Abstract  Background: There is paucity of data on triple drug combination containing low dose (7.5 mg) pioglitazone in Indian type 2 diabetes patients (T2DM). Objective: Comparative evaluation of efficacy and safety of glimepiride, metformin (GM) plus low dose pioglitazone fixed dose combination (FDC) in T2DM. Material and methods: In this open label study, 75 insulin naïve T2DM subjects inadequately controlled on GM oral therapy were randomized into Group A: FDC of G 1mg + M 500 mg SR + Pioglitazone 7.5 mg; Group B: FDC of G 2mg + M 500 mg SR + Pioglitazone 7.5 mg or Group C: Insulin 70/30 Mix + M 500mg SR. The primary outcome measure was reduction in HbA1c at 180 days. The secondary end points included reduction in fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and change in lipid parameters and weight. Results: At baseline mean age, weight, HbA1c, body weight, FPG, PPG, C peptide level, LDL-C, triglyceride and HDL-C were similar in three groups.  All treatments resulted in significant reduction in mean HbA1c. At the end of 180 days, reduction in HbA1c was 1.49%, 1.51% and 1.11% in Group A, B and C respectively. The difference in HbA1c reduction between groups was not statistically significant. At the end of 180 days, the mean reduction in FPG was -66.72+27.12 mg/dl, -79.68+23.87 mg/dl and -69.60+25.34 mg/dl in Group A, B and C respectively. The difference in the reduction of FPG and PPG was not significant between the groups at day 30, 90 and 180. Significant reduction in LDL-C, TG and increase in HDL-C was observed in all groups without significant difference between the groups. No hypoglycemic episodes requiring hospitalization were observed in any group. Change in weight was comparable between groups. Conclusion: Metformin, glimepiride plus low dose pioglitazone FDC is equally efficacious and well tolerated compared to insulin plus metformin in uncontrolled T2DM. This combination may help in postponing insulin therapy.

Key words: Efficacy, glimepiride, metformin, pioglitazone, safety

 

 

Introduction

Type 2 Diabetes Mellitus (T2DM) is characterized by progressive deterioration in the functions of pancreatic β cells resulting in hyperglycemia, and subsequent complications.1 The treatment of type 2 diabetes mellitus is usually started with a single agent. However, secondary failure in type 2 diabetes is common.2 The secondary failure rate of sulfonylurea and metformin has been reported to be 5-7%3 and 12% per year respectively.4 In these patients, addition of drugs from other classes is required. Fixed-dose combinations simplify the need for oral combination therapy regimen.  Many studies have evaluated the safety and efficacy of triple oral therapy with combinations of a metformin, sulfonylurea and thiazolidinedione in T2DM patients.5-8  The triple drug combination has been shown to be effective in significantly reducing triglycerides, low-density lipoproteins and total cholesterol in addition to the primary effect of reducing blood sugar.6  Fixed dose combination (FDC) has also been shown to improve adherence in the management of diabetic patients.9 In India, triple drug combination of metformin, sulfonylureas and thiazolidinedione (pioglitazone 15 mg) is available since few years. Recently, triple drug FDC with low dose pioglitazone i.e. 7.5 mg has also been introduced. A study in Japanese women showed similar efficacy and better tolerated profile of low dose 7.5 mg pioglitazone compared to 15 mg pioglitazone.10 However, there is paucity of data with triple drug combination containing low dose (7.5 mg) pioglitazone.

Objective:

The objective of this study was to evaluate the efficacy and safety of triple drug FDC of glimepiride, metformin and low dose pioglitazone versus combination of insulin and metformin in T2DM patients who are inadequately controlled with dual therapy of metformin plus glimepiride.

Materials & Methods:

This randomized, open label, comparative study included 75 patients with type 2 diabetes from Madras Medical College, Chennai, India. The study was conducted according to the Declaration of Helsinki (Seoul, 2008), and the Indian GCP Guidelines after obtaining Ethics Committee approval. After written informed consent, the subjects were screened for the eligibility criteria. Adult subjects  >18 years of age with BMI 20 – 35 Kg/m2 and inadequately controlled [HbA1c > 8.0 % and HbA1c < 11 %] type 2 diabetes with glimepiride (up to 4 mg) and metformin 1000 mg in addition to nutrition and lifestyle modifications were enrolled in this study. All the patients were insulin naïve and previously received at least three months treatment with oral dual therapy of metformin and glimepiride with inadequate control of blood sugar levels.

Subjects with stroke, myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, angina pectoris within the last 12 months or urinary bladder cancer were not considered for inclusion in the study. Similarly, patients with cardiac status III-IV according to New York Heart Association (NYHA) classification and those with uncontrolled blood pressure were excluded from the study. Subjects with impaired renal function, clinically significant peripheral edema, acute infection, acute or chronic history of metabolic acidosis, clinical evidence of active liver disease, or serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 2.5 times the upper limit of the normal range were also excluded from the study.

The subjects were randomized into the three treatment groups (1:1:1) to receive either FDC of Glimepiride 1mg + Metformin 500 mg SR + Pioglitazone 7.5 mg (Group A), FDC of Glimepiride 2mg + Metformin 500 mg SR + Pioglitazone 7.5 mg (Group B)  or Insulin 70/30 Mix + Metformin 500mg SR (Group C). Post screening the subjects were followed up for four visits [Baseline visit (visit 1), visit 2 (day 30), visit 3(Day 90) and visit 4 at 180 days]. The duration of treatment was 180 days. The randomization was done using permuted block design. The subjects were given treatment according to the predetermined randomization schedule.

The primary efficacy parameter was reduction in HbA1c at day 180 compared to baseline. Similarly, reduction of fasting plasma glucose (FPG), postprandial plasma glucose (PPG), weight change, changes in lipid parameters, change in C peptide level were the secondary end points.

The safety was assessed by monitoring adverse events, vital signs, physical examination and clinically significant changes in laboratory parameters. Number of patient with hypoglycemic event was also noted as a part of safety assessment. The global assessment for efficacy and tolerability by investigator and patients was done at day 180.

Statistical analysis:

Descriptive statistics (mean, SD) is used to summarize the quantitative data. ANOVA was used to evaluate the difference in age, weight and height at baseline. Difference in HbA1c, FPG, PPG, C peptide level and laboratory parameters compared to baseline in each group was evaluated by using ANOVA with Bonferroni post hoc test. Similarly, ANOVA was also used to evaluate difference in the weight, HbA1c, laboratory parameters (C peptide level and lipid parameters) and FPG and PPG between three groups. P < 0.05 was considered as statistically significant.

Results:

Out of a total of 85 screened subjects, 75 subjects (M: 21.33%; F: 78.67%) between 20-68 years of age were enrolled in this study. The flow chart shows the number of patients and the process of the study (figure 1).

 

Figure 1: Flow chart of the study

 

 

 

 

At baseline, the mean age, weight and height were similar in three groups (ANOVA p>0.05; table 1). Percentage of male and female participants was not significantly different between three groups (Chi-square test P>0.05; table 1).  At baseline, mean HbA1c (table 2), body weight (table 3), FPG and PPG were also similar between three groups. The mean FPG at baseline in Group A, B and C was 181.76 ±  29.98 mg/dl, 181.24 ±  28.44 mg/dl and 184.92 ±  29.46 mg/dl respectively. The PPG level in three groups was 278.56 ±  38.86 mg/dl 277.92 ±  28.37 mg/dl and 290.32 ±  36.06 respectively. Baseline C peptide level, LDL-C, Triglyceride and HDL-C were comparable between three groups (table 4).

 

At the end of 30, 90 and 180 days, all three treatments resulted in significant reduction in mean HbA1c. Compared to baseline, the HbA1c reduction in group A and B was higher, but not significant compared to group C at the end of 30, 90 and 180 days. At the end of 180 days, the reduction in HbA1c was 1.49%, 1.51% and 1.11% in Group A, B and C respectively (Table 2). The reduction in mean FPG (Figure 2) and PPG (Figure 3) was significant at the end of 30, 90 and 180 days in all three groups compared to baseline. At the end of 180 days, the mean reduction in FPG was -66.72+27.12 mg/dl, -79.68+23.87 mg/dl and -69.60+25.34 mg/dl in Group A, B and C respectively. The difference in the reduction of FPG and PPG was not significant between the groups at day 30, 90 and 180. Compared to baseline, significant reduction in LDL-C, TG and increase in HDL-C was observed in all groups without significant difference between the groups (table 4).

All subjects had satisfactory to very good improvement on Global Assessment of Efficacy of treatment as evaluated by physician as well as patients at 90 days and 180 days (table 5).

The medications were well tolerated by the subjects. No patient reported poor tolerability as evaluated by patients as well as investigator (table 6). No hypoglycemic episodes requiring hospitalization were observed during the study period. There was no significant increase in weight throughout study period in all three groups. The change in weight was comparable between groups without significant difference (table 3).

Discussion:

In type 2 diabetes management, combination therapy with different and complimentary mechanisms of action may have clinically beneficial effects.11 Studies have shown that the triple anti-diabetic regimen improves glycemic control in uncontrolled diabetic patients.5-8 Thiazolidinediones particularly pioglitazone has been an important component of type 2 diabetes treatment even in triple drug combination. This is because glitazones offer many beneficial effects beyond glycemic control. However, because of the controversy about side effect profile most drugs from this class have gone off the therapeutic armamentarium. However, pioglitazone is commonly used in the management of type 2 diabetes mellitus.

 

Pioglitazone use has been shown to reduce high sensitivity C-reactive protein in patients with coronary spastic angina and reduce coronary spasm in such patients.12 Pioglitazone has been shown to be associated with a lower risk of mortality compared to insulin.13 Triple drug combination studies with pioglitazone have used daily dose of 15 mg.5,6 We evaluated efficacy of triple drug fixed dose combination of glimepiride (1 mg and 2 mg), sustained release metformin 500 mg plus pioglitazone 7.5 mg versus insulin 70/30 mix plus sustained release metformin 500 mg in uncontrolled T2DM. We observed that triple drug fixed dose combination with low dose (7.5 mg) pioglitazone achieves similar glycemic control compared to insulin plus metformin combination.

 

C-peptide is an in-expensive, widely used method to measure endogenous insulin secretion in diabetes. This simple investigation can assist the management of diabetes mellitus14. In our study, there was significant increase in C peptide level after treatment in all three groups. However, the difference between groups was not significant.  Reduced glycemic load might be the reason for improvement in C peptide level.

 

In PROactive study, a large scale clinical trial, pioglitazone has shown to improve glycemic control and additionally a possible cardio-protective effect has been suggested.15 The PERISCOPE trial also showed that pioglitazone was associated with improvement in CV risk factors and slow progression of atherosclerosis compared to glimepiride.16  In this study, all three treatment arms resulted in significant reduction in LDL-C and triglyceride while increase in HDL-C was statistically significant with each treatment. The changes in lipid parameters were not significantly different between the groups.

 

Pioglitazone usage was also questioned and it has been a matter of debate among diabetes fraternity because of it controversial association with the risk of urinary bladder cancer. Use of pioglitazone for more than 2 years has been shown to be weakly associated with increased risk of bladder cancer.17 Zhu et al8 have reported in a meta-analysis that there is a risk of bladder cancer is increased twice following pioglitazone especially at a cumulative dose of > 28,000 mg and/ or > 2 years. If this cumulative dose is considered, it suggests daily dose of 40 mg or more. There is now enough evidence to show why this risk is not significant. In India higher dose (more than 30 mg) pioglitazone are generally not used.19A recently published large cohort study involving data of patients between 2001 and 2010 concluded that pioglitazone does not appear to increase the risk of bladder cancer in T2DM.20 Another large study involving pooled data from six different populations across the world concluded that cumulative use of pioglitazone is not associated with the higher rates of bladder cancer.21 The results of ten year epidemiology study have demonstrated no significant increased risk of bladder cancer among patients exposed to pioglitazone.22 American Diabetes Association (2015) has also specified that the concerns regarding bladder cancer risk are reducing after subsequent study.23

Similarly, in a retrospective study from India no link was observed between any specific drug including pioglitazone and bladder cancer. Number of diabetic patients on pioglitazone with bladder cancer was less than on other medications.24

Thus, recent evidence shows no risk of bladder cancer with pioglitazone. In our study, no cases of bladder cancer were reported. However, duration of our study was very small to evaluate the incidence of bladder cancer.

A recent study from Japanese women has shown that the low-dose of pioglitazone (7.5mg) is equally efficacious compared to the conventional preparation with decreased incidence of peripheral edema and weight gain.10  The results of our study show significant improvement in glycemic control with low dose pioglitazone containing triple drug therapy. The improvement in glucose control and lipid parameters is seen without significant adverse events. No cases of severe hypoglycemia requiring hospitalization were seen in any of the study groups.

Since a similar glycemic control was achieved with FDC pill as compared to insulin regimen, we feel, uncontrolled diabetic patients can be started on triple drug FDC containing low dose pioglitazone to avoid or prolong complications associated with insulin therapy.

The limitations of the study include open label study design, short duration of treatment and follow up and small sample size. The duration of follow in this study was inadequate to study the incidence of bladder cancer and evaluate the improvement in beta cell function.

 

Conclusion:

An anti-diabetic fixed dose combination of glimepiride, metformin and low dose (7.5 mg) pioglitazone achieved similar glycemic control to insulin plus metformin combination and resulted in a trend towards lower HbA1c levels as compared to insulin plus metformin therapy. This combination may help in postponing insulin therapy.

Acknowledgement: The authors of this study wish to thank Dr. Anant D Patil for assistance in writing and editing the manuscript.

 

References:

  1. Garber AJ. Incretin Effects on β-Cell Function, Replication, and Mass The human perspective. Diabetes Care  2011 ;34 (Supplement 2):S258-S263
  2. Wright A, Burden AC, Paisey RB, Cull CA, Holman RR, the U.K. Prospective Diabetes Study Group: Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care 2002; 25: 330 –336.
  3. DeFronzo RA. Pharmacologic therapy for Type 2 diabetes mellitus. Ann. Intern. Med 1999;131: 281–303

 

  1. Brown JB, Conner C, Nichols GA. Secondary failure of metformin monotherapy in clinical practice. Diabetes Care 2010; 33:501–506

 

  1. Bell DSH, Dharmalingam M, Kumar S Sawakhande RB. Triple oral fixed-dose diabetes polypill versus insulin plus metformin efficacy demonstration study in the treatment of advanced type 2 diabetes (TrIED study-II). Diabetes, Obesity and Metabolism 2011; 13: 800–05.
  2. Meshram DM, Langade DG, Kinagi SB, Naikwadi AA, Morye V, Chopra D. Evaluation of efficacy and safety of fixed dose combination of glimepiride 2 mg plus  pioglitazone 15 mg plus metformin SR 500 mg in the management of patients with type-2 diabetes mellitus. J Indian Med Assoc. 2005; 103: 447-50.
  3. Rosenstock J, Sugimoto D, Strange P, Stewart JA, Soltes-RAK E, Dailey G et al. Insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients. Diabetes Care 2006; 29: 554 –59.
  4. Roberts VL, Stewart J, Issa M, Lake B, Melis R. Triple therapy with glimepiride in patients with type 2 diabetes mellitus inadequately controlled by metformin and a thiazolidinedione: results of a 30-week, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2005; 27: 1535-47.
  5. Melikian C, White TJ, Vanderplas A, Dezil CM, Chang E. Adherence to oral antidiabetic therapy in a managed care organization: A comparison of monotherapy, combination therapy, and fixed-dose combination therapy. Clinical Therapeutics 2002; 24: 460-67.
  6. Majima T, Komatsu Y, Doi K, Shigemoto M, Takagi C, Fukao A, et al. Safety and efficacy of low-dose pioglitazone (7.5 mg/day) vs. standard-dose pioglitazone (15 mg/day) in Japanese women with type 2 diabetes mellitus. Endocr J. 2006; 53: 325-30.
  7. Einhorn D, Rendell M, Rosenzweig J, Egan JW, Mathisen AL. Schneider RL. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. The Pioglitazone 027 Study Group. Clin Ther 2000; 22:1395-409
  8. Sumio M, Yuji M, Eisaku H, Yusuke K, Michiro Y, Toyoaki M et al. Pioglitazone, a peroxisome proliferator-activated receptor (gamma) activator, suppresses coronary spasm. Coronary Artery Disease 2014: DOI: 10.1097/MCA.000000000000014
  9. Yang J, Vallarino C, Bron M, Perez A, Liang H, Joseph G et al. A comparison of all-cause mortality with pioglitazone and insulin in type 2 diabetes: an expanded analysis from a retrospective cohort study. Current Medical Research & Opinion 2014; 1-9
  10. Jones AG, Hattersley AT. The clinical utility of C-peptide measurement in the care of patients with diabetes. Diabet. Med. 2013; 30: 803–817
  11. Charbonnel B. Glitazones in the treatment of diabetes mellitus: clinical outcomes in large scale clinical trials. Fundam Clin Pharmacol 2007; 21 (Suppl 2):19-20
  12. Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 2008; 299:1561-73
  13. Lewis JD. Ferrara A, Peng T, Hedderson M, Biker WB, Quesenberry CP Jr et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care 2011; 34:916-22
  14. Zhu Z, Shen Z, Lu Y, Zhong S, Xu C. Increased risk of bladder cancer with pioglitazone therapy in patients with diabetes: a meta-analysis. Diabetes Res Clin Pract. 2012; 98: 159-63.
  15. Mohan V, Bedi S, Unnikrishnan R, Sahay BK, Joshi S, Misra A. Pioglitazone – Where do we Stand in India ? J Assoc Phys India 2012; 60: 68-70.
  16. Wei T, MacDonald TM, Mackenzie IS. Pioglitazone and bladder cancer: a propensity score matched cohort study. Br J Clin Pharmacol 2012; 75:24-259
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  18. Takeda Announces Completion of the Post-Marketing Commitment to Submit Data to the FDA, the EMA and the PMDA for Pioglitazone Containing Medicines Including ACTOS available at http://www.tpi.takeda.com/media/news-releases/2014/completion-of-the-post-marketing-commitment-to-submit-data-to-the-fda/ accessed on 6th February 2015
  19. American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetesd 2015. Diabetes Care 2015;38(Suppl. 1):S41–S48
  20. Balaji V, Seshiah V, Ashtalakshmi G. Ramanan SG, Janarthinakani M. A retrospective study on finding correlation of pioglitazone and incidences of bladder cancer in the Indian population. Indian J Endocrinol Metab. 2014;18:425-427

 

 

Table 1: Baseline Characteristics of study participants

Parameters Group A

(n=25)

Mean ± SD

Group B

(n=25)

Mean ± SD

Group C

(n=25)

Mean ± SD

Age (yrs) 48.44 ± 9.31 46.56± 9.17 46.92± 6.46
Height (cms) 154.88 ±7.97 153.48 ± 8.62 152.92 ±7.55
Male

Female

28%

72%

20%

80%

16%

84%

 

Table 2: Changes in Mean HbA1c after Treatment

 

Duration in days

Mean HbA1c (%)
Group A  (N=25)

Mean ± SD

Group B (N=25)

Mean ± SD

Group C (N=25)

Mean ± SD

Baseline 9.40 ±  0.89 9.57 ±  079 9.46 ±  0.99
Reduction at day 30 *-0.32 ±  0.59 *-0.41 ±  0.70 *-0.28 ±  0.48
Reduction at day 90 *-0.81 ±  0.71 *-1.23 ±  0.98 *-0.76 ±  0.83
Reduction at day 180 *-1.49 ±  0.72 *-1.51 ±  0.69 *-1.11 ±  0.76

*p < 0.05

 

 

Table 3: Change in body weight

  Mean weight (kg) (Mean + SD)
Duration in days Group A (n=25)

Mean ± SD

Group B (n=25)

Mean ± SD

Group C (n=25)

Mean ± SD

Baseline 62.68 ±  11.22 61.84 ±  06.88 60.16 ±  07.85
Day 30 62.92 ±  11.19 62.24 ±  06.85 59.56 ±  07.20
Day 90 63.92 ±  11.17 63.04 ±  06.72 60.04 ±  07.14
Day 180 65.00 ±  11.18 63.92 ±  06.57 60.72 ±  07.42

P > 0.05 Not Significant

Table 4: Change from baseline in fasting lipid parameters at 180 days

 

 

Parameter

Mean ± SD
Group A Group B Group C
Baseline

Mean ± SD

At 180 days

Mean ± SD

Baseline

Mean ± SD

At 180 days

Mean ± SD

Baseline

Mean ± SD

At 180 days

Mean ± SD

 

C peptide levels

1.83 ± 0.95 *2.95 ± 0.87 1.32 ± 0.65 *2.58 ± 0.65 1.11 ± 0.66 *1.55 ± 0.55
 

LDLc  (mg/dl)

152.52 ± 12.42 *128.28 ±9.03 153.52 ± 10.40 *129.00 ± 08.79 158.88 ± 08.83 *136.28 ± 07.78
 

TG (mg/dl)

157.76 ± 35.10 *120.92 ± 27.55 158.16 ± 31.98 *119.84 ± 19.02 149.16 ± 32.26 *115.12 ± 17.16
 

HDLc (mg/dl)

36.92 ± 5.73 *40.32 ± 2.95 37.04 ± 4.36 *40.32 ± 4.18 36.88 ± 5.17 *39.64 ± 3.39

*p < 0.05

 

 

Table 5: Global assessment of efficacy of treatment

   

Assessment

Group A

(N=24)

Group B

(N=25)

Group C

(N=25)

Day 90

%

Day 180

%

Day 90

%

Day 180

%

Day 90

%

Day 180

%

Very Good Investigator 00 00 00 00 00 4%
Patient 00 4.2% 00 00 00 00
Good Investigator 95.8% 95.8% 72% 72% 88% 84%
Patient 95.8% 91.6% 92% 92% 92% 96%
Satisfactory Investigator 4.2% 4.2% 28% 28% 12% 12%
Patient 4.2% 4.2% 8% 8% 8% 4%

 

Table 6: Global assessment of tolerability

   

Assessment

Group A

(N=24)

Group B

(N=25)

Group C

(N=25)

Day 90

%

Day 180

%

Day 90

%

Day 180

%

Day 90

%

Day 180

%

Good Investigator 84% 100% 100% 100% 100% 100%
Patient 32% 100% 92% 92% 76% 88%
Moderate Investigator 16% 00 00 00 00 00
Patient 68% 00 8% 8% 24% 12%
Poor Investigator 00 00 00 00 00 00
Patient 00 00 00 00 00 00

 

 

 

 

Figure 2: Reduction in FPG

 

Group A: Glimepiride 1mg + Metformin 500 mg SR + Pioglitazone 7.5 mg; group B: FDC of Glimepiride 2mg + Metformin 500 mg SR + Pioglitazone 7.5 mg; Group C: Insulin 70/30 Mix + Metformin 500mg SR; P<0.05 for all three groups at day 30, 90 and 180

Figure 3: Reduction in PPG

 

Group A: Glimepiride 1mg + Metformin 500 mg SR + Pioglitazone 7.5 mg; group B: FDC of Glimepiride 2mg + Metformin 500 mg SR + Pioglitazone 7.5 mg; Group C: Insulin 70/30 Mix + Metformin 500mg SR;  P<0.05 for all three groups at day 30, 90 and 18

Drug Utilization patterns of Antihypertensives in various wards in a tertiary care hospital in Tamilnadu V.Gowri,K.Punnagai, K.Vijaybabu, Darling Chellathai