NIHR Signal Sulfonylureas can be considered safe for those with type 2 diabetes

Published on 20 July 2016

This large review finds that sulfonylurea drugs are not associated with an increased risk of death, heart attack or stroke when compared with placebo, diet control or other diabetes drugs.

Sulfonylureas are commonly used in the treatment of adults with type 2 diabetes. The drugs in this class are relatively cheap and have been available for many decades, but there have been conflicting views on their safety. The trials in this review were large enough and sufficiently long to pick up relatively rare harmful events like death. Therefore the researchers were confident that, even if there is a small risk, less than one in 200 people treated with sulfonylureas are likely to be harmed.

These findings provide reassuring evidence for continued use of sulfonylureas. Clinically, the benefits and low costs of sulfonylureas in treating type 2 diabetes need to be weighed against their potential risks of leading to very low blood sugar levels or weight gain. The evidence needs to be considered alongside the benefits and safety of newer drugs now available for treatment.

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Why was this study needed?

There are currently 3.9 million people living with diabetes in the UK, more than 90% of whom have type 2 diabetes.

Sulfonylureas are an inexpensive group of drugs frequently used in the treatment of type 2 diabetes. They work to improve blood sugar control by increasing insulin release from the pancreas. It is estimated that 20-30% of people with type 2 diabetes in developed countries take a newer second or third generation sulfonylurea, such as glipizide or glimepiride.

There is conflicting evidence about the safety of these drugs regarding deaths and cardiovascular outcomes. Therefore, this study aimed to assess the safety of second and third generation sulfonylureas by looking at rates of death, heart attack and stroke.

What did this study do?

This was a systematic review and meta-analysis of 47 randomised controlled trials (37,650 patients), including data from the large multicentre UKPDS trial. Trials were included if they were at least a year long and compared second or third generation sulfonylureas with a control group of diet, inactive placebo or other diabetes drugs in adults with type 2 diabetes.

The main outcomes of interest were death from any cause, cardiovascular-related death and rates of heart attack and stroke. The researchers looked at the effect of giving sulfonylureas as a first-line treatment alone, as second-line or add-on therapy to another drug such as metformin, or unspecified use.

Trial duration ranged from one to 11 years. The quality of evidence was considered high for all-cause or cardiovascular-related death, and moderate for heart attack and stroke outcomes.

What did it find?

  • When compared with any control, sulfonylureas had no significant effect on risk of:
    • death from any cause (odds ratio [OR] 1.12, 95% confidence interval [CI] 0.96 to 1.30; 37 trials),
    • death from cardiovascular cause (OR 1.12, 95% CI 0.87 to 1.42; 21 trials),
    • heart attack (OR 0.92, 95% CI 0.76 to 1.12; 23 trials),
    • stroke (OR 1.16, 95% CI 0.81 to 1.66; 23 trials).
  • Sulfonylurea drugs, individually, were not associated with risk of death from any cause or cardiovascular cause when compared separately with placebo or diet, or with other diabetes drugs.
  • There was also no significant difference in death from any cause or cardiovascular cause when looking at the timing of use of sulfonylureas – as first-line treatment, second-line treatment, unspecified, or specifically as add-on therapy to metformin.
  • Statistical analysis found that the overall sample size was large enough to conclude that the number of people harmed by sulfonylureas is likely to be less than 1 in 200.

What does current guidance say on this issue?

NICE’s 2015 guidance on type 2 diabetes recommends a sulfonylurea as an initial treatment option if the standard first-choice drug metformin is contraindicated or not tolerated.

Sulfonylureas are also recommended as add-on therapy to metformin (or other first-choice drug) if that drug alone has not adequately controlled sugar levels. It is also an option as part of triple drug therapy.

What are the implications?

These findings provide reassuring evidence that second and third generation sulfonylureas are not associated with increased rates of death, heart attack or stroke.

These trials were non-randomised and ran for up to 11 years, meaning that despite the risk of some bias in the findings the designs were able to identify over 200 deaths from heart disease. This would not have been possible from smaller, shorter randomised controlled trials.

The researchers calculated that the sample size was large enough to conclude that an adverse mortality risk, if any, must affect less than one in 200 people treated with sulfonylureas. Further research on whether all individual sulfonylureas are associated with similar risk would be useful.

From a clinical view the low cost and benefits of sulfonylureas also needs to be weighed against the potential risks of leading to very low blood sugar levels and weight gain.

Citation and Funding

Rados DV, Pinto LC, Remonti LR, et al. The association between sulfonylurea use and all-cause and cardiovascular mortality: a meta-analysis with trial sequential analysis of randomized clinical trials. PLoS Med. 2016;13(4):e1001992.

This project was funded by the Brazilian Conselho Nacional de Desenvolvimento Clientifico e Tecnologico (CNPq).

Bibliography

NHS Choices. Type 2 diabetes. London: Department of Health; updated 2014.

NICE. Type 2 Diabetes in adults: management. NG28. London: National Institute for Health and Care Excellence; 2015.

Why was this study needed?

There are currently 3.9 million people living with diabetes in the UK, more than 90% of whom have type 2 diabetes.

Sulfonylureas are an inexpensive group of drugs frequently used in the treatment of type 2 diabetes. They work to improve blood sugar control by increasing insulin release from the pancreas. It is estimated that 20-30% of people with type 2 diabetes in developed countries take a newer second or third generation sulfonylurea, such as glipizide or glimepiride.

There is conflicting evidence about the safety of these drugs regarding deaths and cardiovascular outcomes. Therefore, this study aimed to assess the safety of second and third generation sulfonylureas by looking at rates of death, heart attack and stroke.

What did this study do?

This was a systematic review and meta-analysis of 47 randomised controlled trials (37,650 patients), including data from the large multicentre UKPDS trial. Trials were included if they were at least a year long and compared second or third generation sulfonylureas with a control group of diet, inactive placebo or other diabetes drugs in adults with type 2 diabetes.

The main outcomes of interest were death from any cause, cardiovascular-related death and rates of heart attack and stroke. The researchers looked at the effect of giving sulfonylureas as a first-line treatment alone, as second-line or add-on therapy to another drug such as metformin, or unspecified use.

Trial duration ranged from one to 11 years. The quality of evidence was considered high for all-cause or cardiovascular-related death, and moderate for heart attack and stroke outcomes.

What did it find?

  • When compared with any control, sulfonylureas had no significant effect on risk of:
    • death from any cause (odds ratio [OR] 1.12, 95% confidence interval [CI] 0.96 to 1.30; 37 trials),
    • death from cardiovascular cause (OR 1.12, 95% CI 0.87 to 1.42; 21 trials),
    • heart attack (OR 0.92, 95% CI 0.76 to 1.12; 23 trials),
    • stroke (OR 1.16, 95% CI 0.81 to 1.66; 23 trials).
  • Sulfonylurea drugs, individually, were not associated with risk of death from any cause or cardiovascular cause when compared separately with placebo or diet, or with other diabetes drugs.
  • There was also no significant difference in death from any cause or cardiovascular cause when looking at the timing of use of sulfonylureas – as first-line treatment, second-line treatment, unspecified, or specifically as add-on therapy to metformin.
  • Statistical analysis found that the overall sample size was large enough to conclude that the number of people harmed by sulfonylureas is likely to be less than 1 in 200.

What does current guidance say on this issue?

NICE’s 2015 guidance on type 2 diabetes recommends a sulfonylurea as an initial treatment option if the standard first-choice drug metformin is contraindicated or not tolerated.

Sulfonylureas are also recommended as add-on therapy to metformin (or other first-choice drug) if that drug alone has not adequately controlled sugar levels. It is also an option as part of triple drug therapy.

What are the implications?

These findings provide reassuring evidence that second and third generation sulfonylureas are not associated with increased rates of death, heart attack or stroke.

These trials were non-randomised and ran for up to 11 years, meaning that despite the risk of some bias in the findings the designs were able to identify over 200 deaths from heart disease. This would not have been possible from smaller, shorter randomised controlled trials.

The researchers calculated that the sample size was large enough to conclude that an adverse mortality risk, if any, must affect less than one in 200 people treated with sulfonylureas. Further research on whether all individual sulfonylureas are associated with similar risk would be useful.

From a clinical view the low cost and benefits of sulfonylureas also needs to be weighed against the potential risks of leading to very low blood sugar levels and weight gain.

Citation and Funding

Rados DV, Pinto LC, Remonti LR, et al. The association between sulfonylurea use and all-cause and cardiovascular mortality: a meta-analysis with trial sequential analysis of randomized clinical trials. PLoS Med. 2016;13(4):e1001992.

This project was funded by the Brazilian Conselho Nacional de Desenvolvimento Clientifico e Tecnologico (CNPq).

Bibliography

NHS Choices. Type 2 diabetes. London: Department of Health; updated 2014.

NICE. Type 2 Diabetes in adults: management. NG28. London: National Institute for Health and Care Excellence; 2015.

The Association between Sulfonylurea Use and All-Cause and Cardiovascular Mortality: A Meta-Analysis with Trial Sequential Analysis of Randomized Clinical Trials

Published on 14 April 2016

Rados DV, Pinto LC, Remonti LR, et al.

PLoS Med Volume 13 , 2016

BACKGROUND: Sulfonylureas are an effective and inexpensive treatment for type 2 diabetes. There is conflicting data about the safety of these drugs regarding mortality and cardiovascular outcomes. The objective of the present study was to evaluate the safety of the sulfonylureas most frequently used and to use trial sequential analysis (TSA) to analyze whether the available sample was powered enough to support the results. METHODS AND FINDINGS: Electronic databases were reviewed from 1946 (Embase) or 1966 (MEDLINE) up to 31 December 2014. Randomized clinical trials (RCTs) of at least 52 wk in duration evaluating second- or third-generation sulfonylureas in the treatment of adults with type 2 diabetes and reporting outcomes of interest were included. Primary outcomes were all-cause and cardiovascular mortality. Additionally, myocardial infarction and stroke events were evaluated. Data were summarized with Peto odds ratios (ORs), and the reliability of the results was evaluated with TSA. Forty-seven RCTs with 37,650 patients and 890 deaths in total were included. Sulfonylureas were not associated with all-cause (OR 1.12 [95% CI 0.96 to 1.30]) or cardiovascular mortality (OR 1.12 [95% CI 0.87 to 1.42]). Sulfonylureas were also not associated with increased risk of myocardial infarction (OR 0.92 [95% CI 0.76 to 1.12]) or stroke (OR 1.16 [95% CI 0.81 to 1.66]). TSA could discard an absolute difference of 0.5% between the treatments, which was considered the minimal clinically significant difference. The major limitation of this review was the inclusion of studies not designed to evaluate safety outcomes. CONCLUSIONS: Sulfonylureas are not associated with increased risk for all-cause mortality, cardiovascular mortality, myocardial infarction, or stroke. Current evidence supports the safety of sulfonylureas; an absolute risk of 0.5% could be firmly discarded. REVIEW REGISTRATION: PROSPERO CRD42014004330.

Sulphonylurea (sulfonylurea) drugs work by increasing the amount of insulin produced in the body. However they can increase the risk of hypoglycaemia (low blood sugar).

Examples of sulphonylurea drugs available in the UK include:

  • glibenclamide
  • gliclazide
  • glimepiride
  • glipizide
  • gliquidone

Expert commentary

This article is the latest of several meta-analyses to examine the question of whether sulphonylurea drugs, commonly used in the treatment of type 2 diabetes, increase the risk of cardiovascular morbidity and mortality. This question was first posed over 45 years ago and remains controversial, hence the continuing analyses which employ statistics way beyond the comfort zone of the average specialist clinician.

This article suggests that an increase in absolute risk of 0.5% 'could be firmly discarded' but this may now not be enough. Two cardiovascular safety studies of newer type 2 diabetes therapies have shown superiority over placebo, with a third to report later this year. Cardiovascular neutrality (at best) may no longer be sufficient to justify the high-ranking of sulphonylurea drugs in type 2 diabetes treatment algorithms.

Steven Bain, Professor in Medicine (Diabetes), Swansea University