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RESEARCH PAPER
Year : 2021  |  Volume : 12  |  Issue : 1  |  Page : 1-9
 

Efficacy and safety comparison between pioglitazone and linagliptin in combination with metformin among patients with Type 2 diabetes mellitus: A meta-analysis of randomized controlled trials


1 Department of Pharmacy Practice, Pharm.D student, Gulf Medical University, Ajman, UAE
2 Department of Pharmacy Practice, Acting Chair and Associate Professor, Gulf Medical University, Ajman, UAE

Date of Submission30-Nov-2020
Date of Decision28-Feb-2021
Date of Acceptance17-Mar-2021
Date of Web Publication05-Jul-2021

Correspondence Address:
Dr. Syed Wasif Gillani
Department of Pharmacy Practice, Acting Chair and Associate Professor, Gulf Medical University, Ajman
UAE
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpp.JPP_154_20

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   Abstract 


Objective: To compare the safety and efficacy of linagliptin with pioglitazone in combination therapy of metformin for the management of type 2 diabetes mellitus (T2DM). Materials and Methods: A meta-analayis research design is applied to evaluate the primary and secondary outcomes. Literature search was carried out using databases such as PubMed, Cochrane Library, MEDLINE Complete, Scopus, Clinical Trial Registry, and Web of Science. Studies were considered eligible if the eligibility criteria were met. Cochrane Collaboration Tool was used to assess the risk of bias in randomized clinical trials. Results: A total of 170 citations were identified during the database search. Further evaluation of articles confirmed 16 clinical trials suitable for the research which were randomized, double-blinded, and published as full articles. The articles were evaluated with low risk of bias and high-quality evidence. The mean baseline hemoglobin A1c (HbA1c) ranged from 6.93% to 9.99% and 7.1% to 8.89% for linagliptin with metformin and pioglitazone with metformin groups, respectively. Two among the 12 groups show a slight increase in the mean HbA1c levels which is nonsignificant due to their sample size. Overall, the combination therapy of linagliptin with metformin led to a reduction of 1.35% which is significantly higher than pioglitazone combined with metformin which led to a 1.27% reduction. The mean baseline values of fasting plasma glucose levels varied from 158.2 mg/dl to 198.0 mg/dl in linagliptin plus metformin group, whereas in pioglitazone plus metformin group, the values varied from 137.0 mg/dL to 212.4 mg/dL. The high heterogeneity could refer to the inconsistencies between the studies. The combination of linagliptin with metformin showed a significant reduction of 0.56% in body mass index, whereas pioglitazone with metformin led to a 0.37% reduction. Conclusion: The findings showed better efficacy profiling of lingaliptin–metformin combination compared with pioglitazone combination therapy.


Keywords: Diabetes mellitus, dipeptidyl peptidase-4Is, linagliptin, management, meta-analysis, SGLT2s


How to cite this article:
Toufiq O, Gillani SW, Mohamed F, Pasha N, Chiraparambil M, Parveen A. Efficacy and safety comparison between pioglitazone and linagliptin in combination with metformin among patients with Type 2 diabetes mellitus: A meta-analysis of randomized controlled trials. J Pharmacol Pharmacother 2021;12:1-9

How to cite this URL:
Toufiq O, Gillani SW, Mohamed F, Pasha N, Chiraparambil M, Parveen A. Efficacy and safety comparison between pioglitazone and linagliptin in combination with metformin among patients with Type 2 diabetes mellitus: A meta-analysis of randomized controlled trials. J Pharmacol Pharmacother [serial online] 2021 [cited 2021 Aug 2];12:1-9. Available from: http://www.jpharmacol.com/text.asp?2021/12/1/1/320712





   Introduction Top


The occurrence of diabetes mellitus has increased over the years and it became the most prevalent disease worldwide among the chronic diseases, rising up to 9.9% by the year 2045.[1],[2] The statistics in International Diabetes Federation estimates a death every 7 s due to diabetes, with 50% commonly taking place in the population below the age of 60 years.[1] Long-term diabetes therapy includes both pharmacological approaches including combinations of drugs along with a nonpharmacological approach which focuses on modifying lifestyle to reach the ultimate glycemic targets.[3]

Thiazolidinediones (TZDs) are a class of drugs used to treat type 2 diabetes which differ in activity from other antidiabetic medications due to their ability to bind to the nuclear peroxisome proliferator-activated receptors-γ (PPARγ) and modify the transcriptional activity.[4],[5] These PPARγ play a role in regulating the metabolism of carbohydrates and lipid.[2] TZDs increase the insulin secretion in the peripheral areas leading to adipogenesis and decreasing the glucose production.[6],[7] This mechanism enhances insulin sensitivity, hence lowering fasting and postprandial glucose levels.[6] Prolonged use of TZDs can lead to adverse effects in terms of bone loss and higher possibilities of fractures in women with type 2 diabetes mellitus (T2DM).[2],[8]

Dipeptidyl peptidase 4 (DPP 4), also called CD 26, is a cell marker that is found in plenty of tissues including lymphocytes, T-cells, B-cells, and natural killer cells.[9] The DPP 4 inhibitors preferably known as gliptins are generally prescribed in combination.[1] They contribute to lowering the glycemic status by blocking the activity of DPP-4 and act as incretin enhancers.[10] Incretins are an enzyme which puts down the action of gastrointestinal (GI) hormones.[10] Insulin is produced by incretins when they are stimulated and inhibit the glucagon secretion by the liver depending on when the body needs it or not.[8] Gliptins show relatively lower adverse effects when compared to other oral antidiabetic medications. The incidence of cardiovascular mortality, GI disturbances, and other general infections is reduced with the use of gliptins when compared to sulfonylureas.[10],[11]

Linagliptin was observed to show a modest decrease in hemoglobin A1c (HbA1c) levels without causing hypoglycemia, hence is considered in patients with established kidney disease.[12] Linaglipin when taken as an add-on therapy for long term along with insulin or other antihyperglycemic drugs, a significant higher change in mean HbA1c levels from baseline was observed.[1]

No long-term data were published on risk factors associated with complications of the disease and comorbidities of patients. Patient-oriented outcomes such as side effects of the medication, quality of life, and metabolic control are briefly defined yet require more elucidated data.

The objective of the study is to evaluate the safety and efficacy of linagliptin with pioglitazone with metformin combination in patients with T2DM.


   Materials and Methods Top


Search strategy

A thorough literature search was carried out using databases such as PubMed, Cochrane Library, MEDLINE Complete, Scopus, Clinical Trial Registry, and Web of Science.

While carrying out the search, different keywords were used which were combined using Boolean operators (AND and OR) such as Pioglitazone AND Metformin, type 2 Diabetes mellitus AND Clinical Trials AND Linagliptin, Adverse effects OR Side effects, Safety AND Efficacy, and Compliance OR Adherence. Various other keywords included to conduct the search were fasting plasma glucose (FPG), HbA1c, body mass index (BMI), and complications with different combinations.

Eligibility criteria

Studies were considered eligible if the following criteria were met: (1) randomized control trials were conducted on T2DM patients receiving a combination of pioglitazone with metformin, (2) trials conducted on T2DM patients receiving a combination of linagliptin with metformin, (3) showed the efficacy of the treatment on FPG and HbA1C levels, (4) patient's adherence to the given treatment, (5) reports adverse events, (6) studies conducted on patients ≥18 years old including male and female participants, and (7) randomized controlled trials published from 2004 onward, limited to publication in the English language. Everything other than what is mentioned is an exclusion.

Quality assessment

Cochrane collaboration tool[13] was used to assess the risk of bias in randomized clinical trials. The criteria for assessing the quality of articles were random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting. For each study, the risk of bias was graded.

Study process

This study is a systematic review and a meta-analysis article. The studies were selected based on eligibility criteria from various databases. The critical appraisal was performed based on the Cochrane review tool. Data were extracted from Excel sheets for evidence synthesis and evaluation of effectiveness. Further, the publication bias and risk of bias were determined using statistical software.

Outcomes

In relation to drug therapy, fasting blood sugar and HbA1c levels are considered as the primary outcome. The mean changes and mean standard deviation values of fasting blood sugar are compared between pioglitazone with metformin and linagliptin with metformin groups using odds ratio. A comparison of the mean change in HbA1c levels from baseline to the end of the trial is performed between both the groups. The secondary clinical outcomes studied are body weight, adverse effects, and patient compliance. The number of adverse events in the study groups is also reported which results from the combination medications. Patient compliance along with adverse effects and body weight is analyzed in numbers (one in hundred of the trial group).

Statistical analysis

After collecting data, the data are written on a spreadsheet that contains the author's name, then a description which includes what year the study was conducted, type of a study, sample size, and then the forest plot is designed to check point estimates and confidence intervals (CI).

Effect size measures the magnitude of observed effect between two variables. This can be done by three most common methods such as Pearson's R and Cohen's D (for continuous variables) and odds ratio (for categorical variables). Sometimes, meta-analysis depends on fixed-effects or random-effects statistical models. For complex data, multivariate methods for meta-analysis have been used. To assess heterogeneity, I2 test is used. Publication bias is an important aspect to consider when negative findings have less probability of it getting published which will be performed using a funnel plot. Cochrane Review Manager (RevMan) version 5.3 software for analysis and data synthesis is used.


   Results Top


A total of 170 citations were identified during the database search. Further evaluation of articles confirmed 16 clinical trials suitable for the research, which were randomized, double-blinded, and published as full articles. PRISMA flow diagram is illustrated in [Figure 1].
Figure 1: PRISMA flow diagram showing screening of articles

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Eight study groups each were selected for linagliptin and pioglitazone in combination with metformin. All the studies had patients above 18 years old along with HbA1c, FPG, BMI, adverse event, and compliance as either primary or secondary outcome. The duration of studies varied from 12 weeks to 54 weeks. The characteristics for each trial included are shown in [Table 1].
Table 1: Characteristics of randomized controlled trials included in the meta-analysis

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Assessment of risk of bias

Cochrane tool was used to independently assess the risk of bias for all the trials. The following domains were considered selection bias, performance bias, detection bias, attrition bias, and reporting bias. Overall, the articles were evaluated with low risk of bias and high-quality evidence. Detailed quality assessment for each article is mentioned in [Table 2].
Table 2: Quality assessment of included articles based on Cochrane collaboration tool

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   Discussion Top


Glycemic outcomes

Any changes observed in HbA1c and FPG levels were considered to be the primary outcomes. The mean baseline HbA1c ranged from 6.93% to 9.99% and 7.1% to 8.89% for linagliptin with metformin and pioglitazone with metformin groups, respectively. As seen with linagliptin along with metformin group, patients with a higher HbA1c baseline (>9.0%) had reduced HbA1c levels below 7.5%.[15],[18],[21] Patients with a HbA1c baseline >8.0% showed reductions up to 7.1% and below.[14],[16],[19] One among them showed no reduction, whereas one showed increased HbA1c values.[20] Only one group showed the minimum HbA1c level of 7.34% which showed a reduction of 0.08% after the treatment.[17] Observing from the forest plot, 12 groups with patients receiving linagliptin in combination with metformin reported HBA1c levels. Two results showed a decrease in HBA1c levels but are nonsignificant. Two among the 12 groups show a slight increase in the mean hbA1c levels which is nonsignificant due to their sample size [Figure 2].
Figure 2: Forest plot of hemoglobin A1c in linagliptin plus metformin group

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Eight study groups reported HbA1c levels with patients receiving pioglitazone in combination with metformin [Figure 3]. As seen with pioglitazone along with metformin group, patients with a higher HbA1c baseline (>8.0%) had reduced HbA1c levels below 7.5%.[4],[22],[25],[26],[28] Patients with a HbA1c baseline >7.0% showed reductions up to 6.5%.[23],[24],[27] Data analysis revealed considerably higher heterogeneity I2 = 99% and 97% in linagliptin plus metformin and pioglitazone plus metformin groups; respectively, showcasing intragroup variability. Differences among the studies due to various factors led to a diverse result, hence showing high heterogeneity. Overall, the combination therapy of linagliptin with metformin led to a reduction of 1.35% which is significantly higher than pioglitazone combined with metformin which led to a 1.27% reduction.
Figure 3: Forest plot of hemoglobin A1c in pioglitazone plus metformin group

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Combination of metformin with linagliptin and pioglitazone has shown a significant reduction in the FPG levels by 35.64% and 34.63%, respectively, that was collected from 16 clinical trials [Figure 4] and [Figure 5]. As seen with linagliptin along with metformin group, patients with higher FPG baseline (>190 mg/dL) had reduced FPG levels below 150 mg/dL except for one group which showed a reduction up to 162 mg/dL.[15],[16],[18] As seen with pioglitazone with metformin group, patients with higher FPG baseline (>200 mg/dL) reduced below 180 mg/dL.[4],[28] The mean baseline values of FPG levels varied from 158.2 mg/dl to 198.0 mg/dl in linagliptin plus metformin group, whereas in pioglitazone plus metformin group, the values varied from 137.0 mg/dL to 212.4 mg/dL. After performing data analysis, relatively high heterogeneity was observed with linagliptin plus metformin having I2 = 91% and in case of pioglitazone plus metformin I2 = 100%. The high heterogeneity could refer to the inconsistencies between the studies.
Figure 4: Forest plot of fasting plasma glucose in linagliptin plus metformin group

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Figure 5: Forest plot of fasting plasma glucose in pioglitazone plus metformin group

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Nonglycemic outcomes

After analyzing all the data, four groups of linagliptin with metformin and two groups of pioglitazone with metformin included BMI status in their study. As seen with linagliptin along with metformin group, patients with higher BMI baseline (>29) had reduced levels up to 28.56 and 28.8.[14],[18] As seen with pioglitazone with metformin group, patients with higher BMI baseline (>30) reduced by 0.7[24] The mean baseline values of combined therapy of linagliptin with metformin were between 26 kg/m2 and 29.8 kg/m2 and for pioglitazone with metformin were 26.9 kg/m2 and 33.9 kg/m2 [Figure 6] and [Figure 7]. Several study lines crossed the line of null effect illustrating no statistically significant difference in the BMI between the pre- and posttreatment groups. Network meta-analysis reveals I2 of 0% for both the groups indicating no heterogeneity of results between each study data. Overall, the combination of linagliptin with metformin showed a significant reduction of 0.56% in BMI, whereas pioglitazone with metformin led to a 0.37% reduction.
Figure 6: Forest plot of body mass index in linagliptin plus metformin group

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Figure 7: Forest plot of body mass index in pioglitazone plus metformin group

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All the studies reported adverse events and the most common among them was hypoglycemia. From the 16 trials, a total of 6 studies (4 from linagliptin with metformin and 2 from pioglitazone with metformin) outlined hypoglycemia. The odds ratio for hypoglycemia between both the groups was 0.67 (95% CI: 0.1098–4.0496). Data extraction revealed six studies outlined GI events, two studies reported hypertension, and two reported other drug-related adverse effects in linagliptin combined with metformin group. In the pioglitazone + metformin group, three studies reported peripheral edema and only one study reported six patients attaining insomnia. No death events in any of the groups were reported [Table 3].
Table 3: Odds ratio for adverse events (hypoglycemia)

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Patient adherence to the medication is considered a secondary outcome. A total of 6 studies (which comprise 5 for linagliptin with metformin and 1 for pioglitazone with metformin) defined patient compliance. The odds ratio for patient compliance between the groups of linagliptin and pioglitazone is 21.57 (7.5358–61.7355 at 95% Cl) [Table 4].
Table 4: Odds ratio for patient compliance

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   Conclusion Top


Network meta-analysis results provide evidence to prove linagliptin in combination with metformin showed better safety in patients along with efficacy in terms of reducing HbA1c, FPG levels, and BMI in comparison with pioglitazone in combination with metformin.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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