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. 2003 Apr 5;326(7392):762. doi: 10.1136/bmj.326.7392.762/a

Contraindications to use of metformin

Age and creatinine clearance need to be taken into consideration

Andrew T Elder 1
PMCID: PMC1125663  PMID: 12676851

Editor—Jones et al criticise current guidelines highlighting possible contraindications to the use of metformin as too vague and potentially leading to underuse in patients with type 2 diabetes.1 Although their desire for a “less ambiguous” approach seems sensible, their own guidelines still lack clarity.

They note that any specific value of serum creatinine concentration chosen as a cut-off point for prescribing metformin will be arbitrary because of variations in muscle mass and protein turnover. Despite this they then select—for undefined reasons—a serum creatinine value of 150 μmol/l as the cut-off point in their guideline. They then say that caution should therefore be used in prescribing metformin for elderly patients.

This is a vague statement, which could be interpreted as meaning that metformin should not be prescribed at all for elderly people, that specialist opinion should be sought or creatinine clearance calculated before it is prescribed, or that renal function or serum lactate concentration should be monitored after it is prescribed.2 In addition, the authors do not define elderly.

Given that the growing majority of patients with type 2 diabetes are over 65 and that there is already evidence of undertreatment in such patients,3 it seems particularly desirable to be as clear as is possible about this age group if the full benefits of treatment are to be attained.

Although the simple formulas that can be used to estimate creatinine clearance are not completely reliable,4 it may be preferable for prescription to be related to such a calculated estimate of clearance, which takes into account a patient's age, rather than the serum creatinine value alone.

Footnotes

Competing interests: None declared.

References

  • 1.Jones GC, Macklin JP, Alexander WD. Contraindications to the use of metformin. BMJ. 2003;326:4–5. doi: 10.1136/bmj.326.7379.4. . (4 January.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Chehade JM, Mooradian AD. Drug therapy: current and emerging agents. In: Sinclair AJ, Finucane P, editors. Diabetes in old age. Chichester: Wiley; 2001. pp. 202–203. [Google Scholar]
  • 3.Hendra TJ, Sinclair AJ. Improving the care of elderly diabetic patients; the final report of the St Vincent Joint Task Force for Diabetes. Age Ageing. 1997;26:3–6. doi: 10.1093/ageing/26.1.3. [DOI] [PubMed] [Google Scholar]
  • 4.Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31. doi: 10.1159/000180580. [DOI] [PubMed] [Google Scholar]
BMJ. 2003 Apr 5;326(7392):762.

Metformin may be useful in gestational diabetes

W M Hague 1,2,3,4, P M Davoren 1,2,3,4, J Oliver 1,2,3,4, J Rowan 1,2,3,4

Editor—The editorial by Jones et al on contraindications to the use of metformin did not mention pregnancy.1-1 Insulin is usually recommended in women with pregestational type 2 diabetes or gestational diabetes who require drug treatment. Given that pregnancy is a state of insulin resistance, metformin might be a logical alternative.

Cohort data support use of metformin in pregnancy.1-2 In a report about women with polycystic ovary syndrome who conceived while taking metformin, continuation of treatment through pregnancy reduced the incidence of gestational diabetes.1-3 One retrospective study has reported an increased rate of pre-eclampsia in pregnant women treated with metformin, but it is weakened by the lack of matched controls.1-4 The perinatal losses reported in the metformin group cannot be attributed to metformin treatment.

We recently completed a pilot study in 30 women with gestational diabetes diagnosed by the criteria of the Australasian Diabetes in Pregnancy Society (ADIPS). The women were randomised to metformin or insulin treatment. They were matched for age, parity, body mass index, and gestation at entry (table). The study had ethics approval, and the women gave written informed consent.

The outcome measure of fetal β cell activity, assessed by cord C-peptide concentration, was not different in the two groups (P=0.31; Mann-Whitney test; cord blood was stored from 17 women). Perinatal outcomes were not different (table), but numbers are too small to comment further.1-5

Table.

Baseline characteristics and outcome data in women with gestational diabetes receiving insulin or metformin. Values are means (SD) unless stated otherwise

Characteristic
Insulin (n=14)
Metformin (n=16)
Maternal age (years) 34.1 (3.70) 33.7 (4.44)
Median parity (range) 1 (0-5) 1 (0-4)
Maternal weight at trial entry (kg) 101.2 (22.01) 104.4 (22.28)
Maternal body mass index at trial entry 37.9 (6.87) 39.5 (6.94)
Gestation at diagnosis of gestational diabetes (weeks) 27.6 (3.80) 25.8 (5.51)
Blood glucose (glucose tolerance test) (mmol/l)
 Fasting 5.4 (0.52) 5.6 (1.26)
 2 h 9.4 (1.42) 10.0 (2.07)
Gestation at entry into trial (weeks) 30.4 (4.67) 29.8 (4.49)
No (%) with vaginal delivery 11 (79) 5 (31)
No (%) with induction of labour 9 (64) 5 (31)
No (%) with elective caesarean section 2 (14) 8 (50)
No (%) with emergency caesarean section 1 (7) 2 (13)
No (%) with pre-eclampsia 2 (14) 3 (19)
Gestation at delivery (weeks) 38.2 (1.0) 37.8 (1.5)
Birth weight (g) 3450 (510) 3560 (50)
No with birth weight >4000 g 2 2
Median cord C-peptide (range) (No) (pmol/ml) 0.66 (0.45 – 1.71) (7) 0.53 (0.35 – 2.86) (10)
Cord glucose (mmol/l) (No) 4.2 (1.1) (11) 4.2 (1.9) (14)
Cord glucose/C-peptide 5.7 (2.67) 7.4 (1.69)
No of neonates with intravenous dextrose 1 4
Median time in special care nursery (range) (h) 24 (0-102) 48 (0-360)
No of neonates with jaundice 6 3
No of neonates receiving phototherapy 0 2
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A larger trial has been started (the metformin in gestational diabetes (MiG) study). It has adequate power to test the hypothesis that metformin treatment compared with insulin in gestational diabetes will have similar perinatal outcomes, improve insulin sensitivity in both mother and baby, and be associated with improved treatment acceptability. Ethics approval has been obtained, and recruitment has started. A follow up study of the offspring will investigate potential effects of metformin in relation to later insulin sensitivity and subsequent health.1-5

Footnotes

Competing interests: None declared.

References

  • 1-1.Jones GC, Macklin JP, Alexander WD. Contraindications to the use of metformin. BMJ. 2003;326:4–5. doi: 10.1136/bmj.326.7379.4. . (4 January.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 1-2.Coetzee E, Jackson W. The management of non-insulin-dependent diabetes during pregnancy. Diab Res Clin Pract. 1986;1:281–287. doi: 10.1016/s0168-8227(86)80036-5. [DOI] [PubMed] [Google Scholar]
  • 1-3.Glueck CJ, Wang P, Kobayashi S, Phillips H, Sieve-Smith L. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril. 2002;77:520–525. doi: 10.1016/s0015-0282(01)03202-2. [DOI] [PubMed] [Google Scholar]
  • 1-4.Hellmuth E, Damm P, Molsted-Pedersen L. Oral hypoglycaemic agents in 118 diabetic pregnancies. Diab Med. 2000;17:507–511. doi: 10.1046/j.1464-5491.2000.00314.x. [DOI] [PubMed] [Google Scholar]
  • 1-5.Barker D. Mothers, babies and health in later life. Edinburgh: Churchill Livingstone; 1998. [Google Scholar]
BMJ. 2003 Apr 5;326(7392):762.

Blanket banning of metformin two days before surgery may not be a good idea

Philip Jones 1,2, Paul Yate 1,2

Editor—The editorial by Jones et al makes several recommendations about improving the prescription of metformin.2-1 It is a pity that they advised stopping metformin two days before general anaesthesia when there is no evidence to suggest that this is warranted or even safe.

We conducted a Medline search using the keywords “metformin,” “an(a)esthesia,” “an(a)esthetics,” “pre-operative,” and “diabetes.” We found no evidence supporting the unreferenced statement in their editorial.

Jones et al point out that tissue hypoxia is commonly the trigger for metformin associated lactic acidosis and that metformin has a short half life except in advanced renal failure. It follows that it is illogical to suspend metformin earlier than the evening before most surgery unless a degree of tissue hypoxia already exists.

Avoiding metformin in patients with established or expected tissue hypoxia, or when substantial impairment of hepatorenal function perioperatively may be anticipated, is perfectly sensible. May we suggest the recommendations reflect this? Emergency surgery, cardiac surgery, operations requiring deliberate hypotension, and major vascular surgery would be examples where this modified advice would apply.

Much elective surgery, however, does not fit this description, and the recommendation by Jones et al will, necessarily, only be applicable to patients undergoing elective surgery. A blanket recommendation to stop metformin two days before going to theatre is not necessary, safe, or practical.

Footnotes

Competing interests: None declared.

References

  • 2-1.Jones GC, Macklin JP, Alexander WD. Contraindications to the use of metformin. BMJ. 2003;326:4–5. doi: 10.1136/bmj.326.7379.4. . (4 January.) [DOI] [PMC free article] [PubMed] [Google Scholar]
BMJ. 2003 Apr 5;326(7392):762.

Authors' reply

G C Jones 1,2,3, J P Macklin 1,2,3, W D Alexander 1,2,3

Editor—Our aim was to maximise the use of metformin in patients, in whom it would improve cardiovascular risk, using a pragmatic set of guidelines. Although the United Kingdom prospective diabetes study does not include patients aged over 65,3-1 we did not intend to prohibit metformin use in this age group.

Metformin does not affect lactate concentrations or turnover in elderly patients3-2 and, unlike insulin or sulphonylureas, does not cause hypoglycaemia, which can be problematic in older patients. Although, as we stated, a creatinine cut-off point of 150 μmol/l is arbitrary, it is in keeping with guidelines from the Scottish Intercollegiate Group Network and the National Institute for Clinical Excellence for timing of referral for specialist opinion of type 2 diabetic patients with renal disease.3-3,3-4 Any cut-off point based on a calculated creatinine clearance would be equally arbitrary.

Although there are good theoretical reasons why metformin may be useful in gestational diabetes and pregnant type 2 diabetic patients, its safety is yet to be established. The pilot data of Hague et al show an increase in caesarean births, neonatal hypoglycaemia, and need for special care nursery in the metformin group. It will be interesting to see if these trends persist in an adequately powered study.

We agree with Jones and Yates that evidence on the safety of metformin around the time of surgery is lacking. Their recommendations are helpful. Contrast media containing iodine rarely cause renal failure3-5—and, in a similar way, it may be overcautious to withdraw metformin after exposure to contrast media. None the less, prescribers could be open to criticism if they do not stop metformin treatment when there is even a risk of tissue hypoxia.

Footnotes

Competing interests: None declared.

References

  • 3-1.UKPDS Study Group. Effect of Intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 43) Lancet. 1998;352:854–865. [PubMed] [Google Scholar]
  • 3-2.Lalau JD, Vermesh A, Hary L, Andrajek M, Isnard F, Quichaud J. Type 2 diabetes in the elderly: an assessment of metformin use in type 2 diabetes. Int Clin Pharmacol Ther Toxicol. 1990;28:329–332. [PubMed] [Google Scholar]
  • 3-3.Scottish Intercollegiate Guidelines Network. SIGN 55: Management of diabetes. A national clinical guideline. Edinburgh: Scottish Intercollegiate Guidelines Network, Royal College of Physicians; 2001. [Google Scholar]
  • 3-4.National Institute for Clinical Excellence. Management of type 2 diabetes—renal disease, prevention and early management. London: NICE; 2002. www.nice.org.uk/article.asp?a=27964 (accessed 21 Mar 2003). [Google Scholar]
  • 3-5.Deray G, Bellin MF, Boulchfar H, Baumelou B, Koskas F, Baumelou A, et al. Nephrotoxicity of contrast media in high risk patients with renal insufficiency: comparison of low- and high-osmolar contrast agents. Am J Nephrol. 1991;11:309–312. doi: 10.1159/000168328. [DOI] [PubMed] [Google Scholar]

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