INTRODUCTION

Diabetes is a complex metabolic disorder clinically defined by high blood glucose levels resulting from a relative or absolute absence of insulin-production coupled with defective insulin action in body tissues.(1)

Incidences of diabetes are increasing at epidemic proportions. According to the estimates of the World Health Organization, there are more than 180 million people with diabetes worldwide and this number is likely to be more than double by 2030.(2)

Unmanaged diabetes can lead to life-threatening complications such as heart disease, stroke, renal failure, and blindness. Many individuals are not even aware that they have diabetes until they are diagnosed with one of these complications.(2)

In 2000, 3.2 million people died from complications associated with diabetes.(3)

Diabetes continues to be a huge financial burden on patients and Society. According to the American Diabetes Association, the annual-cost of diabetes in U.S. could rise to an estimated $156 billion by 2010.(4)

The increasing global incidence of diabetes has led to major investments by the bio-pharmaceutical industry to develop and acquire therapeutic and diagnostic solutions for diabetes.(1)

The global annual sales of oral anti-diabetic drugs exceed $ 18 billion annually according to the 2007 sales report.(5)

As cardiovascular disease (CVD) is a major complication, recent studies have questioned whether some anti-diabetic drugs increase rather than decrease CVD.(6)

FDA in U.S. announced new recommendations on evaluating cardiovascular risk in drugs intended to treat type 2 diabetes. Manufacturers will have to provide evidence that the therapy will not increase the risk of such cardiovascular events as heart attacks. The recommendation is part of new guidance for industry that applies to all diabetes drugs currently under development.(7)

References:
1. www.news.ulster.ac.uk/releases/2005/
1860.html
2. www.who.int/mediacentre/factsheets/
fs312/en/index.html
3. www.who.int/diabetes/Booklet_HTML/en/
index4.html
4. American Diabetes association "economic costs of diabetes in the US in 2002. Diabetes care volume. 26, pp. 917-32
5.www.mtbeurope.info/bi/reports/
antidiabetics/switching__to_new_molecule_
antidiabetics_drives.
6. www.glgroup.com/Topic/Diabetes.html
7. www.fda.gov/bbs/topics/news/2008/
new0192.html

• Update on adverse drug reactions in Canada
  
• FDA strengthens labelling for cardiovascular risks  
  
• Important safety reminder  
  

LIQUIANG 4 DIETARY SUPPLEMENT

• Presence of glyburide 

METFORMIN

• Risk factors for lactic acidosis 

PIOGLITAZONE

• Fractures in females  
  
• Long-term treatment associated with increased incidence of fractures in women 
  
• ADR update 
  

REPAGLINIDE & GEMFIBROZIL

• Risk of hypoglycaemia with concomitant use  

ROSIGLITAZONE

• Reminder about restrictions in use  
  
• Hemiparesis association
  
• Reports of parotid gland enlargement  
  
• Reports of macular oedema  
  
• Issues of cardiac safety
  
• Revised prescribing information due to adverse cardiac events
  
• Increased risk of fractures in women receiving long-term treatment  
  
• New warnings and contraindications in Europe 

ROSIGLITAZONE, PIOGLITAZONE

• Adverse reactions update

SHORTCLEAN

• Found to contain glibenclamide  

STATINS

• Reports of amnesia 

THIAZOLIDINEDIONES (pioglitazone and rosiglitazone) 

GLITAZONES
Update on adverse drug reactions in Canada

Canada.  The oral thiazo­lidinedione drugs rosiglitazone (Avandia) and pioglitazone (Actos) have been associated with a number of reports of adverse events in Canada between their time of marketing in March and August 2000, respectively, and March 2002, according to a report in the Canadian Adverse Drug Reaction Newsletter. During this time, a total of 282 suspected adverse reactions to rosiglitazone have been reported to Health Canada. Of these reports, 134 were considered serious. There were 60 reports of cardiovascular disorders, including 36 reports of heart failure, and 16 reports of liver and biliary diorders; 10 reports had a fatal outcome. For pioglitazone, 29 reports of suspected adverse reactions have been received, 24 of which were considered serious including 8 reports of cardio­vascular disorders (4 of heart failure), 1 report of liver and biliary disorders and 1 report with a fatal outcome. It is noted that, although people with type 2 diabetes are at increased risk of heart failure, diabetic patients receiving glitazones appear to be at greater risk of heart failure than diabetic patients not using glitazones. In order to minimise the risk of serious adverse events, physicians are reminded to follow all the recommendations and monitor­ing guidelines listed in the product information, which lists serious hepatic impairment and acute heart failure as contraindications for the use of rosiglitazone and pioglitazone.

Reference:
Canadian Adverse Drug Reaction Newsletter 12: 2-3, July 2002.

GLITAZONES
FDA strengthens labelling for cardiovascular risks  

USA. The US FDA has issued a safety alert advising healthcare professionals of changes to the labelling for pioglitazone (Actos) and rosiglitazone (Avandia). The changes more clearly define the cardiovascular risks associated with the use of thiazolidinediones as monotherapy and in combination with other anti­diabetic agents, particularly insulin. The summary from the FDA alerts physicians and patients to the possibility of fluid retention when either pioglitazone or rosiglitazone are used alone or in combination with insulin and warns that fluid retention may lead to, or exacerbate, congestive heart failure (CHF). It notes that cases of CHF have been reported in association with both agents, post-marketing. Included in the labelling for each drug is information from clinical trials in which the use of pioglitazone or rosiglitazone in combination with insulin was associated with an increased incidence of CHF compared with insulin therapy alone. The labelling for pioglitazone and rosiglitazone advises that patients receiving either agent should be observed for signs and symptoms of heart failure and that, if any deterioration in cardiac function occurs, the drug should be discontinued. Patients are advised to report possible symptoms of heart failure to their physician immediately. Neither drug is recommended for use in patients with New York Heart Association Class III and IV cardiac status.

Reports in WHO-file:

Pioglitazone; Cardiac failure 171, Cardiac failure left 5. Rosiglitazone; Cardiac failure 281, Cardiac failure left 19, Cardiac failure right 1

Reference:
Actos-Avandia Safety Information Summary from US FDA, 26 Apr 2002.
Available from URL: http://www.fda.gov/medwatch/ SAFETY /2002/summary-actos­-avandia.PDF

GLITAZONES
Important safety reminder  

Serious hepatic and cardio­vascular adverse drug reactions with rosiglitazone, an oral anti­diabetic drug were discussed in the previous issue of the newsletter (WHO Pharma­ceuticals Newsletter, Nos. 2&3, 2001). The following section details more safety related information on the drug.  

Canada. Health Canada has reminded patients that oral anti­diabetic medications belonging to a class known as thiazo­lidinediones or glitazones can cause fluid retention which can progress to congestive heart failure. Patients who develop oedema, shortness of breath, weakness, fatigue or excessive weight gain should inform their physician immediately and the treatment of these patients should be re-evaluated. If the symptoms are due to congestive heart failure, the medication should be discontinued. This is consistent with the safety information provided when rosiglitazone (Avandia) and pio­glitazone (Actos), two glitazone products, were launched in Canada last year. The present advisory has been issued to reinforce the safety concerns following a review of current safety information and medical literature. The advisory is in addition to letters issued by the manufacturers of these glitazones to health care professionals reminding them of the above mentioned safety issues.  

UK. The UK Medicines Control Agency (MCA) has also issued a reminder of the key safety issues, important contra­indications and precautions regarding the use of the two glitazones. Thus far, the MCA has been made aware of 249 and 17 adverse reactions associated with rosiglitazone and pio­glitazone respectively; the overall number of prescriptions issued for these agents since their launch is 148,000 and 16,000 respectively. The most frequently reported adverse reactions are vomiting, palpitations, headache, pruritus, diarrhoea, oedema, dyspnoea, liver disorders, muscle cramps, bodyweight increase, dizziness and hypercholesterolaemia. The MCA notes that rare reports of hepatocellular dysfunction have been reported with both drugs but a causal relationship has not been established. The agency also draws attention to the fact that these drugs are contra­indicated in the following patient groups:

·        those with, or a history of, heart failure

·        those with liver dysfunction

·        those who are taking insulin

The MCA emphasises that patients who receive either drug should have their liver enzyme levels monitored before initiation of therapy, every 2 months for the next 12 months and periodically thereafter. Patients whose ALT level increases to > 3 times the upper limit of normal should be reassessed as soon as possible, and if this elevation persists, treatment with the drugs should be terminated. 

Reports in WHO file:cardiac failure - rosiglitazone 154, pioglitazone 84; pulmonary oedema - rosiglitazone 28, pioglitazone 11; hepatocellular damage - rosiglitazone 14, pioglitazone 13; hepatic necrosis ­rosiglitazone 4, pioglitazone 5; hepatitis - rosiglitazone 46, pioglitazone 17 

Reference:
1. Advisory from Health Canada, 30 Nov 2001. Available from URL: http://www.hc-sc.ca
2.'Dear Healthcare Professional' letter from Eli Lilly Canada Inc., 6 Nov 2001. Available from URL: http://www.hc-sc.ca
3 'Dear Healthcare Professional' letter from GlaxoSmithKline, 13 Nov 2001. Available from URL: http://www.hc-sc.ca
4. Current Problems in Pharmacovigilance 27: 11, Aug 2001.

Liqiang 4 dietary supplement
Presence of glyburide 

Canada. Health Canada is warning consumers that 'Liqiang 4 dietary supplement capsules' contain glyburide, a prescription drug used to treat type 2 diabetes. The supplement could thus have life-threatening consequences in diabetics and in individuals with low blood sugar if used without medical supervision. Liqiang 4 capsules, promoted for use in the control of diabetes, are not approved for sale in Canada. However, consumers could probably buy them through mail-order or over the Internet. Consumers are advised to immediately stop using these products and to seek medical attention, especially if they are currently being treated with anti-diabetic drugs. 

Reference:
Advisory. Health Canada, 25 October 2005, (http://www.hc-sc.gc.ca).

Sweden. The Medical Products Agency (MPA) in Sweden is drawing attention to the risk factors for the development of lactic acidosis in patients receiving metformin for type 2 diabetes mellitus. The MPA lists various causes of impaired renal function among those risk factors that predominate but adds that additional factors include alcoholism, advanced age and impaired liver function in patients receiving metformin. The MPA has received a total of 52 reports of lactic acidosis and an additional eight reports of acidosis as a diagnosed adverse reaction associated with metformin. 

Reports in the WHO database:
Lactic Acidosis - 1514  

Reference:
Reactions Weekly, No. 1148: 2, 21 April 2007, (http://reactions.adisonline.com).

Pioglitazone
Fractures in females  

USA. Takeda Pharmaceuticals and the US FDA notified health­care professionals of recent safety data concerning pioglitazone-containing products.  The results of an analysis of the manufacturer's clinical trial database of pioglitazone showed more reports of fractures in female patients taking pioglitazone than those taking a comparator (either placebo or active). The majority of fractures observed in female patients were in the distal upper limb (forearm, hand and wrist) or distal lower limb (foot, ankle, fibula and tibia). There were more than 8100 patients in the pioglitazone-treated groups and over 7400 patients in the comparator-treated groups. The duration of pioglitazone treatment was up to 3.5 years. The US FDA advises that health-care professionals should consider the risk of oseltamivir label updates in Canada and in the USA).

Reports in WHO database: Oseltamivir (Tamiflu) - suicide attempts - 3  

References:
1. Adis Reactions (Weekly) No. 1143: 2, 2007.
2. Press Release. European Medicines Agency (EMEA), 23 March 2007 (www.emea.europa.eu).

Pioglitazone
Long-term treatment associated with increased incidence of fractures in women 

Switzerland, Canada, France. The manufacturers of pioglitazone (Eli Lilly in Canada, Takeda in France and Switzerland) have written to health-care professionals about the increased incidence of fractures in women receiving long-term treatment with pioglitazone for type 2 diabetes mellitus. Pioglitazone belongs to the thiazolidinedione (TZD) group of antidiabetic medicines. An analysis of the pioglitazone clinical trial database, with a special focus on fractures reported as adverse events, has shown that significantly more pioglitazone-treated female patients experienced at least one event of bone fracture than patients treated with non- TZD comparator drugs (other diabetes medicines such as metformin or sulfonylureas or placebo). The majority of the fractures involved distal lower limb: ankle, foot (fibul and tibia), or distal upper limb (hand, forearm and wrist). Currently, there is no known explanation for these events. There was no increased risk of fracture identified in men. Health-care professionals are advised to carefully consider the risk of fracture in the care of female patients with type 2 diabetes who are currently being treated with pioglitazone or when initiation of pioglitazone is being considered.
(See WHO Pharmaceuticals Newsletter No.2, 2007 for related communications in the USA).  

Reports in the WHO database:
Fracture - 17 

References:
1.  'Dear health-care professional' letter from Takeda, 5 April 2007 (www.swissmedic.ch).
2.  'Dear health-care professional' letter from Eli Lilly, 18 April 2007 (www.hc-sc.gc.ca).
3.  'Dear health-care professional' letter from Takeda, 19 April 2007 (www.afssaps.fr).

Pioglitazone
ADR update 

Netherlands. Up to 9 October 2007, the Netherlands Pharmacovigilance Centre (Lareb) received 57 reports involving 77 ADRs associated with the oral anti-diabetic drug pioglitazone. Of these reports, two concerning the same patient were filed by two marketing authorization holders. The reported ADRs involved only one report of cardiac failure and no reports of myocardial infarction.  (In 2000 the product labeling for pioglitazone was revised in Japan to include information on adverse cardiac events associated with pioglitazone; see WHO Pharmaceuticals Newsletter No. 4, 2000) 

Reports in WHO ICSR database: 

Pioglitazone
Total 4273 reports from 22 countries (2000 – 2008)

Cardiac failure              405
Cardiac failure left        14
Myocardial infarction     74 

Reference:
Update on reports of pioglitazone, Lareb, May 2008, (www.lareb.nl)

REPAGLINIDE & GEMFIBROZIL
Risk of hypoglycaemia with concomitant use  

Canada. Novo Nordisk Canada Inc. has informed healthcare professionals that the concomitant use of repaglinide and gemfibrozil is now contraindicated, following the publication of a study in healthy volunteers demonstrating a markedly enhanced blood glucose-lowering response to repaglinide (GlucoNorm) with concomitant gemfibrozil. The Company says that these findings indicate a potential risk of severe and prolonged hypoglycaemia and it has therefore contraindicated the concomitant use of these agents. In  addition, Novo Nordisk's international safety database contains five reports of serious hypoglycaemia in patients receiving concomitant repaglinide and gemfibrozil.  

Reference:
'Dear Healthcare Professional' letter from Novo Nordisk Canada Inc, 17 Jul 2002. Available from URL: http://www.hc-sc.qc.ca

ROSIGLITAZONE
Reminder about restrictions in use  

Singapore. The Health Sciences Authority in Singapore has issued a reminder to all prescribers that rosiglitazone is not recommended for use in patients with New York Heart Association class III or IV heart failure or moderate-to-severe hepatic impairment. In addition, they say that rosiglitazone is not recommended for use in combination with insulin. The Singapore Pharmacovigilance Unit has received 4 reports of suspected adverse drug reactions associated with the use of rosiglitazone since its release in Singapore in June 2000. Two of the cases were of heart failure, 1 was of peripheral oedema and the other was of mildly elevated liver enzyme levels. The authority says that liver enzyme levels should be monitored before initiating, and during, therapy with rosi­glitazone. It adds that if liver enzyme levels remain more than 3 times greater than the upper limit of normal, rosiglitazone should be discontinued.

Reference:
Adverse Drug Reaction News 3: 2-­3, Dec 2001.

ROSIGLITAZONE, PIOGLITAZONE
Adverse reactions update

Australia. The Adverse Drug Reactions Advisory Committee (ADRAC) in Australia has received 44 adverse event reports associated with rosiglitazone and 28 with pioglitazone. These include 12 reports of hepatic reactions with rosiglitazone and four with pioglitazone, and six reports of cardiac reactions with pioglitazone and 12 with rosiglitazone. The committee states that these drugs should not be used in patients with liver disease or in patients whose cardiac failure limits their physical activity, and that monitoring of liver and cardiac function is required.

Reference:
Australian Adverse Drug Reactions Bulletin 22: 6-7, Apr 2003.

Rosiglitazone ­–
hemiparesis association

The UMC database contains a number of cases with the association between rosiglitazone and hemiparesis. For the high level term "paralysis", which includes paresis, hemiparesis, hemiplegia and paralysis, there are 12 such cases. Cases date from 1999-present in the database. Total ADRs for rosiglitazone = 9082.  

These twelve cases comprise 8 males and 4 females with an average age of 65.9 years (range 34-77). Country of origin of these cases:  

 Rosiglitazone is an oral anti­diabetic agent.  It is a member of the group of drugs known as thiazolidinediones, a new group of drugs called "insulin sensitizers". Rosiglitazone specifically targets insulin resistance, which is thought to be central to the development of type 2 diabetes and some of the complications of the disease. Rosiglitazone is approved as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus either as monotherapy or in combination with metformin or a sulfonylurea. Rosiglitazone is not indicated for combination therapy with insulin; combined use increases the risk of heart failure or oedema¹.  

Combination therapy is evident in 11 of the subject cases.  It is possible that cases of hemiparesis (and similar disorders) represent a severe neurological deficit such as occurs with cerebrovascular events. In fact, other cases in the data set for rosiglitazone include the terms cerebral haemorrhage (2), and various cerebrovascular disorders [cerebral infarct (5), cerebral ischaemia (3) and cerebrovascular disorders general (26)].  

By comparison, pioglitazone, another thiazolidinedione, shows 8 cases of "paralysis", (hemiparesis 2, hemiplegia 1, paralysis 3, and paresis 2).  Cases are all from the USA. There are 4 males, 4 females with an average age of 64.4 years (range 50-73).  The total number of ADRs for pioglitazone is 14,832, dating from 2000 to present. In addition, there are 11 cases of cerebrovascular disorder and 8 cases of cerebral infarct.  

In contrast, for the more traditional anti-diabetic drug metformin, there are 12 cases of "paralysis" listed from 1995. These cases represent 6 males, 6 females, with an average age of 63.6 years (range 42-79).  The total number of ADRs for metformin from 1969 to present is 13,654. 

In order to understand a possible mechanism for these events, a diabetologist at the Ottawa Health Sciences hospital was consulted. He provided the following observations:  

Both severe hyperglycemia as well as hypoglycemia could lead to neurological insult. Rosiglitazone on its own does not produce hypoglycemia, but could do so if used in conjunction with a sulfonylurea or insulin (it would not do so when used with metformin). Its use with insulin has also been associated with fluid retention and congestive heart failure, which might also potentially affect circulation to the brain if there was a severe cardiac output deficit. 

Thiazolidinedione-induced oedema has been described recently in a publication by Niemeyer and Janney². Considering the relatively high prevalence of cardiovascular disease among diabetic patients, it is likely that a number of cerebrovascular events will be seen in this population.  The following table outlines various types of ADRs that are of interest in this context for the three comparison drugs.  

Thus, although hemiparesis in association with rosiglitazone may not constitute an important signal per se, factors that may contribute to development of neurological insult, such as oedema and cardiac failure seem to have been reported more frequently with this drug than with comparison anti-diabetic drugs. If this association is to be followed, it should be in the context of contributory factors.  

References:
1. Monograph for rosiglitazone, Clinical Pharmacology Online, Gold Standard Multimedia Publications, 2002.
2. Niemeyer NV, Janney LM. Thiazolidinedione -induced edema, Pharmacotherapy 22(7):924-29, 2002.

Rosiglitazone
Reports of parotid gland enlargement  

Canada. Health Canada has received five case reports of parotid gland enlargement suspected of being associated with rosiglitazone (Avandia) use. The reports involved four women and one man, aged 53 -72 years (age not stated in one case), with adverse reaction onset (n = 4) ranging from six to eleven months after rosiglitazone initiation. Some of the reports indicated a complex medical history and multiple concomitant medications. Four of the patients had bilateral parotid gland enlargement; one patient had parotid gland enlargement to five times its normal size. In three cases the reaction was reported as painless. One patient also experienced submandibular gland swelling and, in another patient, parotiditis was considered as a differential diagnosis. Patient outcomes on rosiglitazone withdrawal were: improvement in one week (n = 1), gradual resolution over four months (1) and not yet recovered (1); the outcome was not stated in the remaining two reports.  

Reference:
Canadian Adverse Reaction Newsletter January 2006, 16(1): 3.

Rosiglitazone
Reports of macular oedema  

Canada, USA. GlaxoSmithKline (GSK) has received rare post­marketing reports of new-onset and worsening diabetic macular oedema in patients receiving rosiglitazone products (Avandia and Avandamet), used in treating type 2 diabetes mellitus. GSK advises that the visual impairment improved or resolved in some cases following discontinuation of therapy; in one case, there was resolution of the retinal oedema after a dose reduction. GSK has sent letters to health professionals in Canada (1) and in the USA (2) with the above information. The company says that the majority of patients also reported fluid retention, weight gain or peripheral oedema. In Canada health-care professionals are advised that an ophthalmological consultation should be sought, and cessation of treatment should be considered, in patients reporting visual deterioration; the company also recommends that these drugs be used with caution in patients with pre-existing retinal oedema or diabetic retinopathy. GSK advises that patients using rosiglitazone containing products (Avandia and Avandamet) should see their doctor if they experience blurred or distorted vision, decreased ability to adapt to darker surroundings and/or decreased colour sensitivity (3). The company recommends that patients receiving Avandia or Avandamet, who have been diagnosed with retinal oedema or diabetic retinopathy, should see their doctor to assess whether the medication should be continued. GSK emphasises that patients should not stop taking Avandia or Avandamet without first consulting their doctor (3).

References:
1. 'Dear Health-care Professional' letter from GlaxoSmithKline Inc.,
2. 19 December 2005 (http://www.hc-sc.gc.ca).
3. 'Dear Health-care Professional' letter from GlaxoSmithKline Inc., December 2005 (http://www.fda.gov).
4. Public Communication. Health Canada, 20 December 2005  (http://www.hc-sc.gc.ca).

Rosiglitazone
Issues of cardiac safety

Canada, Europe, USA. An article in the New England Journal of Medicine (NEJM) (1) has generated significant public attention on the cardiac safety of rosiglitazone (Avandamet, Avandaryl, Avandia), a drug approved to treat type 2 diabetes. The article, based on an analysis of data retrieved from 42 clinical studies, showed a small increased risk for myocardial infarction and cardiovascular death among approximately 15 500 patients treated with rosiglitazone. Health Canada, EMEA and the US FDA have issued different statements referring to the article:

US FDA (2): Safety data from controlled clinical trials have 'shown that there is a potentially significant increase in the risk of heart attack and heart-related deaths in patients taking rosiglitazone (Avandia). However, other published and unpublished data from long­term clinical trials (of Avandia) provide contradictory evidence about the risks in patients treated with this product. The Agency has been monitoring several heart­related adverse events based on signals from previous controlled clinical trials of rosiglitazone (Avandia) alone and in combination with other drugs and from postmarketing reports. The Agency has updated the product's labelling to reflect all new data. The most recent labelling change for rosiglitazone (Avandia) included a new warning about a potential increase in heart attacks and heart-related chest pains in some individuals using rosiglitazone (Avandia). This new warning was based on the result of a controlled clinical trial in patients with existing congestive heart failure.