Prudente, Sabrina

Trischitta, Vincenzo

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Archivio della ricerca- Università di Roma La Sapienza

Some Doubts About the Mantra on the DeleteriousCardiovascular Effects of SulfonylureasVincenzo Trischitta1,2 and Sabrina Prudente2Diabetes 2017;66:2069–2071 | https://doi.org/10.2337/dbi17-0023Patients with type 2 diabetes are at increased mortality risk,mainly because of cardiovascular disease (1). On the basis ofthe evidence that a pharmacological approach against hy-pertension, dyslipidemia, and hyperglycemia is needed totackle this devastating clinical outcome (2), such patientsare usually aggressively treated. In the U.S., prescribed retailpharmaceutical spending accounted for approximately halfof the annual diabetes cost, which approximated $100 bil-lion in 2013 (3). How long will we be able to cope with sucha burden, especially considering it is likely to increase overthe next decades (4)? Under this scenario, it is both ethicaland smart to pay attention to the costs.In treating hyperglycemia we are facing a tendency, partlydriven by pressure from pharmaceutical companies, toabandon the old, well-known, and cheap sulfonylureas infavor of new and costly glucose-lowering molecules. One ofthe reasons given is that there is a deleterious effect ofsulfonylureas on cardiovascular disease suggested by variousobservational studies but never proven by randomized clin-ical trials (5–7), the gold standard approach for addressingsimilar issues. Unfortunately, as sulfonylureas entered themarket long before the U.S. Food and Drug Administrationrequest of cardiovascular risk assessment for novel antidia-betes drugs to be approved (8), an adequately powered car-diovascular trial on sulfonylurea therapy is not available.One should, therefore, wonder if the mantra of cardiovas-cular deleterious effects of this class of drugs is destined tolast forever.Recently, genetic studies have been appropriately de-signed to get deeper insights on on-target drug pleiotropiceffects, such as that of GLP-1 agonists on cardiovascularoutcomes (9) or that of statins on the risk of type 2 diabetes(10). Along this line, the study by Emdin et al. (11) in thisissue of Diabetes adds important, and somehow reassuring,evidence on the cardiovascular effect of sulfonylureas.The common p.A1369S nonsynonymous polymorphismin ABCC8 (the gene encoding for SUR1, a component of thesulfonylurea receptor) was used as a naturally occurringmodel of SUR1 activation to test for an association withcoronary heart disease (CHD) in 120,286 participants fromthe UK Biobank and in summary data from several previousgenome-wide association studies. In addition, the authorsinvestigated the association with type 2 diabetes and vari-ous cardiometabolic traits. Data obtained by this intelligentstudy design clearly show that the p.A1369S amino acidchange, previously known 1) to mimic in vitro the pharma-cological effects of sulfonylureas by promoting closure ofthe ATP-sensitive potassium channel (12), 2) to increase invivo insulin secretion (13), and 3) to protect from type 2diabetes (13,14), was in fact associated with a reduced riskof CHD and a composite cardiovascular end point, includingstroke, heart failure, and peripheral vascular disease (perallele reduction equal to 2% and 3%, respectively). Eachcopy of the p.A1369S variant was also associated with a7% lower risk of type 2 diabetes, thus replicating previousfindings (13). This makes it possible to calculate that per10% reduction in type 2 diabetes risk the ABCC8 p.A1369Svariant exerts a 4% reduction on CHD risk. Such a relation-ship is very similar to that reported for a missensevariant in GLP1R, encoding the GLP-1 receptor, the specifictarget of GLP-1 agonists, which—notably, in our specificcontext—have been recently reported to be cardioprotec-tive (15,16).Although association studies cannot provide definitemechanistic evidences, one cannot avoid asking how ABCC8p.A1369S exerts such positive effect on cardiovascular out-comes. Considering that SUR1 is mostly expressed in brain,pancreatic (a, b, and d), and other neuroendocrine cells(17), it is unlikely that ABCC8 p.A1369S acts directly onthe vasculature and heart.By referring to previous studies addressing the role ofgenetic predisposition of diabetes on the risk of CHD (18),Emdin et al. (11) suggest that the cardioprotective effect ofp.A1369S variant is based on more than just diabetes riskreduction. Although this is an intriguing possibility, it re-mains truly impossible to determine whether and to what1Department of Experimental Medicine, Sapienza Universitá di Roma, Rome, Italy2Research Unit of Metabolic and Cardiovascular Diseases, IRCCS Casa Sollievodella Sofferenza, San Giovanni Rotondo, ItalyCorresponding author: Vincenzo Trischitta, vincenzo.trischitta@uniroma1.it.© 2017 by the American Diabetes Association. Readers may use this article aslong as the work is properly cited, the use is educational and not for profit, and thework is not altered. More information is available at http://www.diabetesjournals.org/content/license.See accompanying article, p. 2310.Diabetes Volume 66, August 2017 2069COMMENTARYextent the two favorable outcomes are independent or,conversely, somehow interwoven. An alternative hypothesiscomes from data on adiposity measures, with the p.A1369Svariant being associated with an expected increased BMI(6,7) but also an unexpected lower BMI-adjusted waist-to-hip ratio, an established marker of reduced risk forboth type 2 diabetes and CHD (19). Whether a favorablenonabdominal fat accumulation has played a role on thecardioprotective effect of ABCC8 p.A1369S and whethersuch an effect is observed also under sulfonylurea treat-ment are questions that remain unanswered. A schematicview of possible pleiotropic effects of the p.A1369S gain-of-function amino acid change on cardiometabolic traits isshown in Fig. 1.As Emdin et al. (11) admit and clearly discuss, theirstudy has some limitations. First, although the effect ofABCC8 p.A1369S on CHD has been tested in the generalpopulation, the cardiovascular effect of sulfonylureas, ifany, would occur in patients with diabetes, who are aggres-sively treated and intrinsically prone to CHD. Investigatingthe association between ABCC8 p.A1369S and CHD amongpatients with diabetes is the only way to understandwhether the encouraging finding of Emdin et al. is extend-able to type 2 diabetes. Second, the length and degree ofSUR1 stimulation are very different depending on whetherit is due to ABCC8 p.A1369S or to exogenous sulfonylureaadministration, with the former being lifelong and mild andthe latter initiating in adult life and being definitively moredramatic. For example, in patients with type 2 diabetes,treatment with sulfonylureas is a main cause of severe hypo-glycemic episodes, which are believed to increase cardiovascularrisk (20). The genetic tool used to recapitulate sulfonylurea-mediated SUR1 stimulation certainly does not capture thisdrug side effect. Third, it cannot be totally excluded thatsulfonylureas also have off-target (i.e., not mediated bySUR1) cardiovascular effects, which, by definition, cannotbe replicated by a genetic variant affecting SUR1.In all, although the above-mentioned limitations callfor caution in interpreting and generalizing the reportedresults, the study by Emdin et al. (11) does question themantra of sulfonylureas as burdened by cardiovascular sideeffects, a relevant issue for the entire diabetes community.Acknowledgments. The authors thank Marco Giorgio Baroni (SapienzaUniversità di Roma, Rome, Italy) for reading the manuscript and for providingcomments and suggestions.Funding. V.T. and S.P. are supported by the Italian Ministry of Health (RicercaCorrente 2016 and 2017). V.T. is also supported by the Italian Ministry of Universityand Research (PRIN 2015) and by Fondazione Roma (Biomedical Research: Non-communicable Diseases 2013 Grant).Duality of Interest. No potential conflicts of interest relevant to this articlewere reported.Figure 1—Pleiotropic effects of naturally occurring SUR1 gain-of-function amino acid change on cardiometabolic traits. The ATP-sensitivepotassium channel is composed by SUR1, encoded by ABCC8, and the selective potassium pore Kir6.2, encoded by KCNJ11. The SUR1p.A1369S is a gain–of-function amino acid change, which mimics in vitro the effects of sulfonylureas by promoting the closure of ATP-sensitivepotassium channel (12) that ensues in increasing potassium efflux, cell membrane depolarization, calcium influx and promoting insulin exo-cytosis in pancreatic b-cells. In humans, the p.A1369S variant has been associated with enhanced glucose-induced insulin secretion (13) andreduced risk of type 2 diabetes (13,14). Emdin et al. (11) showed that the SUR1 p.A1369S variant is also associated with lower risk of CHD. Theintimate biology underlying this association is not known. One possibility is that the SUR1 p.A1369S variant affects the risk of CHD, at leastpartly, via its protective effect on type 2 diabetes, a major cardiovascular risk factor. It is also possible that the reduced risk of CHD is aconsequence of the unexpected and difficult-to-understand reduced abdominal adiposity shown by carriers of SUR1 p.A1369S. Finally, SUR1 ismostly expressed in brain, pancreatic, and neuroendocrine cells (17), which are unlikely to be involved in shaping cardiovascular risk. However, itcannot be entirely excluded that part of p.A1369S cardioprotective effect is mediated by low, though physiologically relevant, expression ofSUR1 in other tissues. T2D, type 2 diabetes; WHR, waist-to-hip ratio.2070 Commentary Diabetes Volume 66, August 2017References1. Seshasai SR, Kaptoge S, Thompson A, et al.; Emerging Risk Factors Collab-oration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N EnglJ Med 2011;364:829–8412. 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Some doubts about the mantra on the deleterious cardiovascular effects of sulfonylureas

Vincenzo Trischitta

Sabrina Prudente

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Diabetes

Some Doubts About the Mantra on the Deleterious Cardiovascular Effects of Sulfonylureas

https://iris.uniroma1.it/bitstream/11573/1084021/2/Trischitta_Sulfonylureas%20_2017.pdf

Some doubts about the mantra on the deleterious cardiovascular effects of sulfonylureas

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