- Email: [email protected]
Metformin in cardiac surgery: high expectations
Comment
In The Lancet Diabetes & Endocrinology, Saloua El Messaoudi and colleagues1 report results from a randomised controlled trial (MetCAB) that assessed whether metformin pretreatment reduced myocardial injury in patients without diabetes undergoing coronary artery bypass graft (CABG) surgery. Similar to a glucose-insulin-potassium infusion— which has been studied for its potential effects in cardiac surgery for the past 45 years2—metformin affects glucose metabolism. In a meta-analysis3 of glucose-insulinpotassium infusion in cardiac surgery, myocardial injury was reduced (however, mortality was not reduced). In several preclinical studies, metformin also resulted in a marked decrease in myocardial injury as defined by biomarker release and changes induced in specific signalling cascades.4 The MetCAB trial1 included 111 patients without diabetes who were assigned to 500 mg metformin pretreatment (given three times per day for 3 days) or matching placebo. After dropouts, 52 patients in the metformin group and 48 in the placebo group were included in the final per-protocol analysis. Metformin pretreatment did not have any effect on the primary outcome of plasma concentration of high-sensitive troponin I concentration compared with placebo after on-pump CABG surgery (with or without additional valve surgery; between-group difference was 12·3% [95% CI –12·4 to 44·1], p=0·35). On the day of surgery, fasting plasma glucose concentrations did not differ between the groups (metformin mean 5·3 mmol/L [SD 0·9], placebo 5·2 mmol/L [SD 2·2]). Moreover, insulin treatment after surgery was started in 85% of participants in both groups. Metformin did not affect glucose metabolism in these patients, irrespective of their insulin-resistant state (as determined by the homeostasis model assessment [HOMA-IR] method; metformin mean 4·8 [SD 8·6], placebo 4·5 [SD 4·6], p=0·24). The fact that participants were only slightly insulin resistant suggests that steroids were not routinely used in these patients during on-pump surgery. The use of dexamethasone or methylprednisolone in these patients can lead to hyperglycaemia that needs high doses of insulin to achieve an acceptable level of perioperative glucose control.5 Moreover, in critically ill patients without
diabetes but with hyperglycaemia, metformin is effective in reducing glucose levels.6 Now, results from a total of three randomised studies that have tested metformin in patients without diabetes (MetCAB1, CAMERA7, and GIPS-III8) have not shown an effect of metformin on cardiovascular outcomes. In CAMERA,7 metformin (850 mg twice per day) given to 173 patients without diabetes did not result in a significant reduction in the primary outcome measure of carotid intima-media thickness after 18 months. In GIPS-III,8 metformin (500 mg twice per day) given to 380 patients without diabetes was not associated with a significant effect on left ventricular ejection fraction compared with placebo after 4 months. In our opinion, the results from these studies show how far standard care for cardiovascular patients without diabetes has advanced; as a consequence, the potential benefit of any additional intervention is small. In all three trials the mortality rate was very low—in MetCAB,1 all patients were alive 30 days after surgery; in CAMERA, only one cardiovascular death occurred over an 18-month follow-up period;7 and in GIPS-III, all patients were alive 4 months after acute myocardial infarction.8 Moreover, peak troponin I concentrations in all patients in the MetCAB trial were only 50% of those in the historical cohort that was the basis of the investigators’ power calculation.1 According to the power calculation, to show any effect, metformin needed to lower postoperative troponin I concentrations by an additional 50%. Thus, the expected effect of metformin in patients without diabetes treated to current standards might have been too high. Taking together the results of all studies on metformin in patients without diabetes so far, no proof exists for a beneficial effect of metformin on cardiovascular outcomes. Much larger trials—ie, with thousands of high-risk patients—might identify protective effects of metformin in such patients; however, undertaking such large investigator-driven studies is extraordinarily challenging. Nevertheless, metformin reduces hyperglycaemia in patients with or without diabetes, and glucose reduction, or the absence of hyperglycaemia, is pivotal for a potential beneficial effect of metformin on cardiovascular outcomes.
www.thelancet.com/diabetes-endocrinology Published online July 13, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00209-0
John Bavosi/Science Photo Library
Metformin in cardiac surgery: high expectations
Lancet Diabetes Endocrinol 2015 Published Online July 13, 2015 http://dx.doi.org/10.1016/ S2213-8587(15)00209-0 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(15)00121-7
1
Comment
*Iwan CC van der Horst, Maarten WN Nijsten
4
Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, Netherlands (ICCvdH, MN) [email protected]
5
We declare no competing interests. 1
2 3
2
El Messaoudi S, Nederlof R, Zuurbier CJ, et al. Effect of metformin pretreatment on myocardial injury during coronary artery bypass surgery in patients without diabetes (MetCAB): a double-blind, randomised controlled trial. Lancet Diabetes Endocrinol 2015; published online July 13. http://dx.doi.org/10.1016/S2213-8587(15)00121-7. Braimbridge MV, Clement AJ, Brown AH, Sabar E, Mendel D. Triple Starr valve replacement. Br Med J 1969; 3: 683–88. Fan Y, Zhang AM, Xiao YB, Weng YG, Hetzer R. Glucose-insulin-potassium therapy in adult patients undergoing cardiac surgery: a meta-analysis. Eur J Cardiothorac Surg 2011; 40: 192–99.
6
7
8
Lexis CP, van der Horst IC, GIPS-III Investigators, et al. Metformin in non-diabetic patients presenting with ST elevation myocardial infarction: rationale and design of the glycometabolic intervention as adjunct to primary percutaneous intervention in ST elevation myocardial infarction (GIPS)-III trial. Cardiovasc Drugs Ther 2012; 26: 417–26. Ottens TH, Nijsten MW, Hofland J, et al. Effect of high-dose dexamethasone on perioperative lactate levels and glucose control: a randomized controlled trial. Crit Care 2015; 19: 41. Mojtahedzadeh M, Jafarieh A, Najafi A, Khajavi MR, Khalili N. Comparison of metformin and insulin in the control of hyperglycaemia in non-diabetic critically ill patients. Endokrynol Pol 2012; 63: 206–11. Preiss D, Lloyd SM, Ford I, et al. Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial. Lancet Diabetes Endocrinol 2014; 2: 116–24. Lexis CP, van der Horst IC, GIPS-III Investigators, et al. Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial. JAMA 2014; 311: 1526–35.
www.thelancet.com/diabetes-endocrinology Published online July 13, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00209-0
In The Lancet Diabetes & Endocrinology, Saloua El Messaoudi and colleagues1 report results from a randomised controlled trial (MetCAB) that assessed whether metformin pretreatment reduced myocardial injury in patients without diabetes undergoing coronary artery bypass graft (CABG) surgery. Similar to a glucose-insulin-potassium infusion— which has been studied for its potential effects in cardiac surgery for the past 45 years2—metformin affects glucose metabolism. In a meta-analysis3 of glucose-insulinpotassium infusion in cardiac surgery, myocardial injury was reduced (however, mortality was not reduced). In several preclinical studies, metformin also resulted in a marked decrease in myocardial injury as defined by biomarker release and changes induced in specific signalling cascades.4 The MetCAB trial1 included 111 patients without diabetes who were assigned to 500 mg metformin pretreatment (given three times per day for 3 days) or matching placebo. After dropouts, 52 patients in the metformin group and 48 in the placebo group were included in the final per-protocol analysis. Metformin pretreatment did not have any effect on the primary outcome of plasma concentration of high-sensitive troponin I concentration compared with placebo after on-pump CABG surgery (with or without additional valve surgery; between-group difference was 12·3% [95% CI –12·4 to 44·1], p=0·35). On the day of surgery, fasting plasma glucose concentrations did not differ between the groups (metformin mean 5·3 mmol/L [SD 0·9], placebo 5·2 mmol/L [SD 2·2]). Moreover, insulin treatment after surgery was started in 85% of participants in both groups. Metformin did not affect glucose metabolism in these patients, irrespective of their insulin-resistant state (as determined by the homeostasis model assessment [HOMA-IR] method; metformin mean 4·8 [SD 8·6], placebo 4·5 [SD 4·6], p=0·24). The fact that participants were only slightly insulin resistant suggests that steroids were not routinely used in these patients during on-pump surgery. The use of dexamethasone or methylprednisolone in these patients can lead to hyperglycaemia that needs high doses of insulin to achieve an acceptable level of perioperative glucose control.5 Moreover, in critically ill patients without
diabetes but with hyperglycaemia, metformin is effective in reducing glucose levels.6 Now, results from a total of three randomised studies that have tested metformin in patients without diabetes (MetCAB1, CAMERA7, and GIPS-III8) have not shown an effect of metformin on cardiovascular outcomes. In CAMERA,7 metformin (850 mg twice per day) given to 173 patients without diabetes did not result in a significant reduction in the primary outcome measure of carotid intima-media thickness after 18 months. In GIPS-III,8 metformin (500 mg twice per day) given to 380 patients without diabetes was not associated with a significant effect on left ventricular ejection fraction compared with placebo after 4 months. In our opinion, the results from these studies show how far standard care for cardiovascular patients without diabetes has advanced; as a consequence, the potential benefit of any additional intervention is small. In all three trials the mortality rate was very low—in MetCAB,1 all patients were alive 30 days after surgery; in CAMERA, only one cardiovascular death occurred over an 18-month follow-up period;7 and in GIPS-III, all patients were alive 4 months after acute myocardial infarction.8 Moreover, peak troponin I concentrations in all patients in the MetCAB trial were only 50% of those in the historical cohort that was the basis of the investigators’ power calculation.1 According to the power calculation, to show any effect, metformin needed to lower postoperative troponin I concentrations by an additional 50%. Thus, the expected effect of metformin in patients without diabetes treated to current standards might have been too high. Taking together the results of all studies on metformin in patients without diabetes so far, no proof exists for a beneficial effect of metformin on cardiovascular outcomes. Much larger trials—ie, with thousands of high-risk patients—might identify protective effects of metformin in such patients; however, undertaking such large investigator-driven studies is extraordinarily challenging. Nevertheless, metformin reduces hyperglycaemia in patients with or without diabetes, and glucose reduction, or the absence of hyperglycaemia, is pivotal for a potential beneficial effect of metformin on cardiovascular outcomes.
www.thelancet.com/diabetes-endocrinology Published online July 13, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00209-0
John Bavosi/Science Photo Library
Metformin in cardiac surgery: high expectations
Lancet Diabetes Endocrinol 2015 Published Online July 13, 2015 http://dx.doi.org/10.1016/ S2213-8587(15)00209-0 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(15)00121-7
1
Comment
*Iwan CC van der Horst, Maarten WN Nijsten
4
Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, Netherlands (ICCvdH, MN) [email protected]
5
We declare no competing interests. 1
2 3
2
El Messaoudi S, Nederlof R, Zuurbier CJ, et al. Effect of metformin pretreatment on myocardial injury during coronary artery bypass surgery in patients without diabetes (MetCAB): a double-blind, randomised controlled trial. Lancet Diabetes Endocrinol 2015; published online July 13. http://dx.doi.org/10.1016/S2213-8587(15)00121-7. Braimbridge MV, Clement AJ, Brown AH, Sabar E, Mendel D. Triple Starr valve replacement. Br Med J 1969; 3: 683–88. Fan Y, Zhang AM, Xiao YB, Weng YG, Hetzer R. Glucose-insulin-potassium therapy in adult patients undergoing cardiac surgery: a meta-analysis. Eur J Cardiothorac Surg 2011; 40: 192–99.
6
7
8
Lexis CP, van der Horst IC, GIPS-III Investigators, et al. Metformin in non-diabetic patients presenting with ST elevation myocardial infarction: rationale and design of the glycometabolic intervention as adjunct to primary percutaneous intervention in ST elevation myocardial infarction (GIPS)-III trial. Cardiovasc Drugs Ther 2012; 26: 417–26. Ottens TH, Nijsten MW, Hofland J, et al. Effect of high-dose dexamethasone on perioperative lactate levels and glucose control: a randomized controlled trial. Crit Care 2015; 19: 41. Mojtahedzadeh M, Jafarieh A, Najafi A, Khajavi MR, Khalili N. Comparison of metformin and insulin in the control of hyperglycaemia in non-diabetic critically ill patients. Endokrynol Pol 2012; 63: 206–11. Preiss D, Lloyd SM, Ford I, et al. Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial. Lancet Diabetes Endocrinol 2014; 2: 116–24. Lexis CP, van der Horst IC, GIPS-III Investigators, et al. Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial. JAMA 2014; 311: 1526–35.
www.thelancet.com/diabetes-endocrinology Published online July 13, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00209-0