Peter Davoren
Director
Diabetes and Endocrinology
Gold Coast University Hospital
Associate professor
Griffith University School of Medicine
Southport
Queensland
Summary
Metformin is the first-line pharmacological therapy for type 2 diabetes. It is the only glucose-lowering oral drug that has been shown to reduce mortality in patients with diabetes.
The most common adverse effect is gastrointestinal upset. Starting at a low dose and increasing it slowly reduces this risk. Taking metformin with food also helps.
Numerous contraindications to the use of metformin are listed in the product information, including reduced renal function. Strict adherence to these recommendations may deny a valuable drug to many patients.
Key words: biguanides, lactic acidosis, type 2 diabetes
Aust Prescr 2014;37:2-5
Introduction
Metformin lowers both fasting and postprandial blood glucose. It reduces hepatic glucose output 1 and increases peripheral glucose uptake, and may delay intestinal glucose absorption. Its use is not associated with weight gain and hypoglycaemia is extremely rare when metformin is used on its own. It lowers triglyceride concentrations and has small but beneficial effects on total and high-density lipoprotein cholesterol.
Pharmacokinetics
Metformin is absorbed throughout the gastrointestinal tract with an oral bioavailability of 50–60%. It is extensively distributed to the tissues. Metformin does not significantly bind to plasma proteins and reaches a steady state in 24–48 hours. The plasma half-life is around 3.5 hours. Metformin does not undergo hepatic metabolism and over 90% of the drug is excreted unchanged in the urine.
Clinical use
In the UK Prospective Diabetes Study metformin reduced diabetes-related and all-cause mortality, and reduced the risk of myocardial infarction in obese patients with type 2 diabetes when used as first-line therapy. It also reduced the risk of microvascular complications, but was no more effective than insulin or sulfonylureas. 2 A retrospective cohort study from the USA found a lower rate of hospitalisations for myocardial infarction and stroke and a reduced death rate when metformin was used first-line in type 2 diabetes in comparison with a sulfonylurea. 3
Metformin is effective when used with other glucose-lowering drugs. A standard-release (3000 mg/day maximum dose) and an extended-release preparation of metformin (2000 mg/day maximum dose) are available. The extended-release preparation can be taken once daily.
Contraindications and cautions
As our knowledge of metformin has improved, many cautions have become outdated. Proposed changes to the current contraindications are shown in the Table. According to the product information, metformin is contraindicated in patients with a creatinine clearance less than 60 mL/min, moderate–severe heart failure, acute myocardial infarction, and those undergoing major surgery.
The level of renal function at which metformin becomes unsafe is not clear. Many prescribers use metformin in patients with impaired renal function. A creatinine clearance of 30 mL/min may be an appropriate level at which to consider stopping the drug, although some patients may tolerate small doses with less renal function. Patients with impaired renal function should suspend metformin if they develop vomiting, febrile illness, diarrhoea or poor tissue perfusion. There is no place for routinely measuring serum lactate to determine the safety of metformin as this does not predict those at risk of lactic acidosis. 4
Evidence suggests that, if anything, metformin may be beneficial in people with heart failure. 5 The degree of heart failure may not predict the likelihood of benefit. Metformin should not be prescribed in those with symptomatic heart failure at rest or with minimal exertion where the goals of glucose control are different from those of more mobile patients. Patients with otherwise reasonable overall health can probably take metformin in the presence of renal disease, heart disease or other underlying comorbid conditions. The metformin dose can be reduced depending on the severity of the comorbid conditions and patients should be advised to suspend the drug if they develop any acute illness predisposing them to dehydration or poor tissue perfusion.
The use of metformin around the time of surgery and other acute illnesses requiring hospital admission should be determined by the presence or risk of renal dysfunction or an infection. Metformin may need to be suspended temporarily.
Proposed changes to product information for metformin
Pregnancy
Despite metformin being a category C drug in pregnancy, data are reassuring in terms of the risk of congenital anomalies. 6,7 The product information recommends that metformin be replaced with insulin. However, data do not support this.
Hyperglycaemia is a recognised teratogen and stopping metformin when pregnancy is discovered (with or without the introduction of insulin) often results in significant hyperglycaemia, a state more dangerous than continuing the metformin. Metformin can be continued while adjusting the insulin dose. Many diabetes physicians continue metformin throughout pregnancy, only stopping the drug if pre-eclampsia develops.
Gestational diabetes
A large randomised trial has demonstrated that metformin is a valid alternative to insulin in gestational diabetes. Perinatal outcomes were similar, although the trial was not powered to detect differences in perinatal mortality. 8
Lactation
The product information does not recommend metformin during lactation. However, as in pregnancy, the available data do not support withholding metformin in breastfeeding women.
Infants receive approximately a 0.2% weight-adjusted dose of metformin if the mother is breastfeeding. The concentration of metformin in breast milk is probably relatively constant and so timing doses after breastfeeding probably does not alter exposure. 9
Gastrointestinal adverse effects
Nausea, vomiting, abdominal bloating, diarrhoea, anorexia and abdominal pain are the most common adverse effects of metformin. Symptoms are often self-limiting, but are persistent in some patients.
Metformin should be commenced at a low dose (500 mg/day) and always with food, to reduce the risk of gastrointestinal adverse effects. The dose should be escalated slowly. It is not uncommon for a patient who has tolerated metformin for many years to develop gastrointestinal adverse effects. It is appropriate to stop metformin in any patient who develops gastrointestinal upset to determine if metformin is the culprit. In a retrospective study, gastrointestinal effects were half as likely to occur with extended-release metformin compared with standard metformin.10
Vitamin B12 malabsorption
Metformin causes vitamin B12 malabsorption in some patients. In a placebo-controlled trial, vitamin B12 concentrations below the reference range were observed in 18.2% of patients taking metformin and vitamin B12 deficiency was seen in almost 10% (after four years). This was considerably higher than in the control group.11 It is prudent to measure vitamin B12 yearly in patients taking metformin, and prescribe vitamin B12 if concentrations are below the reference range.
Lactic acidosis
Lactic acidosis is an adaptive physiologic response by the body to energy failure, so that cells may survive. When individuals develop conditions resulting in reduced tissue perfusion and hypoxaemia, lactate will be produced and acidosis will occur as part of the body's compensatory response.
Metformin is plagued by its association with the similar drug phenformin, which was withdrawn from the market many years ago because of its association with lactic acidosis.12 Phenformin is thought to reduce peripheral glucose oxidation and therefore increase circulating lactate. This is not observed with metformin.13 In a Cochrane review, the estimated upper limit for the incidence of lactic acidosis in metformin users was 4.3 cases per 100 000 patient-years compared with 5.4 cases per 100 000 patient-years in those assigned to other treatment groups.14
Many publications indicate that metformin is frequently prescribed to patients with contraindications. However, there are intermittent reports of fatal lactic acidosis. These fatalities are nearly always associated with the use of intravascular iodinated contrast media for radiological investigations. Such patients commonly have underlying renal disease and develop acute renal failure in association with the use of contrast media and then develop marked metformin accumulation.15
Stopping metformin temporarily for the investigation should diminish the risk of lactic acidosis. However, there is much disagreement as to the appropriate schedule to follow.16 The Royal Australian and New Zealand College of Radiologists recommends no withdrawal of metformin in patients with normal renal function and contrast doses up to 100 mL. Patients with impaired renal function should suspend metformin for 48 hours from the day of the procedure and recommence when a test of renal function shows no deterioration.17 In patients undergoing urgent investigations, adequate intravenous hydration should be maintained to preserve renal function. Prolonged withdrawal of metformin may lead to hyperglycaemia and consequent dehydration. This may cause acute deterioration in renal function in patients with diabetes and pre-existing renal disease.
Pre-diabetes
In a randomised trial, metformin reduced the risk of developing type2 diabetes by around 30% in high-risk patients. However in the same study, interventions with diet and exercise were twice as effective as metformin in preventing diabetes.18
Conclusion
Metformin is the drug of first choice in the management of hyperglycaemia in type 2 diabetes. It improves mortality in obese patients with diabetes. The risk of gastrointestinal adverse effects is common. In patients with diabetes, the risk of lactic acidosis in metformin users does not appear to be higher than in non-users. However, the use of intravascular iodinated contrast material in association with metformin may pose the greatest risk of lactic acidosis.
Metformin can be continued despite some of the contraindications in the product information if the dose is reduced in appropriate patients and stopped at the time of acute illness. Warnings about the use of metformin in pregnancy and breastfeeding should be reviewed.
Conflict of interest: none declared
References
Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. NEngl J Med 1995;333:550-4.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65.
Roumie CL, Hung AM, Greevy RA, Grijalva CG, Liu X, Murff HJ, et al. Comparative effectiveness of sulphonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus. Ann Intern Med 2012;157:601-10.
Seidowsky A, Nseir S, Houdret N, Fourrier F. Metformin associated lactic acidosis: a prognostic and therapeutic study. Crit Care Med 2009;37:2191-6.
Eurich DT, McAlister FA, Blackburn DF, Majumdar SR, Tsuyuki RT, Varney J, et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ 2007;335:497.
Hague WM. Metformin in pregnancy and lactation. Aust Prescr 2007;30:68-9.
Gilbert C, Valois M, Koren G. Pregnancy outcome after first-trimester exposure to metformin: a meta-analysis. Fertil Steril 2006;86:658-63.
Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:2003-15.
Gardiner SJ, Kirkpatrick CM, Begg EJ, Zhang M, Moore MP, Saville DJ. Transfer of metformin into human milk. Clin Pharmacol Ther 2003;73:71-7.
Blonde L, Dailey GE, Jabbour SA, Reasner CA, Mills DJ. Gastrointestinal tolerability of extended-release metformin compared to immediate-release metformin tablets: results of a retrospective cohort study. Curr Med Res Opin 2004;20:565-72.
de Jager J, Kooy A, Lehert P, Wulffele MG, van der Kolk J, Bets D, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ 2010;340:c2181.
Shenfield G. Metformin: myths, misunderstandings and lessons from history. Aust Prescr 2013;36:38-9.
Marchetti P, Benzi L, Cechetti P, Giannarelli R, Boni C, Ciociaro D, et al. Plasma biguanide levels are correlated with metabolic effects in diabetic patients. Clin Pharmacol Ther 1987;41:450-4.
Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and non-fatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2010;CD002967.
Thomson KR, Varma DK. Safe use of radiographic contrast media. Aust Prescr 2010;33:19-22.
Goergen SK, Rumbold G, Compton G, Harris C. Systematic review of current guidelines, and their evidence base, on risk of lactic acidosis after administration of contrast medium for patients receiving metformin. Radiology 2010;254:261-9.
Royal Australian and New Zealand College of Radiologists. RANZCR guidelines for iodinated contrast administration. 2009. www.ranzcr.edu.au/quality-a-safety/resources/guidelines [cited 2014 Jan 7]
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.
Further reading
Nestler JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med 2008;358:47-54.
Lipska KA, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care 2011;34:1431-7.
Self-test questions
The following statements are either true or false (click here for the answers)
1. Metformin is always contraindicated in lactation.
2. Vitamin B12 should be measured periodically in patients taking metformin.
Director
Diabetes and Endocrinology
Gold Coast University Hospital
Associate professor
Griffith University School of Medicine
Southport
Queensland
Summary
Metformin is the first-line pharmacological therapy for type 2 diabetes. It is the only glucose-lowering oral drug that has been shown to reduce mortality in patients with diabetes.
The most common adverse effect is gastrointestinal upset. Starting at a low dose and increasing it slowly reduces this risk. Taking metformin with food also helps.
Numerous contraindications to the use of metformin are listed in the product information, including reduced renal function. Strict adherence to these recommendations may deny a valuable drug to many patients.
Key words: biguanides, lactic acidosis, type 2 diabetes
Aust Prescr 2014;37:2-5
Introduction
Metformin lowers both fasting and postprandial blood glucose. It reduces hepatic glucose output 1 and increases peripheral glucose uptake, and may delay intestinal glucose absorption. Its use is not associated with weight gain and hypoglycaemia is extremely rare when metformin is used on its own. It lowers triglyceride concentrations and has small but beneficial effects on total and high-density lipoprotein cholesterol.
Pharmacokinetics
Metformin is absorbed throughout the gastrointestinal tract with an oral bioavailability of 50–60%. It is extensively distributed to the tissues. Metformin does not significantly bind to plasma proteins and reaches a steady state in 24–48 hours. The plasma half-life is around 3.5 hours. Metformin does not undergo hepatic metabolism and over 90% of the drug is excreted unchanged in the urine.
Clinical use
In the UK Prospective Diabetes Study metformin reduced diabetes-related and all-cause mortality, and reduced the risk of myocardial infarction in obese patients with type 2 diabetes when used as first-line therapy. It also reduced the risk of microvascular complications, but was no more effective than insulin or sulfonylureas. 2 A retrospective cohort study from the USA found a lower rate of hospitalisations for myocardial infarction and stroke and a reduced death rate when metformin was used first-line in type 2 diabetes in comparison with a sulfonylurea. 3
Metformin is effective when used with other glucose-lowering drugs. A standard-release (3000 mg/day maximum dose) and an extended-release preparation of metformin (2000 mg/day maximum dose) are available. The extended-release preparation can be taken once daily.
Contraindications and cautions
As our knowledge of metformin has improved, many cautions have become outdated. Proposed changes to the current contraindications are shown in the Table. According to the product information, metformin is contraindicated in patients with a creatinine clearance less than 60 mL/min, moderate–severe heart failure, acute myocardial infarction, and those undergoing major surgery.
The level of renal function at which metformin becomes unsafe is not clear. Many prescribers use metformin in patients with impaired renal function. A creatinine clearance of 30 mL/min may be an appropriate level at which to consider stopping the drug, although some patients may tolerate small doses with less renal function. Patients with impaired renal function should suspend metformin if they develop vomiting, febrile illness, diarrhoea or poor tissue perfusion. There is no place for routinely measuring serum lactate to determine the safety of metformin as this does not predict those at risk of lactic acidosis. 4
Evidence suggests that, if anything, metformin may be beneficial in people with heart failure. 5 The degree of heart failure may not predict the likelihood of benefit. Metformin should not be prescribed in those with symptomatic heart failure at rest or with minimal exertion where the goals of glucose control are different from those of more mobile patients. Patients with otherwise reasonable overall health can probably take metformin in the presence of renal disease, heart disease or other underlying comorbid conditions. The metformin dose can be reduced depending on the severity of the comorbid conditions and patients should be advised to suspend the drug if they develop any acute illness predisposing them to dehydration or poor tissue perfusion.
The use of metformin around the time of surgery and other acute illnesses requiring hospital admission should be determined by the presence or risk of renal dysfunction or an infection. Metformin may need to be suspended temporarily.
Proposed changes to product information for metformin
Pregnancy
Despite metformin being a category C drug in pregnancy, data are reassuring in terms of the risk of congenital anomalies. 6,7 The product information recommends that metformin be replaced with insulin. However, data do not support this.
Hyperglycaemia is a recognised teratogen and stopping metformin when pregnancy is discovered (with or without the introduction of insulin) often results in significant hyperglycaemia, a state more dangerous than continuing the metformin. Metformin can be continued while adjusting the insulin dose. Many diabetes physicians continue metformin throughout pregnancy, only stopping the drug if pre-eclampsia develops.
Gestational diabetes
A large randomised trial has demonstrated that metformin is a valid alternative to insulin in gestational diabetes. Perinatal outcomes were similar, although the trial was not powered to detect differences in perinatal mortality. 8
Lactation
The product information does not recommend metformin during lactation. However, as in pregnancy, the available data do not support withholding metformin in breastfeeding women.
Infants receive approximately a 0.2% weight-adjusted dose of metformin if the mother is breastfeeding. The concentration of metformin in breast milk is probably relatively constant and so timing doses after breastfeeding probably does not alter exposure. 9
Gastrointestinal adverse effects
Nausea, vomiting, abdominal bloating, diarrhoea, anorexia and abdominal pain are the most common adverse effects of metformin. Symptoms are often self-limiting, but are persistent in some patients.
Metformin should be commenced at a low dose (500 mg/day) and always with food, to reduce the risk of gastrointestinal adverse effects. The dose should be escalated slowly. It is not uncommon for a patient who has tolerated metformin for many years to develop gastrointestinal adverse effects. It is appropriate to stop metformin in any patient who develops gastrointestinal upset to determine if metformin is the culprit. In a retrospective study, gastrointestinal effects were half as likely to occur with extended-release metformin compared with standard metformin.10
Vitamin B12 malabsorption
Metformin causes vitamin B12 malabsorption in some patients. In a placebo-controlled trial, vitamin B12 concentrations below the reference range were observed in 18.2% of patients taking metformin and vitamin B12 deficiency was seen in almost 10% (after four years). This was considerably higher than in the control group.11 It is prudent to measure vitamin B12 yearly in patients taking metformin, and prescribe vitamin B12 if concentrations are below the reference range.
Lactic acidosis
Lactic acidosis is an adaptive physiologic response by the body to energy failure, so that cells may survive. When individuals develop conditions resulting in reduced tissue perfusion and hypoxaemia, lactate will be produced and acidosis will occur as part of the body's compensatory response.
Metformin is plagued by its association with the similar drug phenformin, which was withdrawn from the market many years ago because of its association with lactic acidosis.12 Phenformin is thought to reduce peripheral glucose oxidation and therefore increase circulating lactate. This is not observed with metformin.13 In a Cochrane review, the estimated upper limit for the incidence of lactic acidosis in metformin users was 4.3 cases per 100 000 patient-years compared with 5.4 cases per 100 000 patient-years in those assigned to other treatment groups.14
Many publications indicate that metformin is frequently prescribed to patients with contraindications. However, there are intermittent reports of fatal lactic acidosis. These fatalities are nearly always associated with the use of intravascular iodinated contrast media for radiological investigations. Such patients commonly have underlying renal disease and develop acute renal failure in association with the use of contrast media and then develop marked metformin accumulation.15
Stopping metformin temporarily for the investigation should diminish the risk of lactic acidosis. However, there is much disagreement as to the appropriate schedule to follow.16 The Royal Australian and New Zealand College of Radiologists recommends no withdrawal of metformin in patients with normal renal function and contrast doses up to 100 mL. Patients with impaired renal function should suspend metformin for 48 hours from the day of the procedure and recommence when a test of renal function shows no deterioration.17 In patients undergoing urgent investigations, adequate intravenous hydration should be maintained to preserve renal function. Prolonged withdrawal of metformin may lead to hyperglycaemia and consequent dehydration. This may cause acute deterioration in renal function in patients with diabetes and pre-existing renal disease.
Pre-diabetes
In a randomised trial, metformin reduced the risk of developing type2 diabetes by around 30% in high-risk patients. However in the same study, interventions with diet and exercise were twice as effective as metformin in preventing diabetes.18
Conclusion
Metformin is the drug of first choice in the management of hyperglycaemia in type 2 diabetes. It improves mortality in obese patients with diabetes. The risk of gastrointestinal adverse effects is common. In patients with diabetes, the risk of lactic acidosis in metformin users does not appear to be higher than in non-users. However, the use of intravascular iodinated contrast material in association with metformin may pose the greatest risk of lactic acidosis.
Metformin can be continued despite some of the contraindications in the product information if the dose is reduced in appropriate patients and stopped at the time of acute illness. Warnings about the use of metformin in pregnancy and breastfeeding should be reviewed.
Conflict of interest: none declared
References
Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. NEngl J Med 1995;333:550-4.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65.
Roumie CL, Hung AM, Greevy RA, Grijalva CG, Liu X, Murff HJ, et al. Comparative effectiveness of sulphonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus. Ann Intern Med 2012;157:601-10.
Seidowsky A, Nseir S, Houdret N, Fourrier F. Metformin associated lactic acidosis: a prognostic and therapeutic study. Crit Care Med 2009;37:2191-6.
Eurich DT, McAlister FA, Blackburn DF, Majumdar SR, Tsuyuki RT, Varney J, et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ 2007;335:497.
Hague WM. Metformin in pregnancy and lactation. Aust Prescr 2007;30:68-9.
Gilbert C, Valois M, Koren G. Pregnancy outcome after first-trimester exposure to metformin: a meta-analysis. Fertil Steril 2006;86:658-63.
Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:2003-15.
Gardiner SJ, Kirkpatrick CM, Begg EJ, Zhang M, Moore MP, Saville DJ. Transfer of metformin into human milk. Clin Pharmacol Ther 2003;73:71-7.
Blonde L, Dailey GE, Jabbour SA, Reasner CA, Mills DJ. Gastrointestinal tolerability of extended-release metformin compared to immediate-release metformin tablets: results of a retrospective cohort study. Curr Med Res Opin 2004;20:565-72.
de Jager J, Kooy A, Lehert P, Wulffele MG, van der Kolk J, Bets D, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ 2010;340:c2181.
Shenfield G. Metformin: myths, misunderstandings and lessons from history. Aust Prescr 2013;36:38-9.
Marchetti P, Benzi L, Cechetti P, Giannarelli R, Boni C, Ciociaro D, et al. Plasma biguanide levels are correlated with metabolic effects in diabetic patients. Clin Pharmacol Ther 1987;41:450-4.
Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and non-fatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2010;CD002967.
Thomson KR, Varma DK. Safe use of radiographic contrast media. Aust Prescr 2010;33:19-22.
Goergen SK, Rumbold G, Compton G, Harris C. Systematic review of current guidelines, and their evidence base, on risk of lactic acidosis after administration of contrast medium for patients receiving metformin. Radiology 2010;254:261-9.
Royal Australian and New Zealand College of Radiologists. RANZCR guidelines for iodinated contrast administration. 2009. www.ranzcr.edu.au/quality-a-safety/resources/guidelines [cited 2014 Jan 7]
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.
Further reading
Nestler JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med 2008;358:47-54.
Lipska KA, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care 2011;34:1431-7.
Self-test questions
The following statements are either true or false (click here for the answers)
1. Metformin is always contraindicated in lactation.
2. Vitamin B12 should be measured periodically in patients taking metformin.
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