30th September 2018, Dr Chee L Khoo
Sulfonylurea (SU) is still one of the most commonly prescribed anti-diabetic agent for type 2 diabetes (T2D)1. These patients may have put on a few kilograms of weight over the years but then they are overweight anyway. Weight gain when one gets older is pretty much expected anyway. They may have a few cardiovascular events here and there but then patients with T2D are known to have a higher risk of CV events. Their HbA1c is pretty stable although it appears to be drifting up a bit over the years. They do say that T2D is a progressive disease and that is not unexpected. So, if it ain’t broken, do we need to fix it?
There are at least 4 other newer anti-diabetic agents available in Australia. They all have restrictions under the pharmaceutical Benefits Scheme (PBS) but prescribing an SU is just straight forward. In some countries, SU is still recommended as second-line agents after metformin. They are moderately potent in lowering HbA1c although there is evidence that their glycaemic effect is not sustained over time. They increase body weight and there is a risk of hypoglycaemia. Most of the newer agents are either shown to be cardiovascular safe (the DPP4i) or actually improve cardiovascular risk (SGLT2i and GLP1). On the other hand, there have been suggestions that SU, especially the older generation SU, are associated with increased cardiovascular events. However, there are no well powered randomised controlled trials to assess the cardiovascular safety of SU.
So, we have to rely on observational data from studies comparing SU with other agents. The most recent report was published in the July 2018 issue of British Medical Journal. GP data from the UK Clinical Practice Research Datalink were analysed. Patients with T2D on metformin monotherapy between 1998 and 2013 were compared with patients who had either SU added or substituted for metformin. Of 77,138 patients initiated on metformin during that period, 25,699 added or switched to SU. What did they find?
Adding SU to Metformin
Compared to those remaining on metformin alone, adding an SU increased risk of myocardial infarction by 26% (incidence rate 7.8 v 6.2 per 1000 person years), all-cause mortality by 28% (27.3 v 21.5) and severe hypoglycaemia by 760% (5.5 v 0.7). There was also an trend towards (meaning not quite statistically significant) increased risk of ischaemic stroke (24% increase) and cardiovascular deaths (18% increase).
Switching to an SU
Compared to those who were on metformin alone, switching to an SU was associated with an increased risk of myocardial infarction by 51% and all cause mortality by 23%. There were no significant difference with ischaemic stroke, cardiovascular death or severe hypoglycaemia.
Patients with T2D who needed treatment intensification by either adding an SU or switching to an SU may have more severe disease or poorer glycaemic control. They may have higher cardiovascular risk because of the severity of the disease. SU in these patients may have caused more hypoglycaemia and hypoglycaemia is implicated in cardiac arrhythmias and cardiac ischaemia. Perhaps the SU related weight gain may have increased the risk for myocardial infarction.
CAROLINA (Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes) is a randomised controlled trial comparing an SU with a DPP4 inhibitor (linagliptin). The study was completed in August 2018 and is due to report anytime now.
Newer agents are safer and some more beneficial than SU. The most recent American Diabetes Association (ADA) guidelines highlight the cardiovascular benefits of the SGLT2 inhibitors and GLP-1 receptor antagonists, therefore placing those agents preferentially above sulfonylureas, particularly in patients at high cardiovascular risk.
Access the abstract here.
- Christensen DH, Rungby J, Thomsen RW. Nationwide trends in glucose-lowering drug use, Denmark, 1999-2014. Clin Epidemiol2016;8:381-7
- Azoulay L, Suissa S. Sulfonylureas and the Risks of Cardiovascular Events and Death: A Methodological Meta-Regression Analysis of the Observational Studies. Diabetes Care2017;40:706-14
- Hemmingsen B, Schroll JB, Wetterslev J, et al. Sulfonylurea versus metformin monotherapy in patients with type 2 diabetes: a Cochrane systematic review and meta-analysis of randomized clinical trials and trial sequential analysis. CMAJ Open 2014;2:E162-75
- Antonios Douros, Sophie Dell’Aniello, Oriana Hoi Yun Yu, Kristian B Filion, Laurent Azoulay, Samy Suissa, Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population based cohort study. MJ2018;362:k2693