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Journal of Advanced Research 23 (2020) 163–205 Contents lists available at ScienceDirect Journal of Advanced Research journal homepage: www.elsevier.com/locate/jare An overview on medicinal perspective of thiazolidine-2,4-dione: A remarkable scaffold in the treatment of type 2 diabetes Garima Bansal a,1, Punniyakoti Veeraveedu Thanikachalam a,b,1,⇑, Rahul K. Maurya a,c, Pooja Chawla a,⇑, Srinivasan Ramamurthy d a Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Ghal Kalan, Moga, Punjab 142001, India GRT Institute of Pharmaceutical Education and Research, GRT Mahalakshmi Nagar, Tiruttani, India Amity Institute of Pharmacy, Amity University Uttar Pradesh, Lucknow Campus, India d College of Pharmacy and Health Sciences, University of Science and Technology of Fujairah, United Arab Emirates b c h i g h l i g h t s g r a p h i c a l a b s t r a c t
TZDs, an important pharmacophore in the treatment of diabetes.
Various analog-based synthetic strategies and biological significance are discussed.
Clinical studies using TZDs along with other antidiabetic agents are also highlighted.
SAR has been discussed to suggest the interactions between derivatives and receptor sites.
Pyrazole, chromone, and acid-based TZDs can be considered as potential lead molecules. a r t i c l e i n f o Article history: Received 15 October 2019 Revised 7 January 2020 Accepted 18 January 2020 Available online 22 January 2020 a b s t r a c t Diabetes or diabetes mellitus is a complex or polygenic disorder, which is characterized by increased levels of glucose (hyperglycemia) and deficiency in insulin secretion or resistance to insulin over an elongated period in the liver and peripheral tissues. Thiazolidine-2,4-dione (TZD) is a privileged scaffold and an outstanding heterocyclic moiety in the field of drug discovery, which provides various opportunities in Abbreviations: ADDP, 1,10 -(Azodicarbonyl)dipiperidine; AF, activation factor; ALT, alanine transaminase; ALP, alkaline phosphatase; AST, aspartate transaminase; Boc, Butyloxycarbonyl; DNA, deoxyribonucleic acid; DBD, DNA-binding domain; DM, diabetes mellitus; DCM, dichloromethane; DMF, dimethylformamide; DMSO, dimethyl sulfoxide; E, Entgegen; ECG, electrocardiogram; FDA, food and drug administration; FFA, free fatty acid; GAL4, Galactose transporter type; GLUT4, glucose transporter type 4; GPT, glutamic pyruvic transaminase; HCl, Hydrochloric Acid; HDL, high-density lipoprotein; HEp-2, Human epithelial type 2; HFD, high-fat diet; HEK, human embryonic kidney; i.m, Intramuscular; INS-1, insulin-secreting cells; IL-b, interlukin-beta; IDF, international diabetes federation; K2CO3, Potassium carbonate; LBD, ligand-binding domain; LDL, low-density lipoprotein; MDA, malondialdehyde; mCPBA, meta-chloroperoxybenzoic acid; NBS, N-bromosuccinimide; NaH, Sodium Hydride; NA, nicotinamide; NO, nitric oxide; NFjB, nuclear factor kappa-B; OGTT, oral glucose tolerance test; PPAR, peroxisome-proliferator activated receptor; PPRE, peroxisome proliferator response element; Pd, Palladium; PDB, protein data bank; PTP1B, protein-tyrosine phosphatase 1B; KOH, potassium hydroxide; QSAR, quantitative structure-activity relationship; RXR, retinoid X receptor; STZ, streptozotocin; SAR, structure-activity relationship; T2DM, type 2 diabetes mellitus; THF, tetrahydrofuran; TZD, thiazolidine-2,4-dione; TFA, trifluoroacetic acid; TFAA, trifluoroacetic anhydride; TG, triglycerides; TNF-a, tumor necrosis factor-alpha; WAT, white adipose tissue; Z, Zusammen. Peer review under responsibility of Cairo University. ⇑ Corresponding authors at: Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Ghal Kalan, Moga, Punjab 142001, India (P.V. Thanikachalam). E-mail addresses: nspkoti2001@gmail.com (P.V. Thanikachalam), pvchawla@gmail.com (P. Chawla). 1 Authors contributed equally to this work. https://doi.org/10.1016/j.jare.2020.01.008 2090-1232/Ó 2020 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 164 Keywords: Diabetes PPAR-c Thiazolidine-2,4-diones Pioglitazone Rosiglitazone G. Bansal et al. / Journal of Advanced Research 23 (2020) 163–205 exploring this moiety as an antidiabetic agent. In the past few years, various novel synthetic approaches had been undertaken to synthesize different derivatives to explore them as more potent antidiabetic agents with devoid of side effects (i.e., edema, weight gain, and bladder cancer) of clinically used TZD (pioglitazone and rosiglitazone). In this review, an effort has been made to summarize the up to date research work of various synthetic strategies for TZD derivatives as well as their biological significance and clinical studies of TZDs in combination with other category as antidiabetic agents. This review also highlights the structure-activity relationships and the molecular docking studies to convey the interaction of various synthesized novel derivatives with its receptor site. Ó 2020 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Introduction In this modernized industrial world, the ever-growing population rate along with physical inactivity of people has put the life of mankind on an edge of being targeted by various diseases among which diabetes is the most common one. According to the International Diabetes Federation (IDF), the morbidity rate of this insidious disease has been estimated to show an increase from 425 million in 2017 to 629 million by 2045 [1]. Diabetes or diabetes mellitus (DM) is a complex or polygenic disorder which is characterized by increased levels of glucose (hyperglycemia) resulting from defects in insulin secretion, action or both (resistance) to insulin over an elongated period in the liver and peripheral tissues. DM is classified as type 1 i.e. insulin-dependent, type 2 i.e. non-insulin dependent and gestational diabetes (in pregnant women) [2,3]. The symptoms include polyuria, tiredness, dehydration, polyphagia, and polydipsia [4]. Therefore, it is necessary to maintain the proper blood glucose level, mainly during the early stages of diabetes. Several types of anti-hyperglycaemic agents are used as monotherapy or combination therapy to treat DM. These include meglitinides, biguanides, sulphonylurea, and aglucosidase inhibitors. In addition to these, sesquiterpenoids have also been reported as potential anti-diabetic agents by virtue of protecting b-pancreatic cells and improving insulin secretion [5]. The treatment of type 2 diabetes mellitus (T2DM) has been reformed with the origin of thiazolidine-2,4-diones (TZDs) class of molecules that bring down the increased levels of blood glucose to normal [6]. TZDs also called as glitazones are the heterocyclic ring system consisting of five-membered thiazolidine moiety having carbonyl groups at 2 and 4 positions. Various substitutions can only be done at third and fifth positions. A comprehensive research has been done on TZDs resulting in various derivatives [7]. Though, substantial evidence reported with TZDs but none of them have reported up to date review and clinical studies of TZD [7–9]. In this review, we aimed to present the information from synthetic, in vitro, and in vivo studies that had been carried out on various TZD derivatives by collecting research journals published from the date of discovery of TZD in the early 1980s. In addition, we have discussed their molecular target (peroxisome proliferator-activated receptors, PPAR-c), toxicity profiling (hepatotoxicity and cardiotoxicity) and their structure–activity relationship (SAR). Further, we have compiled clinical studies of TZDs that had been done in combination with other categories as antidiabetic agents. We believe that this review will provide sound knowledge, and guidance to carry out further research on this scaffold to mitigate the problems of clinically used TZDs. The general procedure for synthesizing TZDs has been shown in S1. TZDs (3) has been synthesized by refluxing thiourea (1) with chloroacetic acid (2) for 8–12 h at 100–110 °C, using water and conc. HCl as a solvent [10]. Antiquity of TZDs The antihyperglycemic activity of TZDs came into notice by the entry of first drug, ciglitazone in the early 1980s but later on, it was withdrawn due to its liver toxicity. Then, troglitazone was discovered and developed by Sankyo Company in the year 1988. However, it caused hepatotoxicity, as a result, it was banned in 2000. In 1999, Takeda and Pfizer developed two drugs, pioglitazone, and englitazone. However, englitazone was discontinued due to its adverse effects on the liver. Conversely, pioglitazone was described to be safe on the hepatic system. Meanwhile, rosiglitazone and darglitazone developed by Smithkline and Pfizer. However, darglitazone was terminated in the year 1999. Reports in 2001 revealed that rosiglitazone had shown to cause heart failure due to fluid retention and was first restricted by Food and Drug Administration (FDA) in 2010, later on in 2013 in a trial, it fails to show any effect on heart attack, and therefore restriction was removed by FDA (Fig. 1). The structure of various clinically reported TZDs is shown in Fig. 2 [11–13] and the studies, which were carried out in diabetic patients are presented in Table 1 [14–61]. Structure and biological functions of PPAR-c in diabetes Peroxisome proliferator-activated receptors (PPARs) are the transducer proteins belonging to the superfamily of steroid/thyroid/retinoid receptors, which is involved in many processes when activated by a specific ligand. These receptors were recognized in the 1990s in rodents. PPARs help in regulating the expression of various genes that are essential for lipid and glucose metabolism [62,63]. The structure of PPAR consists of four domains, namely A/B, C, D and E/F (Fig. 3A). The NH2-terminal A/B domain consists of ligandindependent activation function 1 (AF-1) liable for the phosphorylation of PPAR. The C domain is the DNA binding domain (DBD) having 2-zinc atoms responsible for the binding of PPAR to the peroxisome proliferator response element (PPRE) in the promoter region of target genes. The D site is responsible for the modular union of the DNA receptor and its corepressors. The E/F domain is the ligand-binding domain (LBD) consists of the AF-2 region used to heterodimerize with retinoid X receptor (RXR), thereby regulating the gene expression [64,65]. There are three major isoforms of PPAR: PPAR-a, PPAR-d/b, and PPAR-c. Their distribution in tissues, biological functions, and their agonists are shown in Table 2 [62–65]. G. Bansal et al. / Journal of Advanced Research 23 (2020) 163–205 FDA approval of troglitazone (1988) Ciglitazone (1980s) Troglitazone withdrawn (2000) FDA approves rosiglitazone & pioglitazone (1999) FDA restricts rosiglitazone (2010) Rosiglitazone cause heart failure but pioglitazone is protective (2007) 165 Rosiglitazone restriction remove (2013) Pioglitazone prevents diabetes (2011) Fig. 1. The history of TZDs (modified and). adapted from [13]. Fig. 2. Chemical structures of clinically used thiazolidine-2, 4-dione compounds (structures are original and made by using chem draw ultra 12.0). Effects of TZDs on PPAR-c molecular pathways involved in diabetes The efficacy of PPAR-c agonists in the management of insulin resistance and T2DM has been confirmed by a number of important experimental assays with TZDs [62]. TZDs act as the selective agonists of PPAR-c. PPARs regulate the gene transcription by two mechanisms: transactivation (DNA dependent) and transrepression (DNA independent) [65]. In transactivation, when TZDs bind to PPAR-c, it gets activated and binds to 9-cis RXR, thereby forming a heterodimer [66]. This causes the binding of PPAR-c-RXR complex to PPRE in target genes, which further regulates the genetic transcription and translation of various proteins that are indulged in cellular differentiation and glucose and lipid metabolism [67]. In transrepression, PPARs negatively interact with other signaltransduction pathways, such as nuclear factor kappa beta (NFjB) pathway that controls many genes involved in inflammation, 166 Table 1 Efficacy of TZDs in diabetes in clinical trials. Clinical Trial No. Population Size Status Interventions Phase End Point Reference NCT00396227 2665 Completed 1. Vildagliptin add- on to metformin 2. TZD (pioglitazone, rosiglitazone) add on to metformin Phase 3 [14] NCT02653209 600 Undergoing 1. Sitagliptin, 2. Canagliflozin 3. Pioglitazone Phase 4 NCT00743002 87 Completed 1. TT223 with Metformin and/or TZD 2. Placebo with Metformin and/or TZD Phase 2 NCT01026194 204 Completed 1. Placebo/Teneligliptin + pioglitazone 2. Teneligliptin/Teneligliptin + pioglitazone Phase 3 NCT00879970 1332 Terminated 1. 2. 3. 4. 5. Phase 4
Mean change in HbA(1c) was 0.68 ± 0.02% in the vildagliptin group and 0.57 ± 0.03% in the TZD group.
Body weight increased in the TZD group (0.33 ± 0.11 kg) and decreased in the vildagliptin group (0.58 ± 0.09 kg).
Adverse events were similar in both groups (vildagliptin: 39.5% and TZD: 36.3%).
HbA(1c) in obese patients (BMI > 30 kg/m2) was compared to non-obese patients.
Test the hypothesis that the patients with BMI > 30 kg/m2 respond well to pioglitazone, and less well to sitagliptin in comparison to non-obese patients or not.
On treatment HbA(1c) levels in patients with an eGFR < 90 mL/min/1.73 m2 compared to patients with an eGFR > 90 mL/min/1.73 m2.
Test the hypothesis that the patients with modestly reduced eGFR (60–90 mL/min/ 1.73 m2) respond poorly to canagliflozin, and well to sitagliptin in comparison to eGFR > 90 mL/min/1.73 m2 eGFR or not.
Prevalence of side effects: weight gain, hypoglycemia, edema, genital tract infection and discontinuation of therapy.
HbA(1c) therapy vs. predefined test of gender heterogeneity (i.e., Females are likely to show an improved response relative to males for pioglitazone).
The safety and tolerability of TT223 was evaluated at 1 mg, 2 mg and 3 mg.
The efficacy of TT223 was evaluated in terms of changes in HbA(1c) value, fasting glucose levels vs. placebo group.
Determining the pharmacokinetic parameter of TT223 in patients.
The changes in HbA(1c) were greater (0.9 ± 0.0%) in the teneligliptin group than that in the placebo group (0.2 ± 0.0%).
The change in FPG was greater in the teneligliptin group than that in the placebo group.
Cardiovascular outcome (MI, stroke or cardiovascular death) is more in the placebo than in the treatment groups [TZD arm (0.4%) than Vitamin D arm (0.3%)].
Hospitalization due to cancer is more in the placebo vs. Vitamin D arm. [26] [37] [48] G. Bansal et al. / Journal of Advanced Research 23 (2020) 163–205 Pioglitazone Rosiglitazone Placebo Vitamin D placebo Vitamin D [15] Table 1 (continued) Clinical Trial No. Population Size Status Interventions Phase End Point Reference NCT00676338 820 Completed 1. 2. 3. 4. 5. Phase 3 [57] NCT00683878 972 Completed 1. Dapagliflozin (5 mg) + TZD 2. Dapagliflozin (10 mg) + TZD 3. Placebo matching dapagliflozin + pioglitazone Phase 3 NCT01135394 134 Completed 1. Pioglitazone Phase 4 NCT00481429 12 Completed 1. Rosiglitazone 2. Diet control + metformin NA NCT00295633 565 Completed 1. Saxagliptin 2.5 mg + Pioglitazone 30 mg + Rosiglitazone 4 mg + Metformin 500–2500 mg 2. Saxagliptin 5 mg + Pioglitazone 30 mg + Rosiglitazone 4 mg + Metformin 500–2500 mg 3. Placebo + Pioglitazone + Rosiglitazone + Metformin Phase 3 NCT00308373 73 Completed 1. Metformin 2. Pioglitazone NA NCT01055223 98,483 Completed 1. TZD only (rosiglitazone or pioglitazone or troglitazone) 2. TZD + spironolactone 3. TZD + amiloride NA
Exenatide was non-inferior to metformin but superior to sitagliptin, and pioglitazone with regard to HbA(1c) reduction.
Exenatide and metformin provided similar improvements in glycemic control along with the benefit of weight reduction and no increased risk of hypoglycemia.
Weight gain was observed in the pioglitazone group.
The mean reduction in HbA(1c) was higher for arm 1 and 2 groups (0.82 and 0.97%) vs. placebo (0.42%).
Pioglitazone alone had greater weight gain (3 kg) than those receiving plus pioglitazone in combination with dapagliflozin (0.7–1.4 kg).
Events of genital infection were reported with dapagliflozin (8.6–9.2%).
Characterize the changes at the physiological, cellular and molecular levels after TZD treatment.
Define genes that are regulated by TZD response.
Identify the SNPs and haplotypes genes that are influenced by TZD.
Glycemic, lipoprotein profile, and weight were monitored.
The performance of baseline biochemical biomarkers (plasma and urine) in patients who respond to TZD therapy from those do not, through the changes in HbA(1c) at 12 weeks.
Changes in baseline levels of key biochemical markers.
Effect of treatment on various novel predictive biomarkers and markers of insulin sensitivity.
Mean changes from baseline HbA(1c) was more in saxagliptin (0.66% and 0.94% for 2.5 and 5 mg, respectively) than that in placebo group (0.30%).
Plasma glucose level was also significantly reduced in the saxagliptin group than that in the placebo group.
Hypoglycemic events were similar between groups.
Impact of TZD on the levels of cortisol.
Effect of TZD on breathing or sleepiness in patients with type 2 diabetes.
Impact on the fracture number/number of fracture of hand/foot/upper arm/wrist fracture and hip in both males and females after 6 and 12-months treatment. Exenatide (once weekly) Metformin Sitagliptin Pioglitazone Placebo [58] [60] [61] G. Bansal et al. / Journal of Advanced Research 23 (2020) 163–205 [59] [16] [17] (continued on next page) 167 168 Table 1 (continued) Clinical Trial No. Population Size Status Interventions Phase End Point Reference NCT00637273 514 Completed 1. 2. 3. 4. 5. Phase 3 [18] NCT00953498 40 Completed 1. Pioglitazone 2.Rosiglitazone Phase 4 NCT02315287 190 Recruiting 1.Metformin + Sitagliptin + Pioglitazone 2. Metformin + Sitagliptin + Lobeglitazone Phase 4
Greater reduction of HbA(1c) in exenatide (1.5%) than sitagliptin (0.9%) or pioglitazone (1.2%).
Weight loss was greater with exenatide (2.3 kg) than sitagliptin (1.5 kg) or pioglitazone (5.1 kg).
Major adverse events were nausea and diarrhea with exenatide and sitagliptin.
HDL from control subjects had significantly shown to reduce the inhibitory effect of oxidised LDL on vasodilatation (Emax = 77.6 ± 12.9 vs. 59.5 ± 7.7%), whereas HDL from type 2 diabetic patients had no effect (Emax = 52.4 ± 20.4 vs 57.2 ± 18.7%).
Change in the level of HbA(1c).
Changes in b-cell function and insulin resistance after 1-year treatment.
Changes in FBS after 5 and 12 months. NCT01147627 416 Completed 1. Exenatide injection 2. Mixed protamine zinc recombinant human Insulin Lispro 25R 3. Pioglitazone NA [21] NCT00700856 3371 Active, not recruiting 1. Metformin + pioglitazone 2. Metformin + sulphonylureas (glibenclamide or gliclazide glimepiride) Phase 4 NCT00329225 630 Completed 1. Rosiglitazone Phase 4 NCT03646292 60 Not yet recruiting 1. Pioglitazone 2. Empagliflozin 3. Pioglitazone + empagliflozin Phase 4 NCT02426294 154 Recruiting 1. Pioglitazone 2. Glimepiride Phase 4 NCT00333723 245 Completed 1. Rosiglitazone Phase 4
Changes in baseline value of HbA(1c) after 48-weeks
Percentage of patients achieving HbA(1c) (<6.5–7) and effect on fasting and postprandial plasma glucose concentration, blood pressure, lipid profiles.
Safety and tolerability in various groups.
Hypoglycemia occurred less in the pioglitazone group (10%) than in the sulfonylurea group (34%).
Moderate weight gain (<2 kg) occurred in both groups.
Rate of adverse events such as heart failure, bladder cancer, and fractures was similar in both groups.
The decrease in HbA(1c), C-reactive protein, fibrinogen and matrix metalloproteinase 9 levels upon addition of rosiglitazone to insulin.
Adverse events were mild to moderate.
Changes in liver fat through MRI-PDFF and liver fibrosis through MRE.
Changes in lipid profile, liver enzyme, glucose metabolism and inflammation status (CRP) were monitored.
Evidence of efficacy of glycemic control by HbA(1c).
Changes in insulin resistance by HOMA and lipid profile from baseline value after 26-weeks treatment.
Efficacy of rosiglitazone combined with glyburide to glyburide monotherapy upon FPG, c-peptide, HOMA and in reducing HbA(1c) after 24-weeks of the treatment period. Exenatide (once weekly) Sitagliptin Pioglitazone Placebo tablet Placebo once weekly [19] [20] [23] [24] [25] [27] G. Bansal et al. / Journal of Advanced Research 23 (2020) 163–205 [22] Table 1 (continued) Population Size Status Interventions Phase End Point Reference NCT02954692 111 Completed Phase 4
Changes from baseline in the levels of HbA (1c), SMBG, FPG and DTSQ scores at 12 and 24weeks.
Percentage of patients reaching targeted fasting SMBG (80–130 mg/dL) at 12 and 24weeks. [28] NCT02475499 886,172 Completed NA
Number of increased risk of pancreatic cancer was measured while using incretin-based drugs in comparison with sulfonylureas. [29] NCT01030679 214 Completed 1. 2. 3. 4. 5. 6. 7. 8. 9. 1. 2. 3. 4. 5. 6. 7. 1. 2. Phase 2 [30] NCT01593371 98 Completed 1. Metformin 2. Pioglitazone NA NCT01223196 29 Completed 1. Pioglitazone 2. Placebo Phase 4 NCT00367055 84 Completed 1. Rosiglitazone + metformin 2. Metformin 3. Metformin + gliclazide Phase 4
Changes from baseline in the levels of FPG, glycemic and lipid parameters at 8-weeks.
Profiling of adverse events at 8-weeks.
No changes in BMI while using pioglitazone and metformin.
Improvements in glycemia and insulin resistance.
Increase in chemerin levels.
Indices of glycemic control and insulin resistance were significantly improved by both groups after 3-months.
Both treatments are equally effective in reducing chemerin concentrations, a novel member of the adipokine family.
Did not alter waist circumference, weight or BMI by both drugs.
Improvements in glycaemic control, b-cell function and inflammatory indices (MCP-1, IL6, FRK, hsCRP, and PAI) at low-dose of pioglitazone (15 mg/day) in obese patients with type 2 diabetes.
Adiponectin levels and TACE enzymatic activity is significantly decreased by pioglitazone than in the placebo group.
Changes from baseline in the insulin secretory capacity, insulin resistance index (HOMA-IR) and b-cell function index (HOMAbeta)
Changes from baseline in HbA(1c), FBG, CPP total and incremental AUC and
Changes from baseline in CPP concentration peak and incremental concentration peak at the month of 36. Insulin glargine Metformin Sulfonylurea Meglitinides TZDs a-glucosidase inhibitors GLP1 receptor agonist DPP-4 inhibitors SGLT-2 inhibitors DPP-4 inhibitors GLP-1 analogs Sulfonylureas Biguanides TZDs a-glucosidase inhibitors Meglitinides CKD-501 (Lobeglitazone) (0.5, 1 and 2 mg) Placebo [31] [32] G. Bansal et al. / Journal of Advanced Research 23 (2020) 163–205 Clinical Trial No. [33] (continued on next page) 169 170 Table 1 (continued) Population Size Status Interventions Phase End Point Reference NCT02476760 1,417,914 Completed NA
No signs of acute pancreatitis while using incretin-based as compared to other oral antidiabetic drugs. [34] NCT01468181 394 Completed Phase 3
Percentage of participants with TEAE and hypoglycemic episodes from baseline to 52weeks.
Changes from baseline in HbA(1c), FBG, SMBG, body weight, and HOMA2. [35] NCT02027103 102 Completed 1. DPP-4 inhibitors 2. GLP-1analogs 3. Insulin 4. Biguanides 5. Sulfonylureas 6. TZDs 7. a-glucosidase inhibitors 8. Meglitinides 1. LY2189265 (Dulaglutide) 2. Sulfonylureas 3. Biguanides 4. a-glucosidase inhibitor 5. TZD 6. Glinides 1.Metformin 2. Pioglitazone NA [36] NCT02887625 410 NA 1. Pioglitazone + exenatide 2. Insulin glargine 3. Insulin Aspart NA NCT00373178 100 Completed 1. Rosiglitazone 2. Metformin 3. Antidiabetic medications Phase 4 NCT01777282 374 Completed 1. Albiglutide + Sulfonylurea 2. Albiglutide + Biguanide 3. Albiglutide + Glinide 4. Albiglutide + TZD 5. Albiglutide + a-glucosidase inhibitor Phase 3 NCT00225225 45 Terminated 1. Rosiglitazone 2. Rosiglitazone + dietary recommendation for weight maintenance NA
Both medications were equally effective in reducing FBG, HbA(1c), fetuin-A and osteoprotegerin levels in both diabetic women and men.
A great decrease in HbA(1c) (6.1 ± 0.1% or 43 ± 0.7 mmol/mol) by combination therapy as compared to insulin therapy (7.1 ± 0.1% or 54 ± 0.8 mmol/mol).
More weight gain and a higher rate of hypoglycemia in insulin therapy than in the combination therapy.
Similar improvement in glycemic profile and apelin levels, whereas lipid parameters, fat mass, and visfatin remained almost unaffected by both rosiglitazone and metformin.
Significant improvement in plasma ghrelin level and reduction in HOMA-IR, hs-CRP and systolic blood pressure from baseline values in the rosiglitazone group than in the metformin group.
Improvement in cardiovascular risk profile.
Common adverse effects were nasopharyngitis (32.6%), constipation (7.2%), and diabetic retinopathy (5.3%).
Hypoglycemia occurred in 6.4% of patients in the first and third groups.
More reduction from baseline in HbA(1c) was observed when albiglutide added to TZD than in the other groups, whereas, reductions in FBG levels were observed in all groups.
The slight increase from baseline in body weight was observed with the addition of albiglutide to TZD.
Change in weight from 270 +/ 54 lbs to 244 +/ 61 lbs was observed with a low-calorie diet and behavioral modification in patients treated with TZDs and is associated with glycemic and blood pressure control. [38] [39] [40] [41] G. Bansal et al. / Journal of Advanced Research 23 (2020) 163–205 Clinical Trial No. Table 1 (continued) Clinical Trial No. Population Size Status Interventions Phase End Point Reference NCT00482183 38 Completed 1. Pioglitazone 2. Sirolimus-eluting stent Phase 3 [42] NCT02285205 38 Completed Lobeglitazone Phase 4 NCT00123643 36 Completed 1. Rosiglitazone 2. Glyburide Phase 4 NCT02365233 5 Terminated Phase 4 NCT00575471 250 Completed 1. 2. 3. 1. 2.
No significant differences in glycemic control levels, lipid levels, and restenosis.
The HOMA-IR was significantly lowered and the incidence of major adverse cardiac events tended to be lower in the pioglitazone than in the sirolimus group after 1-yr therapy.
Significant decrease in controlled attenuation parameter values (313.4 dB/m at baseline vs. 297.8 dB/m) at 24-weeks.
Improvements in HbA(1c) values (6.56%), as well as the lipid and liver profiles and reduction in intrahepatic fat content, was observed in the treated patients.
Changes from baseline on flow-mediated dilation as a measure of endothelial function after 6-months of treatment.
Change in hepatic lipid content from baseline to 6-month follow up. [46] NCT02456428 1,499,650 Completed
Change in HbA(1c) and FPG from baseline for rivoglitazone as compared to placebo at 12weeks.
The rate of hospitalization for heart failure did not increase with the use of incretin-based drugs as compared with oral antidiabetic-drug combinations among patients with heart failure. NCT00819325 50 Completed NCT00994682 176 NCT02730377 1994 Phase 2 1. DPP4 inhibitor 2. GLP-1 analogs 3. Insulins 4. Biguanides 5. Sulfonylureas 6. TZDs 7. a-glucosidase inhibitors 8. Meglitinides 1. Pioglitazone + Oral hypoglycemic agents (sulfonylurea or metformin) 2. Oral hypoglycemic agents NA Completed 1. Pioglitazone study drug 2. Placebo 3. Pioglitazone open label Phase 4 Active, not recruiting 1. Liraglutide add on to metformin 2. Oral antidiabetics (a-glucosidase inhibitors+ DPP4 inhibitor + Meglitinides + SGLT2 inhibitor + Sulphonylurea + TZDs) + metformin Phase 4 Phase 4
Change in 3D-neointimal plaque volume at 6months compared to baseline.
Change in the 2D-neointimal area within the stent at 6-months compared to baseline.
Pioglitazone treatment caused a significant improvement in individual fibrosis score (0.5); reduced hepatic triglyceride content (7%) and improved adipose tissue, hepatic, and muscle insulin sensitivity.
The resolution of NASH was observed a greater number of patients treated with active drug treatment.
The rate of adverse events was similar between the groups, although weight gain was more in the pioglitazone group.
A number of subjects who achieve HbA(1c) below or equal to 6.5% (48 mmol/mol).
A number of subjects who achieve HbA(1c) below or equal to 7.0% (53 mmol/mol) without weight gain.
Changes from baseline in FPG and body weight gain. [44] [45] [47] [49] [50] G. Bansal et al. / Journal of Advanced Research 23 (2020) 163–205 DPP4inhibitor Pioglitazone Lantus insulin Rivoglitazone HCl (0.5, 1 and 1.5 mg) Placebo [43] [51] (continued on next page) 171 172 Table 1 (continued) Clinical Trial No. Population Size Status Interventions Phase End Point Reference NCT00006305 2368 Completed 1, 2. Revascularization with intensive medical therapy (1. Insulin, sulfonylurea; 2. Biguanides, TZDs) along with ACEIs, ARBs, beta-blockers and CCBs) 3, 4. Intensive medical therapy with delayed revascularization (3. Insulin, sulfonylurea, and 4. Biguanides, TZDs) along with ACEIs, ARBs, beta-blockers and CCBs. Phase 3 [57] NCT00575874 150 Completed 1, 2 and 3. Rivoglitazone HCl (0.5, 1.0, and 1.5 mg, respectively) 4. Pioglitazone HCl 5. Placebo Phase 2 NCT00549874 27 Completed 1. Rosiglitazone 2. Glyburide NA NCT02231021 216 Completed 1. Alogliptin 2. Pioglitazone 3. Alogliptin + pioglitazone Phase 4 NCT01001611 173 Completed 1. CKD-501 (Lobeglitazone) (0.5 mg) 2. Placebo Phase 3
The baseline health status was improved significantly at 1-year in the treatment group.
Compared with medical therapy, revascularization was associated with significant improvement in the Duke Activity Status Index and was maintained over a 4-year follow-up.
Duke Activity Status Index was significantly larger in the patients intended for coronary artery bypass surgery than in the patients intended for percutaneous coronary intervention.
Change from baseline in HbA(1c) for rivoglitazone HCl vs. placebo.
Change from baseline in FPG for rivoglitazone HCl vs. placebo.
Change from baseline in HbA(1c) for pioglitazone HCl.
Rosiglitazone significantly reduced plasma nitrotyrosine, hs-CRP, and von Willebrand antigen and significantly increased plasma adiponectin but no significant changes in these parameters were observed with glyburide.
Significant deterioration in both resting and stress myocardial blood flow in the glyburide group but not in the rosiglitazone group.
Change from baseline in HbA(1c), glycated albumin, GA/HbA(1c) ratio, FPG, HOMA-IR, PAI, hs-CRP, BNP, TC, and TGs.
Incidence of hyperglycemia rescue.
Proportion of subjects achieving HbA (1c) < 7.0 and 6.5%.
A number of hypoglycemic event rates.
A number of subjects with adverse events of special interest.
HbA(1c) < 7% was achieved significantly more in the lobeglitazone group.
Lobeglitazone treatment significantly improved markers of insulin resistance, TGs, HDL cholesterol, small dense LDL cholesterol, FFA, and apolipoprotein B/CIII levels.
More weight gain was in the lobeglitazone group than in the placebo. [53] [55] [56] ACEI: angiotensin-converting-enzyme inhibitor; ARB: angiotensin receptor blocker; AUC: area under curve; BMI: body mass index; BNP: brain natriuretic peptide; CCBs: calcium channel blocker; CPP: cerebral perfusion pressure; DTSQ: diabetes treatment satisfaction questionnaire; DPP: dipeptidyl peptidase; eGFR: estimated glomerular filtration rate; FBG: fasting blood glucose; FBS: fasting blood sugar; FPG: fasting plasma glucose; FRK: fractalkine; FFA: free fatty acid; GLP-1: glucagon-like peptide 1; GA: glycated albumin; HbA(1c): glycated hemoglobin; HDL: high-density lipoproteins; hs-CRP: high sensitivity C-reactive protein; HOMA: homeostatic model assessment; IR: insulin resistance; IL: interleukin; LDL: low-density lipoproteins; MRE: magnetic resonance elastography; MRF: magnetic resonance fingerprinting; MRI-PDFF: magnetic resonance imaging proton density fat fraction; MCP-1: monocyte chemoattractant protein-1; MI: myocardial infarction; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; NA: not applicable; PAI: plasminogen activator inhibitor; SMBG: self-monitoring of blood glucose; SNPs: single nucleotide polymorphisms; SGLT-2: sodium-glucose cotransporter-2; TC: total cholesterol; TACE: trans arterial chemoembolization; TEAE: treatment-emergent adverse events; TGs: triglycerides. G. Bansal et al. / Journal of Advanced Research 23 (2020) 163–205 [54]