A Novel Therapeutic Approach for Managing Hidden Epidemic of FLA1c in Patients with T2DM

Changes in liver parameters in NAFLD. Adapted from Belfort R et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355(22):2297-2307.

Clinical Benefits of Vildagliptin:

Vildagliptin has beneficial effects on all those risk factors associated with NAFLD, such as improvement in metabolic syndrome, blood pressure, weight gain, and lipid profiles. It also plays an essential role in preventing the progression and complications of NAFLD with its anti-inflammatory and antioxidant properties. Vildagliptin is an oral antidiabetic incretin-based therapy used in patients of T2DM with a well-tolerated profile and no risk of weight gain and hypoglycemia. (11) Long-term treatment with Vildagliptin 50 mg once daily led to an HbA1c reduction of 0.5% without any reported incidence of hypoglycemia over a period of 2 years. (15)

Benefits of Initial Pioglitazone and Vildagliptin Combination:

A 24-week, multicentre, randomized, double-blind, active-controlled study conducted across 154 centres across eight countries, including India, assessed the effects of vildagliptin, pioglitazone, and a combination of the two among 607 drug-naive patients with T2DM. The results demonstrated HbA1c reduction of up to 1.9% and FBG reduction of 50.4 mg/dl in the vildagliptin combined with pioglitazone treatment arm, significantly higher than individual monotherapy treatments. The study concluded that first-line treatment with pioglitazone/vildagliptin combination in patients with T2DM provides better glycaemic control yet has minimal risk of hypoglycaemia and a tolerability profile comparable with component monotherapy. (16)

A post hoc analysis on Korean patients with T2DM of the same study, published later, reported an HbA1c reduction of up to 2.03%, with about 76% of patients achieving the recommended target HbA1c < 7% with combination treatment pioglitazone and vildagliptin over 24 weeks treatment period. (17)

Mean HbA1c during 24-wk treatment with vildagliptin/pioglitazone combination. Adapted from Kim SW et.al. Efficacy and safety of vildagliptin/pioglitazone combination therapy in Korean patients with diabetes. World J Diabetes. 2010;1(5):153-160.

Take Home Message:

✔ Every 1 out of 2 Indian patients with diabetes may be at risk or suffering from NAFLD.

✔ There is a well-defined concurrent and bidirectional relationship between the development of T2DM and the development and progression of NAFLD.

✔ For such a massive group of T2DM population with comorbid NAFLD, there is a need to specifically define a multipronged approach targeting the interconnected pathophysiology at multiple levels in these patients

✔ It may be prudent to consider tackling HbA1c, lipid parameters, and liver enzymes along with improving NAFLD disease activity and liver fat content, which forms the core culprit of a myriad of metabolic dysfunctions in this patient population. Thus, the treatment goals can be set towards achieving 'FLA1c' goals to improve treatment care outcomes.

✔ Clinical studies have shown that Pioglitazone and Vildagliptin effectively treat NAFLD diabetic patients with glycaemic and beyond glycaemic benefits. While pioglitazone aids in long-term metabolic and histologic improvement, Vildagliptin treatment has reported decreased hepatic fat content and serum transaminase levels in NAFLD patients. Pioglitazone and vildagliptin combination studies, including a subset of Indian patients, have been cited in scientific literature.

✔ Guidelines recommend considering the use of Pioglitazone in individuals with NASH and T2DM

✔ The combination of Pioglitazone and Vildagliptin that aims at achieving FLA1c goals may be a novel consideration for the management of NAFLD with T2DM.

References:

1. Kumar J, Memon RS, Shahid I, et al. Antidiabetic drugs and non-alcoholic fatty liver disease: A systematic review, meta-analysis and evidence map. Dig Liver Dis. 2021;53(1):44-51.

2. Kumar P, Rawat S, Kakar A, Sinha AK. Prevalence of non-alcoholic fatty liver disease among diabetes, prediabetes, and healthy population. J Family Med Prim Care. 2022;11(12):7640-7643.

3. Ren, W., Feng, Y., Feng, Y. et al. Relationship of liver fat content with systemic metabolism and chronic complications in patients with type 2 diabetes mellitus. Lipids Health Dis 22, 11 (2023).

4. Masroor M, Haque Z. HbA_1C as a Biomarker of Non-alcoholic Fatty Liver Disease: Comparison with Anthropometric Parameters. J Clin Transl Hepatol. 2021;9(1):15-21.

5. Diabetes Care 2021;44(Supplement_1):S73–S84.

6. Xia MF, Bian H, Gao X. NAFLD, and Diabetes: Two Sides of the Same Coin? Rationale for Gene-Based Personalized NAFLD Treatment. Front Pharmacol.2019;10:877. 2019.

7. Cusi K, Orsak B, Bril F, et al. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: Randomized Trial. Ann Intern Med. 2016;165(5):305-315

8. Boettcher E, Csako G, Pucino F, Wesley R, Loomba R. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2012;35(1):66-75.

9. Cusi K, Isaacs S, Barb D, et al. American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD). Endocr Pract. 2022;28(5):528-562.

10. Duseja A, Singh SP, De A et Al, Indian National Association for Study of the Liver (INASL) Guidance Paper on Nomenclature, Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease (NAFLD). J Clin Exp Hepatol. 2023 Mar-Apr;13(2):273-302.

11. Hussain M, Babar MZM, Hussain MS, Akhtar L. Vildagliptin ameliorates biochemical, metabolic, and fatty changes associated with non-alcoholic fatty liver disease. Pak J Med Sci. 2016;32(6):1396-1401.

12. Kumar V, Agarwal S, Saboo B, Makkar B. RSSDI Guidelines for the management of hypertension in patients with diabetes mellitus [published online ahead of print, 2022 Dec 15]. Int J Diabetes Dev Ctries. 2022;42(Suppl 1):1-30.

13. Scherbaum WA, Göke B; German Pioglitazone Study Group. Metabolic efficacy and safety of once-daily pioglitazone monotherapy in patients with type 2 diabetes: a double-blind, placebo-controlled study. Horm Metab Res. 2002;34(10):589-595

14. Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355(22):2297-2307.

15. W. A. Scherbaum; A. Schweizer; A. Mari; P. M. Nilsson; G. Lalanne; Y. Wang; B. E. Dunning; J. E. Foley (2008). Evidence that vildagliptin attenuates deterioration of glycaemic control during 2-year treatment of patients with type 2 diabetes and mild hyperglycemia.,10(11), 1114–1124

16. Rosenstock J, Kim SW, Baron MA, et al. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab. 2007;9(2):175-185.

17. Kim SW, Baik SH, Yoon KH, Lee HW, Filozof C. Efficacy and safety of vildagliptin/pioglitazone combination therapy in Korean patients with diabetes. World J Diabetes. 2010;1(5):153-160.