# Rivoglitazone
**Rivoglitazone** (development code CS-011) is an investigational thiazolidinedione (a diabetes drug class that sensitizes tissues to insulin) antidiabetic drug that acts as a potent agonist of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ). It was discovered by the Japanese pharmaceutical company Sankyo, later [Daiichi Sankyo](https://www.edgepedia.org/daiichi-sankyo), and reached phase III clinical trials for type 2 diabetes before development was discontinued in 2009 without regulatory approval.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10586552/) • [2](https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/balaglitazone) • [3](https://www.daiichisankyo.com/files/news/ir/pdf/005139/imm2009_07_31_22_01.pdf)
| Key fact | Detail |
|---|---|
| Drug class and target | Thiazolidinedione; PPARγ agonist that improves insulin resistance[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10586552/) |
| Developer | Sankyo / Daiichi Sankyo, development code CS-011[2](https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/balaglitazone) |
| Receptor selectivity | 445-fold selectivity for PPARγ over PPARα or PPARδ in vitro[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10586552/) |
| Pharmacokinetics | Plasma half-life approximately 13 hours; dose-proportional pharmacokinetics[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10586552/) |
| Glycemic effect (meta-analysis) | HbA1c reduction versus placebo of -0.86% at 1 mg/day and -0.97% at 1.5-2 mg/day; high dose superior to pioglitazone 30-45 mg/day by -0.11%[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10586552/) |
| Development status | Reached phase III (US, EU) and phase II (Japan); program terminated in 2009[4](https://www.daiichisankyo.com/files/news/ir/pdf/005142/ser2009_05_12_4_02.pdf) • [3](https://www.daiichisankyo.com/files/news/ir/pdf/005139/imm2009_07_31_22_01.pdf) |
## Pharmacology
Thiazolidinediones lower blood glucose by activating PPARγ, which reduces insulin resistance in hepatic, muscular, and adipose tissue and improves glucose disposition.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10586552/) Rivoglitazone was designed as a rosiglitazone analog: scientists at Daiichi Sankyo reported it in 2000 as compound CS-011, in which the last two atoms of the ethanolamine linker became part of a benzimidazole-2-yl substitution on the aromatic effector portion.[2](https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/balaglitazone)
**Receptor binding.** [In vitro](https://www.edgepedia.org/in-vitro), rivoglitazone shows 445-fold selectivity for PPARγ over the PPARα and PPARδ isoforms.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10586552/) Its potency to activate PPARγ has been reported as 16.4-fold higher than pioglitazone and 3.6-fold higher than rosiglitazone.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10586552/) A structural study from the [University of Adelaide](https://www.edgepedia.org/university-of-adelaide) solved the first X-ray crystal structure of rivoglitazone bound to any PPAR and found that rivoglitazone forms a unique hydrogen bond network with the PPARγ co-activator binding surface (AF2) and makes more extensive contacts with helix 3 and the β-sheet than rosiglitazone.[5](https://pubmed.ncbi.nlm.nih.gov/28499821/)
**Pharmacokinetics.** Early animal and clinical studies showed a potent, effective blood glucose-lowering agent with dose-proportional pharmacokinetics and a plasma half-life of approximately 13 hours.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10586552/) A comparison cited in the meta-analysis gives the half-life as 12.2 hours, against 4 hours for rosiglitazone and 7 hours for pioglitazone.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10586552/) [Population pharmacokinetic modeling](https://www.edgepedia.org/population-pharmacokinetic-modeling) during development used a two-compartment model with first-order absorption and elimination and an absorption time lag, and indirect-response models characterized changes in fasting plasma glucose, HbA1c, and hemodilution as a function of plasma concentration.[6](https://ptacts.uspto.gov/ptacts/public-informations/petitions/1555709/download-documents?artifactId=0CNgDBKuOkG9iwe9kMp2k02vGXWewrBRp3IOkr-fau7MxnNZADnQ45A) In rodent models, 14 days of treatment suggested reduced hepatic glucose production and modulation of cardiac glucose and fatty acid metabolism.[7](https://www.sciencedirect.com/science/article/pii/S1347861319311144)
## Clinical development
Daiichi Sankyo ran a seven-trial program of rivoglitazone in type 2 diabetes, including monotherapy trials against pioglitazone 15, 30, and 45 mg and add-on trials with metformin, sulfonylureas, and insulin; the program was closed in 2009.[8](https://phmpt.org/wp-content/uploads/2021/12/027-Appendix-in-Support-filed-by-Public-Health-and-Medical-Professionals-for-Transparency-re-26-Brief-Memorandum-in-Support-of-Motion.pdf)
**Dose-ranging study.** A 26-week, randomized, double-blind, double-dummy study randomized 441 subjects with HbA1c between 7.0% and 10.5% to placebo, rivoglitazone 1, 2, or 3 mg once daily, or pioglitazone 45 mg. Placebo-subtracted HbA1c changes from baseline were -0.55% (p = 0.0034), -0.99% (p < 0.0001), -1.10% (p < 0.0001), and -0.59% (p = 0.0016) for pioglitazone. The most common drug-related adverse events with rivoglitazone were peripheral edema and weight gain, which increased with dose and were higher with rivoglitazone 2 and 3 mg than with pioglitazone or rivoglitazone 1 mg. Early discontinuation exceeded 50% of participants.[9](https://pubmed.ncbi.nlm.nih.gov/20370378/)
**Monotherapy study.** A second 26-week trial randomized 1912 subjects with HbA1c above 7.0% and at or below 8.5% in a 2 : 4 : 11 : 11 ratio to placebo (n = 137), rivoglitazone 1.0 mg (n = 274), rivoglitazone 1.5 mg (n = 750), or pioglitazone 45 mg (n = 751). Rivoglitazone 1.5 mg was statistically superior to pioglitazone in reducing HbA1c (changes of -0.7% versus -0.6%), while 1.0 mg was non-inferior (-0.4%). Rivoglitazone also significantly reduced fasting plasma glucose and improved insulin sensitivity estimates, high-density lipoprotein cholesterol, and other metabolic and inflammatory biomarkers. The most common drug-related treatment-emergent adverse events were peripheral edema (5.2-6.2% on active drug versus 0.7% on placebo), increased weight (1.6-3.1% versus 0%), and pitting edema (1.3-2.2% versus 0%).[10](https://pubmed.ncbi.nlm.nih.gov/22686944/)
**Chinese trial.** A 12-week double-blind study in Chinese patients randomized 174 of 287 enrolled patients to placebo, pioglitazone 30 mg, or rivoglitazone 0.5, 1.0, or 1.5 mg daily. HbA1c changes were -0.11%, -0.22%, and -0.17% for the rivoglitazone groups, -0.06% for pioglitazone, and +0.61% for placebo, with all active groups significant against placebo. Drug-related edema occurred in 7.7% of rivoglitazone patients, 16.2% of pioglitazone patients, and 3.0% of placebo patients.[11](https://pubmed.ncbi.nlm.nih.gov/21492364/)
## Meta-analysis findings
A 2023 meta-analysis pooled 3 randomized controlled trials with 3591 patients, the first to analyze rivoglitazone holistically in type 2 diabetes.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10586552/) Against placebo, HbA1c fell by -0.86% (95% CI -1.11 to -0.61) with standard-dose 1 mg/day and -0.97% (95% CI -1.03 to -0.90) with high-dose 1.5-2 mg/day. Against pioglitazone 30-45 mg/day, HbA1c lowering was comparable with the standard dose (MD 0.05%, p = 0.08) and superior with the high dose (MD -0.11%, p < 0.01).[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10586552/)
Triglycerides fell significantly versus placebo, by -17.95 mg/dl with the standard dose and -40.41 mg/dl with the high dose, comparable to pioglitazone. Adiponectin rose by 7.94 ng/ml (standard dose) and 13.82 ng/ml (high dose), and hsCRP, a marker of systemic inflammation, fell by -1.00 mg/L and -1.50 mg/L respectively. High-dose rivoglitazone was superior to pioglitazone on adiponectin and hsCRP, while the standard dose was inferior on both.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10586552/)
**Safety.** Treatment-emergent and severe adverse events were comparable to placebo and to active controls. [Weight gain](https://www.edgepedia.org/weight-gain) occurred with rivoglitazone in a dose-dependent pattern, higher than pioglitazone at the high dose and lower at the standard dose. The authors concluded that rivoglitazone appears better than [lobeglitazone](https://www.edgepedia.org/lobeglitazone) on glycemic efficacy and weight gain, and suggested a starting dose of 1 mg by mouth based on available clinical data.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC10586552/)
## Discontinuation and other uses
Daiichi Sankyo listed rivoglitazone (CS-011) in phase III for the US and EU and phase II for Japan in 2009, with patient enrollment in the phase 3 trials completed.[4](https://www.daiichisankyo.com/files/news/ir/pdf/005142/ser2009_05_12_4_02.pdf) In its May 2009 R&D pipeline update the company moved the drug to discontinued projects, giving the reason as difficulty in sufficiently differentiating the product from existing treatments.[3](https://www.daiichisankyo.com/files/news/ir/pdf/005139/imm2009_07_31_22_01.pdf) A drug-development review states that it progressed to phase III but failed in 2009 for undisclosed reasons.[2](https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/balaglitazone) The drug was therefore never marketed.
Under a 2005 agreement between Sankyo and Santen Pharmaceutical, Santen obtained the sole worldwide rights to develop, produce, and sell CS-011 (rivoglitazone) as a therapy for epithelial disorders of the cornea and conjunctiva, dry eye among them, while Sankyo kept pursuing the compound as an antidiabetic agent.[12](https://www.santen.com/content/dam/santen/global/pdf/en/news/backno/20050926.pdf)
## References
1. [Efficacy and Safety of Novel Thiazolidinedione Rivoglitazone in Type-2 Diabetes: a Meta-Analysis, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10586552/)
2. [Balaglitazone - an overview, ScienceDirect Topics](https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/balaglitazone)
3. [Daiichi Sankyo R&D Pipeline Update, May 2009](https://www.daiichisankyo.com/files/news/ir/pdf/005139/imm2009_07_31_22_01.pdf)
4. [Daiichi Sankyo Consolidated Financial Results reference data (CS-011 pipeline table)](https://www.daiichisankyo.com/files/news/ir/pdf/005142/ser2009_05_12_4_02.pdf)
5. [X-ray crystal structure of rivoglitazone bound to PPARγ and PPAR subtype selectivity of TZDs, PubMed](https://pubmed.ncbi.nlm.nih.gov/28499821/)
6. [Model-Based Development of a PPARγ Agonist, Rivoglitazone, to Aid Dose Selection and Optimize Clinical Trial Designs, Journal of Clinical Pharmacology 2008](https://ptacts.uspto.gov/ptacts/public-informations/petitions/1555709/download-documents?artifactId=0CNgDBKuOkG9iwe9kMp2k02vGXWewrBRp3IOkr-fau7MxnNZADnQ45A)
7. [Potent Antidiabetic Effects of Rivoglitazone, a Novel PPAR-γ Agonist, in Obese Diabetic Rodent Models, ScienceDirect](https://www.sciencedirect.com/science/article/pii/S1347861319311144)
8. [Appendix in Support re 26 Brief Memorandum (seven core trials of rivoglitazone), PHMPT](https://phmpt.org/wp-content/uploads/2021/12/027-Appendix-in-Support-filed-by-Public-Health-and-Medical-Professionals-for-Transparency-re-26-Brief-Memorandum-in-Support-of-Motion.pdf)
9. [A 26-week, placebo- and pioglitazone-controlled, dose-ranging study of rivoglitazone, PubMed](https://pubmed.ncbi.nlm.nih.gov/20370378/)
10. [A 26-week, placebo- and pioglitazone-controlled monotherapy study of rivoglitazone, PubMed](https://pubmed.ncbi.nlm.nih.gov/22686944/)
11. [A randomized-controlled trial to investigate the effects of rivoglitazone on glucose-lipid control in type 2 diabetes, PubMed](https://pubmed.ncbi.nlm.nih.gov/21492364/)
12. [Agreement Concerning CS-011 as Dry Eye Drug Candidate, Santen Pharmaceutical](https://www.santen.com/content/dam/santen/global/pdf/en/news/backno/20050926.pdf)
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*Topic: Encyclopedia › Life and health › Human health and medicine › Medicines and therapeutics › Cardiovascular, metabolic, and endocrine drugs › Metabolic and endocrine drugs › Peroxisome proliferator-activated receptor agonists*
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