Journal Information
Vol. 32. Issue. 6.November 2012
Pages 701-866
Vol. 32. Issue. 6.November 2012
Pages 701-866
DOI: 10.3265/Nefrologia.pre2012.Oct.11783
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Discrepancies between the summary of characteristics and the recommended use of metformin in the treatment of type 2 diabetes mellitus patients (response)
Discrepancias entre ficha técnica y recomendaciones de uso de metformina en el tratamiento de pacientes con diabetes mellitus tipo 2 (respuesta)
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José L. Górriza, Alberto Martínez-Castelaob, Eva Solac, Carlos Morillasc, Ana Joverc, Francisco Coroneld, Juan Navarro-Gonzáleze, Fernando De Álvarof
a Servicio de Nefrolog??a, Hospital Universitario Dr. Peset. GEENDIAB. REDINREN. S.E.N, Valencia,
b Servicio de Nefrolog??a, Hospital Universitario Bellvitge. IDIBELL. GEENDIAB. REDINREN. S.E.N, Hospitalet de Llobregat, Barcelona,
c Servicio de Endocrinolog??a, Hospital Universitario Dr. Peset, Valencia,
d Servicio de Nefrolog??a, Hospital Cl??nico de San Carlos, Madrid,
e Servicio de Nefrolog??a, Hospital Universitario Nuestra Se??ora de Candelaria. GEENDIAB. REDINREN. S.E.N, Santa Cruz de Tenerife,
f Servicio de Nefrolog??a, Hospital Universitario Infanta Sof??a. GEENDIAB. REDINREN. S.E.N, Madrid,
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To the Editor:

We would like to thank Del Pozo et al.1 for their interest in our review2 and their thoughtful question. The use of metformin in patients with a glomerular filtration rate (GFR) <60ml/min/1.73m2, that is to say, outside of the appropriate range established by the drug summary of characteristics, continues to be a source of substantial controversy, prompting discussion in several recent scientific conferences and consensus documents.3-5

The prescription of medications in conditions that fall outside of the recommendations established in summary of characteristics is a common practice in our profession, whenever approved and validated by the scientific community through a process of discussion of pros and cons or with the provision of informed consent. The summary of characteristics is a document that is not set in stone, must contain updated and current information regarding the medication, and tends to be modified whenever aspects of drug safety are updated or new indications come to light. However, this does not always occur, since the cost for modifying technical data sheets can be very high, and this can often produce a situation in which modifications are not cost-effective because the medication in question is quite inexpensive, such as in the case of metformin.

In patients with moderate chronic kidney disease (CKD), the lack of therapeutic alternatives following the suspension of metformin may require the use of much more costly medications (such as dipeptidyl peptidase-4 inhibitors) or insulin treatment, which prompts some reluctance in the affected patients. In addition, the exclusion of patients with CKD from the majority of clinical trials severely limits the breadth of the therapeutic arsenal available to these individuals, as can be seen in paediatric patients as well. In both situations (children and patients with CKD), it is a lack of conclusive study results, not issues with toxicity or efficacy, that limit the indications described on the drug technical data sheet in many cases. In two publications concerning paediatric patients (both in primary care and the hospital setting)6-7 that compiled the available data from 11 studies, between 36% and 100% of patients were prescribed medications under conditions that fell outside of the recommended situations described in the drug summary of characteristics.

With this in mind, to address the question posed by Del Pozo et al1 regarding whether one can say if it is illegal to employ metformin in patients with an estimated GFR<60ml/min/1.73m2, we can state that the use of metformin in patients with an estimated GFR of 30-60ml/min/1.73m2 does not fall within the legal regulations governing its use.

As such, and given the important benefits and low costs associated with this drug, we believe that the implicated scientific societies, health authorities, and pharmaceutical companies should place emphatic priority on the process of reviewing the technical data sheet for metformin in the interest of revising it. This modification should establish the indications for administering metformin in patients based on estimated GFR (ml/min/1.73m2), which is the format recommended by current guidelines and consensus documents,8 instead of using creatinine clearance values as recommended by the current drug technical data sheet. Secondly, the estimated range of GFR within which metformin can be used should be expanded. This modification, which has already been supported by expert consensus opinion, retrospective and observational studies, and meta-analyses,3-5 should express the reasonable use of metformin, with precautionary measures taken and reduced doses, in patients with a GFR of 30-60ml/min/1.73m,2 with suspension of treatment with metformin in patients with a GFR<45ml/min/1.73m2 and risk factors for developing lactic acidosis (peripheral hypoperfusion, diabetic foot, heart failure, advanced liver disease, or a history of previous episodes of lactic acidosis or metabolic acidosis).

It is only a matter of time, but the wait until evidence is provided and clinical trials have been completed could involve years of delay in optimising the treatment of hyperglycaemia in patients with CKD among the millions of people afflicted with diabetes mellitus all over the globe.

 

Conflicts of interest

 

The authors state that they have no potential conflicts of interest related to the contents of this article.

 

Bibliography
[1]
del Pozo-Fern??ndez C, Pardo-Ruiz C, S??nchez-Botella C, L??pez-Menchero R. Discrepancias entre ficha t??cnica y recomendaciones de uso de metformina en el tratamiento de pacientes con diabetes mellitus tipo 2. Nefrologia 2012;32(6):837-8.
[2]
2.??Mart??nez-Castelao A, G??rriz JL, Sola E, Morillas C, Jover A, Coronel F, et al. A prop??sito de las discrepancias entre documentos de consenso, gu??as de pr??ctica cl??nica y normativa legal en el tratamiento de la diabetes tipo 2??. Nefrologia 2012;32(4):419-26.
[3]
NICE. Type 2 diabetes: the management of type 2 diabetes: NICE clinical guideline 87. London: National Institute of Health and clinical Excellence; 2009.
[4]
Shaw JS, Wilmot RL, Kilpatrick ES. Establishing pragmatic estimated GFR thresholds to guide metformin prescribing. Diabet Med 2007;24:1160-3. [Pubmed]
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Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care 2011;34:1431-7. [Pubmed]
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Turner S, Longworth A, Nunn AJ, Choonara I. Unlicensed and off label drug use in paediatric wards: prospective study. BMJ 1998;316:343-5. [Pubmed]
[7]
Schirm E, Tobi H, de Jong-van den Berg LT. Risk factors for unlicensed and off-label drug use in children outside the hospital. Pediatrics 2003;111:291-5. [Pubmed]
[8]
Alc??zar R,??Egocheaga MI,??Orte L,??Lobos JM,??Gonz??lez Parra E,??Alvarez Guisasola F, et al. Documento de consenso SEN-SEMFYC sobre la enfermedad renal cr??nica. Nefrologia 2008;28(3):273-82. [Pubmed]
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