 |
|
 |
 |
 |
 |
| Home > Evidence of the Month |  |
 |
|
Education |
| Evidence of the Month |
 |
Metformin: Contraindicated or Indicated in Chronic Heart Failure?
Paul Van Crombrugge
Onze-Lieve-Vrouwziekenhuis
Aalst, Belgium
Comment on:
Background
Heart failure is nearly twice as frequent in people with diabetes (prevalence 25%) as in non-diabetic people, and has a particularly poor prognosis in people with the condition.
The United Kingdom Prospective Diabetes Study (UKPDS) showed impressive results with the use of metformin in obese people with newly diagnosed Type 2 diabetes: a 36% reduction in all-cause mortality, a 42% reduction in diabetes-related mortality, a 39% reduction in acute myocardial infarction, and a 32% reduction in diabetes-related endpoints. This biguanide does not cause hypoglycaemia, and it is the only oral glucose-lowering agent which is weight neutral.
However, the use of metformin is often limited by a list of classical contraindications: impaired renal function (even mild), heart failure, respiratory failure, cardiovascular disease, liver disorders, alcohol abuse, advanced age, use of radiocontrast agents, and others. Most of these contraindications are related to concerns about the risk of lactic acidosis, a not unusual side effect of another biguanide phenformin, withdrawn from the US market in 1977 after 306 cases of lactic acidosis. This fear was also the reason for a delay in US Food and Drug Administration (FDA) approval of metformin (only in 1995) in the USA.
Heart failure was found in 38% of the postmarketing reports of lactic acidosis associated with the use of metformin. However, this association is not necessarily causative. There are no clear data that the risk of lactic acidosis in patients with heart failure is higher among metformin users than among non-metformin users; lactic acidosis is of course a complication of cardiac pump failure even in the absence of diabetes or metformin.
Several recent population-based surveys have shown that a significant proportion of people treated with metformin have a potential contraindication to it (18% to 70%), without a rise in the number of reports of lactic acidosis. Accordingly, it can be questioned if the present contraindications are appropriate (at least for moderate heart failure, moderate renal failure, and advanced age), and if withholding metformin is not more dangerous than beneficial, by depriving people of an effective cardioprotective therapy.
Methods and Key Results
Masoudi and colleagues analysed in a retrospective observational study the risk for all-cause mortality at 1 year in 16 417 elderly (≥65 yr) Medicare (USA) members with diabetes and a hospital discharge diagnosis of heart failure.
The 1-year mortality rates were lower amongst the 1861 patients treated with metformin (25%) and the 2226 people treated with a thiazolidinedione (30%) compared with the 12 069 people treated with neither of these drugs (36%; P<0.001 for both comparisons).
In multivariable models, similar results were found regarding risk of death:
- metformin: hazard ratio (HR) 0.87 (95% CI 0.78 to 0.97)
- thiazolidinedione: 0.87 (0.80 to 0.94)
- sulfonylurea: 0.99 (0.91 to 1.08)
- insulin: 0.96 (0.88 to 1.05)
There was a lower risk of readmission for heart failure with metformin treatment (HR 0.92 [0.86 to 0.99]) and a higher risk with thiazolidinediones (1.06 [1.00 to 1.09]). The readmission for metabolic acidosis was not higher for the metformin group than for those treated with a thiazolidinedione or not treated with an insulin sensitizer.
Limitations to this study were the rather short follow-up (1 year), the age group (≥65 yr), and the selection on a hospitalization basis. However the higher age gives a higher risk population (and therefore more study power), while the hospitalization criteria may do the same by providing a hard endpoint rather than a soft one such as oedema. A selection bias of less at-risk people being given metformin or a thiazolidinedione cannot be excluded.
Eurich and colleagues analysed in the Saskatchewan (Canada) health databases a group of 12 272 new users of oral glucose-lowering agents, age ≥30 yr. They identified 1833 people with new-onset heart failure (hospital or physician record). Average age was 72 yr, and follow-up 2.5 ± 2.0 (SD) yr. At the end of the study, in the heart failure group, 69 people using metformin had died (33%; HR 0.70 [0.54 to 0.91]), compared with 404 patients (52%) on sulfonylurea alone (HR 1.0) and 263 (31%) on combination therapy (HR 0.61 [0.52 to 0.72]). Adjustment for potential confounding variables (age, sex, chronic disease score, drug therapies) did not change the findings.
Limitations of both studies were the lack of data on the severity of the heart failure, and on the level of glycaemic control. Selection bias again cannot be excluded.
Clinical Implications
These two retrospective studies suggest that metformin can be used safely within the population of people with chronic heart failure and actually may decrease all-cause mortality overall in this group. Although these findings normally should mandate a prospective randomized clinical trial to test this hypothesis, clinical judgment of the results from these and other metformin studies indicates that clinical scientists should push to liberalise the careful use of metformin in patients with stable chronic heart failure (and for some of the other contraindications). Perhaps more caution is required in those with more severe left ventricular dysfunction. These balanced views are excellently summarised in the opinion articles of Misbin (Diabetes Care) and of Holstein and Stumvoll (Diabetologia).
In summary, Holstein and Stumvoll propose that the use of metformin should be considered in patients with stable heart failure that is under chronic treatment (New York Heart Association [NYHA] Class I and II) and that metformin should not be used in patients with unstable heart failure (NYHA Class III and IV) and should be stopped when this might be developing.
This Website Feature is funded by an unrestricted educational grant from sanofi-aventis and Pfizer Inc.
|
 |
|
Print this page |
|
||
 |
Add to Favourites |
|
|