We read with interest the paper by Shelbaya and RakhaCitation1 reporting the results of the GUARD (vildaGliptin clinical Use in the reAl woRlD) study in patients (n = 2786) with type 2 diabetes mellitus (T2DM) from Egypt. They found that vildagliptin alone or in combination with metformin was well tolerated and significantly lowered glycated hemoglobin A1c (HbA1c) (mean reductions: 1.47% and 1.62% with vildagliptin monotherapy and vildagliptin + metformin, respectively) in a real-world setting involving Egyptian T2DM patientsCitation1.
Vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is not recommended in T2DM patients with hepatic impairment (defined by baseline alanine aminotransferase [ALT] or aspartate aminotransferase [AST] levels >3× the upper limit of normal [ULN])Citation2. In this context, did the authorsCitation1 measure liver tests? Furthermore, chronic liver diseases including hepatitis C, hepatitis B and non-alcoholic fatty liver disease (NAFLD) have been related to elevated levels of dipeptidyl peptidase-4Citation3. Egypt has the highest prevalence of hepatitis C virus (HCV) infection worldwide (up to 40% in some areas of the country)Citation4,Citation5. The prevalence of hepatitis B virus (HBV) infection is significantly lower, approximately 8% in adults and even less in children, possibly due to the introduction of the HBV vaccineCitation6. Furthermore, HBV and HCV infected patients frequently have hepatic steatosis as these liver diseases share common pathophysiological mechanismsCitation7–9. A link between HBV and HCV infections with metabolic disorders such as NAFLD, metabolic syndrome (MetS) and T2DM has also been reportedCitation10,Citation11. T2DM may aggravate HCV infection progression and attenuate the response to antiviral therapyCitation12. Similarly, T2DM development in HBV infected patients significantly increases the risk of liver cirrhosisCitation13. On the other hand, sustained virological response improves insulin resistance and pancreatic beta cell functionCitation14. In this context, what was the prevalence of these liver diseases in the Shelbaya and RakhaCitation1 study?
NAFLD, a hepatic manifestation of MetS that has been associated with an increased risk for cardiovascular morbidity and mortalityCitation15–17, frequently co-exists with T2DMCitation18. Certain antidiabetic drugs may beneficially affect NAFLD including vildagliptinCitation19,Citation20 which has been shown to improve both biochemical and ultrasonographical features of NAFLDCitation21,Citation22. Therefore, it would have been useful to evaluate the effects of vildagliptin on NAFLD in the Shelbaya and RakhaCitation1 study.
Elevated serum uric acid (SUA) levels have been linked to T2DM, NAFLD and CVDCitation23–26. Vildagliptin has previously been reported to decrease SUA levels in T2DM patientsCitation27. Were SUA levels recorded in the Shelbaya and RakhaCitation1 study?
Transparency
Declaration of funding
This letter was written independently; no company or institution supported the authors financially or by providing a professional writer.
Declaration of financial/other relationships
N.K. has disclosed that she has given talks, attended conferences and participated in trials sponsored by Amgen, Angelini, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Novo Nordisk, Sanofi and WinMedica. V.G.A. has disclosed that he has given talks, attended conferences and participated in trials sponsored by MSD, Angelini, Sanofi, and Amgen. A.K. has disclosed that he has given talks and attended conferences sponsored by AstraZeneca, Novartis and WinMedica.
CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
References
- Shelbaya S, Rakha S. Effectiveness and safety of vildagliptin and vildagliptin add-on to metformin in real-world settings in Egypt – results from the GUARD study. Curr Med Res Opin 2017;33:797-801
- Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000771/WC500020327.pdf [Last accessed 25 April 2017]
- Itou M, Kawaguchi T, Taniguchi E, et al. Dipeptidyl peptidase-4: a key player in chronic liver disease. World J Gastroenterol 2013;19:2298-306
- Elgharably A, Gomaa AI, Crossey MM, et al. Hepatitis C in Egypt – past, present, and future. Int J Gen Med 2016;10:1-6
- El-Akel W, El-Sayed MH, El Kassas M, et al. National treatment programme of hepatitis C in Egypt: hepatitis C virus model of care. J Viral Hepat 2017;24:262-7
- Lehman EM, Wilson ML. Epidemiology of hepatitis viruses among hepatocellular carcinoma cases and healthy people in Egypt: a systematic review and meta-analysis. Int J Cancer 2009;124:690-7
- Lim CT, Kumar R. Hepatitis B and concomitant hepatic steatosis. Ann Transl Med 2017;5:38
- Shi YX, Huang CJ, Yang ZG. Impact of hepatitis B virus infection on hepatic metabolic signaling pathway. World J Gastroenterol 2016;22:8161-7
- Chang ML. Metabolic alterations and hepatitis C: from bench to bedside. World J Gastroenterol 2016;22:1461-76
- Ballestri S, Nascimbeni F, Romagnoli D, et al. Type 2 diabetes in non-alcoholic fatty liver disease and hepatitis C virus infection – liver: the “musketeer” in the spotlight. Int J Mol Sci 2016;17:355
- Haga Y, Kanda T, Sasaki R, et al. Nonalcoholic fatty liver disease and hepatic cirrhosis: comparison with viral hepatitis-associated steatosis. World J Gastroenterol 2015;21:12989-95
- García-Compeán D, González-González JA, Lavalle-González FJ, et al. Current concepts in diabetes mellitus and chronic liver disease: clinical outcomes, hepatitis C virus association, and therapy. Dig Dis Sci 2016;61:371-80
- Huang YW, Wang TC, Lin SC, et al. Increased risk of cirrhosis and its decompensation in chronic hepatitis B patients with newly diagnosed diabetes: a nationwide cohort study. Clin Infect Dis 2013;57:1695-702
- Younossi ZM, McCullough AJ. Metabolic syndrome, non-alcoholic fatty liver disease and hepatitis C virus: impact on disease progression and treatment response. Liver Int 2009;29(Suppl2):3-12
- Katsiki N, Mikhailidis DP, Mantzoros CS. Non-alcoholic fatty liver disease and dyslipidemia: an update. Metabolism 2016;65:1109-23
- Athyros VG, Tziomalos K, Katsiki N, et al. Cardiovascular risk across the histological spectrum and the clinical manifestations of non-alcoholic fatty liver disease: an update. World J Gastroenterol 2015;21:6820-34
- Katsiki N, Athyros VG, Karagiannis A, et al. Should we expand the concept of coronary heart disease equivalents? Curr Opin Cardiol 2014;29:389-95
- Bril F, Cusi K. Nonalcoholic fatty liver disease: the new complication of type 2 diabetes mellitus. Endocrinol Metab Clin North Am 2016;45:765-81
- Katsiki N, Athyros VG, Mikhailidis DP. Non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus: effects of statins and antidiabetic drugs. J Diabetes Complications 2017;31:521-2
- Athyros VG, Alexandrides TK, Bilianou H, et al. The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. an expert panel statement. Metabolism 2017;71:17-32
- Hussain M, Majeed Babar MZ, Hussain MS, et al. Vildagliptin ameliorates biochemical, metabolic and fatty changes associated with non alcoholic fatty liver disease. Pak J Med Sci 2016;32:1396-401
- Macauley M, Hollingsworth KG, Smith FE, et al. Effect of vildagliptin on hepatic steatosis. J Clin Endocrinol Metab 2015;100:1578-85
- Katsiki N, Doumas M, Athyros VG, et al. Hyperuricemia as a risk factor for cardiovascular disease. Expert Rev Cardiovasc Ther 2015;13:19-20
- Katsiki N, Papanas N, Fonseca VA, et al. Uric acid and diabetes: is there a link? Curr Pharm Des 2013;19:4930-7
- Katsiki N, Karagiannis A, Athyros VG, et al. Hyperuricaemia: more than just a cause of gout? J Cardiovasc Med (Hagerstown) 2013;14:397-402
- Katsiki N, Athyros VG, Karagiannis A, et al. Hyperuricaemia and non-alcoholic fatty liver disease (NAFLD): a relationship with implications for vascular risk? Curr Vasc Pharmacol 2011;9:698-705
- Shimodaira M, Niwa T, Nakajima K, et al. Beneficial effects of vildagliptin on metabolic parameters in patients with type 2 diabetes. Endocr Metab Immune Disord Drug Targets 2015;15:223-8