42 Insulin, other hypoglycemic drugs, and glucagon

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Insulin, other hypoglycemic drugs, and glucagon

INSULIN (SED-15, 1761; SEDA-26, 461; SEDA-27, 446; SEDA-28, 509) Respiratory Pulmonary edema secondary to hypoglycemia was reported particularly in the 1930s when insulin shock treatment was used for schizophrenia. It is less common nowadays, but has been reported after insulin overdose (1A ). Metabolism Hypoglycemia In a 12-month open study of 64 patients with type 2 diabetes (mean age 58 years) who used either once-daily bedtime NPH insulin + tablets or twice-daily 30% soluble + 70% NPH, there was less hypoglycemia in the former (2.7 hypoglycemic events per person compared with 4.3); the improvement in HBA1c was similar (2c ). Weight gain was also less in those who used once-daily NPH (1.3 kg compared with 4.2 kg). The use of insulin during intensive therapy for critically ill patients has been reviewed (3R ). In a safety study from the GIST (poststroke hyperglycemic management) trial in 25 patients using a GKI (glucose, potassium, insulin) infusion one patient required therapy for symptomatic hypoglycemia (4c ). Of 452 patients, mean age 75 years, 20 had blood glucose concentrations below 4 mmol/l within 30 minutes of stopping the GKI infusion and required intravenous dextrose. The patients had been randomized to GKI infusion or saline to maintain blood glucose concentrations at 4– 7 mmol/l, and only 69 of the 452 had type 2 diabetes. Side Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29042-1 © 2007 Published by Elsevier B.V.

In 1500 patients in intensive care, there was hypoglycemia (4 mmol/l and less) in 5.2% of the intensively treated group and 0.8% of those who received conventional therapy (3R ). It has been reported that 11% of drug errors are from insulin administration errors and it has been recommended that frequent checks be made of infusion systems (3R ). Electrolyte balance Hypokalemia occurred in 29 children undergoing insulin tolerance tests; the mean serum potassium concentration at the start was 4.1 mmol/l, falling to a mean of 3 mmol/l at 30 minutes (5Ac ). Ten children had a serum potassium concentration below 2.9 mmol/l and one had a concentration of 2.2 mmol/l. There were no cardiac events. • An 8-year-old girl had an insulin tolerance test with 0.05 IU/kg to assess growth hormone concentrations. The blood glucose concentration fell to 0.9 mmol/l and she was given intravenous dextrose. She had a generalized seizure and developed ventricular flutter. The serum potassium concentration was 2.6 mmol/l. Catecholaminergic polymorphous ventricular tachycardia was later diagnosed.

Fluid balance Insulin edema, a syndrome of unidentified origin that occurs in patients with either type 1 or type 2 diabetes after the introduction or intensification of insulin treatment, has been reviewed (6R ). In studies in the 1970s peripheral edema developed in 15 of 86 middleaged insulin-treated patients (7C ) and between 4 and 10% of intensively treated people with type I diabetes (8C ). In more recent studies of patients with type 2 diabetes, 5.4% of 408 patients treated with insulin developed edema compared with 15% of those who received insulin and a glitazone. In a further study edema occurred in 4.8% of patients who used rosiglitazone alone (9S ). Insulin can cause edema that can become clinically significant, particularly when it is combined with other therapies that cause edema.

523

524 • A 39-year-old man developed type 1 diabetes and lost 9 kg over 6 months (10AR ). He was treated with intravenous fluids and insulin. Within 1 month he developed bilateral edema to the knees. The jugular venous pressure was not raised.

Liver Four girls aged 11–14 years with poorly controlled type 1 diabetes had hepatomegaly and raised transaminase activities up to 30 times the upper limit of the reference range (11A ). Their diabetes was poorly controlled (HBA1c 9.2–15%) despite high doses of insulin (1.3–2.2 units/kg/day). After admission for diabetes control their insulin requirements fell to 0.9–1.2 units/day and their liver function normalized within days. A biopsy in one case showed abundant deposits of glycogen. In these patients diabetes was poorly controlled, as shown by the HbA1c , but the doses of insulin were high. Because insulin promotes glycogenesis, the authors suggested that when high blood glucose concentrations are treated intermittently with high doses of insulin, glucose is driven into the liver, which then promotes abnormal liver function. When insulin is used regularly, less insulin is needed and the liver problem resolves. This is in contrast to nonalcoholic steatohepatitis (NASH), which does not resolve promptly. Susceptibility factors Renal disease In renal insufficiency the renal metabolism of insulin is impaired and generation of glucose reduced (12A ). • A 64-year-old man who had had type 2 diabetes for 15 years used insulin 35 units/day without problematic hypoglycemia, but within 2 weeks had three episodes. He was found to have developed renal insufficiency secondary to diclofenac and his serum creatinine concentration had increased to 440 µmol/l.

Drug administration route Subcutaneous Injection of insulin into abnormal subcutaneous tissues can result in poor control of blood glucose (13A ). • A 42-year-old man who had had type 1 diabetes for 24 years had deteriorating blood glucose control despite increasing insulin doses (HBA1c increased from 11% to 17%). He was injecting into two areas that contained 4 cm hard woody nodules. Biopsy showed collagen with fibroblasts and necrosis. When he avoided the areas his blood glucose improved with reduced insulin doses.

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The authors went on to audit 73 consecutive patients; 32 had clinical lipohypertrophy and a further two had hard nodular lumps. Continuous subcutaneous insulin infusion (CSII) Continuous subcutaneous insulin infusion (CSII) has been compared with multiple daily injections of insulin in a randomized study in 32 patients, mean age 13 years, over 16 weeks (14C ). Of the 16 patients who used CSII one returned the pump twice and one returned the pump once, in both cases for pump software errors. Medtronic MiniMed 508 or Paradigm 511 pumps were used in the study. In two randomized crossover trials metabolic deterioration occurred earlier and was of greater amplitude with insulin lispro than with regular insulin when a pump was discontinued (15R ). However, when the pump was restarted, insulin lispro was more effective than regular insulin in correcting metabolic deterioration. CSII is associated with infections at the site of infusion, about 40 episodes per 100 patient years (15c ). One-third required oral antibiotics. Surgical drainage was very rarely needed (16r ). Lipoatrophy, although rare, has been reported in patients using both regular and lispro insulin in CSII pumps (17A , 18A ). Inhalation Insulin-binding IgG antibodies are found in about 75% of patients with type 2 diabetes using inhaled insulin (19r ). This is more than one would expect from the use of subcutaneous insulin. The antibodies appear to plateau after 1 year. There are no obvious clinical effects. In an open study of 107 patients with type 2 diabetes using the AERx insulin diabetes management system (n = 54) or subcutaneous insulin (n = 53), the number of people with insulin antibodies increased from 6% to 35% in those who used the AERx insulin diabetes management system (20c ). The number of patients with antibodies remained stable at about 10% in those who used subcutaneous insulin. There were no obvious clinical consequences. Similar results were found in a study of patients with type 1 diabetes: 29% of those who used inhaled insulin compared with 3% of those who used subcutaneous insulin (21c ). Most trials of inhaled insulin exclude smokers and patients with severe asthma or chronic obstructive pulmonary disease. Mild to moderate cough is a common adverse effect (19r ).

Insulin, other hypoglycemic drugs, and glucagon

Smoking can reduce the dosage requirements of inhaled insulin, because of increased permeability of the alveolar capillary barrier (22R ). A reduction in carbon monoxide diffusion capacity has been reported in phase III trials with an insulin aerosol delivery system, Exubera. In further studies to investigate this, the changes in lung function were transient or reversible. In patients who used AERx for 12 weeks there were no changes in lung function (23R ). The risk of hypoglycemia with inhaled insulin has been reported to be similar to that with subcutaneous insulin (22R ). In an open study of 107 patients with type 2 diabetes, mean age 58 years, using liquid insulin aerosol droplets + subcutaneous NPH insulin (n = 54) compared with Actrapid + NPH (n = 53) for 24 weeks, there were three major episodes of hypoglycemia in two patients using inhaled insulin and none in the other group (20c ). Of 335 patients with type 1 diabetes randomized to receive preprandial inhaled insulin as a dry powder formulation via an aerosol delivery system (Exubera) plus bedtime subcutaneous Ultralente insulin, or to continue NPH and regular insulins subcutaneously, 170 received inhaled insulin (mean age 33 years) (21c ). Six discontinued inhaled insulin, one because of mild cough, two because of hypoglycemia, and three because of insufficient responses. The risk of hypoglycemia was slightly lower in those who used inhaled insulin, at 8.6 events per month compared with 9.0 events per month in the conventional insulin group. Both powdered insulin formulations and liquid inhaled insulin formulations are being developed. There have been no direct comparisons of these formulations, and it is therefore difficult to make definitive statements about whether one is superior to the other (23R ). Further information will need to be obtained about the possible long-term adverse effects of inhaled insulin.

525

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Weakness, headache, ataxia, thirst, dry mouth, and nausea were reported, among other symptoms.

NEW ULTRASHORT-ACTING INSULINS (SEDA-26, 463; SEDA-27, 449; SEDA-28, 512)

Insulin lispro

(SED-15, 1788)

Skin Lipoatrophy has previously been reported with lispro (SEDA-27, 449). • A 35-year-old woman with type 1 diabetes was transferred after 7 years to lispro subcutaneously tds and NPH twice daily (25A ). Within 2 years she developed lipoatrophy and further lipoatrophy at another site 6 months later.

Pregnancy Maternal and fetal outcomes have been investigated when insulin lispro has been used during pregnancy (15R ). Insulin lispro is unlikely to cross the placenta when used in a single standard dose. Lispro was not found in the cord blood of neonates whose mothers had received a continuous intravenous infusion of lispro. These data and data from controlled studies showing similar outcomes in women treated with conventional insulin are reassuring. In a prospective comparison in 69 pregnant women of lispro (n = 36) with conventional insulin (n = 33), there was no adverse impact on the progression of diabetic retinopathy (15R ).

LONG-ACTING INSULINS (SEDA-26, 463; SEDA-27, 450; SEDA-28, 513)

Insulin detemir Oral In a phase I trial of oral modified insulin (HIM 2), 16 patients (mean age 37 years) with type 1 diabetes using CSII over 2 separate days used basal CSII on one day and basal CSII and oral insulin on another (24c ). There were 58 adverse events in 15 patients, although it was not clear whether they were drug-related.

(SED-15, 1785;

SEDA-28, 513) Metabolism Phase 3 trials have suggested that insulin detemir is associated with less weight gain (0.4 kg) than NPH insulin (1.3 kg); the mechanism is uncertain (26R ).

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OTHER HYPOGLYCEMIC DRUGS (SEDA-26, 466; SEDA-27, 452; SEDA-28, 514)

ALPHA GLUCOSIDASE INHIBITORS (SED-15, 85; SEDA-26, 466; SEDA-27, 452; SEDA-28, 514)

Acarbose Gastrointestinal A meta-analysis of seven double-blind, randomized, placebo-controlled studies in which acarbose was used for a minimum of 52 weeks for the management of type 2 diabetes has shown that the frequency of the most common adverse events of flatulence, diarrhea, and abdominal pain varied from country to country: 53% of those taking acarbose reported symptoms in Germany compared with 73% in Canada (27M ). The frequency of adverse effects with placebo was also higher in Canada (39%) than in Germany (29%).

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co-administered with insulin. It received FDA approval in 2005 for both type 1 and type 2 diabetes. Placebo-controlled studies In 18 subjects with type 1 diabetes, mean age 37 years, who received in random order on separate days pramlintide 60 micrograms or placebo plus their usual doses of regular insulin, hypoglycemia (pramlintide 28% versus 16%) and mild nausea (17% versus 11%) were the most common adverse effects (30c ). Nausea has also occurred in other long-term studies (29R ). Weight loss rather than weight gain has been reported in association with reductions in HBA1c concentrations in patients with type 2 diabetes. Whether this relates to a reduction in insulin dose while using pramlintide, especially in those who are more obese, is uncertain.

BIGUANIDES

(SED-15, 506; SEDA-26, 467; SEDA-27, 453; SEDA-28, 514)

Metformin Miglitol Gastrointestinal In 33 patients with type 2 diabetes treated with sulfonylureas and insulin who took miglitol 50 mg bd for 1 week and then over the next month increased the dose to 50 mg tds, 15% developed adverse effects (6% diarrhea, 6% abdominal distension), which disappeared within 3 weeks of continuing therapy (28c ).

Metabolism Hypoglycemia is uncommon with metformin. When it does occur it should lead to a search for other potential problems. • A 72-year-old man taking metformin 1 g bd for type 2 diabetes began to have episodes of hypoglycemia, which resolved on stopping the metformin; he also had anterior pituitary failure (31A ).

Metformin and lactic acidosis AMYLIN ANALOGUES

(SEDA-27,

453; SEDA-28, 514)

Pramlintide Amylin is a peptide hormone that is co-secreted with insulin from pancreatic beta cells. Its actions include delayed gastric emptying, inhibition of glucagon secretion, and reduced food intake. Pramlintide is an amylin analogue (29R ). It is administered subcutaneously, but it precipitates above pH 5.5 and therefore cannot be

Case reports Further cases of lactic acidosis attributed to metformin have been reported. • A 42-year-old man developed nausea and vomiting and felt suicidal. He had type 2 diabetes and was taking metformin (32A ). His blood lactate concentration was 8.9 mmol/l, bicarbonate 16 mmol/l, and pH 7.2. Severe hypotension required intensive care. The lactate concentration rose to 22 mmol/l and the bicarbonate fell to 6.7 mmol/l and the pH to 6.89. The metformin concentration was high at 191 mg/l. He survived, having been treated with intermittent hemodialysis.

Insulin, other hypoglycemic drugs, and glucagon • A 61-year-old woman developed a bradydysrhythmia after a cardiac arrest (33AM ). Her lactate concentration was 18 mmol/l, pH 6.60, blood glucose 19 mmol/l, and creatinine 1136 µmol/l. She had a 5-year history of type 2 diabetes treated with glimepiride 3 mg/day and metformin 850 mg tds, and 4 months before admission had had a serum creatinine concentration of 1.1 mg/dl. In the few days before admission she had had abdominal pain, nausea, and a speech disorder. She was treated with hemodialysis, and 6 weeks later the creatinine was 0.54 mg/dl. Further information about events leading to the acute renal insufficiency was not given, but a diagnosis of metforminassociated lactic acidosis was made.

There is no doubt from reports such as this in people who take overdoses that metformin can cause lactic acidosis. In a review of enquires to a poison center relating to metformin between 1995 and 2003 there were 109 enquires, of which 62 were for attempted suicide and 47 for adverse effects; 14 patients had had lactic acidosis (33AM ). Eight were taking metformin as regular therapy, of whom one died; of six who had attempted suicide, three died. Reviews The questions “Does metformin cause lactic acidosis?” (34r ) and “What is the risk of lactic acidosis accompanying metformin therapy for patients with type 2 diabetes?” (35r ) have been posed and answered using data from a Cochrane review (SEDA-28, 516). The reports suggested that there was no evidence of an association between metformin and lactic acidosis. In another review it was suggested that the risk of lactic acidosis when metformin is used as recommended is close to zero (36r ). The author discussed the COSMIC study, which compared metformin treatment for 1 year (n = 7227) with usual care with other antidiabetic agents (n = 1505). There were no cases of lactic acidosis. The findings in controlled trials contrast with case reports of lactic acidosis. About one million patients have received metformin in the USA and the FDA has received 47 reports of lactic acidosis (20 fatal). Of these, 43 patients had renal insufficiency or susceptibility factors for lactic acidosis, such as congestive cardiac failure. Only four cases appeared to have no other susceptibility factors, one of which may have been precipitated by urinary sepsis; none of these four died. Six experts in intensive care or metabolic disease reviewed all case reports of lactic acidosis from 1957 to 1999—37 articles reporting

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80 cases (37M ). To be assessed the reports had to meet strict criteria, including: a diagnosis of type 2 diabetes, metformin therapy before lactic acidosis, a pH of 7.35 or less, or a plasma bicarbonate concentration below 22 mmol/l and a lactic acid concentration of at least 5 mmol/l. Because of lack of information, 33 cases were excluded. There were other susceptibility factors for lactic acidosis besides metformin in 46 of 47 cases. Only 13 of the 47 cases were classified as probably due to metformin by at least three experts. The authors suggested a rethink about the relation between lactic acidosis and metformin. However, they still recommended withdrawing therapy in acute renal insufficiency and when contrast dyes are used for radiological investigation. In a review of reports to the Australian Adverse Drugs Reactions Advisory Committee between 1985 and 2001 there were 48 cases of lactic acidosis with metformin (38r ). In 35 of the 48 cases known susceptibility factors were identified. The estimated frequency was one case of lactic acidosis in 30 000 patients taking metformin. The authors discussed the arbitrary cut-off point of a creatinine concentration of 150 µmol/l often set for withdrawal of metformin. They suggest that the concentration should be individualized and that age, muscle mass, and protein turnover should also be considered. They recommended using the Cockcroft–Gault equation to estimate creatinine clearance, and an absolute cut-off point of 30 ml/minute, below which metformin should be withdrawn. In patients with a creatinine clearance of 30–50 ml/minute there should be caution. Metformin should be withdrawn during significant intercurrent illnesses and when using iodinated contrast agents. Skin Erythema multiforme has been attributed to metformin after 4 days of therapy in a 58year-old man with type 2 diabetes; the rash resolved within 2 weeks of stopping the drug (39A ). Pregnancy Metformin crosses the placenta, and although there is no evidence that it is not safe in pregnancy there are insufficient data to say that it is (40r ). In an audit in Auckland there was no increase in perinatal mortality or pre-eclampsia (41c ). The MIG (metformin in gestational diabetes) prospective randomized

528 comparison of metformin and insulin aims to recruit 750 women; 70 have been recruited so far without serious adverse events in the metformin arm. In a review of 60 publications on metformin and pregnancy malabsorption of vitamin B12 , which occurs in non-pregnant women, was thought to be a potential problem (42R ). The data did not suggest an increased risk of teratogenesis. Teratogenicity In 126 infants born to 109 mothers with polycystic ovary syndrome who conceived while taking metformin and continued to take it during pregnancy, there were no differences in infant growth up to 18 months of age or in motor and social development (43c ). The doses during pregnancy were 2.55 g/day (n = 74), 1.5–2 g/day (n = 43), and 1 g/day (n = 5). In 18 pregnancies the metformin was stopped at a median of 12 weeks because the obstetrician did not want it to continue. Preeclampsia occurred in five of 122 pregnancies (4.1%), which was no different to community controls (nine of 252 (3.6%)). Drug formulations Adverse effects are more likely to occur with metformin at the start of therapy. In retrospective case note review comparison of modified-release and immediaterelease metformin 9.2% of those newly started on modified-release metformin (n = 65) had gastrointestinal adverse effects compared with 20% of those who started on immediate-release metformin (n = 363) (44c ). The main gastrointestinal adverse effect was diarrhea. The mean doses were 1258 mg/day for modified-release metformin and 1282 mg/day for immediaterelease metformin.

Incretin mimetics Incretins are compounds that increase insulin secretion from the pancreas in a glucose-dependent manner; they are therefore potential therapies for the treatment of diabetes mellitus. Glucagon-like peptide-1 (GLP-1) (30 amino acids) is a naturally occurring incretin. It is largely produced in the distal ileum and colon in response to food that contains carbohydrate and fat. Other incretins include gastric

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inhibitory polypeptide (GIP). The half-life of GLP-1 is only minutes, as it is rapidly metabolized by dipeptidyl peptase IV, which is another therapeutic target. Other actions of GLP-1 include delayed gastric emptying, appetite suppression, and increased beta cell mass. There is suppression of raised glucagon concentrations, but the counter-regulatory response remains intact. Subcutaneous GLP-1 also has a short halflife (about 30 minutes) and so longer-acting GLP-1 receptor agonists are being developed. These drugs are known as incretin mimetics. Exenatide (39 amino acids) is the first to have received FDA approval. Liraglutide (32 amino acids) is undergoing trials. Exenatide is injected subcutaneously into the thigh, abdomen, or upper arm. It is administered twice daily. The pharmacokinetics of exenatide 10 micrograms subcutaneously are: Cmax 211 pg/ml, tmax median 2.1 hours, apparent volume of distribution 28 liters, clearance 9.1 l/hour, terminal half-life 2.4 hours. Elimination is by glomerular filtration followed by proteolytic degradation. The clearance is not affected by mild or moderate renal impairment. However, clearance is reduced in end-stage renal insufficiency and dialysis. It is recommended that exenatide should not be used in such patients. Liraglutide is also injected subcutaneously, but once daily because of its longer half-life. Incretin mimetics are an exciting development, because when used alone they do not promote hypoglycemia, as their actions on insulin and glucagon are strictly glucose dependent. They are accompanied by weight loss, and they may preserve beta cell mass. Reviews of incretin mimetics (45R , 46R ) have suggested that nausea and vomiting are adverse effects common to all those currently in clinical trials. The adverse effects occur transiently and in association with peak plasma concentrations of glucagon-like peptide (GLP)-1. The doses of both exenatide and liraglutide that have maximum glucose lowering effects are similar to the doses that are associated with these adverse effects. Metabolism Hypoglycemia is more common when incretin mimetics are taken with sulfonylureas but not metformin. Many of the actions of GLP-1 and incretin mimetics are glucose dependent and do not on their own provoke hypoglycemia. However, it is thought that because

Insulin, other hypoglycemic drugs, and glucagon

of the ability of sulfonylureas to open KATP channels at low blood glucose concentrations, GLP-1 can augment insulin secretory responses at lower concentrations than it would normally. The same problem may occur when incretin mimetics are combined with meglitinides. Gastrointestinal Both exenatide and liraglutide cause slowed gastric emptying; this may have an effect on the speed of absorption of other drugs (45R ).

Exenatide Patients with type 2 diabetes treated with a sulfonylurea alone, aged 22–76 years, were randomized to placebo (n = 123) or subcutaneous exenatide 5 micrograms bd (n = 254); after 4 weeks 129 patients increased their dose to 10 micrograms bd (47C ). During the 30 weeks of the study 12 subjects had mild to moderate transient abnormalities of creatine kinase. Serious adverse events were no more frequent with exenatide (4% with 10 micrograms and 3% with 5 micrograms) than with placebo (8%). The adverse events that were related to treatment included nausea, which occurred in 49 patients (39%) of those who used 5 micrograms and 66 (51%) of those who used 10 micrograms, compared with 9 (7%) of those who used placebo. The nausea was worst during the first 8 weeks then abated. Other adverse effects included hypoglycemia, dizziness, and a jittery feeling. There was hypoglycemia in 36% of those taking 10 micrograms, 14% of those taking 5 micrograms, and 3% of those using placebo. One subject withdrew owing to hypoglycemia. Weight loss was progressive over 30 weeks and was most apparent in those taking 10 micrograms (−1.6 kg). Those who did not report nausea also lost weight.

Liraglutide Liraglutide is a long-acting incretin mimetic designed for once-daily subcutaneous injection. Phase II trials have been completed and phase III trials are planned. In 190 patients, mean age 57 years, randomized to different doses of liraglutide (0.045–0.75 mg/day) for 12 weeks,

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gastrointestinal events increased with increasing doses; 10 of 135 patients exposed to liguratide reported nausea (five in the highest dose group), compared with 1 of 29 who took placebo (48c ). Diarrhea, vomiting, and constipation also occurred. Most (two-thirds) of the gastrointestinal symptoms resolved within 3 days. Headache was also reported.

MEGLITINIDES (SED-15, 2238; SEDA-26, 468; SEDA-27, 455; SEDA-28, 518) Comparative studies Repaglinide has been compared with nateglinide in an open 16-week study (49c ). Repaglinide was started in a dose of 0.5 mg per meal and increased up to 4 mg per meal if necessary. Nateglinide was started in a dose of 60 mg per meal and increased up to 120 mg per meal. Of those who used repaglinide, 54% achieved an HBA1c concentration of less than 7%, compared with 42% of those who used nateglinide. There were 0.016 hypoglycemic events per patient in those who used repaglinide compared with none in those who used nateglinide. Weight gain was 1.8 kg with repaglinide and 0.7 kg with nateglinide. There were no noticeable differences in the pattern of adverse events, which included constipation, arthralgia, and headache.

Nateglinide Susceptibility factors Age Of 358 patients aged 35–84 years who were given nateglinide over 12 weeks, 115 took 120 mg before main meals (group 1) and 214 took metformin and nateglinide in combination (group 2) (50c ). There were no differences in rates of hypoglycemia. Three patients in group 2 had serious adverse events, one of which was thought to be related to the study drug (details not given). Adverse events included nausea, vomiting, and headache. There was no information about how these events related to age.

Repaglinide Liver Hepatotoxicity has been attributed to repaglinide (51A ).

530 • A 70-year-old man developed diabetes and started to take repaglinide 1 mg tds. After 2 weeks he developed malaise, anorexia, and jaundice. Liver function tests, including bilirubin, were raised. Repaglinide was withdrawn and the liver function tests returned to normal. There were no other obvious causes.

Drug interactions Gemfibrozil has previously been reported to increase plasma concentrations of repaglinide (SEDA-27, 456). However, in a formal study bezafibrate and fenofibrate did not affect the pharmacokinetics or pharmacodynamics of a single dose of repaglinide 0.25 mg (52c ). Rifampicin Studies involving rifampicin and repaglinide have yielded conflicting results, perhaps because of timing and dosages. In one study rifampicin had no effect on the pharmacokinetics and pharmacodynamics of a single dose repaglinide given after 7 days of rifampicin (53C ). In contrast, in another study there was a 57% reduction in the AUC of repaglinide, with a reduction in its effect on blood glucose (54C ). These studies differed in timing and doses. In a more recent study, 12 male volunteers took rifampicin 600 mg/day for 7 days followed by two doses of repaglinide 4 mg 24 hours apart; the AUC for repaglinide was reduced by 50% on day 7, and by 80% on day 8 (55c ). Timing of the drugs may alter the clinical effects. Trimethoprim CYP2C8 and CYP3A4 are involved in the metabolism of repaglinide (56c ). Trimethoprim is a selective inhibitor of CYP2C8. When nine healthy volunteers aged 19–23 years, 8 men) took placebo or trimethoprim 160 mg bd for 3 days followed by 0.25 mg of repaglinide 1 hour after the last dose of trimethoprim, the AUC of repaglinide increased by 61% and the Cmax increased by 41% compared with placebo.

SULFONYLUREAS

(SED-15, 3230; SEDA-26, 469; SEDA-27, 456; SEDA-28, 518)

Glibenclamide Cardiovascular In a randomized study of 48 patients with type 2 diabetes, mean age

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58 years, those who took glibenclamide for 8 weeks had a mean increase in systolic blood pressure of 3.1 mmHg (57c ). In the same study the systolic and diastolic blood pressures fell in those who took rosiglitazone. The authors speculated whether changes in insulin concentrations and sympathetic activity were responsible. Hematologic Anemia has been attributed to glibenclamide (58A ). • After taking metformin 850 mg tds and glibenclamide 5 mg bd for 5 days, a 58-year-old woman of Burkina Faso origin became anemic. The hemoglobin concentration was 9.4 g/dl, the reticulocyte count was 6.6%, and the glucose-6-phsophate dehydrogenase (G6PD) activity was low (0.4 UI/g Hb, reference range 4.0–6.8). Glibenclamide was withdrawn and metformin continued. The hemoglobin rose to 11.5 g/dl.

There have been rare reports of autoimmune hemolytic anemia attributed to glibenclamide and the manufacturer’s product leaflet also mentions reports of pancytopenia. Immunologic Hypersensitivity reactions have been described with glibenclamide. • A 67-year-old man developed Stevens–Johnson syndrome after taking glibenclamide 20 mg/day for 4 weeks, having previously used insulin. He died from hemorrhagic bronchopneumonia. Post mortem examination also showed features of granulomatous arteritis and cholestatic interface hepatitis, suggestive of a hypersensitivity reaction (59A ).

Pregnancy Of 197 patients with gestational diabetes, 73 took glibenclamide, and 59 (81%) achieved satisfactory blood glucose control (60c ). Of these 59, nine had adverse effects, including malaise and weakness (n = 4), nausea (n = 2), lightheadedness (n = 1), and hypoglycemia (n = 2). Glibenclamide was withdrawn in one patient because of adverse effects; 11 of the 59 had babies who weighed over 4 kg. No anomalies were identified, but glibenclamide was started at a mean of 30 weeks. Drug interactions Ciprofloxacin can precipitate hypoglycemia in patients taking glibenclamide. • A 68-year-old man with type 2 diabetes, who was taking glibenclamide 1.25 mg bd, warfarin, furosemide 40 mg/day, fosinopril 10 mg/day,

Insulin, other hypoglycemic drugs, and glucagon clopidogrel 75 mg/day, lovastatin 40 mg/day, and metoprolol XL 50 mg/day, took ciprofloxacin 250 mg bd for 1 day (61A ). He had renal impairment (creatinine 203 µmol/l). On admission he was hypoglycemic with a capillary blood glucose concentration of 1.1 mmol/l (20 mg/dl). The hypoglycemia continued for 24 hours.

There has been a previous report of hypoglycemia in a patient taking glibenclamide and ciprofloxacin (62A ). A similar effect has been reported with another fluoroquinolone, gatifloxacin (63R ). • A 79-year-old man with type 2 diabetes taking glibenclamide 10 mg/day and metformin 2.5 g/day became hypoglycemic after taking one dose of gatifloxacin 400 mg. The hypoglycemia continued for 24–48 hours. • An 84-year-old woman taking glibenclamide 5 mg/day and metformin 2 g/day became hypoglycemic after taking gatifloxacin 400 mg. The hypoglycemia continued for 24–36 hours.

In 48 patients with type 2 diabetes on diet, gatifloxacin reduced blood glucose concentration by 1.1 mmol/l (20 mg/dl) (64C ). In Japan gatifloxacin is contraindicated in patients with diabetes. Low blood glucose concentrations were reported in 75 patients, 58 of who had diabetes (63R ).

Gliclazide Metabolism In a 2-year study in 507 patients, mean age 61 years, the incidence of symptoms suggestive of hypoglycemia was 4.8 per 100 patient years (65c ). Seven patients withdrew after 1 year because of adverse events, which were thought to be unrelated to the gliclazide.

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the hydroxymetabolite was detectable 4–8 hours longer than glimepiride itself. This may be useful in suspected poisoning. The clinical relevance of the hydoxymetabolite is uncertain (68r ). In a meta-analysis of 1444 patients who took glimepiride for a year there was no change in weight (69M ).

Glipizide Drug dosage regimens Continuous exposure to high concentrations of sulfonylureas impairs rather than improves therapeutic efficacy (70R ). The authors suggested that the sulfonylurea receptor is desensitized during long-term therapy. This suggests either that the concentration– effect curve of sulfonylurea drugs is shifted to the right with time or that it is not sigmoidal but bell-shaped. The optimum dosage for a specific drug should not be exceeded. It has been suggested that this might be 10 mg/day for glipizide and 7–10 mg/day for glibenclamide (70R ). In a 3-month crossover study of placebo or glipizide 10, 20, or 40 mg in randomized order, glipizide 10 mg/day produced higher insulin concentrations and lower glucose concentrations than 20 or 40 mg/day (71C ). Drug interactions Drugs that potentiate the actions of sulfonylureas and the mechanisms responsible have been reviewed (72R ). Mechanisms include: • displacement from plasma proteins, e.g. salicylates; • reduced hepatic metabolism, e.g. monoamine oxidase inhibitors; • reduced urinary excretion, e.g. allopurinol; • intrinsic hypoglycemic activity, e.g. alcohol.

Glimepiride Glimepiride has been reviewed (66R , 67R ). It is metabolized by the liver and its active metabolites are excreted by the kidneys. It should be used with caution in patients with renal or liver disease. Metabolism Hypoglycemia appears to be less of a problem with glimepiride than with other sulfonylurea drugs. In nine patients who had severe hypoglycemia associated with glimepiride

THIAZOLIDINEDIONES (GLITAZONES) (SED-15, 3380; SEDA-26, 471; SEDA-27, 457; SEDA-28, 519)

Peripheral edema due to thiazolidinediones In patients who had taken either rosiglitazone (n = 96) or pioglitazone (n = 107) for at least

532 2 months, adverse effects included peripheral edema (33% and 21% respectively), and 7% and 4% respectively had treatment withdrawn (73c ). The edema was not related to dose. Pulmonary edema occurred in two patients taking pioglitazone and three taking rosiglitazone. In another study the combination of a thiazolidinedione with insulin increased the prevalence of edema and the dose of thiazolidinedione was important (74c ). Of 319 patients taking insulin, 13% developed edema when taking rosiglitazone 4 mg/day compared with 16% taking 8 mg/day and 4.7% taking placebo (75C ). In 556 patients taking insulin, edema developed in 18% of those who took pioglitazone 30 mg/day, 13% of those who took 15 mg/day, and 7.0% of those who took placebo (76C ). The authors undertook a retrospective review of 79 subjects taking thiazolidinediones and insulin; 20 had developed edema. The mean dose of pioglitazone was 24 mg/day and rosiglitazone 6 mg/day. The mean time to edema was 135 days. They reported a 77% resolution rate with various interventions. Whether thiazolidinediones need to be withdrawn in patients with edema has been discussed in several papers. • A 58-year-old man with type 2 diabetes and angina, weight 106 kg, taking metformin and insulin took rosiglitazone 2 mg bd, increased to 4 mg bd 4 months later (77A ). HbA1c improved from 9.6% to 8% after a further 2 months, although his weight had increased to 113 kg and he had developed ankle edema. Therapy was continued and furosemide 20 mg/day was added. After a further 2 months the edema had increased, his weight was 115 kg, and HbA1c had improved to 7.5%. The furosemide was increased to 20 mg bd. Two months later his weight had increased further to 117 kg and he was short of breath on exertion. Metformin was withdrawn, furosemide was increased to 80 mg bd, and irbesartan 75 mg bd was added. However, his symptoms worsened. Two weeks later the rosiglitazone was stopped and his symptoms gradually improved. • A 73-year-old man with angina and hypertension had an HbA1c concentration of 16% while taking insulin (77A ). He weighed 114 kg. Since he was unable to take a sulfonylurea or metformin, he was given rosiglitazone 2 mg bd with an increased dose of insulin. Two months later his HbA1c had improved to 11%, his weight had risen to 120 kg, and there was a trace of edema. After 7 months he de-

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veloped paroxysmal dyspnea and bilateral edema. The rosiglitazone was withdrawn and the dose of furosemide was increased. His symptoms improved within 3 months.

There have been other reports of resolution of edema while continuing therapy with thiazolidinediones (78A ). • A 54-year-old obese woman with type 2 diabetes had rosiglitazone 4 mg bd added to insulin and metformin. Five months later she reported shortness of breath on exertion, paroxysmal nocturnal dyspnea, and peripheral edema. One month later a chest X-ray confirmed bilateral pulmonary edema. The dose of rosiglitazone was reduced to 4 mg/day and furosemide 20 mg/day was added. Her symptoms improved. • Ten months after adding rosiglitazone 4 mg bd to insulin and metformin a 68-year-old woman developed shortness of breath on exertion and edema. The rosiglitazone was continued in the same dosage, and her symptoms resolved. • An 80-year-old man taking insulin developed edema 10 months after starting to take rosiglitazone. The rosiglitazone was withdrawn and pioglitazone 30 mg/day started instead. The edema initially improved but then worsened. Furosemide was given and the pioglitazone withdrawn.

These reports suggest that edema can improve with continued therapy of thiazolidinediones, but in some patients reducing or withdrawing therapy is necessary for resolution of symptoms. The time of onset of symptoms suggests that in some patients the edema can occur as part of the natural disease process and that the thiazolidinedione can exacerbate symptoms and impairs the response to diuretic therapy. Fluid retention with thiazolidinediones may be dose-dependent and a class effect (79R ). There is little or no evidence to suggest a direct negative effect on cardiac performance. Because the symptoms may be due to increased permeability of the microcirculation, they may respond more quickly to drug withdrawal than to diuretic therapy. In a retrospective cohort study of interventions for chronic heart failure before and after the use of rosiglitazone in 139 patients aged 66–75 years (mainly men), 20 had received treatment for heart failure before therapy with rosiglitazone and 50 needed it within 6 months of starting therapy (80c ).

Insulin, other hypoglycemic drugs, and glucagon

The pre-treatment plasma concentration of natriuretic peptide type B may be a good marker for pioglitazone-induced congestive heart failure but this needs confirmation (79R ).

Pioglitazone Metabolism Weight gain occurs with thiazolidinediones, which cause recruitment and conversion of pre-adipocytes into adipocytes and are therefore adipogenic (79R ). In 18 patients without diabetes, mean age 46 years, who took pioglitazone 30 mg/day for 48 weeks for non-alcoholic steatohepatitis, there was a mean weight gain of 3.5 kg in 72% (81c ). Similarly, in 91 patients with type 2 diabetes who took pioglitazone 30 or 45 mg/day for 1 year there was a mean weight gain of 3 kg, compared with 1.1 kg in the 109 who took glibenclamide (82c ). Liver Hepatotoxicity has been reported with pioglitazone. • A 42-year-old man took pioglitazone 30 mg/day for 6 weeks and developed abnormal liver function tests, which returned to normal 1 month after withdrawal (83A ). • A 63-year-old man was given pioglitazone instead of gliclazide and within 3 months developed jaundice and malaise (84A ). Liver function was deranged, with aspartate transaminase activity of 1984 IU/l, alanine transaminase 455 IU/l, alkaline phosphatase 1053 IU/l, and bilirubin 522 µmol/l. He died 9 days later. Histology showed parenchymal damage with steatohepatitis, including Mallory bodies superimposed on a severely fibrotic liver.

The authors of the second report speculated that this patient had pioglitazone-induced acute liver damage superimposed on chronic liver disease related to diabetes. Susceptibility factors Age Pioglitazone was as effective in those aged over 65 years as in those under 65 years. Adverse events were also similar, with similar numbers of cardiovascular and hypoglycemic events in the studies reviewed (85R ).

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Rosiglitazone Endocrine It has been suggested that thiazolidinediones may be novel candidates for redifferentiation therapy of various cancers. Five patients with papillary or follicular thyroid cancer took rosiglitazone 4 mg/day for 1 month and 8 mg/day for 2 months (86c ). There were increased thyroglobulin concentrations in four. The significance of this increase was uncertain. Although the authors suggested that redifferentiation might have been the cause, thyroglobulin concentrations also increase with increased tumor mass. Metabolism Lipoma formation has been attributed to rosiglitazone. • A 58-year-old HIV-positive man with type 2 diabetes was given rosiglitazone and over the next 3 months developed several dozen lipomas measuring 1–4 cm in diameter. Biopsy showed well circumscribed tumors of normal appearing fat cells, beneath normal-looking skin. The rosiglitazone was withdrawn and the lipomas resolved (87A ).

In a placebo-controlled study in 108 nondiabetic adults with HIV-1 infection and lipoatrophy, rosiglitazone 4 mg/day for 48 weeks had no beneficial effect on the lipoatrophy (88c ). However 30 of those who took rosiglitazone developed hypertriglyceridemia, compared with 20 taking placebo, and 11 developed hypercholesterolemia, compared with four taking placebo. Triglycerides have been reported to increase by a mean of 0.99 mmol/l in patients taking rosiglitazone, with no change in those taking pioglitazone (73c ). A more profound change in triglycerides has also been reported with rosiglitazone, although this is likely to be rare (89A ). • A 64-year-old woman who had taken metformin for 3 years had a high-density lipoprotein concentration of 1.2 mmol/l, which fell to 0.26 mmol/l when she took rosiglitazone. The HbA1c fell from 10.1% to 7.9%. Fenofibrate was added and the HDL concentration fell further to 0.11 mmol/l. Triglycerides, 2.7 mmol/l before treatment, increased to 4.7 mmol/l. Apolipoprotein A1 concentrations were low at 0.14 g/l (reference range 1.1–2.05 g/l). On withdrawing both the rosiglitazone and the fenofibrate the HDL concentration rose to 0.95 mmol/l.

534 • A 64-year-old man took metformin and glipizide. The HbA1c concentration was 11.4%, HDL 0.99 mmol/l, and triglycerides 3.8 mmol/l. Bezafibrate was added and the HbA1c fell to 8.7%, HDL was unchanged at 0.98 mmol/l, and triglycerides fell to 1.9 mmol/l. After starting rosiglitazone 4 mg/day the HDL fell to 0.44 mmol/l, and on increasing the dose of rosiglitazone to 8 mg/day the HDL fell to 0.26 mmol/l, triglycerides rose to 5.2 mmol/l and apo-1 concentrations were 0.27 g/l. On withdrawal of rosiglitazone the HDL returned to 0.98 mmol/l. • A 64-year-old man had rosiglitazone added to his therapy and the HDL concentration fell from 0.90 to 0.31 mmol/l. Triglycerides rose from 4.0 to 8.0 mmol/l. Apo-1 concentrations were reduced (0.57 g/l).

Hypolipoproteinemia is likely to be a rare adverse effect. The measurement of HDL cholesterol and triglycerides before and after staring thiazolidinedione therapy will allow its detection. On withdrawing therapy concentrations return to normal. This effect may be specific to rosiglitazone, as it is becoming apparent that the PPAR-γ agonists vary in their effects. Liver In a review it has been suggested that hepatotoxicity with pioglitazone and rosiglitazone may not be causal but due to confounding medical factors (66R ). For example, hepatotoxicity has been attributed to rosiglitazone, secondary to cardiac failure (90A ). • An 84-year-old man took rosiglitazone 4 mg/day for 11 months in combination with metformin 1 g bd and gliclazide 160 mg bd. He developed abnormal liver function tests, with alanine transaminase activity of 4336 IU/l, which later increased to 7776 IU/l, alkaline phosphatase activity of 358 IU/l, and a normal bilirubin. Serum lactate was high at 8.59 mmol/l. Rosiglitazone was withdrawn and his diabetes was treated with insulin. His liver function normalized within 4 weeks, but he died after developing a chest infection.

The authors speculated about the role of rosiglitazone, suggesting that it may have precipitated congestive cardiac failure, which then led to ischemic hepatitis. A direct hepatotoxic effect was thought to be unlikely. Drug interactions Rosiglitazone is metabolized by CYP2C8 and to a lesser extent by CYP2C9. No unchanged drug is excreted in the urine. Rifampicin induces hepatic and intestinal CYP isozymes. When 10 healthy Korean men aged 22–26 years were given rifampicin

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600 mg/day for 6 days and then rosiglitazone 8 mg on day 7 the plasma AUC was reduced to 65% and the half-life shortened from 3.9 to 1.5 hours compared with placebo (91c ). Similar studies have shown increased plasma concentrations of rosiglitazone after the addition of ketoconazole (92c ) and trimethoprim (93c ).

COMBINATIONS OF ORAL HYPOGLYCEMIC DRUGS Sulfonylureas + metformin Death In the United Kingdom Prospective Diabetes Study a subgroup of patients taking sulfonylurea therapy to which metformin was added appeared to have had excess mortality. Data from 263 general practices in the UK were analysed; 8488 patients took a sulfonylurea initially, to which metformin was added in 1868 (94c ). The crude mortality rates per 1000 person years were 59 and 40 respectively. Metformin was used initially in 3099 patients and a sulfonylurea was added in 867. The crude mortality rates per 1000 person years were 25 and 20 respectively. These results suggest there is no increased mortality risk with a combination of a sulfonylurea and metformin.

Glibenclamide + metformin + rosiglitazone Metabolism Glibenclamide 2.5 mg/day + metformin 500 mg/day in a combination tablet was increased to a maximum of 10 mg/day + 2000 mg/day in patients with type 2 diabetes, mean age 57 years and weight 93 kg; 181 patients also took rosiglitazone and 184 took placebo for 24 weeks (95c ). Rosiglitazone was added to a maximum of 8 mg/day aiming to reduce the HBA1c concentration to less than 7.0%. There was hypoglycemia in 140 patients; 95 (53%) of those who took rosiglitazone reported hypoglycemia compared with 45 (25%) of those who took placebo. One patient taking rosiglitazone withdrew owing to hypoglycemia.

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HbA1c concentrations were less than 7% in 42% of those taking rosiglitazone compared with 14% of those taking placebo. Weight gain was

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greater in those taking rosiglitazone, 3 kg compared with 0.03 kg.

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