Oldies but Goodies: Thiazolidinedione as an Insulin Sensitizer with Cardioprotection

Eun-Hee Cho

doi:10.4093/dmj.2022.0372

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Editorial Oldies but Goodies: Thiazolidinedione as an Insulin Sensitizer with Cardioprotection: Eun-Hee Cho; Diabetes & Metabolism Journal 2022;46(6):827-828.
DOI: https://doi.org/10.4093/dmj.2022.0372
Published online: November 24, 2022

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Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea

Corresponding author: Eun-Hee Cho

Department of Internal Medicine, Kangwon National University School of Medicine, 1 Gangwondaehak-gil, Chuncheon 24341, Korea E-mail: ehcho@kangwon.ac.kr

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Diabetes is a heterogeneous chronic disease which affects 16.7% among the Korean adult aged 30 years and older and more than half of people with diabetes (55.1%) in Korea are obese (body mass index ≥25.0 kg/m²) in 2020 [1] suggesting the insulin resistance as a core mechanism to develop type 2 diabetes mellitus (T2DM).

Among Korean adults with T2DM, new antidiabetic medications such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors had dramatically increased from 2002 to 2018; however, the use of insulin and thiazolidinediones (TZDs) remained low and stable from 2002 to 2018 [1].

TZDs are peroxisome proliferator-activated receptor γ (PPARγ) agonists, which improve insulin sensitivity in skeletal muscle and reduce hepatic glucose production in patients with T2DM [2]. They have long glycemic durability and more weight gain, more edema and less hypoglycemia than metformin or glyburide [3].

Currently, pioglitazone, now generically affordable, and lobeglitazone are available for T2DM in Korea. Lobeglitazone (Chong Kun Dang Pharmaceutical Corporation, Seoul, Korea) was a novel PPARγ agonist, which was developed and approved in Korea in 2013. Introduction of a p-methoxyphenoxy group at the 4-position of the pyrimidine moiety, which was based on a modification of the rosiglitazone structure induces 12 times higher affinity to PPARγ compared to rosiglitazone and pioglitazone [4] to meet the demands for a more effective and safer TZD with lower dose.

Lobeglitazone 0.5 mg showed a favorable glycosylated hemoglobin (HbA1c) reduction (–0.44% vs. 0.16% in the placebo group, P<0.0001) and safety profile over 24 weeks as a monotherapy [5]. In add-on study to metformin with lobeglitazone, it showed similar HbA1c reduction in the pioglitazone to metformin combination group [6] and non-inferior to sitaglitpin add-on therapy [7]. In a Korean real-world study, lobeglitazone showed good glycemic-lowering effect, long-term durability of glycemic control and long-term safety profile with no cases of bladder cancer, one case of CHF, and 1.17% fracture rate of all patients [8].

The American Diabetes Association (ADA) 2022 guidelines [9] recommends that first-line therapy depends on comorbidities, patient-centered treatment factors and a GLP-1RA or a SGLT2 inhibitor is recommended as an appropriate initial therapy for individuals with T2DM with comorbidity such as atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and/or chronic kidney disease (CKD).

For those without compelling comorbidity indication, second-line options may be selected depending on if the highest priority is minimizing hypoglycemia, weight gain, or cost and access. In the current guidelines, TZDs may be considered as second-line agents if the priority is to minimize cost and access or risk of hypoglycemia. However, TZDs are the only class of glucose-lowering agents that primarily target the insulin resistance and have benefit of reducing the risk of ASCVD and improving nonalcoholic steato-hepatitis and β-cell function [10-12]. Considering the adverse effects as edema, HF, and weight gain, SGLT2 inhibitors or GLP-1RAs combined with TZDs could be a better option to improve insulin resistance and to target different pathophysiology thereby, minimizing the TZDs-related side effects.

The PROactive trial showed that pioglitazone decreased the ‘main secondary endpoint’ of all-cause mortality, non-fatal myocardial infarction, and stroke compared to placebo in 5,238 patients with T2DM with prior cardiovascular (CV) event, but there was no significant difference in the primary composite endpoint including additional acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle [10]. As for lobeglitazone, additional clinical studies are expected to provide further evidence of the beneficial CV effects of lobeglitazone because the choice within same TZDs class is to be based on whether there was proven beneficial CV outcome trial. Regarding the limitation of current ADA and Korean guidelines focusing only on the co-morbidities such as ASCVD, HF, or CKD, clinician should consider the aspect of pathophysiology of T2DM as insulin resistance together which concur with obesity when to choose the anti-diabetic agents.

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CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

REFERENCES

1. Bae JH, Han KD, Ko SH, Yang YS, Choi JH, Choi KM, et al. Diabetes fact sheet in Korea 2021. Diabetes Metab J 2022;46:417-26.Article PubMed PMC PDF
2. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 2004;351:1106-18.Article PubMed
3. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427-43.Article PubMed
4. Lee MA, Tan L, Yang H, Im YG, Im YJ. Structures of PPARγ complexed with lobeglitazone and pioglitazone reveal key determinants for the recognition of antidiabetic drugs. Sci Rep 2017;7:16837.Article PubMed PMC PDF
5. Kim SG, Kim DM, Woo JT, Jang HC, Chung CH, Ko KS, et al. Efficacy and safety of lobeglitazone monotherapy in patients with type 2 diabetes mellitus over 24-weeks: a multicenter, randomized, double-blind, parallel-group, placebo controlled trial. PLoS One 2014;9:e92843.Article PubMed PMC
6. Jin SM, Park CY, Cho YM, Ku BJ, Ahn CW, Cha BS, et al. Lobeglitazone and pioglitazone as add-ons to metformin for patients with type 2 diabetes: a 24-week, multicentre, randomized, double-blind, parallel-group, active-controlled, phase III clinical trial with a 28-week extension. Diabetes Obes Metab 2015;17:599-602.PubMed PMC PDF
7. Kim SG, Kim KJ, Yoon KH, Chun SW, Park KS, Choi KM, et al. Efficacy and safety of lobeglitazone versus sitagliptin as an add-on to metformin in patients with type 2 diabetes with two or more components of metabolic syndrome over 24weeks. Diabetes Obes Metab 2020;22:1869-73.Article PubMed PDF
8. Kim BY, Kwon HS, Kim SK, Noh JH, Park CY, Park HK, et al. A real-world study of long-term safety and efficacy of lobeglitazone in Korean patients with type 2 diabetes mellitus. Diabetes Metab J 2022;46:855-65.Article PubMed PMC PDF
9. American Diabetes Association Professional Practice Committee, Draznin B, Aroda VR, Bakris G, Benson G, Brown FM, et al. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2022. Diabetes Care 2022;45(Suppl 1):S125-43.
10. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, MassiBenedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279-89.Article PubMed
11. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374:1321-31.Article PubMed PMC
12. DeFronzo RA, Inzucchi S, Abdul-Ghani M, Nissen SE. Pioglitazone: the forgotten, cost-effective cardioprotective drug for type 2 diabetes. Diab Vasc Dis Res 2019;16:133-43.Article PubMed PDF

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Oldies but Goodies: Thiazolidinedione as an Insulin Sensitizer with Cardioprotection

Diabetes Metab J. 2022;46(6):827-828. Published online November 24, 2022

DOI: https://doi.org/10.4093/dmj.2022.0372

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