Ldr abcd rosiglitazone.qxp

The Association for British Clinical
Diabetologists: recommendations following
suspension of rosiglitazone (Avandia)

On 23 September 2010, the European Medicine’sAgency (EMA) Committee on Medicinal Products for Human Use (CHMP) recommended the suspension ofmarketing authorisation for Avandia (rosiglitazone) • For all new prescriptions of thiazolidinediones, and Avandamet (rosiglitazone/metformin) as it was felt that the risks of this treatment outweighed the benefits.
• Patients already taking rosiglitazone should have a The chair of the Commission on Human Medicines medication review in order to consider alternative (CHM) has written to health care professionals to inform them of the advice of the CHM following this • Replacement therapy should be tailored according to the clinical needs of the individual patient and should There have been concerns about a possible increase be in line with existing NICE guidance when possible. in cardiovascular events in patients treated with rosiglita- Those patients whose glycaemic control requires zone since 2007 when a meta-analysis of 42 separate consideration of alternatives to sulphonylureas and studies involving rosiglitazone was published in the New England Journal of Medicine.2 This found that subjects who cardiovascular risk status, heart failure, osteoporosis had been allocated rosiglitazone had a significant fracture risk, weight, hepatic and renal function, increase in the risk of myocardial infarction and an increase in the risk of death from cardiovascular disease.
• Patients already taking rosiglitazone who do not wish It was well known that the thiazolidinedione (TZD) class to change to alternative therapy should be advised that of drugs caused fluid retention and oedema.3 As a result it is not possible to continue rosiglitazone as this of this TZDs could exacerbate pre-existing heart failure therapy has been suspended and will be withdrawn and therefore were already contraindicated in this group • Prior evidence of heart failure or impairment of left of patients. However, the suggestion that rosiglitazone ventricular function remains a strict contraindication for caused adverse cardiovascular outcomes outside of this the use any thiazolidinediones. Osteoporosis and known contraindication was of concern.
previous fracture may also be considered a GlaxoSmithKline, the manufacturer of rosiglitazone, disagreed strongly with the findings in this paper and hasargued that the RECORD study (Rosiglitazone Evaluated It is essential that any treatment for type 2 diabetes has for Cardiovascular Outcomes and Regulation of glycaemia demonstrated cardiovascular safety (even if not cardiovas- in Diabetes) has shown no evidence of cardiovascular cular benefit). There is evidence that good glycaemic harm.4 However, significant concerns have been raised control using older treatments such as metformin, regarding the design and conduct of this study.5 sulphonylureas and insulin results in a reduction of Although a few retrospective case control database microvascular complications and is safe from the cardio- studies have suggested equivalent cardiovascular risk for vascular standpoint.9,10 It should also be noted that, to pioglitazone,6 there is superior evidence in the form of a date, the newer alternative comparator therapies such as large-scale, multicentre, randomised control study the DPP-IV inhibitors or GLP-1 mimetics have no pub- (PROactive) which studied the cardiovascular effects of lished cardiovascular safety data from controlled trials.
pioglitazone.7 Although the primary endpoint of this trialdid not show significant benefit, this was associated with increased interventions for peripheral vascular The following recommendations should be read in disease and this study found that treatment with pioglita- conjunction with Table 1. The Association for British zone did significantly reduce the secondary composite Clinical Diabetologists (ABCD) recommends that: endpoint of myocardial infarction, stroke or all-cause • Patients currently taking rosiglitazone should bemortality. It should be noted that the individuals recruited switched to an alternative medication. This should be to this study were all patients with type 2 diabetes with done via a medication review which provides a useful evidence of pre-existing vascular disease (i.e. a very high opportunity to reassess the patient’s diabetes manage- risk group of patients). Therefore, there is reasonable ment as a whole. Options for switching are summarised evidence that pioglitazone does not cause adverse cardio- vascular outcomes outside the known contraindication of • The choice of drug should depend on the current heart failure. Reassuringly, these findings are supported by concomitant medication and the individual needs of the meta-analysis data suggesting that pioglitazone offers some patient. The risks and benefits of each therapy should be protection against cardiovascular disease.8 discussed with the patient prior to switching.
Pract Diab Int November/December 2010 Vol. 27 No. 9 Copyright 2010 John Wiley & Sons 1
• Replacement therapy should be consistent with exist- • Careful consideration should be made prior to switch- ing National Institute for Health and Clinical Excellence ing patients to alternative newer therapies (such as GLP-1 mimetics and DPP-IV inhibitors) which also do • Cautions, contraindications and up-to-date guidance not have published cardiovascular safety data from from the MHRA (Medicines and Healthcare products Regulatory Agency) should be taken into account prior • Note that risk of pregnancy should be taken into account. Women of child-bearing age should not be Table 1. Options for switching from rosiglitazone (in order of preference)
Patients who have very tight glycaemic control, i.e. HbA1c <6.5% (48mmol/mol) on rosiglitazone. Note that this may result in loss of glycaemic control, and HbA1c should be reviewed within 2 months Should be the preferred choice for patients who are able to tolerate metformin and have no contraindication to its use Stop rosiglitazone and then start metformin 500mg after meals once a day and titrate. People experiencing limiting GI side effects may tolerate the slow release formulation Likely to be suitable for many patients currently on rosiglitazone as long as they have not had previous Stop rosiglitazone and then start gliclazide 40mg bd or another SU about 4 weeks later. Titrate according to response Suitable for patients who have previously responded very well to rosiglitazone. Caution in post-menopausal women Stop rosiglitazone and start pioglitazone according to recommended titration algorithm (see Table 2) May be suitable for some patients in whom weight gain may be particularly undesirable (in line with NICE CG87 guidance) Stop rosiglitazone and then start sitagliptin 100mg od, saxagliptin 5mg od or vildagliptin 50mg bd May be suitable for some patients in whom weight loss may be particularly desirable (in line with NICE CG87 guidance) Stop rosiglitazone and start exenatide 5µg bd. Titrate to 10µg bd. Alternatively liraglutide 0.6mg od titrated to Small pancreatitis risk. 1.2mg could also be used. Consider delayed start by No cardiovascular May be suitable for some patients in whom HbA1c is particularly high and/or who are on maximum or near maximum Stop rosiglitazone and then start insulin (choice is accordingto patient’s individual needs) 2 Pract Diab Int November/December 2010 Vol. 27 No. 9
Copyright 2010 John Wiley & Sons offered medications for which there are no safety data Table 2. Switching from rosiglitazone to pioglitazone
in pregnancy (such as incretin-based therapies or piogli-tazone) unless they are using effective contraception.
Also, all such women should be given appropriate • The local diabetes specialist team should be contactedfor advice if needed.
• Prior evidence of heart failure or impairment of left ventricular function remains a contraindication for the use of these medications and this should be rigidly adhered to. Osteoporosis and previous fracture may alsobe considered a relative contraindication to a TZD in If on Avandamet (rosiglitazone/metformin fixed dose combination) then individualised therapy as appropriate,or consider pioglitazone/metformin fixed dose ABCD will keep this advice under review as new informa- combination if appropriate. The licensed starting doses of Niru Goenka, Aled Roberts, Susannah Rowles,
Algorithm based on advice from Takeda (manufacturer of Bob Ryder and Peter Winocour; on behalf of the
pioglitazone) and on a review by Derosa, 2010.12 Association of British Clinical Diabetologists 2. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocar- dial infarction and death from cardiovascular causes. N Engl J Med We would like to thank Frank Joseph and David Ewins 2007; 356: 2457–71.
3. Nesto RW, et al. Thiazolidinedione use, fluid retention, and conges- tive heart failure: a consensus statement from the American HeartAssociation and American Diabetes Association. Diabetes Care 2004; 27: 256–63.
Dr Niru Goenka has given lectures or attended meetings 4. Home PD, et al. Rosiglitazone evaluated for cardiac outcomes and sponsored by MSD, Eli Lilly, Novo Nordisk and Bristol- in oral agent combination therapy for type 2 diabetes (RECORD):
a multicentre, randomised, open-label trial. Lancet 2009; 373:
Myers Squibb. Any honoraria from these meetings are paid either to the departmental diabetes education and 5. Nissen SE. Setting the RECORD straight. JAMA 2010; 303: 1194–5.
research trust fund, or to other registered charities.
6. Wertz DA, et al. Risk of cardiovascular events and all-cause mortal- Dr Aled Roberts has received educational sponsor- ity in patients treated with thiazolidinediones in a managed-care
population. Circ Cardiovasc Qual Outcomes 2010; 3: 538–45. Epub 24
ship and/or honoraria for lectures from Astra Zeneca, 7. Dormandy JA, et al. Secondary prevention of macrovascular events Dr Susannah Rowles has previously received speaker’s in patients with type 2 diabetes in the PROactive Study fees from a number of pharmaceutical companies includ- (PROspective pioglitAzone Clinical Trial In macroVascular Events): ing Eli Lilly, GlaxoSmithKline, Sanofi-Aventis and Takeda.
a randomised controlled trial. Lancet 2005; 366: 1279–89.
8. Lincoff AM, et al. Pioglitazone and risk of cardiovascular events in Dr Bob Ryder has previously received educational patients with type 2 diabetes mellitus: a meta-analysis of random- sponsorship from a number of pharmaceutical compa- ized trials. JAMA 2007; 298: 1180–8.
nies including Eli Lilly, GlaxoSmithKline, Novo Nordisk, 9. Effect of intensive blood-glucose control with metformin on com- Sanofi-Aventis and Takeda. He has served on advisory plications in overweight patients with type 2 diabetes (UKPDS 34).
UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:
panels and has received speaker’s fees from both 10. Intensive blood-glucose control with sulphonylureas or insulin Dr Peter Winocour has received support to attend compared with conventional treatment and risk of complications meetings and honoraria from Eli Lilly, Novo Nordisk, in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 837–53.
11. National Institute for Health and Clinical Excellence. Type 2 dia- betes: newer agents. NICE short clinical guideline 87. May 2009.
1. www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsand 12. Derosa G. Switching from rosiglitazone to pioglitazone: clinical recalls/Safetywarningsandmessagesfmedicines/CON094121 implications. Terapia Evidence Based 2010; 3(2). Epub ahead of print
Pract Diab Int November/December 2010 Vol. 27 No. 9 Copyright 2010 John Wiley & Sons 3

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Leonard c. thomas

Characterization of Polymorphic Transitions in a Pharmaceutical by DSC and MDCS  TA Instruments, 109 Lukens Drive, New Castle DE 19720, USA BACKGROUND Because crystalline drugs generally have better storage stability, pharmaceutical companies prefer to use crystalline compounds for development of new drug formulations. However, a frequently encountered problem is the ability


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