Comparison of Metformin and Repaglinide Monotherapy in the Treatment of New-Onset Type 2 Diabetes Mellitus

Objectives We intend to investigate the feasibility of using repaglinide as initial therapy in patients with newly diagnosed type 2 diabetes mellitus naive to the oral anti-hyperglycemic agents by validating the effects of repaglinide on glycemic control (HbA1c) in comparison with metformin monotherapy. Methodology This parallel-controlled, randomized study was carried at the outpatient department of a tertiary care hospital. Two-hundred patients of both genders with newly diagnosed type 2 diabetes mellitus were included. After taking relevant history and physical examination, we drew venous blood samples of each patient and sent them to the institutional laboratory for analysis of fasting blood sugar (FBS) levels, HbA1c, and lipid profile. We divided the patients into two subgroups based on the lottery method. Group A was prescribed metformin, and group B was prescribed repaglinide, while the dosages were adjusted according to the blood sugar levels. All data were analyzed using SPSS Software 25.0 (SPSS Inc., Chicago, USA). We reported the data as means along with the standard error. Results All patients completed the study. There was a decline in fasting blood glucose levels after three months of therapy, both in the metformin (135 mg/dl ± 6 mg/dl versus 115 mg/dl ± 7 mg/dl, p < 0.01) and repaglinide groups (145 ± 6 mg/dl versus 122 ± 6 mg/dl, p < 0.01). Similarly, significant reductions in HbA1c were seen in both metformin (7.12 ± 0.15% versus 6.67 ± 0.06%, p < 0.01) and repaglinide treatment groups (7.83 ± 0.67% versus 6.81 ± 0.07%, p < 0.01). After three months of treatment, body mass index (BMI) was significantly decreased in the metformin group (26.87±1.1 kg/m2 versus 25.11 ± 0.44 kg/m2, p < 0.05). However, the patients in repaglinide group demonstrated a very slight decrease in BMI (27.11 ± 1.6 kg/m2 versus 26.47 ± 0.40 kg/m2). On follow-up, we found a significant decrease in triglyceride levels in both groups (p < 0.01 and p < 0.05. respectively). We also found that only the patients in metformin group showed some improvements in total cholesterol and low-density lipoprotein (LDL) levels (p < 0.05). Conclusion Our study concluded that both metformin and repaglinide have similar anti-hyperglycemic effects. Repaglinide can be prescribed as an alternative drug to metformin in patients with new-onset diabetes mellitus.


Introduction
Diabetes mellitus is a polygenic syndrome characterized by persistent hyperglycemia associated with derangement in metabolism [1]. In the modern era, due to exponential economic growth and lifestyle changes, diabetes mellitus has now become a global epidemic. As of 2016, the prevalence of type 2 diabetes mellitus is 11.7% in Pakistan. Males are affected more, with a prevalence of 11.20% as compared to females, who have a prevalence of 9.19% [2]. Diabetes mellitus leads to various life-threatening complications increasing both morbidity and mortality. Glycemic disturbances are the major risk factors for cardiovascular disease [3]. This increase in cardiovascular diseases ultimately leads to increased deaths [4]. Various research studies have concluded that diabetic complications are directly related to the degree of dysglycemia [5,6].
Twelve classes of anti-hyperglycemic agents are available, along with several fixed-dose combinations of Among all kinds of anti-diabetic medications, metformin inhibits glucose uptake by the liver. It also increases peripheral glucose uptake and consumption. The UK Prospective Diabetes Study (UKPDS) revealed that obese patients with newly diagnosed type 2 diabetes taking metformin as monotherapy had good results. It not only reduced their HbA1c levels but also decreased the risk of diabetes-related endpoints significantly [8]. Due to its efficient blood-glucose-lowering ability, significant effects on body weight, and cardiovascular protectiveness [9], metformin is recommended as the first-line anti-hyperglycemic drug for type 2 diabetes mellitus [6].
Meglitinide is another anti-hyperglycemic class with benzoic acid in its structure [10]. Repaglinide is the most commonly used drug of this class. It decreases the blood glucose level by stimulating the release of insulin in a rapid-acting style. A previous study has shown that the repaglinide is efficiently involved in improving first-phase insulin secretion. It also regulates postprandial blood glucose levels [11]. Various studies have demonstrated that both metformin and repaglinide have equal efficacy in maintaining blood glucose levels and cardiovascular risk profile in patients with type 2 diabetes mellitus [12,13].
There are few studies comparing the effects of these two medications on glycemic control in patients with new-onset type 2 diabetes mellitus. We did this study to investigate the feasibility of using repaglinide as initial therapy in patients with newly diagnosed T2DM naive to oral anti-hyperglycemic agents by validating the effects of repaglinide on glycemic control (HbA1c) in comparison with metformin monotherapy.

Study setting
This study was carried out at the outpatient department of a tertiary care hospital in Multan.

Subjects, sample size, and sampling technique
Two-hundred patients of both genders with newly diagnosed type 2 diabetes mellitus were approached. Simple random sampling was done.

Study design
The research approach employed a parallel-controlled, randomized study to compare the efficacy of metformin and repaglinide in newly onset type 2 diabetes mellitus.

Inclusion criteria
Patients with newly diagnosed type 2 diabetes mellitus with age ranging from 25 to 60 years were included in this study.

Exclusion criteria
Those excluded from the study were patients having liver disease, kidney disease, ischemic heart disease, or any other acute or chronic disorder. Patients taking other hypoglycemic drugs, systemic or inhaled glucocorticoids, or any other medications known to interfere with glucose metabolism were also excluded.

Data collection procedure
After taking consent from the ethical committee of the hospital, this study was carried out in the outpatient department of the hospital. After taking relevant history and physical examination, we drew venous blood samples of each patient and sent them to the institutional laboratory for analysis of fasting blood sugar (FBS) levels, HbA1c, and lipid profile. We divided the patients into two subgroups based on the lottery kg/m 2 ) was prescribed repaglinide, while the dosages were adjusted according to the blood sugar levels. We designed a specialized proforma to handle all the study information. Patients were followed up after three months to record the glycemic index, and the values were recorded.

Data analysis
All data were analyzed using SPSS Software 25.0 (SPSS Inc., Chicago, USA). We reported the data as means along with the standard error. For comparison of values before and after three months of treatment, we employed independent t-tests. Paired t-tests were employed for comparison between groups. For consideration of results to be statistically significant, a p value of <0.05 was selected. Conclusions were made accordingly.

Results
All patients completed the study. The demographic details and baseline investigation values of the patients of both groups are given in Table 1.

Fasting blood glucose concentration
There was a decline in fasting blood glucose levels after three months of therapy, both in the metformin (135 mg/dl ± 6 mg/dl versus 115 mg/dl ± 7 mg/dl, p < 0.01) and repaglinide groups (145 ± 6 mg/dl versus 122 ± 6 mg/dl, p < 0.01). Fasting blood glucose did not show any statistically significant difference between the two groups ( Figure 1).

Body mass index (BMI)
After three months of treatment, BMI was significantly decreased in metformin group (26.87 ± 1.1 kg/m 2 versus 25.11 ± 0.44 kg/m 2 ; p < 0.05). However, the patients in the repaglinide group demonstrated a very slight decrease in BMI (27.11 ± 1.6 kg/m 2 versus 26.47 ± 0.40 kg/m 2 ). Repaglinide group did not show any statistically significant reduction of body mass index ( Figure 3).

Serum lipids
On follow-up, we found a significant decrease in triglyceride levels in both groups (p < 0.01 and p < 0.05, respectively). We also found that only the patients in the metformin group showed some improvements in total cholesterol and LDL levels (p < 0.05). HDL-C was not affected by treatment with both drugs.

Discussion
We showed that both metformin and repaglinide significantly decreased fasting blood glucose and HbA1c in newly diagnosed type 2 diabetes. The anti-diabetic effect of repaglinide was greater than metformin. There was a significant reduction in triglyceride levels in both groups, but only the metformin group showed improvement in total cholesterol and LDL levels.
The UKPDS has demonstrated that patients with good glycemic control have a lower risk of both micro-and macro-vascular complications of diabetes mellitus. HbA1c is the best laboratory investigation for the evaluation of glycemic control [8,14]. Both fasting and postprandial hyperglycemia contributes to different levels of HbA1c variations [15,16]. However, studies have shown that fasting blood glucose contributes fairly high to the overall glycemic control [5,16]. Furthermore, fasting hyperglycemia is more frequent than postprandial hyperglycemia in the prevalence of diabetes. Therefore, we compared the efficacy of metformin and repaglinide by evaluating the fasting blood glucose levels and HbA1c in patients with new-onset type 2 diabetes.
In the light of evidence-based medicine, almost all international guidelines recommend metformin as the only first-line oral anti-diabetic drug for patients with new-onset type 2 diabetes mellitus [6,17]. Due to contraindications and gastrointestinal complications occurring in more than 20% of patients taking metformin, other anti-hyperglycemic agents are considered first-line pharmacological therapy [18,19]. Our study showed that both metformin and repaglinide had a similar anti-hyperglycemic effect, which was in parallel with previous studies [5,12,13].
Hyperlipidemia is an isolated risk factor for a broad spectrum of cardiovascular diseases in patients with coexisting diabetes mellitus. The additive effect of oral anti-hyperglycemic agents on lowering lipid profile and body mass index is an extra benefit for patients with type 2 diabetes mellitus. Our study demonstrated that there was a significant reduction in triglyceride levels in both groups, but only the metformin group showed improvement in total cholesterol and LDL levels. These results are parallel with previous studies [5].
Our study has some limitations. First, the result might be biased by the open-label design in this study. Second, the mean BMI of patients in the metformin group was higher than those in the repaglinide group. Third, we did not measure plasma insulin concentrations and postprandial glucose levels as they can also be affected after three months of therapy. Finally, the duration of our study was short, along with a small study population.

Conclusions
Our study concluded that both metformin and repaglinide have similar anti-hyperglycemic effects. Repaglinide can be prescribed as an alternative drug to metformin in patients with new-onset diabetes mellitus.

Additional Information Disclosures
Human subjects: Consent was obtained by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.
Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.