Switching therapy from metformin to a sulfonylurea increases the risk for adverse outcomes in patients with type 2 diabetes, new research suggests.
Results of a study using data from the UK Clinical Practice Research Datalink were published online July 18 in BMJ by epidemiologist Antonios Douros, MD, PhD, of McGill University, Montreal, Quebec, and colleagues.
Patients taking sulfonylureas as second-line therapy had increased risks for myocardial infarction, all-cause mortality, and severe hypoglycemia compared with those remaining on metformin monotherapy, even when the latter was in the face of suboptimal glycemic control.
The associations with myocardial infarction and mortality were driven by switching from metformin to sulfonylureas, rather than the addition of sulfonylureas to metformin.
"Thus, in-line with current recommendations on the treatment of type 2 diabetes, continuing metformin when introducing sulfonylureas is safer than switching," Douros and colleagues write.
In an accompanying editorial, the writers point out that sulfonylureas remain the most common second-line agent for type 2 diabetes despite their consistent association with higher cardiovascular risk and the availability of newer classes of medications.
Penned by postdoctoral fellow Lucy D'Agostino McGowan, of Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, and internist/epidemiologist Christianne L. Roumie, MD, of Vanderbilt University, Nashville, Tennessee, they caution that "it is hard to define clinical practice based on an observational study, as patients using different treatments may differ in ways that are unmeasured."
But nevertheless they agree with the authors regarding the clinical implications: "Continuing metformin alone and accepting higher HbA1c targets is preferable to switching to sulfonylureas when considering both macrovascular outcomes and hypoglycemia."
The editorialists also point out that the study findings support the beneficial effects of metformin, as the increased risk from sulfonylureas was primarily seen among those who stopped metformin.
Dangers of Switching to Sulfonylureas Identified
The study included 77,138 patients aged 40 years and older with a first prescription for metformin between April 1998 and March 2013, of whom 25,699 added, or switched to, sulfonylureas during follow-up through March 2014.
A total of 23,592 patients who added, or switched, to sulfonylureas were matched with the same number who remained on metformin monotherapy.
The most frequent causes of death were cancer (31%), cardiovascular diseases (31%), and respiratory diseases (10%).
Use of sulfonylureas as second-line treatment — whether by adding or switching — was associated with a significant 26% increased risk of myocardial infarction compared with continuing metformin monotherapy (incidence rate 7.8 vs 6.2 per 1000 patient-years; HR, 1.26).
Sulfonylurea users also had a 28% greater risk for all-cause mortality compared with metformin monotherapy (27.3 vs 21.5 per 1000 patient-years; HR, 1.28) and a nearly eight-fold higher rate of severe hypoglycemia (5.5 vs 0.7 per 1000 patient-years; HR, 7.6).
There were also nonsignificant trends toward increased risks for ischemic stroke and cardiovascular death.
Adding a sulfonylurea to ongoing metformin treatment did not significantly increase macrovascular events compared with continuing metformin monotherapy, however.
In a head-to-head comparison between patients who added, or switched to, a sulfonylurea, switching was associated with a significant 51% increased risk of myocardial infarction compared with adding (HR, 1.51) and a 23% increase in all-cause mortality, which was of borderline significance (HR, 1.23). There were no significant differences in ischemic stroke, cardiovascular death, or severe hypoglycemia.
Are Sulfonylureas Risky or Is Metformin Protective, or Both?
Several potential mechanisms could account for the increase in risk from switching to sulfonylureas compared with remaining on metformin monotherapy, Douros and colleagues say.
Sulfonylureas are associated with weight gain and well as hypoglycemia, which may contribute to arrhythmias and cardiac ischemia.
In addition, the absence of an increased risk for myocardial infarction associated with the addition of sulfonylureas to metformin suggests that metformin may have a protective effect.
Alternatively, McGowan and Roumie observe, "It is still possible that the observed difference in risk between adding and switching could be driven by the possibility that higher doses of sulfonylureas are needed by those who switched, and this deserves further study."
BMJ. Published online July 18, 2018. Abstract, Editorial
Abstract och hela artikeln i sin helhet som pdf utan lösenord
Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population based cohort study
BMJ 2018; 362 doi: https://doi.org/10.1136/bmj.k2693 (Published 18 July 2018)Cite this as: BMJ 2018;362:k2693
Antonios Douros, postdoctoral fellow123, Sophie Dell’Aniello, statistician1, Oriana Hoi Yun Yu, endocrinologist14, Kristian B Filion, assistant professor125, Laurent Azoulay, associate professor126, Samy Suissa, professor125
Objective To assess whether adding or switching to sulfonylureas is associated with an increased risk of myocardial infarction, ischaemic stroke, cardiovascular death, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy in patients with type 2 diabetes.
Design Population based cohort study.
Setting General practices contributing data to the UK Clinical Practice Research Datalink.
Participants Patients with type 2 diabetes initiating metformin monotherapy between 1998 and 2013.
Main outcome measures Using the prevalent new-user cohort design we matched 1:1 patients adding or switching to sulfonylureas with those remaining on metformin monotherapy on high-dimensional propensity score, haemoglobin A1c, and number of previous metformin prescriptions. The two groups were compared using Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals for the study outcomes.
Results Among 77 138 metformin initiators, 25 699 added or switched to sulfonylureas during the study period. During a mean follow-up of 1.1 years, sulfonylureas were associated with an increased risk of myocardial infarction (incidence rate 7.8 v 6.2 per 1000 person years, hazard ratio 1.26, 95% confidence interval 1.01 to 1.56), all cause mortality (27.3 v 21.5, 1.28, 1.15 to 1.44), and severe hypoglycaemia (5.5 v 0.7, 7.60, 4.64 to 12.44) compared with continuing metformin monotherapy. There was a trend towards increased risks of ischaemic stroke (6.7 v 5.5, 1.24, 0.99 to 1.56) and cardiovascular death (9.4 v 8.1, 1.18, 0.98 to 1.43). Compared with adding sulfonylureas, switching to sulfonylureas was associated with an increased risk of myocardial infarction (hazard ratio 1.51, 95% confidence interval, 1.03 to 2.24) and all-cause mortality (1.23, 1.00 to 1.50). No differences were observed for ischaemic stroke, cardiovascular death, or severe hypoglycaemia.
Conclusions Sulfonylureas as second line drugs are associated with an increased risk of myocardial infarction, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy. Continuing metformin when introducing sulfonylureas appears to be safer than switching.
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New evidence helps individualise treatment decisions and minimise harm
Sulfonylureas and insulin were the cornerstone of diabetes management until 1998 when metformin became recommended as initial treatment by the American Diabetes Association and the European Association for the Study of Diabetes Before 2008, treatments for diabetes were often approved on the basis of their ability to lower glycated haemoglobin (HbA1c) by 0.5% (5.5 mmol/mol) or other surrogate outcomes. After the controversy surrounding cardiovascular risk associated with thiazolidinediones, regulatory agencies such as the US Food and Drug Administration and the European Medicines Agency issued guidance for industries to evaluate the cardiovascular safety of antidiabetes drugs.
Sulfonylureas have a consistent association with a higher risk of cardiovascular disease and hypoglycaemia compared with metformin. Despite this increased risk they remain the second most common initial treatment for diabetes and when combined with metformin, the most common combination regimen.
Many people who are initially prescribed metformin either add or switch to a sulfonylurea owing to increased HbA1c levels. Clinicians and patients have for many years focused on HbA1c, perhaps rightly, even though it remains a surrogate marker for diabetes outcomes and death. Whether a patient should add a drug, switch to a different regimen, or simply continue with metformin monotherapy for a slightly increased HbA1c level remains an important clinical question.
To answer this question, in a linked article Douros and colleagues (doi:10.1136/bmj.k2693) conducted an observational study using the UK Clinical Practice Research Datalink comparing key macrovascular clinical outcomes for people with type 2 diabetes who continue metformin monotherapy compared with those who either add or switch to sulfonylureas.6 The authors “prevalent new user design” accounts for comparisons at different stages of disease duration7 by using time varying propensity scores.
Douros and colleagues defined time based and prescription based exposure sets and computed propensity scores to closely match participants who either added or switched to a sulfonylurea (the new users) with those who continued treatment with metformin alone (the prevalent users). Participants entered the cohort when they added or switched to a sulfonylurea, along with a similar matched control who continued metformin. Matching characteristics included date of study entry, number of metformin prescriptions (surrogate for diabetes duration), HbA1c level (surrogate for diabetes severity), and a high dimensional propensity score,8 built considering 500 covariates that represent possible confounders.
The resultant participants resembled those commonly seen in clinical practice—average age 64 years, 43% women, and 53% with an HbA1c level >8% (63.9 mmol/mol). Sulfonylurea use (switching and adding combined) was associated with an increased risk of myocardial infarction, all cause mortality, and hypoglycaemia. Compared with similar participants who continued taking metformin, switching to a sulfonylurea was associated with a greater risk of myocardial infarction, cardiovascular death, and all cause mortality than adding a sulfonylurea.
The results of the UK Prospective Diabetes Study (UKPDS) in 1998 left unanswered questions about whether a sulfonylurea is harmful or metformin is beneficial. UKPDS showed that among 5102 people with new type 2 diabetes no difference in mortality existed between those randomised to insulin or sulfonylurea and controls randomised to diet; tighter glycaemic control with sulfonylurea was associated only with reduced microvascular outcomes (neuropathy and retinopathy).9 In a subgroup of 342 overweight participants, however, metformin was associated with a 46% decrease in diabetes related mortality compared with diet control.
The study by Douros and colleagues supports the beneficial effects of metformin, by showing that the increased risk from sulfonylurea use was primarily among those who switched, and completely stopped metformin. Adding a sulfonylurea to ongoing metformin treatment was not associated with a statistically significant increase in macrovascular events, including cardiovascular death compared with those who maintained metformin rather than escalating therapy (8.1 per 1000 person years for metformin alone v 6.3 per 1000 for adding a sulfonylurea; adjusted hazard ratio 0.95, 95% confidence interval 0.75 to 1.20). Event rates were highest (18.3 cardiovascular deaths per 1000 person years) among those who switched to a sulfonylurea.
It is still possible that the observed difference in risk between adding and switching could be driven by the possibility that higher doses of sulfonylureas are needed by those who switched, and this deserves further study.
It is hard to define clinical practice based on an observational study, as patients using different treatments may differ in ways that are unmeasured. This study, however, is well designed and the relations appear strong and consistent when examining several important macrovascular clinical outcomes. The results were also robust to sensitivity analyses, which varied the definitions of the patient’s exposure and tested the sensitivity to unmeasured confounders.
These data suggest that adding a sulfonylurea to metformin treatment is preferable to switching to sulfonylurea monotherapy. It also suggests that continuing metformin alone and accepting higher HbA1c targets is preferable to switching to sulfonylureas when considering both macrovascular outcomes and hypoglycaemia.
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