, M.S. (1980): Chlorpropamide/alcohol flushing and prostaglandins. Lancet, 1, 935. 54. Strakosch, C.R., Jefferys, D.B. and Keen, H. (1980): Blockade of chlorpropamide alcohol flush by aspirin. Lancet, I, 394. 55. Barnett, A.H., Spiliopoulos, A.J. and Pyke, D.A. (1980): Blockade of chlorpropamidealcohol flushing by indomethacin suggests an association between prostaglandins and diabetic
412 vascular complications. Lancet, II, 164. 56. Leslie, R.D.G., Bellamy, D. and Pyke, D.A. (1980): Asthma induced by enkephalin. Brit. med. J., 1, 16. 57. Leslie, R.D.G., Pyke, D.A. and Stubbs, W.A. (1979): Sensitivity to enkephalin as a cause of non-insulin-dependent diabetes. Lancet, I, 341. 58. KObberling, J., and Weber, M. (1980): Facial flush after chlorpropamide alcohol and enkephalin. Lancet, 1, 538. 59. Radder, J.K., Box, M.C.J.G. and Lemkes, H.H.P.J. (1980): Facial skin temperature and the chlorpropamide/alcohol flush in diabetics. Lancet, 11, 1037. 60. DeSilva, N.E., Tunbridge, W.M.G. and Alberti, K.G.M.M. (1981): Low incidence of chlorpropamide-alcohol flushing in diet-treated, non-insulindependent diabetes. Lancet, 1, 128. 61. K6bberling, J., Bengsch, N., Briiggeboes, B. et al. (1980): The chlorpropamide alcohol flush. Lack of specificity of familial non-insulin dependent diabetes. Diabetologia, 19, 359. 62. Micossi, P. (1981): The prevalence of chlorpropamide alcohol flushing in non-insulin dependent diabetics. Diabetologia, 20, 510. 63. Dreyer, M., Kfihnau, J. and Rildiger, H.W. (1980): Chlorpropamide-alcohoi flushing is not useful for individual genetic counseling of diabetic patients. Clin. Genet., 18, 189. 64. Capretti, L., Speroni, G., Girone, M. et al. (1981): Chlorpropamide- and tolbutamide-alcohol flushing in non-insulin-dependent diabetes. Brit. reed. J., 283, 1361. 65. Hockaday, T.D.R. and Hillson, R.M. (1980): Chlorpropamide-alcohol flushing in non-insulindependent diabetics. Brit. reed. J., 2, 620. 66. Pugesgaard, T. and Kreutzfeldt, A.M. (1981): Hypoglycemia following ingestion of glibenclamide (Daonil) with suicidal intent. Report of a lethal case (in Danish). Ugeskr. Laeg., 143, 1712. 67. Wongpaitoon, V., Mills, P.R., Russell, R.I. et al. (1981): Intrahepatic cholestasis and cutaneous bullae associated with glibenclamide therapy. Postgrad. med. J., 5 7, 244. 68. Levy, W.J. and Sheeler, L.R. (1981): Surrep-
H.M.J. Krans titious hypoglycemia secondary to tolazamide. Sth. med. J., 74,63. 69. Bondi, E. and Slater, S. (1981): Tolazamideinduced chronic eosinophflic pneumonia. Chest, 80, 652. 70. Hermann, L.S., Magnusson, S., M6lier, B. et al. (1981): Lactic acidosis during metformin treatment in an elderly diabetic patient with impaired renal function. Acta reed. scand., 209, 519. 71. Lunetta, M., Mughini, M.T. and Mughini, L. (1980): Considerazioni critiche sulla iperlattacidemia da biguanidi. Clin. Ter., 96,475. 72. Ghirlanda, G., Greco, V., Altomonte, L. et al. (1981): Acidosi lattica associata a terapia con fenformina. Minerva. Med., 72, 893. 73. Greco, A.V., Grieco, A. and Barone, C. (1981): Acidosi lattica (B 2) da fenformina. Progr. reed. Roma, 37, 609. 74. Bosisio, E., Gall] Kienle, M., Galli, G. et al. (1981): Defective hydroxylation of phenformin as a determinant of drug toxicity. Diabetes, 30, 644. 75. Oates, N.S., Shah, R.R., Idle, J.R. et al. (1981): Phenformin-induced lactic acidosis associated with impaired debrisoquine hydroxylation. Lancet, I, 837. 76. Wiholm, B-E., Alvan, G., Bertilsson, L. et al. (1981): Hydroxylation of debrisoquine in patients with lactic acidosis after phenformin. Lancet, 1, 1098. 77. Crabb, D.W., Yount, E.A. and Harris, R.A. (1981): The metabolic effects of dichloroacetate. Metabolism, 30, 1024. 78. Jenkens, D.J.A., Taylor, R.H., Goff, D.V. et al. (1981): Scope and specificity of acarbose in slowing carbohydrate absorption in man. D/abetes, 30, 951. 79. Creutzfeldt, W. (Ed.) (1982)" Proceedings, 1st International Symposium on Acarbose, Effects on Carbohydrate and Fat Metabolism. ICS 594, Excerpta Medica, Amsterdam, Oxford, Princeton. 80. Anon. (1982): Acarbose: safety question. Scrip, 754, 15.
44
Insulin, glucagon and oral hypoglycemic drugs
INSULIN (SED 9, 705; SEDA-4, 298; SEDA-5, 386; SEDA-6, 367) The availability of human insulin may affect the insulin market in the near future. It has not yet been proven that the theoretical advantages o f synthetic human insulin (less allergic reactions and a decrease in insulin resistance) justify the increased cost of prescription; the psychological effect of treatment with a 'natural' insulin, however, will certainly stimulate a substantial use of synthetic human insulin. The major sources of human insulin are recombinant DNAtechniques or a chemical modification of porcine insulin in which the C-terminal amino acid of the B-chain phenylalanine is replaced by threonine (see SEDA-6, 367). A short review paper on the control of drugs produced by recombinant DNA-technology has been published ( 1). Allergic reactions (SED 9, 707; SEDA-4, 299; SEDA-5, 389; SEDA-6, 369) It has become increasingly evident that some allergic reactions are elicited by insulin itself and not by impurities or additions. The type of allergy is variable. In a randomized clinical study 20 diabetic patients were treated with Des-phe-insulin (insulin from which the C-terminal amino acid in the B-chain has been deleted) mixed with cristalline insulin of the same species (bovine or porcine) (2c). In two patients allergic reactions were seen. One patient showed local allergy, the other showed generalized urticaria, Quincke's edema and Arthus phenomenon. Lipohypertrophy was found in 20% of 126 patients using highly purified insulins and in 14% of 96 patients using conventional beef insulin (3c). It was associated with the repeated use of a restricted injection site in a single anatomical area. Lipoatrophy was con-
fined to patients using conventional insulin (16% of the cases). It is not established y e t if and how lipohypertrophy influences insulin absorption. Of 335 patients in another series, 26 showed insulin allergy (7 generalized and 19 localized) (4C). There was no sex preference. All were being treated with Lente insulin, regular insulin or a combination of Lente and Actrapid. After a switch-over to highly purified insulin the allergic symptoms disappeared in all patients. In 22 patients (17 females) treated with Lente, Rapitard, NPH or Ultralente insulin lipodystrophy on the site where insulin was injected was present. Twenty patients were transferred to highly purified insulin, and the lesions subsided in 16 of them within 1 - 1 2 months; injections into the atrophic area seemed to speed up recovery. In the other four cases lipoatrophy was still present after 2 - 4 years. Four patients had lipohypertrophy (combined with lipoatrophy); highly purified insulins had no beneficial effect in these cases. Lipohypertrophy without lipoatrophy was not seen. A patient described by Schernthaner et al. showed an extended, localized allergic reaction (type I reaction) three days after the onset o f treatment with highly purified insulin (5c). It was highly unlikely that she had had earlier contact with insulin. She had relatively high IgE antibody titers and low IgG insulin antibodies. Detailed skin testing with various insulin preparations of different species, including pancreatic, biosynthetic and semisynthetic human insulin, indicated an allergy against the insulin molecule itself. Nine out of 15 diabetics (6 r) with recurrent painful local manifestations were intensively studied by deShazo et al. All patients had been started on beef pork neutral insulin. The dermal insulin reactions failed to resolve when purified insulin was substi-
404 tuted during a number of months. Three types of reactions were seen: (a)A wheal and flare reaction followed by an induration after 5-6 hours. These reactions lasted 24 hours and were transferred with Pransnitz-Ktistner testing. They were histologically 'late phase' reactions with increased IgE levels. (b) A tuberculin type late phase hypersensitivity. These reactions developed 8-12 hours after testing and peaked after 24 hours without a preceding wheal and flare. They were not transferable with Pransnitz-Kilstner testing. (e) A third type emerged after 4-6 hours, peaked after 12 hours, was not transferable with Prausnitz-Kiistner testing and showed histologically the local vasculitis characteristic of the Arthus phenomenon. IgG type antibodies were in none of the patients found to be higher than in comparable diabetic patients without dermal reactions. No specific contribution of zinc to the allergic reactions could be demonstrated. Of 85 patients (7 R ) with allergic reactions during insulin treatment six showed an immediate reaction (type I), 76 a late reaction (type IV) and 3 a combined reaction (type I and IV). Extensive testing to various types of insulin, surfen, solbrol (a preservative) and NaC1 revealed that the immediate and combined allergies were exclusively pure insulin allergies. In the late reactions nine patients had surfen allergy, 34 pure insulin allergy and 11 pure bovine insulin allergy. This means, as pointed out above, that m a n y allergic reactions are induced by insulin itself. This does not support the common belief that additives are the most frequent cause of insulin allergy. The in vitro binding of insulin of various species sources (bovine, porcine and human) and the IgE levels were investigated by Kumar in 10 patients with systemic insulin allergy and five non-allergic insulin-resistant cases (8). A high ratio of IgE/IgG seems to be more typically associated with insulin allergy than does an absolute high titer of IgE. The avidity for porcine insulin was also significantly higher when compared with human or desphenylalanine-porcine insulin. However, a patient has been described (9 c ) with an anaphylactic reaction to highly purified pork insulin, without allergy for beef insulin. The insulin was here the allergen. IgE antibodies were high and IgG antibodies low. The RAST method (10) was used in this paper, but the value of the RAST method is debatable. In 100 con-
H.M.J. Krans secutive patients Melioli et al. (11 c) found that whilst six patients were allergic, only one had a positive (P)RAST-test. The allergic reactions (type IV) caused by surfen (a constituent of various insulin preparations which delays the uptake of insulin) have been investigated (12) in 240 patients with local (infiltration, erythema, necrosis) or systemic (exanthema, urticaria) eruptions. Skin testing with a great variety of insulins (some containing surfen) and various additives to insulin revealed in 30 of the 240 patients tested a tuberculoid granulomatous reaction of the delayed type. Histological examination revealed a granulomatous inflammation without signs of foreign body reaction. This type of reaction was caused only by surfen or surfen-containing insulins. Painful indurations and redness of the skin were traced by questioning in most patients within a few days or weeks after the start of therapy with surfen-containing insulin. A 27-year-old patient with giant urticaria three years after institution of insulin therapy, and who had a history of childhood rheumatic fever, mild asthma and pernicious anemia, benefited only for one month from a transfer to m o n o c o m p o n e n t insulin. Then the urticaria worsened (13 C). Cimetidine 300 mg stopped the reaction within two weeks. After two months all antiurticarial therapy had been stopped. No relapse was seen during the subsequent two years. The authors point to various conflicting studies regarding the effect o f cimetidine in chronic idiopathic urticaria. A strong urticarial reaction 15 days after institution of b e e f insulin (14 C) had to be treated with cortisone and antihistamines. Other beef insulins induced the same reaction. Rapid desensitization with highly purified insulin permitted resumption of insulin therapy with no unwanted side effects. A generalized allergy may induce insulin resistance. A patient reported from Japan (15 c ) developed urticaria nine days after restarting NPH insulin therapy; treatment was continued. On the 13th day ketoacidosis developed, and 450 units of regular insulin and fluid administration did n o t prevent coma. Switch-over to Actrapid ameliorated the situation. Evidence for the presence of anti-insulin IgE antibodies and insulin binding antibodies was not presented.
Insulin, glucagon and oral hypoglycemic drugs A case of transient generalized edema in the initial stage of insulin therapy (16 C ) in a 26-year-old man has been presented. Newer routes o f administration o f insulin
(SEDA-4, 301; SEDA-5, 388; SED-6, 367) Constant s.c. and i.v. infusion by pumps was discussed in SEDA-6 (p. 367). The major goal is to achieve normalization of blood glucose levels. This may prevent or retard the complications of diabetes mellitus. Besides pump failures (breakdown or irregularities), however, infections, allergic reactions and hypoglycemic reactions are reported. Hypoglycemic coma in a highly complient and intelligent patient treated with continuous subcutaneous insulin infusion (CSII) (17 c) was not caused by failure of the pump or wrong handling, but the tight glucose control and the failure to recognize hypoglycemic symptoms were major factors. The recommendation was made that pumps must only be used by experienced physicians and that constant supervision of these patients has to be provided for. This recommendation is supported in the conclusion of a panel of diabetes experts convened by the (American) centers of disease control. Reports of 11 deaths in patients with pumps prompted a review of the cases. Pump malfunction was excluded as cause. The panel concluded that none of the deaths could be attributed to the infusion pumps, but advised that the physicians should be careful when choosing blood target levels of glucose (18). One death could be attributed to hypoglycemia. In others the role of hypoglycemia was uncertain. No data are available yet on deaths in patients in whom very strict diabetic control is sought by means other than CSII. Over a period of 2 years both infections and local allergic reactions were seen (19 c ) in 20 patients on CSII for periods ranging from 2 - 2 2 months. Six patients had on seven occasions evidence of infection at the site of needle insertion. Three patients developed large areas of erythema and induration with subcutaneous abscess formation. Cultures showed Staphylococcus aureus. Four patients had minor infections (erythema and induration). When the need for proper hygiene and care was stressed, when the needle site was changed at least every other day (instead of leaving the
405 infusion needle in place for 4 - 6 days) and when the needle was changed immediately at the first sign of inflammation no further skin infections were seen. Allergic reactions were seen in five patients. They started from one day to three months after starting CSII. The local induration and erythema emerged 4 - 8 hours after the start of the infusion and persisted for 2 4 - 3 6 hours after the infusion site had been changed. Three had no previous history of insulin allergy during subcutaneous administration, but two had a previous history of local skin reaction to beef or pork insulin. All five patients involved had used pork insulin (with a purity of 10 ppm). The three patients with no previous allergic reaction responded well to a changeover to Novo Actrapid; the two other patients showed no change after the switch-over. In three of eight patients (20 c) treated from 9 months to 289 years with CSII infections were seen. The infections precipitated in two patients ketoacidosis, whilst in one patient multiple abscesses were preceded by local allergic reactions. A list of major and minor complications during 289 years of daily use of the Mill Hill perfusor in an unspecified number of patients had been presented (21); it comprises changes in the basal pumping rate or total breakdown of the pump (changes in the sound of the pump or in timing are alerting signals), expiration of the battery (change the battery about every three weeks, or use it after three weeks only in the daytime), problems in delivery system (such as an obstructed butterfly, disconnection of tubing from needle, needle falling out of the skin, insulin leakage), and intradermal (inflammation), or intravenous (hypoglycemia) location of the needle. In addition, subcutaneous nodules or irritation by surgical tape were seen. Nocturnal pump failure may represent a greater danger than failure of the pump during the day. Alternative ways to administer insulin are increasingly being used. Insulin has been administered intranasally (22) in a small number of patients. It may be effective when subcutaneous injections elicit unwanted reactions. No hypoglycemic reactions have as yet been reported. Hypoglycemia (SED 9, 705; SEDA-4, 298;
SEDA-5, 386; SEDA-6, 368) Hypoglycemia remains the most frequent
406 unwanted effect of insulin therapy. In a study of 71 cases of the hypoglycemic syndrome in an emergency unit (23 r) 84% were caused by insulin or oral drugs. In 40% of the patients accompanying diseases were present. Alcoholism was the most frequent one, but chronic renal insufficiency, hepatic cirrhosis, gastrectomy, congestive heart insufficiency and drugs like salieylates, betablockers, or beta-stimulating agents also contributed. Hypoglycemia induced b y oral hypoglycemic drugs more frequently caused hospitalization exceeding 24 hours and relapses during hospitalization. When the cases were further analyzed b y studying two subgroups where blood glucose was above or below 35 mg/100 ml (+2 mmol/1) excessive perspiration was seen in about 50% of the eases in both groups, but neurological manifestations were more prominent in the group with lower blood glucose levels. The danger of hypoglycemic attacks to patients in developing countries is stressed in a publication from Ethiopia (24). Of 25 cases seen in one hospital, 18 were being treated with insulin and seven with oral hypoglycemic agents. Infrequent control and poor education o f diabetics contributed to the hypoglycemic episodes, which otherwise could have been prevented. Hypoglyeemic periods may not only be due to an increased action of hypoglycemic drugs. Deficiency of counterregulatory hormones (glucagon, growth hormone, epinephrine, norepinephrine and cortisol) leading to permanent brain damage has been described as a cause (25c). Frequent home monitoring may then help to prevent the attacks. Other unwanted effects
Abscesses caused by insulin injections are relatively rare. The problem has been discussed in an editorial (26). A moist environm e n t may favor the growth of bacteria in the syringe. Experience with repeated use of dry plastic syringes is encouraging as regards the appearance o f infections. Two reports have been published about (presumed) unnecessary or excessive insulin treatment. In the first report (27 c) seven patients are described with diabetes mellitus who used fairly high amounts of insulin ( 3 6 - 8 8 units daily) and in whom control was difficult to achieve. They had frequent (unrecognized) hypoglycemias. All could be
H.M.J. Krans treated better with diet, though sometimes oral hypoglycemic drugs had to be added. The patients were clearly being overtreated with insulin, and the same effect could probably have been obtained when the amount of insulin was significantly reduced. A second report (28 C) deals with two patients with renal glucosuria who had been diagnosed as having diabetes mellitus and were treated for 33 and 51 years. They had hypoglycemic attacks and showed suppressed C-peptide secretion in the urine. In both patients the antibody titer fell after interruption of the insulin therapy. The glucosuria was still present but no high blood sugars were seen. It is of interest to note that after such a long period of suppression the islets could still function normally. No signs of microangiopathy could be found in the patients. ORAL AGENTS (SED 9, 709; SEDA-4, 303; SEDA-5, 390; SEDA-6, 369) The number of reported side effects of oral drugs used in diabetes therapy is decreasing. No new oral drugs are being marketed and most unexpected effects have been reported already. Even the vigorous discussion about the dangers and benefits of oral therapy in the treatment of diabetes generated by the UGDP-study (SEDA-5, 391) has apparently come to an 8nd. The use of hypoglycemic drugs may be stimulated by reports about an increase in the number of insulin receptors induced by these drugs. Many studies are based upon the concept that changes in the number of insulin binding sites (often in non-diabetic persons or animals) determines insulin action. Receptors are, however, only one step in the transfer of the message of insulin. Affinity changes, post-receptor defects and the very rapid changes which can occur in numbers of receptors tend to be ignored in the discussion on the binding sites. Some recent reviews about the pharmacology of sulfonylureas (29 R, 30 R) discuss the interactions of the various sulfonylureas with other drugs. They do not treat the subject of side effects. Only one review (31 R) includes an extensive treatment of the latter. Bone loss is a common feature of longstanding diabetes mellitus and not an adverse reaction to the drugs used to treat it. Treatment with oral hypoglycemic drugs may be
Insulin, glucagon and oral hypoglycemic drugs less effective in the prevention. A decrease in 25-hydroxycholecalciferol, a rise in the bone fraction o f alkaline phosphatase isoenzymes and of hydroxyproline excretion was found in 22 patients on (not specified) oral hypoglycemics (32) when compared with non-diabetics. The changes in these parameters in insulin-treated patients were intermediate, but the groups were not totally identical.
Chlorpropamide(SED 9, 604, 709, 711; SEDA-4, 305; SEDA-5, 391; SEDA-6, 370) A 64-year-old woman (33 C) developed hemolytic anemia with hematuria within one week after starting treatment with 300 mg of chlorpropamide daily. No haptoglobin was found and a strong direct positive Coombs test was present. An IgG was found in vitro. Lysis of the complement-sensitive cells was seen when the patient's serum, taken during the period of paroxysmal nocturnal hemoglobinuria, was incubated with normal fresh serum and chlorpropamide. In addition a positive Coombs test was found in an incubation mixture of red cells o f the patient, normal serum and chlorpropamide. Withdrawal of chlorpropamide reversed the symptoms. Optic neuropathy was described in a 65-year-old woman who used chlorpropamide 250 mg for one year (34c). She had a bilateral visual loss (20/400) of unknown duration but present for at least six months. Bilateral optic disc drusen were found. The patient was a member of a family with an autosomal dominant syndrome in which the affected women were mildly mentally deficient and the affected men were severely retarded. A daughter affected by the syndrome had normal visual acuity and no disc drusen. Four days before admittance to the hospital the patient stopped chlorpropamide; the visual acuity was 20/40+ in both eyes. During five days on chlorpropamide the visual acuity decreased to 20/70 OD and 20/60 OS. Discontinuation resulted in rapid return to a visual acuity of 20/50 OD and 20/40 OS. The syndrome o f inappropriate antidiuretic hormone secretion (see SEDA-4, 303) was described (35 c ) in two patients in whom the dose of chlorpropamide was doubled after they had been treated for 13 years and 10 years respectively with 250 mg daily.
Hypoglycemic attacks with neurological s y m p t o m s and confusion in a 72-year-old
407 man were reported (36c). He developed watery diarrhea. When he took no oral food no attacks were seen. The reinstitution of a normal diet induced recurrence of the symptoms. Further investigation revealed celiac disease. The reduced resorption of food may have contributed to the hypoglycemic attacks. A crossover study (37 c) of chlorpropamide once daily and glibenclamide once and twice daily was carried out in 12 patients: doses were increased until the fasting blood glucose concentrations were under 6 mmol/l. Six patients on glibenclamide twice daily had postprandial hypoglycemic reactions and four had such reactions when glibenclamide was given, in one reduced dose. One patient on chlorpropamide had a similar reaction. No patient had overnight symptomatic hypoglycemia. Four patients on chlorpropamide complained about flushing when using alcohol. T h e rise a n d f a l l o f t h e chlorpropamide a l c o h o l f l u s h i n g t e s t ( C P A F )
(SEDA-5, 391; SEDA-6, 370) In 1978 Leslie and Pyke reported (38) that small amounts o f alcohol (40 mt o f sherry, containing 18% alcohol) 12 hours after 250 mg o f ehlorpropamide could induce a facial flush reaction. This reaction was seen in 81% o f patients with noninsulindependent diabetes mellitus (NIDDM, type II) with a first degree family history o f diabetes and in only 31% o f NIDDM patients without a family history. The test was only positive in 10% o f normal subjects and in 10% o f patients with insulin-dependent diabetes mellitus (IDDM, type 1). The test was reported to be specific. Only one out o f 193 patients flushed after placebo and alcohol. In some patients the flush was more noticeable i f alcohol was used f o r a second time 36 hours after chlorpropamide. The challenged flushing was also f o u n d in family members o f NIDDM (39} with a positive family history f o r diabetes. Half the offspring o f CPAF-positive diabetics showed CPAF even though carbohydrate tolerance might be normal (40). The CPAF test was therefore propagated as a specific genetic marker for NIDDM. Families with mild diabetes o f early onset (sometimes called "Mason-type') seemed to f i t very well in the flushing pattern (39).
408
Further investigations revealed that the development o f secondary complications was less severe in diabetic patients with a positive CPAF as compared to patients with a negative CPAF. Retinopathy was reported to be less common and less severe (41, 42). Only one o f 191 CPAF-positive patients was blind, compared to eight o f 100 CPAFnegative patients. When nephropathy was studied with reagent strips (albustix) on at least three consecutive visits, 2% o f the CPAF-positive patients showed persistent proteinuria versus 14% in CPAF-negative patients, indicating that nephropathy was less frequent (43}. When insulin-dependent diabetics were investigated only 9% o f the patients with severe microangiopathy were CPAF-positive versus 28% o f the insulin treated patients with no complications (44). In a group o f 22 patients large vessel disease was seen in 45% o f the non-flushers and in 24% o f the flushers (45). In CPAF-positives a less frequent history o f myocardial infarction, angina pectoris, claudicatio intermittens or absent foot pulses were found. All these data were produced by the group o f Pyke, indicating that CPAF could be used as a genetic marker and might be indicative o f reduced secondary complications. Alcohol intolerance as a side effect o f sulfonylureas has been known for a long time (SED 8, 909-911). The disulfiramlike effects are most frequently seen with chlorpropamide, especially if alcohol is also taken (SEDA-6, 370). The pharmacological action o f disulfiram is not identical to the action o f chlorpropamide. Disulfiram blocks the aldehyde degradation, but sulfonylureas block the ethanol degradation itself (SED 9, 710). The symptoms are a vasomotor reaction o f the skin (redness and hot feelings), sometimes accompanied by tachycardia, giddiness, angina pectoris or headache. In early studies chlorpropamide did not induce a rise in acetaldehyde (46). When more sensitive methods were available acetaldehyde levels appeared to be increased (47, 48, 49) and a significant correlation between flush and acetaldehyde levels could be demonstrated (50). There is also a suggestion that the metabolism o f chlorpropamide is related to the CPAF reaction. In CPAFpositive patients the chlorpropamlde concentration in the blood is significantly higher than in chlorpropamide-negative
H.M.J. Krans persons {51, 52}. Prostaglandins may also play a role; sulfonylureas may enhance prostaglandin synthesis in platelets (53}, or inhibit the alcohol-stimulated prostaglandin release in the nervous system (54). The flush can be blocked by aspirin, 300 mg (54), or by indomethacin if major vessel disease is absent (55). Naproxene (a prostaglandin synthesis inhibitor), however, could not abolish the flush and aspirin reduced the flush without reduction o f the rise in aldehyde levels (50). Enkephalin release in the brain may be involved as well. The breathlessness seen in some CPAF-positive patients could be prevented by giving naloxone, as in an asthmatic reaction (56}. It was reported that the CPAF could be blocked by naloxone and could be produced by an enkephalin analogue (57), but this observation has not been confirmed (58). When other groups tried to use the CPAF-test, however, it emerged that the CPAF was less unequivocal than had been stated. The subjective feelings o f the patient were the most important factors for the decision as to whether the patient belonged to the CPAF-positive or -negative group. Measurements o f skin temperature did not always correlate with the subjective feelings o f the patient (59, 60, 61, 62). Nor was the reaction always by any means an all or none reaction. The reaction may improve when chlorpropamide is given for at least one week (52}, but this does not help the investigation in family members with normal GTT's. Nor could the great discrepancy in percentages between flushers and nonflushers be confirmed by other authors. False-positives and false-negatives were found in a frequency that made the test unfit for genetic counseling (63). Numbers reported by other investigators differed substantially from the original ones: Ki~bberling found 69% positive flushers in control subjects, 23.3% in IDDM and 60.5% in NIDDM (61), whilst according to De Silva 24% were positive in NtDDM, but 18% also flushed when a placebo was given (60}. There may be a faster rise in facial temperature in CPAF-positive subjects than in alcohol flushers. The induction o f the flush is not specific for chlorpropamide, all sulfonylureas can elicit the flush. A patient has been described (64 c) who flushed on tolbutamide but not on chlorpropamide. We have to conclude that the CPAF test-
Insulin, glucagon and oral hypoglycemic drugs ing only has clear discriminatory value when used by certain specific workers. In general we have to be cautious in drawing conclusions from CPAF investigations (65). The test appears to be neither specific f o r chlorpropamide, nor capable o f discriminating as well as has been postulated by its proponents.
Glibenclamide (SED 9, 712; SEDA-4, 305; SEDA-5, 387, 391; SEDA-6, 370} A case of fatal severe hypoglycemia after ingestion of an u n k n o w n a m o u n t o f glibenclamide in a suicidal a t t e m p t has been reported (66 c). Blood glucose could be c o r r e c t e d but c o m a persisted. The patient died after f o u r days. H y p o g l y c e m i a with intrahepatic cholestasis and cutaneous bullae (67 C) has been r e p o r t e d in a 61-year-old m a n using 10 mg of glibenclamide. In the course of three weeks he became gradually unwell with loss of appetite and drowsiness. On admittance he was unconscious with a blood glucose of 1.5 mmol/1. He had two clear colorless bullae 3 cm in diameter on the sole of his right foot, resembling those seen in barbiturate poisoning or porphyria cutanea tarda; both diagnoses were, however, excluded. No signs of extrahepatic biliary obstruction were seen and an ultrasound scan of liver and gall bladder revealed no abnormality. After seven days the alkaline phosphatase was normalized from a level of 2420 U/I. The other liver functions were normalized after four days. A liver biopsy on the 1 lth day was normal. The buUae dried up in a month.
Tolazamide (SED 9, 714) Factitious hypoglycemia was described in a nurse who appeared to have been taking t o l a z a m i d e (68 c ) after a history of h y p o glycemic episodes which eventually led to l a p a r o t o m y and removal o f 2/3 o f t h e pancreas and splenectomy. The multiple biopsies were described as showing focal islet hyperplasia. Three months later she was referred to another hospital for the same complaints. Local and general investigations (including a tolbutamide test) gave no signs of insulinoma. The patient was treated with diazoxide and hydroehlorothiazide. When she was admitted on a later occasion a level of 30 vg/1 tolazamide was found when blood was investigated for sulfonylurea levels. The patient declined contact with a psychiatrist. In a later episode she asked for a
409 medical alert, requesting tolazamide levels to be obtained if she was found to be hypoglycemic. Chronic eosinophitic pneumonia was described in a 70-year-old man with a nineyear history of diabetes mellitus treated with tolazamide ( 6 9 c ) . When tolazamide was o m i t t e d the patient b e c a m e afebrile and asymptomatic. When tolazamide was restarted i n t e r m i t t e n t fever, cough and weakness reccurred and after six weeks bilateral upper lobe infiltrates had reappeared. A f t e r discontinuance o f tolazamide the s y m p t o m s disappeared within a week.
Biguanides (SED 9, 714; SEDA-4, 306; SEDA-5, 393; SEDA-6, 3 71) A case of fatal lactic acidosis (70 r ) during metformin therapy has been described in an 84-year-old w o m a n . Years earlier m e t f o r m i n 1.5 g/day had been instit u t e d ; creatinine was then 93.7 /~mol/1. One m o n t h later the creatinine level was 110 #moI/1. During admission to hospital creatinine was high: 234/.tmol/1. She had a plasma m e t f o r m i n level o f 16.3 /lg/1 (normal levels in chronic t r e a t m e n t being 0.06-2.25/~g/1). In a series of 595 diabetic patients treated w i t h biguanides or c o m b i n a t i o n s of biguanides and other h y p o g l y c e m i c agents (71 R) hyperlactemia (although still within the range of normal values) correlated with the dosage and t y p e of biguanides m o r e as regards p h e n f o r m i n than m e t f o r m i n . Hyperlactemia is rarely f o u n d in c o m b i n a t i o n therapy and appears to represent a metabolic effect due to biguanide treatment. Cases of lactic acidosis after phenformin therapy c o n t i n u e to be r e p o r t e d (73 c ) including fatalities (72 c ) . The prevalence of lactic acidosis m a y be related to the rate o f h y d r o x y l a t i o n o f p h e n f o r m i n . The excretion of p h e n f o r m i n has been found n o t to be related to the rate o f renal i m p a i r m e n t (74); the excretion of p-hydroxyphenethylbiguanide, a metabolite of phenformin, was variable. R e d u c t i o n in f o r m a t i o n of this m e t a b o l i t e was c o n c o m i t ant with an increase in the a m o u n t of circulating phenformin. A reduced h y d r o x y l a t i o n of debrisoquine has been found in two patients who had had lactic acidotic c o m a and were o f f p h e n f o r m i n since that time (75). No direct parallel b e t w e e n the rate of i m p a i r m e n t of phenformin metabolism (in seven patients with a history of lactic acidosis) and debriso-
410 quine m e t a b o l i s m (in 138 healthy persons and in seven patients) could be found, but the Study indicated that the changed debrisoquine metabolism m a y be only one among the several factors involved in the d e v e l o p m e n t o f lactic acidosis (76). Genetic factors seem at all events to be involved in the metabolism o f p h e n f o r m i n ; slow metabolizers have an increased risk in developing lactic acidosis. D i c h l o r o a c e t a t e has been propagated for the t r e a t m e n t o f lactic acidosis (SEDA-3, 348). A recent review (77 r) concludes that it is n e u r o t o x i c , can cause cataract and m a y be mutagenic. New d e v e l o p m e n t s A p o t e n t i a l n e w d e v e l o p m e n t in the treatm e n t of diabetes is the use o f specific enz y m e inhibitors, which retard the carbohydrate and fat absorption f r o m the gut. The search for these drugs has been stimulated
H.M.J. Krans w h e n s u p p l e m e n t i n g fibers to the diet appeared to slow d o w n the absorption of carbohydrates. Acarbose, a bacterial aglucoside hydrolase inhibitor, has a retarding effect on glucose and fat absorption and reduces glucose levels in blood (78). The m a j o r side effects are excessive flatulence and meteorism. S o m e patients react with m a l a b s o r p t i o n diarrhea. Until n o w the drug has been used e x p e r i m e n t a l l y only. The effects and side effects are summarized in the proceedings o f a c o n f e r e n c e (79R). An F D A c o m m i t t e e decided in D e c e m b e r 1982 that acarbose should n o t be approved for clinical trials in the US until the q u e s t i o n o f possible carcinogenicity had been satisfactorily dealt with. The manufacturers had r e p o r t e d the occurrence of renal adenomas and h y p e r n e p h r o i d carcinomas in rats during chronic t o x i c i t y testing. These tumors are unusual in that species. T h e c o m p o u n d also appears to raise alkaline phosphatase in animals (80).
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