|Year : 2019 | Volume
| Issue : 2 | Page : 76-82
Comparison of efficacy of add-on therapy of teneligliptin versus pioglitazone among type 2 diabetes mellitus patients ineptly controlled on dual therapy of metformin plus sulfonylurea
Vanjari Nikhil Kumar1, Sandeep Reddy Konyala1, Siva Subrahmanyam Bandaru2, Goverdhan Puchchakayala1
1 Department of Clinical Pharmacy, Vaagdevi College of Pharmacy, Hanamkonda, Telangana, India
2 Sri Bhadrakali Diabetes Care Centre, Consultant Physician and Diabetologist, Warangal, Telangana, India
|Date of Web Publication||26-Apr-2019|
Dr. Vanjari Nikhil Kumar
Department of Clinical Pharmacy, Vaagdevi College of Pharmacy, Hanamkonda, Warangal - 506 002, Telangana
Source of Support: None, Conflict of Interest: None
Aim: The main aim of the study is to compare the efficacy of add-on therapy of teneligliptin (20 once daily) versus pioglitazone (15 mg once daily) among type 2 diabetes mellitus (T2DM) patients inadequately controlled on dual therapy of metformin (MF) plus sulfonylurea (SU). Materials and Methods: It is a prospective, observational, comparative study conducted in patients from the outpatient department of Sri Bhadrakali Hospital located at Warangal, Telangana state, India. The efficacy of pioglitazone and teneligliptin was assessed by measuring the change in the glycated haemoglobin (HbA1c), Fasting Plasma Glucose (FPG), Post Prandial Blood Glucose (PPBH) levels after 12 weeks of treatment. FPG, PPBG and HbA1c levels at baseline and 12 weeks. The primary endpoint was changed in HbA1c levels at 12 weeks as compared to the baseline levels in both groups. The secondary endpoints were changes in FPG, PPBG levels at 12 weeks as compared to baseline levels. Along with, serum cholesterol, triglycerides (TG), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels were measured both at baseline and after 12 weeks. Results: At study end, HbA1c levels were reduced from baseline by 0.7% (P = 0.0049) in the pioglitazone group and 1% (P = 0.0002) in the teneligliptin group. The mean changes in FPG levels from baseline to week 12 were −39.8 mg/dl (P ≤ 0.0001) in teneligliptin and −11.48 mg/dl (P = 0.00380) in pioglitazone group. The mean PPG levels from −47.8 mg/dl (P = 0.0003) in teneligliptin and −25.5 mg/dl (P = 0015) in pioglitazone group. After 12 weeks of study, the levels of TG, total cholesterol (TC), LDL −71.5 (P = 0.0973), −15 (P = 0.0501), 18.8 (P ≤ 0.0008) mg/dl and −31.38 (P ≤ 0.0001), −21 (P ≤ 0.0001), −11.68 (P = 0.0028) mg/dl in teneligliptin group and pioglitazone group, respectively. There was significant increase in HDL levels 5.3 (P ≤ 0.0001) mg/dl in teneligliptin group and 5.2 (P = 0.0001) mg/dl in pioglitazone group. Conclusion: Both teneligliptin 20 mg and Pioglitazone 15 mg provided additional HbA1c lowering to that achieved with MF and SU. Teneligliptin showed more effective reductions in HbA1c, FPG, PPBG, HDL and LDL levels. Pioglitazone showed significant changes in HbA1c, HDL, TC, triglyceride levels and significant changes in FPG, PPBG and LDL levels. Reduction in HbA1c and plasma lipids slows down the diabetes progression and decreases the risk of microvascular and macrovascular complications.
Keywords: Dipeptidyl peptidase 4 inhibitors, thiazolidinedione, glycated haemoglobin, glycaemic control, lipid profile, peroxisome proliferator-activated receptors, type 2 diabetes mellitus
|How to cite this article:|
Kumar VN, Konyala SR, Bandaru SS, Puchchakayala G. Comparison of efficacy of add-on therapy of teneligliptin versus pioglitazone among type 2 diabetes mellitus patients ineptly controlled on dual therapy of metformin plus sulfonylurea. J Diabetol 2019;10:76-82
|How to cite this URL:|
Kumar VN, Konyala SR, Bandaru SS, Puchchakayala G. Comparison of efficacy of add-on therapy of teneligliptin versus pioglitazone among type 2 diabetes mellitus patients ineptly controlled on dual therapy of metformin plus sulfonylurea. J Diabetol [serial online] 2019 [cited 2021 Nov 28];10:76-82. Available from: https://www.journalofdiabetology.org/text.asp?2019/10/2/76/257208
| Introduction|| |
The population of diabetes is increasing due to the growth of population, urbanisation, ageing and increasing prevalence of obesity and torpidity. In 2013, 382 million people throughout the world had diabetes, and it is expected to rise to 592 million by 2035. With the discovery of new pathophysiology associated with diabetes, patients are gaining access to newer therapeutic classes of drugs. The overall goal in the management of diabetes mellitus is the prevention of complications and improvement in the individual's quality of life.
In conjunction with lifestyle interventions, the use of metformin (MF) as a first-line treatment for type 2 diabetes is well established. However, when additional treatment is required to achieve or maintain glycosylated haemoglobin (HbA1c) levels at <7%, the update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes recommends concomitant treatment with sulfonylurea (SU), a thiazolidinedione (TZD), a dipeptidyl peptidase 4 (DPP-4) inhibitor, a sodium/glucose cotransporter 2 inhibitor, a Glucagon-like peptide-1 receptor agonist or insulin.
Glycaemic control is enhanced following the addition of SUs to MF, but deterioration resumes as early as 6 months. The high proportion of patients remaining on MF plus SU therapy despite having HbA1c ≥8% suggests that there are significant barriers to starting insulin or adding a third agent when treatment goals are not achieved with this combination.
Teneligliptin has been shown to produce clinically significant improvements in HbA1c, fasting plasma glucose (FPG) and postprandial glucose levels in patients with Type 2 Diabetes Mellitus (T2DM), both alone and in combination with other oral anti-hyperglycaemic drugs.,, Elderly patients with T2DM, including those with cardiac complications, teneligliptin may show benefit in improving vascular endothelial function within 2 weeks of administration. Fluctuations in blood glucose levels have been shown to cause oxidative stress and induce inflammatory markers leading to endothelial dysfunction and arteriosclerosis. There is also evidence that the postprandial glycemic state contributes to atherosclerotic risk. Pleiotropic effects of teneligliptin such as those on endothelial function and metabolic syndrome are currently of particular interest because skeletal muscle insulin resistance may be caused by impaired insulin signalling not only in myocytes but also in endothelial cells.
The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptors superfamily, and there are three subtypes currently identified, PPAR α, PPAR γ and PPARβ, which play a significant role in lipid metabolism. TZDs lower fasting and postprandial insulin and glucose plasma concentrations, increase glucose uptake in peripheral tissues and reduce free fatty acid levels. Pioglitazone has been shown to increase high-density lipoprotein (HDL)-C and to reduce triglycerides (TG) more than rosiglitazone, which may be due to its greater PPAR binding affinity. PPARs can also bind fibrates, which are drugs that exhibit a great triglyceride-lowering effect. Microalbuminuria is an important predictor of cardiovascular disease in patients with type 2 diabetes. TZDs prevent hypertension in angiotensin II-infused rats and abrogate the structural, functional and molecular changes induced by angiotensin II in blood vessels, leading to inhibition of cell growth and inflammation. In addition, they reduce microalbuminuria, which is a manifestation of early nephropathy in diabetic patients., Pioglitazone, as monotherapy or combined with an SU, reduced the ratio of urinary albumin to creatinine compared with MF. The incidence of weight gain is greater when TZDs are used in combination with insulin and lower when it is co-administered with MF, SU or used as monotherapy. Various fatty acids and natural eicosanoids serve as endogenous ligands for PPARs, whereas fibrates and TZDs are potent synthetic ligands affecting lipid and glucose metabolism.
Diabetes greatly increases the risk of cardiovascular disease and mortality, and microvascular complications such as retinopathy, nephropathy and neuropathy strongly affect the quality of life of affected patients. The HbA1c level, which provides an indication of the average glucose level over a long period, is an established treatment target in diabetes. Comparative evidence is required to guide appropriate therapy to attain adequate control and prevent complications of diabetes.
| Materials and Methods|| |
It is a prospective, observational, comparative study conducted in patients from Sri Badrakali Hospital located at Warangal, Telangana state.
Patients with T2DM, age >30 and <70 years of either gender, taking a combination of MF + SUs (Glimiperide or Gliclazide or Glipizide or Glibenclamide) for at least 3 months with uncontrolled hyperglycemia, i.e., HbA1c >7% ≤11%, abnormal plasma lipids and body mass index (BMI) >23 kg/m2.
Pregnant and lactating females, patients on insulin therapy, history of type 1 DM, signs of diabetic complications (nephropathy, neuropathy and retinopathy) and patients with clinical signs and symptoms of acute myocardial infarction, liver failure, chronic heart failure and renal failure were excluded from the study.
It is a prospective, observational, comparative study design, measuring the changes from primary end-point to the secondary end-point for each diabetic patient in 2017 and the included are on Oral Hypoglycemic Agents taking a combination of MF + sulphonylureas. The goal was to achieve glycemic control by addition of pioglitazone 15 mg to one group and teneligliptin 20 mg to the other group.
Of the initial 157 patients who were recruited, 26 were excluded, 131 patients during the 12-week treatment follow-up period, either teneligliptin 20 mg once daily or pioglitazone 15 mg once daily as an add-on treatment to inadequately controlled T2DM patients on dual therapy of MF + SU.
Clinical response assessment
The efficacy of pioglitazone and teneligliptin was assessed by measuring the change in the HbA1c, FPG, Post Prandial Blood Glucose levels after 12 weeks of treatment. FPG, PPBG and HbA1c levels at baseline and 12 weeks. Clinical characteristics of both Teneligliptin and Pioglitazone are given in [Table 1] and [Table 2] respectively.
|Table 1: Effects of teneligliptin 20 mg with metformin plus sulfonylurea|
Click here to view
The primary endpoint was changes in HbA1c levels at 12 weeks as compared to the baseline levels in both the groups.
The secondary endpoints were changes in FPG, PPBG levels at 12 weeks as compared to baseline levels.
Along with, Serum cholesterol, TG, HDL, low-density lipoprotein (LDL) levels were measured both at baseline and after 12 weeks.
All parameters were expressed as mean ± standard error (or standard deviation where indicated). Data analyses were performed using the GraphPad prism 7.0. An unpaired t-test was used to assess significant differences between values obtained before and 3 months after the addition of pioglitazone and teneligliptin. P < 0.0001 was considered statistically significant.
| Results|| |
The mean age for teneligliptin was 50.95 ± 10.15 (Group I: Males 32 and females 32).
Mean age for Pioglitazone was 53.92 ± 9.73 (Group II: Males 39 and females 28) [Figure 1].
Changes in glycosylated haemoglobin levels
The mean HbA1c levels at the beginning of the study were 8.81% ±1.4% and 9.2 ± 1.45 in teneligliptin and Pioglitazone respectively. At study end, HbA1c levels were reduced from baseline by 1% (P = 0.0002) in the teneligliptin group and 0.7% (P = 0.0049) in the Pioglitazone group [Figure 2].
The mean changes in FBG levels from baseline to week 12 were −39.8 mg/dl (P ≤ 0.0001) in teneligliptin and −11.48 mg/dl (P = 0.00380) in pioglitazone group.
The mean PPBG levels from −47.8 mg/dl (P = 0.0003) in teneligliptin and −25.5 mg/dl (P = 0015) in pioglitazone group [Figure 3].
The fasting triglyceride, total cholesterol, LDL levels averaged 189.87 ± 118.34, 187.25 ± 46.39, 114.17 ± 33.1 mg/dl and 200.24 ± 33.53, 191.49 ± 26.76, 115.88 ± 22.13 in teneligliptin group and pioglitazone group, respectively [Figure 4].
After 12 weeks of study, the levels of TG, TC, LDL −71.5(P = 0.0973), −15(P = 0.0501), 18.8 (P ≤ 0.0008) mg/dl and −31.38 (P ≤ 0.0001), −21 (P ≤ 0.0001), −11.68 (P = 0.0028) mg/dl in teneligliptin group and pioglitazone group, respectively [Figure 4].
There was the significant increase in HDL levels 5.3 (P ≤ 0.0001) mg/dl in teneligliptin group and 5.2 (P = 0.0001) mg/dl in pioglitazone group were observed [Figure 5].
The mean changes in body weight from baseline to week 12 were −0.5 kg (P = 0.4368) in teneligliptin group and 1.0 kg P = 0.0807) in pioglitazone group, which were significantly different from each other.
| Discussion|| |
We evaluated two different add-on therapies among patients having inadequately controlled T2DM even after treatment with dual therapy of MF and SU. Add-on therapy with teneligliptin and pioglitazone provided a significant reduction in HbA1c, FPG, 2-h PPG and significant changes in Lipid profile.
In this study, the addition of teneligliptin to MF and SU therapy for 12 weeks provided a greater reduction in HbA1c (1%) relative to pioglitazone (0.7%).
Kim et al., 2015 show that as an add-on treatment to MF, DPP-4 inhibitors (vildagliptin) is as effective and well-tolerated as TZD (pioglitazone) and also has beneficial effects on PPG levels, lipid profiles and body weight. As add-on therapy to MF, mean HbA1c levels were significantly reduced from baseline (by 0.87% at 16 weeks; P < 0.0001) in the teneligliptin group.
The findings of our study in mean changes of FPG and PPBG levels from baseline to week 12 were −39.8 mg/dl and −47.8 mg/dl in teneligliptin are in agreement with that of the study conducted by Kadowaki et al., which identified that, In combination with glimepiride, teneligliptin significantly improved glycaemic control at 12 weeks. The mean changes in HbA1c, FPG and 2-h PPG were −1.0 ± 0.1%, −27.1 ± 3.2 and −49.1 ± 6.2 mg/dl, respectively.
Previous studies have shown that TZDs, used as monotherapy, or in combination with either sulphonylureas, MF, or insulin,,, improve glycaemic control in T2DM. Better glycaemic control among diabetic patients may help in the prevention of dyslipidaemia. In the present study, pioglitazone showed remarkable mean changes in FBG and PPBG levels from baseline to week 12 were −11.48 mg/dl −25.5 mg/dl.
At 12 weeks, teneligliptin significantly improved lipid control significant with mean changes of TC, TG, LDL −15, −71.5, −18.8 mg/dl and increase in in HDL levels (5.3 mg/dl). These data are supported by a 14-week study on treatment with teneligliptin 20 mg/day which showed significant improvement in lipids along with improvement in blood glucose and HbA1c. The baseline values of Total cholesterol, TG, LDL, HDL were 196 ± 43, 189 ± 140, 122 ± 43, 55 ± 15 and after 14 weeks of administration were 174 ± 29, 114 ± 44, 103 ± 29, 62 ± 16.
The data from a study provide strong indication that, when added to MF, pioglitazone provides good sustainability of glycaemic control in terms of insulin processing and the modulation of unique dyslipidaemia associated with type 2 diabetes. Pioglitazone in our study showed a notable decrease in the levels of TG, TC, LDL −31.38, −21, −11.68 mg/dl and increase in HDL levels 5.2 mg/dl.
The mean changes in BMI from baseline to week 12 were −0.5 kg in teneligliptin group and +1.0 kg in pioglitazone group, which were significantly different from each other. Weight gain observed in the present study may be attributed to increased adipocyte differentiation,, fluid retention,, or increased appetite. Improved glycaemic control, despite weight gain, has been reported with TZDs.,,, TZDs associated weight gain is due to increased subcutaneous fat and a simultaneous decrease in visceral abdominal fat.
Randomized controlled trials (RCTs) cogitate a high profile evidence in clinical medicine. But often results from RCTs are not engrossed in real-world clinical practice. Real-world evidence contributes RCT data and feeds clinical efficacy of a drug. This Prospective, Comparative study has certain limitations. Because of the observational design of the study, the possibility of selection bias cannot be ruled out. Information related to diet and lifestyle modification was not analysed. It is not possible to comment on dropouts and adverse events. Data were collected only for 3 months, so there are limitations in commenting on the durability of the treatment. Long-term studies to concentrate on the shortcomings of the present study are endorsed.
| Conclusion|| |
Both teneligliptin 20 mg and pioglitazone 15 mg provided additional HbA1c lowering to that achieved with MF and SU. Reduction in HbA1c and Plasma lipids slows down the Diabetes progression and decreases the risk of microvascular and macrovascular complications. The DPP-4 inhibitor teneligliptin is relatively new to the market and evidence of its long-term efficacy and usability will be beneficial. The main goal in this field is improved quality of life for diabetic patients. To achieve this, studies of longer duration designed to measure parameters other than glycaemic control are needed. Over the coming years, rates of obesity and associated T2DM will increase globally, with subsequent lowering of quality of life and increased complications and costs to healthcare systems. Therefore, there is a pressing need for treatments that are effective and well tolerated with long-term use.
The present study includes a small number of patients, and the duration of the study is short. Although the measurement of HbA1c levels after 12 weeks shows the glycaemic variability during this period. The results of the study show that both pioglitazone and teneligliptin provided additional HbA1c lowering and lipid control to that achieved with a combination of MF and SU.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014;103:137-49.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al
. Management of hyperglycemia in type 2 diabetes, 2015: A patient-centered approach: Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140-9.
Cook MN, Girman CJ, Stein PP, Alexander CM, Holman RR. Glycemic control continues to deteriorate after sulfonylureas are added to metformin among patients with type 2 diabetes. Diabetes Care 2005;28:995-1000.
Kadowaki T, Kondo K. Efficacy, safety and dose-response relationship of teneligliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus. Diabetes Obes Metab 2013;15:810-8.
Kadowaki T, Kondo K. Efficacy and safety of teneligliptin added to glimepiride in Japanese patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled study with an open-label, long-term extension. Diabetes Obes Metab 2014;16:418-25.
Kadowaki T, Kondo K. Efficacy and safety of teneligliptin in combination with pioglitazone in Japanese patients with type 2 diabetes mellitus. J Diabetes Investig 2013;4:576-84.
Takase B, Nagata M. Subacute effect of a novel dipeptidyl peptidase-4 inhibitor teneligliptin on endothelial function inhumans. J N Remedies Clin 2013;50:698-704.
Ceriello A. The post-prandial state and cardiovascular disease: Relevance to diabetes mellitus. Diabetes Metab Res Rev 2000;16:125-32.
Kubota T, Kubota N, Kumagai H, Yamaguchi S, Kozono H, Takahashi T, et al.
Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle. Cell Metab 2011;13:294-307.
Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: Nuclear control of metabolism. Endocr Rev 1999;20:649-88.
Miyazaki Y, Glass L, Triplitt C, Matsuda M, Cusi K, Mahankali A, et al.
Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in type II diabetic patients. Diabetologia 2001;44:2210-9.
van Wijk JP, de Koning EJ, Martens EP, Rabelink TJ. Thiazolidinediones and blood lipids in type 2 diabetes. Arterioscler Thromb Vasc Biol 2003;23:1744-9.
Mattock MB, Morrish NJ, Viberti G, Keen H, Fitzgerald AP, Jackson G, et al.
Prospective study of microalbuminuria as predictor of mortality in NIDDM. Diabetes 1992;41:736-41.
Diep QN, El Mabrouk M, Cohn JS, Endemann D, Amiri F, Virdis A, et al.
Structure, endothelial function, cell growth, and inflammation in blood vessels of angiotensin II-infused rats: Role of peroxisome proliferator-activated receptor-gamma. Circulation 2002;105:2296-302.
Buchanan TA, Meehan WP, Jeng YY, Yang D, Chan TM, Nadler JL, et al.
Blood pressure lowering by pioglitazone. Evidence for a direct vascular effect. J Clin Invest 1995;96:354-60.
Imano E, Kanda T, Nakatani Y, Nishida T, Arai K, Motomura M, et al.
Effect of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy. Diabetes Care 1998;21:2135-9.
Erdmann E. Microalbuminuria as a marker of cardiovascular risk in patients with type 2 diabetes. Int J Cardiol 2006;107:147-53.
Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, et al.
Thiazolidinedione use, fluid retention, and congestive heart failure: A consensus statement from the American Heart Association and American Diabetes Association. October 07, 2003. Circulation 2003;108:2941-8.
Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med 2002;53:409-35.
Kim JH, Kim SS, Baek HS, Lee IK, Chung DJ, Sohn HS, et al.
Comparison of vildagliptin and pioglitazone in Korean patients with type 2 diabetes inadequately controlled with metformin. Diabetes Metab J 2016;40:230-9.
Kim MK, Rhee EJ, Han KA, Woo AC, Lee MK, Ku BJ, et al.
Efficacy and safety of teneligliptin, a dipeptidyl peptidase-4 inhibitor, combined with metformin in Korean patients with type 2 diabetes mellitus: A 16-week, randomized, double-blind, placebo-controlled phase III trial. Diabetes Obes Metab 2015;17:309-12.
Mori Y, Murakawa Y, Okada K, Horikoshi H, Yokoyama J, Tajima N, et al.
Effect of troglitazone on body fat distribution in type 2 diabetic patients. Diabetes Care 1999;22:908-12.
Phillips LS, Grunberger G, Miller E, Patwardhan R, Rappaport EB, Salzman A, et al.
Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes. Diabetes Care 2001;24:308-15.
Horton ES, Whitehouse F, Ghazzi MN, Venable TC, Whitcomb RW. Troglitazone in combination with sulfonylurea restores glycemic control in patients with type 2 diabetes. The troglitazone study group. Diabetes Care 1998;21:1462-9.
Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: A randomized controlled trial. JAMA 2000;283:1695-702.
Rubin C, Egan J, Schneider R. Combination therapy with pioglitazone and insulin in patients with type 2 diabetes. Diabetes 1999;48:SA110.
Raskin P, Dole JF, Rappaport EB. Rosiglitazone (RSG) improves glycemic control in poorly controlled, insulin-treated type 2 diabetes (T2D). Diabetes 1999;48:SA94.
Yale JF, Valiquett TR, Ghazzi MN, Owens-Grillo JK, Whitcomb RW, Foyt HL, et al.
The effect of a thiazolidinedione drug, troglitazone, on glycemia in patients with type 2 diabetes mellitus poorly controlled with sulfonylurea and metformin. A multicenter, randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;134:737-45.
Kaithala C, Namburi HK, Bandaru SS, Bandaru SB, Adla N, Puchchakayala G. Prevalence of dyslipidemia and its association with glycemic control in Indian type 2 diabetes population. Rom J Diabetes Nutr Metab Dis 2016;23:277-83.
Kusunoki M, Sato D, Nakamura T, Oshida Y, Tsutsui H, Natsume Y, et al.
DPP-4 inhibitor teneligliptin improves insulin resistance and serum lipid profile in Japanese patients with type 2 diabetes. Drug Res (Stuttg) 2015;65:532-4.
Charbonnel B, Schernthaner G, Brunetti P, Matthews DR, Urquhart R, Tan MH, et al.
Long-term efficacy and tolerability of add-on pioglitazone therapy to failing monotherapy compared with addition of gliclazide or metformin in patients with type 2 diabetes. Diabetologia 2005;48:1093-104.
Day C. Thiazolidinediones: A new class of antidiabetic drugs. Diabet Med 1999;16:179-92.
Hallakou S, Doaré L, Foufelle F, Kergoat M, Guerre-Millo M, Berthault MF, et al.
Pioglitazone induces in vivo
adipocyte differentiation in the obese Zucker fa/fa rat. Diabetes 1997;46:1393-9.
Young MM, Squassante L, Wemer J, van Marle SP, Dogterom P, Jonkman JH, et al.
Troglitazone has no effect on red cell mass or other erythropoietic parameters. Eur J Clin Pharmacol 1999;55:101-4.
Shimizu H, Tsuchiya T, Sato N, Shimomura Y, Kobayashi I, Mori M, et al.
Troglitazone reduces plasma leptin concentration but increases hunger in NIDDM patients. Diabetes Care 1998;21:1470-4.
Patel J, Anderson RJ, Rappaport EB. Rosiglitazone monotherapy improves glycaemic control in patients with type 2 diabetes: A twelve-week, randomized, placebo-controlled study. Diabetes Obes Metab 1999;1:165-72.
Seidell JC, Hautvast JG, Deurenberg P. Overweight: Fat distribution and health risks. Epidemiological observations. A review. Infusionstherapie 1989;16:276-81.
Evans DJ, Hoffmann RG, Kalkhoff RK, Kissebah AH. Relationship of body fat topography to insulin sensitivity and metabolic profiles in premenopausal women. Metabolism 1984;33:68-75.
Kelly IE, Han TS, Walsh K, Lean ME. Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Diabetes Care 1999;22:288-93.
Silverman SL. From randomized controlled trials to observational studies. Am J Med 2009;122:114-20.
Sahay BK, Seshiah V. Importance of observational studies in understanding regional clinical practice: Rationale and design of the A1chieve study. J Assoc Physicians India 2013;61:6-8.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]