Diabetes, Obesity and Metabolism 2014. © 2014 John Wiley & Sons Ltd
Mortality risk with sulphonylureas compared to metformin S. E. Holden & C. J. Currie Cochrane Institute of Public Health, School of Medicine, Cardiff University, Cardiff, UK
Current clinical guidelines in the USA and the UK recommend first-line glucose-lowering treatment with metformin monotherapy for glucose control in type 2 diabetes, where not contraindicated. Consequently, the proportion of people treated with sulphonylureas is decreasing. The purpose of this commentary is to discuss the risks and benefits associated with sulphonylurea monotherapy versus metformin monotherapy and the evidence that, in comparison with metformin, sulphonylureas cause increased harm to people with type 2 diabetes. Keywords: metformin, sulphonylureas, type 2 diabetes Date submitted 1 November 2013; date of first decision 2 January 2014; date of final acceptance 11 February 2014
Current American Diabetes Association (ADA) and National Institute for Health and Care Excellence (NICE) guidelines in the UK recommend the use of metformin as first-line therapy for type 2 diabetes [1,2]. NICE suggests that a sulphonylurea should be considered as an option when the patient is not overweight, when metformin is contraindicated or not tolerated, or when a rapid response to therapy is required to combat hyperglycaemia symptoms [1]. However, the ADA makes no specific recommendation on the use of sulphonylureas to control type 2 diabetes, preferring to recommend the adoption of a more patient-centred approach based on financial cost, efficacy, potential side effects, patient preference and diabetes co-morbidities [1]. In line with these clinical guidelines, the percentage of people with type 2 diabetes using sulphonylureas has decreased in both the UK and the USA. In the UK, the proportion of people with type 2 diabetes treated with sulphonylureas at any point in the natural history of their disease decreased from 45% in 1996 to 33% in 2005, and the number of people using metformin increased from 30% to 57% over the same period [3]. We have estimated that the proportion of people with type 2 diabetes in the UK using sulphonylurea monotherapy first-line was 5% in 2012 (see Figure 1, unpublished data). Between 2000 and 2010, the number of people using sulphonylurea monotherapy second-line following failure with metformin monotherapy decreased from 12% in 2000 to 7% in 2010 [4]. In the USA, the percentage of patients initially treated with sulphonylureas decreased from 26% in 2006 to 18% in 2008, whereas the proportion of patients starting therapy with metformin increased from 51% to 65% [5]. However, metformin has only been licensed by the US FDA since 1995 [6]. A decrease in the prescribing of sulphonylureas and an increase Correspondence to: Craig J. Currie, Professor of Applied Pharmacoepidemiology, Cochrane Institute of Public Health, School of Medicine, Cardiff University, Cardiff Medicentre, Cardiff CF144UJ, UK. E-mail: [email protected]
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Sulfonylurea
Metformin
Figure 1. Percent of patients treated with first-line sulphonylurea monotherapy versus metformin monotherapy in the UK.
in the prescribing of metformin have also been observed in Germany, Italy and Japan [7–10]. Since the publication of the results from the University Group Diabetes Programme (UGDP) in 1969, there has been controversy surrounding the use of sulphonylureas to lower blood glucose in people with type 2 diabetes. In this large, multicentre, placebo-controlled trial, patients were randomized to placebo plus diet, fixed-dose tolbutamide (a first-generation sulphonylurea), fixed-dose insulin or a variable dose of insulin dependent on fasting plasma glucose. In the tolbutamide-treated patients, an unexpected, statistically significant increase in the number of cardiac deaths relative to placebo resulted in the termination of the tolbutamide-treated arm of the study [11]. An excess of all-cause mortality was also found in the group treated with the biguanide phenformin [12]. However, the study design has since been heavily criticized [11]. Unlike metformin, sulphonylureas can cause weight gain and hypoglycaemia. Weight gain is associated with an increased
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review article cardiovascular risk and should be minimized in type 2 diabetes [13,14]. Hypoglycaemia has been linked to prolongation of the QT interval, an arrhythmogenic effect that is thought to be greatest in patients with pre-existing cardiovascular disease and diabetes [15]. Zoungas and colleagues analysed data from the Action in Diabetes and Vascular Disease-Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study and found a strong association between severe hypoglycaemia and the risk of major macrovascular events, major microvascular events, cardiovascular death or death from any cause. However, it is unknown whether severe hypoglycaemia contributes to, or is a marker for these outcomes [16]. In addition, results from two meta-analyses suggest that hypoglycaemia counteracts any benefits associated with intensive glucose-lowering treatment [17,18]. Both low and high HbA1c values have been linked to an increased risk of all-cause mortality and cardiovascular events [19,20]. Phenformin, a biguanide and the predecessor of metformin, was withdrawn from US and European markets in 1977 because of the risk of lactic acidosis [21]. Lactic acidosis is also the most serious possible side effect associated with treatment with metformin, particularly in people with renal impairment. However, a recent Cochrane review found no cases of lactic acidosis in 70 490 patient-years of metformin use (and none in 55 451 patient-years for people not treated with metformin) [22]. The low incidence of lactic acidosis observed may be due, at least in part, to the avoidance of metformin in high risk groups. Nevertheless, when used appropriately, lactic acidosis associated with metformin use is likely to be a relatively rare event. As cardiovascular disease accounts for approximately 50% of deaths in people with type 2 diabetes [23], it is important to determine whether any medications used to lower blood glucose exacerbate this risk. Sulphonylureas stimulate pancreatic β cells to secrete insulin by binding to a subunit of the ATP-dependent potassium (KATP ) channel known as the sulphonylurea receptor (SUR1) [24–26]. This inhibits the flow of potassium through the channel, leading to β-cell depolarization and the release of insulin through exocytosis [23,24]. However, cardiac muscle also contains sulphonylurea-sensitive KATP channels (via the SUR2 receptor), and it is hypothesized that sulphonylureas may cause cardiovascular side effects by blocking ischaemic preconditioning (a cardioprotective mechanism) through the inhibition of these KATP channels [25,27]. Metformin on the other hand is associated with beneficial effects that include a cardioprotective effect that cannot be solely explained by its ability to lower blood glucose [28–30]. Any cardiovascular side effects associated with sulphonylureas may differ between drugs, and could be dependent on the affinity that each individual sulphonylurea has for the different types of SUR receptors. Unlike glibenclamide and glimepriride, which have an affinity for both SUR1 and SUR2 receptors, sulphonylureas such as gliclazide are relatively selective for SUR1 receptors, and they therefore show specificity for the KATP channels in the β cells of the pancreas rather than the channels in cardiac and smooth muscle [31–33]. Although all sulphonylureas can cause hypoglycaemia, some
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are associated with a higher risk than others. A systematic meta-analysis has shown that gibenclamide, which has a long duration of action, was associated with a higher risk of hypoglycaemia than gliclazide, glimepiride and glipizide, with no added improvement in glucose control [34]. Consequently glibenclamide is not recommended in the elderly [35]. The same meta-analysis, however, did not find any increased risk of cardiovascular events, death or weight gain associated with glibenclamide [33]. The propensity to cause weight gain may also differ between sulphonylureas. In the UKPDS, people using chlorpropamide in the intensive cohort at 10 years gained 2.6 kg versus conventional treatment, whereas those using glibenclamide only gained 1.7 kg [36]. Conversely, some sulphonylureas may confer additional benefits. For example, gliclazide may reduce platelet reactivity, stimulate endothelial prostacyclin synthesis and enhance fibrinolysis [37], and glibenclamide may have an antiarrhythmic effect in transient myocardial ischaemia [38]. A study using data from the French Registry on Acute ST-Elevation and non-ST-Elevation Myocardial Infarction (FAST-MI) showed that the use of gliclazide or glimepiride compared with glibenclamide prior to an acute myocardial infarction was associated with a decreased risk of in-hospital mortality (OR 0.15; 95% CI 0.04–0.56) and overall in-hospital complications (0.39; 95% CI 0.21–0.72) [39]. Other studies have also shown that glibenclamide was associated with a higher risk of all-cause mortality when compared with glipizide [40] and gliclazide [41]. Type 2 diabetes is characterized by relative insulin deficiency and insulin resistance. Hyperinsulinaemia is a predictable consequence of the action of insulin secretagogues such as sulphonylureas and also of exogenous insulin and has been linked to an increased risk of mitogenic and arthrogenic effects [42]. Insulin plays a role in several tissues. For example, in type 2 diabetes, the kidney and sympathetic nervous system remain sensitive to insulin, and hyperinsulinaemia can lead to sodium retention and increased sympathetic nervous system activity, which could increase blood pressure [43]. Metformin on the other hand increases insulin sensitivity and reduces plasma insulin levels [44]. Metformin also improves endothelial dysfunction, which may help to explain the reduced risk of cardiovascular disease associated with its use [45–47]. Both metformin and sulphonylureas are financially cheap generic drugs. Sulphonylureas have been shown to reduce HbA1c by 1.5% compared with placebo [48]. However, a Cochrane review has demonstrated that metformin was associated with improved HbA1c, fasting plasma glucose, LDL cholesterol and triglyceride levels and body mass index when compared with sulphonylureas [49]. Evidence in support of the use of metformin as a firstline, glucose-lowering therapy originates largely from the UKPDS and subsequent complementary observational data. The UKPDS found that overweight patients receiving intensive treatment with metformin monotherapy had a lower risk of any diabetes-related endpoint, stroke or all-cause mortality when compared with intensive treatment with insulin or sulphonylureas [50]. Retrospective observational studies using the Clinical Practice Research Datalink (CPRD) have confirmed that, compared with metformin monotherapy, sulphonylurea
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monotherapy was associated with an increased risk of allcause mortality in type 2 diabetes [51,52]. A retrospective cohort analysis using the Saskatchewan Health Administrative Databases in Canada found that, relative to sulphonylurea monotherapy, metformin monotherapy was associated with a lower risk of a composite endpoint defined as the first non-fatal hospitalization or death (adjusted hazard ratio (aHR) 0.81; 95% CI 0.68–0.97) [53]. Furthermore, two large retrospective studies using data from the Veterans Health Administration found that, relative to metformin monotherapy, sulphonylurea monotherapy was associated with a greater risk of mortality or hospital admission due to myocardial infarction or stroke [54,55]. Other observational data comparing sulphonylureas with metformin have also supported the observation that sulphonylureas are associated with a higher risk of mortality as a class [56–58], and glipizide, glimepriride, tolbutamide and glibenclamide specifically [59]. Conversely, a retrospective study using data from VHA Diabetes Epidemiology Cohort found that the risk of all-cause mortality was not significantly different for metformin monotherapy and sulphonylurea monotherapy [adjusted odds ratio (OR) 0.87; 95% CI 0.68–1.10] [60]. In addition, a meta-analysis of available data from randomized, controlled trials (RCTs) did not find that metformin had a statistically significant effect on all-cause mortality. However, as the authors concluded, short follow-up time (average 2.8 years) was a limitation of their meta-analysis [61]. The UKPDS did not find any increased risk of all-cause mortality associated with intensive treatment with glibenclamide or chlorpropamide when compared with conventional treatment [49]. Several observational studies have demonstrated an increased risk of cardiovascular events [50,51,54] and cardiovascular deaths [55] when sulphonylurea monotherapy was compared with metformin monotherapy. A randomized, double-blind, placebo-controlled trial showed that the risk of cardiovascular events in people with type 2 diabetes and a history of coronary heart disease was lower for metformin than for glipizide (aHR 0.54; 95% CI 0.30–0.90) [62]. A metaanalysis of clinical and observational studies by Phung and colleagues [63] found that, relative to metformin, the risk associated with sulphonylureas was 1.26 (95% CI 1.17–1.35) and 1.18 (1.13–1.24) for cardiovascular death and cardiovascular events, respectively. Selvin and colleagues showed that the risk of cardiovascular mortality was lower for metformin than any other comparator (OR 0.74; 95% CI 0.62–0.89) but that the risk for sulphonylurea was not significantly different to other comparators (OR 0.92; 95% CI 0.68–1.26) [64]. Forst and colleagues [65] compared a combined group of patients using sulphonylurea alone or in combination with a group of people not prescribed a sulphonylurea, and found that the sulphonylurea group was associated with a significantly higher risk of all-cause and cardiovascular mortality risks (OR 1.92; 95% CI 1.48–2.49 for all-cause mortality and 2.72; 1.95–3.79 for cardiovascular mortality). In a meta-analysis of observational studies, Eurich and colleagues [66] found that people with heart failure treated with metformin had a 20% lower mortality rate compared with the control group who were predominantly treated with sulphonylureas, and no increased risk of lactic
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review article acidosis was observed in the metformin-treated subjects. Compared with diet and exercise, treatment with sulphonylureas has been shown to significantly increase the risk of mortality for up to one year following the treatment with thrombolysis for acute myocardial infarction, but group sizes were small and confidence intervals (CIs) were wide [67]. On the other hand, results from a study using data from administrative databases in Canada indicated that there was no excess risk of death associated with the use of KATP channel inhibitors, including sulphonylureas, meglitinide and repaglinide, within 30 days of an acute coronary syndrome event [68]. Furthermore, Danish patients with type 2 diabetes treated with metformin in the 90 days following hospital admission with a myocardial infarction had a similar risk of death, a further myocardial infarction and heart failure in the first year following the event as patients treated with sulphonylureas (aHR 0.96, 95% CI 0.71–1.31; 1.21, 0.77–1.92; and 0.81, 0.51–1.29, respectively) [69]. A meta-analysis by Monami and colleagues [70] also found no statistically significant difference in the risk of death from all-causes for sulphonylureas compared with metformin (OR 1.29; 95% CI 0.80–2.13). In addition, the randomized double-blind controlled trial A Diabetes Outcome Progression Trial (ADOPT) showed that glibenclamide was associated with a lower risk of cardiovascular events when compared with rosiglitazone, and that metformin was associated with a similar risk to rosiglitazone. However, this study was not designed to evaluate cardiovascular outcomes [71]. Results from a nationwide French registry found that the use of sulphonylureas was not associated with an increased risk of in-hospital mortality following myocardial infarction [72]. However, it should be noted that this study is not a clear comparison of one treatment versus another, and 34% of the no sulphonylurea group were using insulin and 17% using metformin compared with 6% and 29% in sulphonylurea group, respectively [71]. In terms of cancer, one observational study utilizing data from CPRD found that there was no significant difference in the risk of malignant solid tumours and haematological malignancies when comparing sulphonylureas with metformin (aHR 1.06; 95% CI 0.98–1.15 and 0.98; 0.67–1.43, respectively) [73]. However, two other studies using the CPRD and The Health Improvement Network datasets found that when metformin was used as the referent, sulphonylurea monotherapy was associated with an increased risk of cancer (aHR 1.10; 95% CI 1.00–1.20 and 1.36; 1.19–1.54, respectively) [50,74]. Other observational data [75–77] and meta-analyses [78,79] support the thesis that there is an increased risk of cancer with sulphonylureas in comparison with metformin. Due to their mode of action, sulphonylureas can increase circulating insulin levels, and insulin is thought to have mitogenic properties [80]. Conversely, metformin may have protective effects mediated through the activation of the AMP kinase pathway [81]. People with type 2 diabetes treated with metformin have been shown to have reduced risk of cancer compared with the general population [82]. However, a recent Cochrane meta-analysis combining data from RCTs did not find any significant beneficial effects of metformin on cancer [83]. The CIs calculated were broad, but the authors concluded that even if a beneficial effect of metformin on cancer exists, it is
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review article likely to be smaller than those estimated from the observational data [82]. Current evidence supporting the use of metformin as firstline therapy for the control of blood glucose largely originates from observational studies and a small subgroup of patients in the UKPDS study. A serious concern in evaluating the safety of these two medicines is the disproportionate and undue influence of RCT data vs observational data. The number of endpoints observed in the relevant RCTs is very small. For instance, the estimates of the risk of all-cause mortality for sulfonylureas versus metformin reported in the meta-analyses conducted by Monami et al [71], Stevens et al [61] and also the Cochrane systematic review conducted by Hemmingsen et al [83] are largely dominated by the ADOPT study which contributes the majority of the events (only 62 deaths). Observational studies are far more highly powered. For example, a study presented by our group at the 49th Annual Meeting of the European Association for the Study of Diabetes in September last year included relevant data characterising 5,381 deaths in patients exposed to sulfonylurea vs metformin monotherapy [84]. However, confounding by indication and unmeasured confounding may bias the results of observational studies. More high-quality RCTs with hard endpoints are therefore required to determine the place sulphonylurea monotherapy has in the control of glucose in type 2 diabetes, a conclusion also reached by the authors of the recent Cochrane systematic review [83]. In addition, when comparing metformin monotherapy with sulphonylurea monotherapy, it is difficult to discern whether any increased risk associated with sulphonylureas is due to beneficial effects associated with metformin or adverse effects associated with sulphonylureas. What we can conclude though is that the available clinical and observational data largely support the clinical guidelines from NICE and the ADA recommending the use of metformin as first-line glucose-lowering therapy in type 2 diabetes, provided no contraindications exist [1,2].
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Acknowledgements
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No specific funding was received for this article. We thank the anonymous reviewers for their helpful advice.
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Conflict of Interest
15. Nordin C. The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence. Diabetologia 2010; 53: 1552–1561.
C. C. is a director of and S. H. is employed by Pharmatelligence, a research consultancy receiving funding from pharmaceutical companies. S. H. receives a fully funded PhD studentship from Cardiff University and is employed by Alliance Boots. C. C. has received research grants from various health-related organizations, including Abbott, ALK, Astellas, Diabetes UK, the Engineering and Physical Sciences Research Council, the EASFD, Ferring, GSK, Jenson (Internis), Lilly, the Medical Research Council, Medtronic, MSD, the National Health Service, Norgine, Pfizer, Sanofi-Aventis, Shire, and Wyeth and consults for Amylin, Aryx, Astellas, Boehringer Ingelheim, BMS, Diabetes UK, Eisel, Ferring, GSK, Ipsen, Lilly, Medtronic, MSD, Pfizer, Sanofi-Aventis, Takeda and Wyeth. S. H. wrote the first draft and C. C. amended subsequent versions.
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65. Forst T, Hanefeld M, Jacob S et al. Association of sulphonylurea treatment with all-cause and cardiovascular mortality: a systematic review and meta-analysis of observational studies. Diab Vasc Dis Res 2013; 10: 302–314.
77. Bowker SL, Yasui Y, Veugelers P, Johnson JA. Glucose-lowering agents and cancer mortality rates in type 2 diabetes: assessing effects of time-varying exposure. Diabetologia 2010; 53: 1631–1637.
66. Eurich DT, Weir DL, Majumdar SR et al. Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circ Heart Fail 2013; 6: 395–402.
78. Thakkar B, Aronis KN, Vamvini MT, Shields K, Mantzoros CS. Metformin and sulfonylureas in relation to cancer risk in type II diabetes patients: a meta-analysis using primary data of published studies. Metabolism 2013; 62: 922–934.
67. Halkin A, Roth A, Jonas M, Behar S. Sulfonylureas are not associated with increased mortality in diabetics treated with thrombolysis for acute myocardial infarction. J Thromb Thrombolysis 2001; 12: 177–184.
79. Soranna D, Scotti L, Zambon A et al. Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis. Oncologist 2012; 17: 813–822.
68. Nagendran J, Oudit GY, Bakal JA, Light PE, Dyck JRB, McAlister FA. Are users of sulphonylureas at the time of an acute coronary syndrome at risk of poorer outcomes? Diabetes Obes Metab 2013; 15: 1022–1028.
80. Draznin B. Mechanism of the mitogenic influence of hyperinsulinemia. Diabetol Metab Syndr 2011; 3: 10.
69. Horsdal HT, Johnsen SP, Søndergaard F, Rungby J. Type of preadmission glucose-lowering treatment and prognosis among patients hospitalised with myocardial infarction: a nationwide follow-up study. Diabetologia 2008; 51: 567–574. 70. Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2013; 15: 938–953. 71. Kahn SE, Haffner SM, Heise MA et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355: 2427–2443. 72. Danchin N, Charpentier G, Ledru F et al. Role of previous treatment with sulfonylureas in diabetic patients with acute myocardial infarction: results
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81. Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 2006; 66: 10269–10273. 82. Currie CJ, Poole CD, Jenkins-Jones S, Gale EAM, Johnson JA, Morgan CL. Mortality after incident cancer in people with and without type 2 diabetes impact of metformin on survival. Diabetes Care 2012; 35: 299–304. 83. Hemmingsen B, Schroll JB, Lund SS et al. Sulphonylurea monotherapy for patients with type 2 diabetes mellitus. Cochrane Database Syst Rev 2013; 4: CD009008. 84. Jenkins-Jones S, Currie CJ, Mukherjee J, Morgan CLl. Association between first-line monotherapy with sulfonylurea versus metformin and risk of all-cause mortality. Diabetologia 2013; 56: S89.
2014
Mortality risk with sulphonylureas compared to metformin S. E. Holden & C. J. Currie Cochrane Institute of Public Health, School of Medicine, Cardiff University, Cardiff, UK
Current clinical guidelines in the USA and the UK recommend first-line glucose-lowering treatment with metformin monotherapy for glucose control in type 2 diabetes, where not contraindicated. Consequently, the proportion of people treated with sulphonylureas is decreasing. The purpose of this commentary is to discuss the risks and benefits associated with sulphonylurea monotherapy versus metformin monotherapy and the evidence that, in comparison with metformin, sulphonylureas cause increased harm to people with type 2 diabetes. Keywords: metformin, sulphonylureas, type 2 diabetes Date submitted 1 November 2013; date of first decision 2 January 2014; date of final acceptance 11 February 2014
Current American Diabetes Association (ADA) and National Institute for Health and Care Excellence (NICE) guidelines in the UK recommend the use of metformin as first-line therapy for type 2 diabetes [1,2]. NICE suggests that a sulphonylurea should be considered as an option when the patient is not overweight, when metformin is contraindicated or not tolerated, or when a rapid response to therapy is required to combat hyperglycaemia symptoms [1]. However, the ADA makes no specific recommendation on the use of sulphonylureas to control type 2 diabetes, preferring to recommend the adoption of a more patient-centred approach based on financial cost, efficacy, potential side effects, patient preference and diabetes co-morbidities [1]. In line with these clinical guidelines, the percentage of people with type 2 diabetes using sulphonylureas has decreased in both the UK and the USA. In the UK, the proportion of people with type 2 diabetes treated with sulphonylureas at any point in the natural history of their disease decreased from 45% in 1996 to 33% in 2005, and the number of people using metformin increased from 30% to 57% over the same period [3]. We have estimated that the proportion of people with type 2 diabetes in the UK using sulphonylurea monotherapy first-line was 5% in 2012 (see Figure 1, unpublished data). Between 2000 and 2010, the number of people using sulphonylurea monotherapy second-line following failure with metformin monotherapy decreased from 12% in 2000 to 7% in 2010 [4]. In the USA, the percentage of patients initially treated with sulphonylureas decreased from 26% in 2006 to 18% in 2008, whereas the proportion of patients starting therapy with metformin increased from 51% to 65% [5]. However, metformin has only been licensed by the US FDA since 1995 [6]. A decrease in the prescribing of sulphonylureas and an increase Correspondence to: Craig J. Currie, Professor of Applied Pharmacoepidemiology, Cochrane Institute of Public Health, School of Medicine, Cardiff University, Cardiff Medicentre, Cardiff CF144UJ, UK. E-mail: [email protected]
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Sulfonylurea
Metformin
Figure 1. Percent of patients treated with first-line sulphonylurea monotherapy versus metformin monotherapy in the UK.
in the prescribing of metformin have also been observed in Germany, Italy and Japan [7–10]. Since the publication of the results from the University Group Diabetes Programme (UGDP) in 1969, there has been controversy surrounding the use of sulphonylureas to lower blood glucose in people with type 2 diabetes. In this large, multicentre, placebo-controlled trial, patients were randomized to placebo plus diet, fixed-dose tolbutamide (a first-generation sulphonylurea), fixed-dose insulin or a variable dose of insulin dependent on fasting plasma glucose. In the tolbutamide-treated patients, an unexpected, statistically significant increase in the number of cardiac deaths relative to placebo resulted in the termination of the tolbutamide-treated arm of the study [11]. An excess of all-cause mortality was also found in the group treated with the biguanide phenformin [12]. However, the study design has since been heavily criticized [11]. Unlike metformin, sulphonylureas can cause weight gain and hypoglycaemia. Weight gain is associated with an increased
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review article cardiovascular risk and should be minimized in type 2 diabetes [13,14]. Hypoglycaemia has been linked to prolongation of the QT interval, an arrhythmogenic effect that is thought to be greatest in patients with pre-existing cardiovascular disease and diabetes [15]. Zoungas and colleagues analysed data from the Action in Diabetes and Vascular Disease-Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study and found a strong association between severe hypoglycaemia and the risk of major macrovascular events, major microvascular events, cardiovascular death or death from any cause. However, it is unknown whether severe hypoglycaemia contributes to, or is a marker for these outcomes [16]. In addition, results from two meta-analyses suggest that hypoglycaemia counteracts any benefits associated with intensive glucose-lowering treatment [17,18]. Both low and high HbA1c values have been linked to an increased risk of all-cause mortality and cardiovascular events [19,20]. Phenformin, a biguanide and the predecessor of metformin, was withdrawn from US and European markets in 1977 because of the risk of lactic acidosis [21]. Lactic acidosis is also the most serious possible side effect associated with treatment with metformin, particularly in people with renal impairment. However, a recent Cochrane review found no cases of lactic acidosis in 70 490 patient-years of metformin use (and none in 55 451 patient-years for people not treated with metformin) [22]. The low incidence of lactic acidosis observed may be due, at least in part, to the avoidance of metformin in high risk groups. Nevertheless, when used appropriately, lactic acidosis associated with metformin use is likely to be a relatively rare event. As cardiovascular disease accounts for approximately 50% of deaths in people with type 2 diabetes [23], it is important to determine whether any medications used to lower blood glucose exacerbate this risk. Sulphonylureas stimulate pancreatic β cells to secrete insulin by binding to a subunit of the ATP-dependent potassium (KATP ) channel known as the sulphonylurea receptor (SUR1) [24–26]. This inhibits the flow of potassium through the channel, leading to β-cell depolarization and the release of insulin through exocytosis [23,24]. However, cardiac muscle also contains sulphonylurea-sensitive KATP channels (via the SUR2 receptor), and it is hypothesized that sulphonylureas may cause cardiovascular side effects by blocking ischaemic preconditioning (a cardioprotective mechanism) through the inhibition of these KATP channels [25,27]. Metformin on the other hand is associated with beneficial effects that include a cardioprotective effect that cannot be solely explained by its ability to lower blood glucose [28–30]. Any cardiovascular side effects associated with sulphonylureas may differ between drugs, and could be dependent on the affinity that each individual sulphonylurea has for the different types of SUR receptors. Unlike glibenclamide and glimepriride, which have an affinity for both SUR1 and SUR2 receptors, sulphonylureas such as gliclazide are relatively selective for SUR1 receptors, and they therefore show specificity for the KATP channels in the β cells of the pancreas rather than the channels in cardiac and smooth muscle [31–33]. Although all sulphonylureas can cause hypoglycaemia, some
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are associated with a higher risk than others. A systematic meta-analysis has shown that gibenclamide, which has a long duration of action, was associated with a higher risk of hypoglycaemia than gliclazide, glimepiride and glipizide, with no added improvement in glucose control [34]. Consequently glibenclamide is not recommended in the elderly [35]. The same meta-analysis, however, did not find any increased risk of cardiovascular events, death or weight gain associated with glibenclamide [33]. The propensity to cause weight gain may also differ between sulphonylureas. In the UKPDS, people using chlorpropamide in the intensive cohort at 10 years gained 2.6 kg versus conventional treatment, whereas those using glibenclamide only gained 1.7 kg [36]. Conversely, some sulphonylureas may confer additional benefits. For example, gliclazide may reduce platelet reactivity, stimulate endothelial prostacyclin synthesis and enhance fibrinolysis [37], and glibenclamide may have an antiarrhythmic effect in transient myocardial ischaemia [38]. A study using data from the French Registry on Acute ST-Elevation and non-ST-Elevation Myocardial Infarction (FAST-MI) showed that the use of gliclazide or glimepiride compared with glibenclamide prior to an acute myocardial infarction was associated with a decreased risk of in-hospital mortality (OR 0.15; 95% CI 0.04–0.56) and overall in-hospital complications (0.39; 95% CI 0.21–0.72) [39]. Other studies have also shown that glibenclamide was associated with a higher risk of all-cause mortality when compared with glipizide [40] and gliclazide [41]. Type 2 diabetes is characterized by relative insulin deficiency and insulin resistance. Hyperinsulinaemia is a predictable consequence of the action of insulin secretagogues such as sulphonylureas and also of exogenous insulin and has been linked to an increased risk of mitogenic and arthrogenic effects [42]. Insulin plays a role in several tissues. For example, in type 2 diabetes, the kidney and sympathetic nervous system remain sensitive to insulin, and hyperinsulinaemia can lead to sodium retention and increased sympathetic nervous system activity, which could increase blood pressure [43]. Metformin on the other hand increases insulin sensitivity and reduces plasma insulin levels [44]. Metformin also improves endothelial dysfunction, which may help to explain the reduced risk of cardiovascular disease associated with its use [45–47]. Both metformin and sulphonylureas are financially cheap generic drugs. Sulphonylureas have been shown to reduce HbA1c by 1.5% compared with placebo [48]. However, a Cochrane review has demonstrated that metformin was associated with improved HbA1c, fasting plasma glucose, LDL cholesterol and triglyceride levels and body mass index when compared with sulphonylureas [49]. Evidence in support of the use of metformin as a firstline, glucose-lowering therapy originates largely from the UKPDS and subsequent complementary observational data. The UKPDS found that overweight patients receiving intensive treatment with metformin monotherapy had a lower risk of any diabetes-related endpoint, stroke or all-cause mortality when compared with intensive treatment with insulin or sulphonylureas [50]. Retrospective observational studies using the Clinical Practice Research Datalink (CPRD) have confirmed that, compared with metformin monotherapy, sulphonylurea
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monotherapy was associated with an increased risk of allcause mortality in type 2 diabetes [51,52]. A retrospective cohort analysis using the Saskatchewan Health Administrative Databases in Canada found that, relative to sulphonylurea monotherapy, metformin monotherapy was associated with a lower risk of a composite endpoint defined as the first non-fatal hospitalization or death (adjusted hazard ratio (aHR) 0.81; 95% CI 0.68–0.97) [53]. Furthermore, two large retrospective studies using data from the Veterans Health Administration found that, relative to metformin monotherapy, sulphonylurea monotherapy was associated with a greater risk of mortality or hospital admission due to myocardial infarction or stroke [54,55]. Other observational data comparing sulphonylureas with metformin have also supported the observation that sulphonylureas are associated with a higher risk of mortality as a class [56–58], and glipizide, glimepriride, tolbutamide and glibenclamide specifically [59]. Conversely, a retrospective study using data from VHA Diabetes Epidemiology Cohort found that the risk of all-cause mortality was not significantly different for metformin monotherapy and sulphonylurea monotherapy [adjusted odds ratio (OR) 0.87; 95% CI 0.68–1.10] [60]. In addition, a meta-analysis of available data from randomized, controlled trials (RCTs) did not find that metformin had a statistically significant effect on all-cause mortality. However, as the authors concluded, short follow-up time (average 2.8 years) was a limitation of their meta-analysis [61]. The UKPDS did not find any increased risk of all-cause mortality associated with intensive treatment with glibenclamide or chlorpropamide when compared with conventional treatment [49]. Several observational studies have demonstrated an increased risk of cardiovascular events [50,51,54] and cardiovascular deaths [55] when sulphonylurea monotherapy was compared with metformin monotherapy. A randomized, double-blind, placebo-controlled trial showed that the risk of cardiovascular events in people with type 2 diabetes and a history of coronary heart disease was lower for metformin than for glipizide (aHR 0.54; 95% CI 0.30–0.90) [62]. A metaanalysis of clinical and observational studies by Phung and colleagues [63] found that, relative to metformin, the risk associated with sulphonylureas was 1.26 (95% CI 1.17–1.35) and 1.18 (1.13–1.24) for cardiovascular death and cardiovascular events, respectively. Selvin and colleagues showed that the risk of cardiovascular mortality was lower for metformin than any other comparator (OR 0.74; 95% CI 0.62–0.89) but that the risk for sulphonylurea was not significantly different to other comparators (OR 0.92; 95% CI 0.68–1.26) [64]. Forst and colleagues [65] compared a combined group of patients using sulphonylurea alone or in combination with a group of people not prescribed a sulphonylurea, and found that the sulphonylurea group was associated with a significantly higher risk of all-cause and cardiovascular mortality risks (OR 1.92; 95% CI 1.48–2.49 for all-cause mortality and 2.72; 1.95–3.79 for cardiovascular mortality). In a meta-analysis of observational studies, Eurich and colleagues [66] found that people with heart failure treated with metformin had a 20% lower mortality rate compared with the control group who were predominantly treated with sulphonylureas, and no increased risk of lactic
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review article acidosis was observed in the metformin-treated subjects. Compared with diet and exercise, treatment with sulphonylureas has been shown to significantly increase the risk of mortality for up to one year following the treatment with thrombolysis for acute myocardial infarction, but group sizes were small and confidence intervals (CIs) were wide [67]. On the other hand, results from a study using data from administrative databases in Canada indicated that there was no excess risk of death associated with the use of KATP channel inhibitors, including sulphonylureas, meglitinide and repaglinide, within 30 days of an acute coronary syndrome event [68]. Furthermore, Danish patients with type 2 diabetes treated with metformin in the 90 days following hospital admission with a myocardial infarction had a similar risk of death, a further myocardial infarction and heart failure in the first year following the event as patients treated with sulphonylureas (aHR 0.96, 95% CI 0.71–1.31; 1.21, 0.77–1.92; and 0.81, 0.51–1.29, respectively) [69]. A meta-analysis by Monami and colleagues [70] also found no statistically significant difference in the risk of death from all-causes for sulphonylureas compared with metformin (OR 1.29; 95% CI 0.80–2.13). In addition, the randomized double-blind controlled trial A Diabetes Outcome Progression Trial (ADOPT) showed that glibenclamide was associated with a lower risk of cardiovascular events when compared with rosiglitazone, and that metformin was associated with a similar risk to rosiglitazone. However, this study was not designed to evaluate cardiovascular outcomes [71]. Results from a nationwide French registry found that the use of sulphonylureas was not associated with an increased risk of in-hospital mortality following myocardial infarction [72]. However, it should be noted that this study is not a clear comparison of one treatment versus another, and 34% of the no sulphonylurea group were using insulin and 17% using metformin compared with 6% and 29% in sulphonylurea group, respectively [71]. In terms of cancer, one observational study utilizing data from CPRD found that there was no significant difference in the risk of malignant solid tumours and haematological malignancies when comparing sulphonylureas with metformin (aHR 1.06; 95% CI 0.98–1.15 and 0.98; 0.67–1.43, respectively) [73]. However, two other studies using the CPRD and The Health Improvement Network datasets found that when metformin was used as the referent, sulphonylurea monotherapy was associated with an increased risk of cancer (aHR 1.10; 95% CI 1.00–1.20 and 1.36; 1.19–1.54, respectively) [50,74]. Other observational data [75–77] and meta-analyses [78,79] support the thesis that there is an increased risk of cancer with sulphonylureas in comparison with metformin. Due to their mode of action, sulphonylureas can increase circulating insulin levels, and insulin is thought to have mitogenic properties [80]. Conversely, metformin may have protective effects mediated through the activation of the AMP kinase pathway [81]. People with type 2 diabetes treated with metformin have been shown to have reduced risk of cancer compared with the general population [82]. However, a recent Cochrane meta-analysis combining data from RCTs did not find any significant beneficial effects of metformin on cancer [83]. The CIs calculated were broad, but the authors concluded that even if a beneficial effect of metformin on cancer exists, it is
doi:10.1111/dom.12280 3
review article likely to be smaller than those estimated from the observational data [82]. Current evidence supporting the use of metformin as firstline therapy for the control of blood glucose largely originates from observational studies and a small subgroup of patients in the UKPDS study. A serious concern in evaluating the safety of these two medicines is the disproportionate and undue influence of RCT data vs observational data. The number of endpoints observed in the relevant RCTs is very small. For instance, the estimates of the risk of all-cause mortality for sulfonylureas versus metformin reported in the meta-analyses conducted by Monami et al [71], Stevens et al [61] and also the Cochrane systematic review conducted by Hemmingsen et al [83] are largely dominated by the ADOPT study which contributes the majority of the events (only 62 deaths). Observational studies are far more highly powered. For example, a study presented by our group at the 49th Annual Meeting of the European Association for the Study of Diabetes in September last year included relevant data characterising 5,381 deaths in patients exposed to sulfonylurea vs metformin monotherapy [84]. However, confounding by indication and unmeasured confounding may bias the results of observational studies. More high-quality RCTs with hard endpoints are therefore required to determine the place sulphonylurea monotherapy has in the control of glucose in type 2 diabetes, a conclusion also reached by the authors of the recent Cochrane systematic review [83]. In addition, when comparing metformin monotherapy with sulphonylurea monotherapy, it is difficult to discern whether any increased risk associated with sulphonylureas is due to beneficial effects associated with metformin or adverse effects associated with sulphonylureas. What we can conclude though is that the available clinical and observational data largely support the clinical guidelines from NICE and the ADA recommending the use of metformin as first-line glucose-lowering therapy in type 2 diabetes, provided no contraindications exist [1,2].
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Acknowledgements
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No specific funding was received for this article. We thank the anonymous reviewers for their helpful advice.
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Conflict of Interest
15. Nordin C. The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence. Diabetologia 2010; 53: 1552–1561.
C. C. is a director of and S. H. is employed by Pharmatelligence, a research consultancy receiving funding from pharmaceutical companies. S. H. receives a fully funded PhD studentship from Cardiff University and is employed by Alliance Boots. C. C. has received research grants from various health-related organizations, including Abbott, ALK, Astellas, Diabetes UK, the Engineering and Physical Sciences Research Council, the EASFD, Ferring, GSK, Jenson (Internis), Lilly, the Medical Research Council, Medtronic, MSD, the National Health Service, Norgine, Pfizer, Sanofi-Aventis, Shire, and Wyeth and consults for Amylin, Aryx, Astellas, Boehringer Ingelheim, BMS, Diabetes UK, Eisel, Ferring, GSK, Ipsen, Lilly, Medtronic, MSD, Pfizer, Sanofi-Aventis, Takeda and Wyeth. S. H. wrote the first draft and C. C. amended subsequent versions.
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