Comparing dual oral agents plus insulin vs. Triple oral agents in uncontrolled type II diabetes: A pilot study

Nadia Gul; Inayat Ur Rehman; Yasar shah; Arbab Muhammad Ali; Zahid Ali; Omer Shehzad; Khang Wen Goh; Long Chiau Ming; Amal K Suleiman

doi:10.1371/journal.pone.0311435

. 2024 Nov 21;19(11):e0311435. doi: 10.1371/journal.pone.0311435

Comparing dual oral agents plus insulin vs. Triple oral agents in uncontrolled type II diabetes: A pilot study

Nadia Gul ¹, Inayat Ur Rehman ^1,², Yasar shah ¹, Arbab Muhammad Ali ^3,^*, Zahid Ali ⁴, Omer Shehzad ¹, Khang Wen Goh ⁵, Long Chiau Ming ^6,^*, Amal K Suleiman ⁷

Editor: Nimesh Lageju⁸

PMCID: PMC11581212 PMID: 39570934

Abstract

Introduction

Type II Diabetes mellitus (T2DM) patients often do not achieve glycemic control with oral hypoglycemic agents (OHAs). There are two main approaches to address this challenge: transitioning to a triple OHA regimen, or adding Insulin to the existing dual OHA regimen.

Aim

This study aimed to compare the efficacy of adding Insulin to dual OHAs (Sitagliptin + Metformin) against adding a third OHA to Sitagliptin + Metformin in achieving glycemic control among patients with uncontrolled T2DM.

Method

A pre-post study was conducted between 21 September 2023 and 21 December 2023 at Services Hospital Peshawar, Pakistan. Patients with uncontrolled T2DM with >7% HbA1c were divided into group 1 (Sitagliptin + Metformin plus a third OHA), and group 2 (Sitagliptin + Metformin plus pre-mixed Insulin 70/30). Glycemic control based on HbA1c values, fasting and random blood sugar levels, lipid profile, and body weight were evaluated after 3 months of therapy. The pre- and post- effect was compared by using a paired t-test.

Results

The study included n = 80 patients with T2DM. Between groups 1 and 2, no significant difference was found in HbA1c values (9.1 vs. 9, with p = 0.724). However, BMI, cholesterol, and LDL significantly decreased in group 1 compared to group 2 (p<0.001 vs. p = 0.131, p = 0.023 vs. p = 0.896, and p = 0.003 vs. p = 0.395, respectively). Additionally, the incidence of hypoglycemic episodes was significantly lower in group 1 (7.5%) than in group 2 (47.5%, p = 0.004). No significant difference was observed between the triple OHA and dual OHA plus Insulin regimens in achieving glycemic control.

Conclusion

The triple OHA regimen improved BMI, cholesterol, and LDL levels, and reduced hypoglycemic episodes more effectively than dual OHA plus Insulin, despite similar HbA1c outcomes, suggesting it may be preferable for uncontrolled T2DM.

Introduction

Diabetes mellitus (DM) is a serious, long-term condition with a major impact on the lives and well-being of individuals, families, and societies worldwide [1]. In 2021, diabetes affected around 537 million adults globally between the ages of 20 to 79 [2]. Due to its accelerated prevalence, it is projected that this number may rise to 783.2 million in 2045 [3]. A total of 6.7 million deaths were attributed to DM in 2021 [4]. The increasing trend of T2DM is the result of ageing [5], a rapid increase in urbanization [6], obesogenic environments [7], sedentary lifestyles [8], an increasing trend in Type 1 DM worldwide as well [9, 10], and genetic susceptibility [11]. Nearly 80% of people with T2DM are living in low- and middle-income countries [12].

According to the International Diabetes Federation, the Asian population has a significantly higher risk of developing diabetes and its related complications [13]. About 80% of patients that contribute to the global diabetes burden come from low- and middle-income countries, and of the total, more than 60% live in Asia [14]. Pakistan is ranked no 1 in the world in its proportion of diabetic patients, with a prevalence rate of 30.8% [15]. According to a 2019 study, the prevalence of T2DM was 17.1% [16]. The prevalence was higher in men (11.20%) than women (9.19%), and it was more common in cities than in rural areas [17]. Different factors are contributing to the increased prevalence of T2DM in Pakistan: a carbohydrate-rich diet and physical inactivity [18], a rapid increase in urbanization [6], no formal education, and obesity [19]. In Pakistan, the majority of patients with T2DM remain undiagnosed [19]. DM and hypertension are considered the major and leading causes of chronic kidney disease (CKD) [20, 21].

T2DM is a metabolic disorder affecting multiple organs, with complications more prevalent in uncontrolled cases, contributing to morbidity and mortality [22, 23]. Complications are classified as microvascular, including neuropathy [24], nephropathy [25], and retinopathy [26] and microvascular complications, such as stroke [24], cardiovascular disease (CVD) [27], and peripheral vascular disease (PVD) [28] are macrovascular complications. PVD may lead to bruises or injuries not healing over time, which can lead to gangrene and amputation [22].

Diabetes mellitus can be controlled by using pharmacological and non-pharmacological interventions [29]. Blood pressure, lipid profile, body weight, and HbA1c are essential in the clinical management of T2DM patients [30–32]. HbA1c is a marker of the average glucose levels spread over a two- to three-month period [33]. Another study also confirms the effectiveness of diabetes mellitus self-care management, showing improvement in metabolic markers like blood pressure, HbA1c, total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) [34]. As the first-line treatment for T2DM, an OHA monotherapy is recommended [35]. Initiation of combination therapy has been proposed as an approach to maintain target blood glucose levels in T2DM patients [36, 37]. Previous studies demonstrate that in the initial management of diabetes, Metformin and sulfonylureas were frequently used agents in dual therapy [38–41], whereas thiazolidinediones and dipeptidyl peptidase-4 inhibitors were considered as other treatment option in cases when dual therapy was not effective [40, 42, 43]. Clinical research has shown that combination therapy’s synergy is safer and more effective than monotherapy [44].

At present, the literature lacks substantial clinical evidence regarding treatment decisions for patients with uncontrolled T2DM treated with dual oral OHA combinations. In order to effectively achieve and maintain glycemic control, the majority of T2DM patients will require Insulin, either alone or in combination with other OHAs [45, 46]. Considering the heightened prevalence of DM in Pakistan, along with a substantial number of patients experiencing uncontrolled DM, a significant portion of patients require triple therapy. Hence, this study aimed to compare the efficacy of adding Insulin to dual OHAs (Sitagliptin + Metformin) against adding a third OHA to Sitagliptin + Metformin in achieving glycemic control among patients with uncontrolled T2DM.

Method

Study design and setting

A pre- and post- study design was used for this study. The data was collected from 21 September 2023 to 21 December 2023 to compare the effectiveness of dual OHAs with additional Insulin as compared to triple OHAs for optimum control of HbA1c among uncontrolled T2DM patients. This study was conducted in a tertiary health care setting in the city of Peshawar, Pakistan.

Inclusion/exclusion criteria

The inclusion criteria comprised T2DM patients who were aged 18 years and above, either gender, and with a history of poor glycemic control, having HbA1c > 7% for the last year or more despite using dual OHAs (full doses of Sitagliptin and Metformin). The exclusion criteria comprised T2DM patients with severe cognitive impairments, exposed to multiple drug combination before, and those not willing to participate in this study.

Process of measurement

The patients were approached and the purpose of the study was explained to them in the presence of a consultant endocrinologist. From those who were willing to participate, informed written consent was obtained. Blood samples from the patients were collected in heparinized tubes, unless these were not available at that specific time, in which case the samples were collected in non-heparinized tubes. The non-heparinized tube samples were immediately centrifuged for 20 minutes at 2000 rpm. A clear serum supernatant was then used to evaluate various biochemical diagnostic factors, including serum creatinine, HbA1c, random blood sugar (RBS), fasting lipid profile (HDL, LDL, Triglycerides and cholesterol), urea, and fasting blood sugar (FBS).

Study procedure

The demographic characteristics of the patients were recorded, including age, gender, weight, BMI, geographic location, comorbidities and biochemical diagnostic factors including HbA1c, fasting blood sugar (FBS), random blood sugar (RBS), lipid profile (HDL, LDL, Triglycerides, cholesterol), urea.

After meeting the inclusion criteria, the patients were randomly assigned into two groups (1 and 2).

Group 1

This cohort comprised a total of 40 T2DM patients. These patients were already on dual OHAs (Sitagliptin and Metformin), and a third agent (Empagliflozin, Glimepiride, or Gliclazide) was added to their existing therapy. Patients were advised to take the Sitagliptin + Metformin combination tablet twice a day, either with a meal or right after eating. Empagliflozin, Glimepiride and Gliclazide should be taken once in the morning, along with breakfast.

Group 2

This cohort also comprised a total of 40 T2DM patients. For these patients, pre-mixed Insulin (70/30) was added to their existing dual OHA therapy of Sitagliptin and Metformin.

After a 3-month interval, all laboratory parameters were repeated and recorded to assess the effectiveness of triple OHAs, and dual OHAs with Insulin, looking at glycemic control by comparing HbA1c levels at the baseline and endpoint.

Ethics and dissemination

The study received approval from the Ethics Committee of Abdul Wali Khan University, Mardan, Pakistan. All procedures involving human participants adhered to the ethical standards set forth by this committee and were in accordance with the principles outlined in the 1964 Helsinki Declaration. Informed written consent was obtained from all patients who voluntarily participated in the study, with the understanding that they retained the right to withdraw at any point. Each patient was assigned a unique patient identity number for future reference. To minimize any bias, all data were treated with utmost confidentiality to prevent disclosure.

Sample size

The study sample size was calculated based on previous studies for detecting the difference of 1% reduction for HbA1c (effect size), with a standard deviation of 1.4%, at 3 months in the intervention group [47]. A significance level of 0.05 is considered with a study power of 80%. Based on these numbers, the calculated sample size was 62 (31 for Cohort 1 and 31 for Cohort 2). To compensate for the 25% attrition rate, an additional 25% was added to the sample size. Overall, a total sample of 80 patients was assumed to be sufficient for this study.

Statistical analysis

The data analysis was performed using SPSS version 22^®. For data that was categorical, frequency and percentages were reported, while for data that was continuous, mean and standard deviation were reported. In order to compare the pre- and post-effects of drugs to assess improvement in HbA1c and other laboratory parameters, a paired t-test was performed, while the comparison between two treatment groups were performed by using an independent t-test. A p-value <0.05 was considered statistically significant.

Results

A total of n = 80 T2DM patients were included in this study (patients recruitment flow chart shown in Fig 1). Patients fulfilling the inclusion criteria were divided into two treatment groups. In group 1, 57.5% the patients were females and 47.5% were aged 41–55 years old, while in group 2, 52.5% were males and 60% of the patients were > 55 years old. Geographically, group 2 were mainly from Charsadda (52.5%) followed by 35% from Peshawar, whereas in group 2 the majority of patients (67.5%) were from Peshawar followed by 27.5% from Charsadda. Baseline weight and BMI distributions showed higher number of patients weighed 66–85 kg in both groups; while for BMI, 40% of the patients in group 1 had a BMI of 24.5–29.9, and in group 2, 35% had a BMI of 18.5–24.9. Both groups showed high baseline HbA1c levels: 50% of patients in group 1 had HbA1c >10, while in group 2, 57.5% of patients had HbA1c levels of 8.1–10, as shown in Table 1.

Table 1. Demographics and baseline characteristics of patients.

Variables	Treatment Groups
Variables	Group-1		Group-2
Gender	n	%	n	%
Female	23	57.5	19	47.5
Male	17	42.5	21	52.5
Age (Years)
18–40	9	22.5	5	12.5
41–55	19	47.5	11	27.5
= >55	12	30	24	60
Address
Afghanistan	2	5	0	0
Bajaur	1	2.5	0	0
Charsadda	21	52.5	11	27.5
Dir Lower	0	0	1	2.5
Malakand	1	2.5	1	2.5
Peshawar	14	35	27	67.5
Swat	1	2.5	0	0
Baseline Weight (Kg)
35–65	10	25	14	35
66–85	22	55	18	45
>85	8	20	8	20
Baseline BMI
Below18.4	2	5	2	5
18.5–24.9	9	22.5	14	35
24.5–29.9	16	40	12	30
>29.9	13	32.5	12	30
Baseline HbA1c (%)
4–6.5	0	0	0	0
6.6–7	0	0	0	0
7.1–8	2	5	2	5
8.1–10	18	45	23	57.5
>10	20	50	15	37.5
Comorbidities
Chronic Kidney Disease	0	0	2	5
Diabetic Retinopathy	0	0	2	5
Hypertension	9	22.5	4	10
Ischemic Heart Disease	2	5	7	17.5
Ischemic stroke	0	0	1	2.5
No comorbidity	29	72.5	26	65

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Group 1: Dual OHAs (Sitagliptin and Metformin), and a third agent (Empagliflozin, Glimepiride, or Gliclazide) was added to their existing therapy; Group 2: Insulin was added to their existing dual OHA therapy (Sitagliptin and Metformin).

All the included patients in this study were on dual OHAs, i.e., Sitagliptin + Metformin. The patients were assigned into two groups. In group 1, the patients were started on an additional OHA (Empagliflozin, Gliclazide or Glimepiride) by their consultant endocrinologist. In group 2, patients were started on Insulin in addition to their dual OHAs.

Table 2 shows the comparison of treatment groups based on patients’ clinical profiles. In groups 1 and 2, HbA1c significantly decreased compared to baseline values (p = <0.001, and p = 0.002, respectively). In both the groups, weight, random and fasting blood sugar levels showed significant decreases at endpoint (p = <0.001, <0.001, and 0.006, respectively). BMI, cholesterol, and LDL significantly decreased among group 1 patients vs group 2 patients (p = <0.001 vs p = 0.131, p = 0.023 vs p = 0.896, and p = 0.003 vs p = 0.395, respectively). However, no significant change in triglycerides, HDL, urea, and serum creatinine were observed in either group.

Table 2. Comparison of study groups based on patients’ variables before and after administration of study drugs.

Variables	Group-1				Group-2
	Pre	Post	Pre-Post	P-value	Pre	Post	Pre-Post	P-value
	Mean ± SD	Mean ± SD	% Diff	P-value	Mean ± SD	Mean ± SD	%Diff	P-value
Weight (Kg)	75.1 ± 14.4	73.8 ± 13.9	1.74%	<0.001*	73.0 ± 14.9	71.8 ± 14.8	1.65%	<0.001*
Body Mass Index (BMI)	28.0 ± 5.1	27.5 ± 5.1	1.08%	<0.001*	27.3 ± 6.3	27.0 ± 6.2	1.10%	0.131
HbA1c	10.3 ± 1.7	9.1 ± 1.6	12.37%	<0.001*	9.9 ± 1.6	9.0 ± 1.7	9.52%	0.002*
Random Blood Sugar (RBS)	282.6 ± 77.2	248.6 ± 77.3	12.80%	<0.001*	280.0 ± 79.7	258.3 ± 85.6	8.06%	0.013*
Fasting Blood Sugar (FBS)	181.4 ± 58.3	160.3 ± 52.3	12.35%	0.006*	190.8 ± 56.7	169.8 ± 58.6	11.64%	0.005*
Triglycerides	191.2 ± 36.1	184.9 ± 37.7	3.35%	0.151	227.5 ± 106	224.2 ± 110.9	1.46%	0.83
Cholesterol	188.0 ± 25.0	181.3 ± 24.9	3.62%	0.023*	181.3 ± 42.4	182.1 ± 40.2	-0.44%	0.896
Low-Density Lipoprotein (LDL)	110.8 ± 20.3	104.0 ± 23	6.33%	0.003*	103.5 ± 29.4	108.0 ± 26.3	-4.25%	0.395
High-Density Lipoprotein (HDL)	43.7 ± 2.8	44.6 ± 3.7	-2.03%	0.149	43.3 ± 8.8	42.8 ± 4	1.16%	0.732
Serum Creatinine	0.9 ± 0.2	0.8 ± 0.2	11.76%	0.878	1.3 ± 1.1	1.2 ± 1.2	8.0%	0.303
Urea	32.0 ± 8	30.7 ± 6.4	4.14%	0.34	38.9 ± 20.2	39.3 ± 24	-1.02%	0.885

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Pair t-test was used, * p-value <0.05 was statistically significant

Fig 2 shows the impact of group 1 drugs on hyperglycemia based on HbA1c levels after 3 months of administration. At baseline, in the majority of the patients, HbA1c was poorly controlled (n = 38, 95%), whereas, after 3 months, the frequency of patients with poorly controlled diabetes decreased to 30 (75%), constituting a 20% improvement in HbA1c values. At baseline, none of the patients had HbA1c values lower than 7%; after 3 months of administering the study drugs, 10% of the patients had <7% HbA1c.

In group 2, HbA1c was poorly controlled in 95% of the patients at baseline, but after 3 months of treatment, the number of patients with poorly controlled diabetes decreased to 28 (70%), constituting a 25% improvement in HbA1c values. At baseline, none of the patients had controlled diabetes based on HbA1c values. 5% of patients achieved normal HbA1c values after 3 months of treatment, while in only one patient were HbA1c values < 7%.

The comparison between two treatment groups revealed significant differences. Patients in Group1 were younger the ages of patients, and had lower triglyceride and urea levels compared to group 2, with p-values of 0.039, and 0.033, respectively. Additionally, group 1 had lower HDL levels than group 2, with a p-value of 0.036, as shown in Table 3.

Table 3. Comparative analyses of group 1 vs group 2 based on various patient characteristics.

Variables	Group 1	Group 2	P-value
Variables	Mean ± SD	Mean ± SD	P-value
Age (Years)	49.6 ± 12.6	56.9 ± 13.9	0.017*
Weight (Kg)	73.8 ± 13.9	71.8 ± 14.8	0.541
Body Mass Index (BMI)	27.5 ± 5.1	27.0 ± 6.2	0.683
HbA1c	9.1 ± 1.6	9.0 ± 1.70	0.724
Random Blood Sugar (RBS)	248.6 ± 77.3	258.3 ± 85.6	0.594
Fasting Blood Sugar (FBS)	160.3 ± 52.3	169.8 ± 58.6	0.443
Triglyceride	184.9 ± 37.7	224.2 ± 110.9	0.039*
Cholesterol	181.3 ± 24.9	182.1 ± 40.2	0.91
Low-Density Lipoprotein (LDL)	104.0 ± 23.0	108.0 ± 26.3	0.468
High-Density Lipoprotein (HDL)	44.6 ± 3.7	42.8 ± 40	0.036*
Urea	30.7 ± 6.4	39.3 ± 24	0.033*

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An Independent T-test was used; a p-value <0.05 was considered statistically significant

The number of hypoglycemic episodes in group 1 patients was significantly less (n = 7; 7.5%) than in group 2 patients (p = 0.004) where 19 (47.5%) patients experienced hypoglycemic episodes, as shown in Fig 3.

Discussion

T2DM is characterized by the gradual decline of beta-cell function and subsequent loss of glycemic control. When glycemic control is suboptimal, patients are at increased risk of developing microvascular and macrovascular complications [48]. Hence, it is crucial to identify treatment strategies that can effectively manage blood glucose levels, while also being convenient and adherable for patients.

Given the heightened prevalence of DM in Pakistan, along with a substantial number of patients experiencing uncontrolled DM, a significant portion of patients require triple therapy. The American Diabetes Association recommends the early initiation of Insulin, whereas commonly gliptins and SGLT-2 inhibitors are considered second-line treatment options. The addition of Insulin to oral regimens is a well-established approach that is effective for many patients [43]. Over the course of five years following the start of treatment, the incidence of secondary failure of OHAs in T2DM patients varies from 30% to 60% [49, 50]. The addition of a third agent, such as Insulin or an oral agent, is necessary for all patients with progressing T2DM in the future because the dual OHA regimen can only lower HbA1c levels by an average of 1.2–2.0% [51]. A study by Wallia et al. [52] reported that Insulin in combination with OHA is effective in achieving rapid glycemic control vs triple OHA regimens. Nevertheless, these guidelines were criticized for the fact that Insulin treatment can lead to frequent hypoglycemic episodes, weight gain, and limited patient satisfaction and compliance [53]. Furthermore, other studies reported the increased incidence of hypoglycemic episodes with Insulin [54–56]. Hence, this study aimed to compare the effectiveness of dual OHAs with additional Insulin versus triple OHAs in T2DM patients in improving HbA1c levels.

Our study found no statistically significant difference between the two treatment groups based on HbA1c, random blood sugar, and fasting blood sugar levels. These results are inconsistent with the findings of other studies which report significant differences between Insulin-based OHA regimens vs triple OHA regimens [53, 57]. Similarly, another study demonstrates that Insulin in combination with other OHA regimens provides better glycemic control [58], but at the cost of increased incidence of hypoglycemic episodes [53–56, 59]. These inconsistencies in results might be due to patients administering lower doses of Insulin or missing doses altogether out of concern for hypoglycemia [53, 60, 61], as our data reveals a notably higher occurrence of hypoglycemic episodes associated with Insulin use.

In this study, despite a triple OHA regimen, 4 (10%) of the patients in group 1 achieved less than 7% HbA1c values vs 3 (7.5%) in group 2 after 3 months of treatment, which is consistent with a study reporting one-fifth of patients being able to achieve HbA1c values lower than 7% [53]. Failure to achieve target HbA1c (<7%) may be attributed to non-compliance because of polypharmacy, as the majority of diabetic patients have comorbid illnesses (hypertension/ischemic heart disease, dyslipidemia), meaning polypharmacy is inevitable, which compromises compliance to therapy for these patients [62]. Other barriers to achieving target HBA1c values include the long-term duration of diabetes, the severity of the disease, and the low effectiveness of some hypoglycemic drug classes [60, 61].

In the present study, group 1 patients showed a statistically significant reduction in triglycerides, HDL, and urea levels vs group 2 patients. Furthermore, patients in group 2 experienced a significantly higher number of hypoglycemic episodes compared to patients in group 1. These results are consistent with the findings of other studies where a higher incidence of hypoglycemic events was observed with Insulin-based regimens [53–56, 59].

An increase in body weight is one of the major side effects of Insulin therapy. A notable reduction in body weight was seen among patients of both groups. In group 1, a 1.3 kg reduction in body weight was seen after 3 months of treatment compared to baseline, whereas in group 2 patients, a 1.2 kg reduction in body weight was seen. These reductions in weight are consistent with the findings of other studies and may be attributed to Metformin which can be used in both non-obese and obese patients as a single agent or in combination for weight loss [63, 64]. Similarly, in Group 1 the weight reduction may be attributed to Empagliflozin, as 20% of patients were using Empagliflozin as a third OHA, which is consistent with the findings of another study [65]. However, we found no significant difference between the two groups based on body weight, which is inconsistent with the findings of other studies where weight gain is reported with Insulin [53, 66].

Despite numerous published studies, the dilemma of finding an optimal therapeutic option following the failure of two OHA regimens in T2DM patients still exists. Previous research has demonstrated that Insulin in combination with Metformin is a viable, short-term treatment option that offers both safety and effectiveness in achieving rapid glycemic control, but at the cost of increased hypoglycemic episodes. Nevertheless, we did not find any significant difference based on glycemic control between triple OHAs (group 1) and dual OHAs plus Insulin (group 2). Hence, we suggest triple therapy as the effective treatment option for these patients based on the following points. Firstly, there is poor adherence to Insulin therapy: >50% of patients fail to continue Insulin therapy as prescribed by their physician, approximately 60% of patients intentionally skip Insulin injections, and on top of it all, fear of injection and patient stigma are still big hurdles [67]. Secondly, weight gain [66], hypoglycemic episodes [53], and the higher cost of Insulin are major deterrents to the lifelong use of Insulin-based therapies, especially in developing countries where the majority of patients have few financial resources [68]. Similarly, triple therapy led to a significant reduction in triglycerides, and a notable increase in HDL levels compared to Insulin-based therapy.

The study has several limitations. Firstly, the duration of 3 months was short. Secondly, the third OHA with Sitagliptin and Metformin in group 1 was not uniform. Thirdly, the study was conducted in a single center; incorporating patients from different centers might have resulted in more reliable results. Lastly, data on the duration of diabetes was not collected during data collection and it was realized after analyzing the data that the patients in group 2 were significantly older.

Overall, this study demonstrates the promising role of triple therapy vs dual therapy plus Insulin for glycemic control among T2DM patients. However, these findings must be treated with caution, since the sample size and follow-up duration of this study was small, and adherence to therapy was also not ascertained. Therefore, before these results may be endorsed, stringent clinical studies evaluating the long-term effects of these therapies, including therapy adherence, must be conducted.

Conclusion

This study found no significant difference between a triple OHA regimen and a dual OHA plus Insulin regimen based on glycemic control. However, triple therapy may be preferable due to its lower incidence of hypoglycemic episodes, lower cost, and improvement in dyslipidemia compared to dual OHA plus Insulin therapy. It is important to note that further clinical research with rigorous designs is highly recommended to confirm these findings.

Data Availability

At the time of data collection and obtaining permission to communicate with patients for this research, the data owner, Abdul Wali Khan University Mardan (AWKUM), established stringent guidelines to ensure the confidentiality and privacy of patient information are maintained. Therefore the data may not be shared publicly. Data will be provided upon reasonable request if the requestor provides a valid justification for access. Data access requests may be sent to Prof. Dr. Haroon Khan, Chairperson of the Department of Pharmacy, AWKUM, at chairmanpharmacy@awkum.edu.pk.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0311435.r001

Decision Letter 0

Nimesh Lageju

23 Jun 2024

PONE-D-24-14159Effectiveness of Dual Oral Hypoglycemic Agents plus Insulin versus Triple Oral Hypoglycemic Agents in Uncontrolled Type 2 Diabetes: A Pre- and Post-AnalysisPLOS ONE

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Reviewer #1: The authors address a subject of crucial importance as Diabetes mellitus is increasing its prevalence each year. Despite the variety of drugs and insulin, it's still a challenge to decide the best regimen for better glycemic control and reduce its complications. Although a few studies suggest that starting with combined OHA may achieve better results, others suggest that the better approach is a shared decision with the patient; there isn't a definitive study to show whether adding a third OHA or insulin to achieve satisfactory glycemic control is better. Although a pre-post study design is less expensive than the RCT, does not require randomization, and can provide some information about the effect of the intervention alongside its use, it has some limitations as it cannot avoid bias either state for sure if the outcome can be attributed to the procedure. Some other points need to be clarified, mainly related to the methods.

#1 In the abstract, some methods are described in the results.

#2 Page 4, line 105: The item inclusion/exclusion criteria don't say that only patients using sitagliptin+ metformin would be included or whether there is a protocol that patients use these drugs as the first line of treatment. It would be helpful to determine whether the patients were in total doses of the medications when they started the third OHD or insulin. And explain how they began and titrated the drug or insulin dose.

#3Page 5-6, Table 1: I would not expect that Table 1 shows the baseline treatment; all patients in group 1 were already on a 3-drug regimen. Was that a mistake?

#4 In the results, it would be helpful to include, if available, the data on dropouts or compliance with the treatment.

#5 From page 10 to the end, the lines are not numbered

#6 Page 11, in the discussion, what do you mean by...' despite aggressive regimens'?

#7 On page 11, the authors attribute the weight loss to metformin. Is there any other data to support that? All patients were using metformin at the baseline, and 20% of group 1 started taking Empagliflozin.

#8 The manuscript needs corrections in the grammar and punctuation.

Reviewer #2: Review Comments

1. On the scope and title: The title is too long and needs adequate shortening. It should be guided by the scope of the study. Commonly we write as “type II Diabetes Mellitus” not “type 2 Diabetes Mellitus”.

2. On the abstract: The abstract lacks clarity and logical presentation E.g., the type of study design and analysis is missed. The result and the conclusion are inconsistent.

3. On the background: It is little bit far from the study objective. E.g., Very few points are described regarding the treatment of uncontrolled type II Diabetes and its outcome. In addition, it contains mixed of ideas and lacks linking between points. E.g., It directly jumps from global prevalence to Pakistan. Most importantly, the section lacks the main problem statement of the study.

4. On the methods section: Similarly, the methods section is incomplete for the study design, process of measurements, the sampling procedure and selection of participants as well as the type of analysis. Ethics should be presented in detail in line with the protocol of the study.

5. On the result: it lacks logical flow and brief presentation including lack of self-explanatory of tables.

6. The discussion is inadequate and needs rich explanation.

7. Others: In addition, lacks consistency E.g., you have used inclusion criteria in line 105-109 and ‘illegibility criteria’ in line 115.

Regards,

Reviewer #3: Thank you, Editor, for inviting me to review this research paper.

Authors, your research paper provides valuable insights in the field. However, some aspects need clarification and additional details to enhance the comprehensibility and robustness of your work. Below are my comments and suggestions:

Abstract:

1. Aim: Please rewrite the aim of the study to be clearer.

2. Glycemic Episodes: In the results section of the abstract, add the p-value (p=0.004) at the end of the sentence discussing glycemic episodes for better clarity.

Introduction:

3. Line 71: It would be interesting to include the prevalence of glycemic episodes among men and women in Pakistan to provide context and relevance to your study.

Methods:

4. Rationale for Criteria: Explain why you chose those with HbA1c more than 7 as the threshold. What is the rationale behind this choice? Educating the readers on this decision would enhance understanding.

5. Participant Assignment: Clarify how participants were assigned to group 1 and group 2. Were they randomly allocated? This information is crucial for assessing the validity of your study design.

6. Study Awareness: Describe how patients were informed about the study. This could include recruitment strategies.

7. Literature Support: Include literature that supports the notion that three months is a sufficient period to observe changes in patients' HBA1c levels.

8. Data Distribution: Indicate whether your data were normally distributed. This affects the choice of statistical tests and the interpretation of results.

Results:

9. Terminology: On line 157, change "the majority" were females to reflect the actual percentage. Referring to 52% as a majority is misleading. Similarly, clarify that 50% does not constitute the majority.

10. Follow-Up: Specify if there were any losses to follow-up. If yes, provide the number of patients lost and discuss the potential impact on your results.

11. Compliance: Discuss how you ensured patients' compliance with the treatment regimen. How did you confirm that they took their medications on time? I am aware that the authors mentioned this as a limitation, but did the researchers not address patient compliance at all?

12. Group Allocation: Reiterate how patients were allocated to each group. This should be clear and transparent to readers.

13. Rationale for Grouping: Explain the rationale behind your age groups, weight, and BMI categories. Providing a justification for these groupings would help in understanding your results.

14. Table 1: The oral glycemic agents in Table 1 are confusing. Please present this information more clearly.

Discussion:

15. HbA1c Values: Refer to HbA1c as a value and not a percentage.

16. Study Limitations: Given the study limitations, particularly the lack of tracking patient compliance, consider adding "A Pilot Study" to your title to accurately reflect the scope and preliminary nature of your research.

Your research is valuable, and with these revisions, it can provide even more robust and clear insights. I look forward to seeing the revised version.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Mona Abdelrehim

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PLoS One. 2024 Nov 21;19(11):e0311435. doi: 10.1371/journal.pone.0311435.r002

Author response to Decision Letter 0

10 Aug 2024

Dear Editor and Reviewers,

Thank you for taking the time to provide such detailed and helpful comments on our manuscript. We appreciate your constructive criticisms and suggestions, and we believe they will significantly improve the quality of our manuscript. We have revised the manuscript based on your feedback and would like to provide the following responses to your concerns.

Reviewer #1:

The authors address a subject of crucial importance as Diabetes mellitus is increasing its prevalence each year. Despite the variety of drugs and insulin, it's still a challenge to decide the best regimen for better glycemic control and reduce its complications. Although a few studies suggest that starting with combined OHA may achieve better results, others suggest that the better approach is a shared decision with the patient; there isn't a definitive study to show whether adding a third OHA or insulin to achieve satisfactory glycemic control is better. Although a pre-post study design is less expensive than the RCT, does not require randomization, and can provide some information about the effect of the intervention alongside its use, it has some limitations as it cannot avoid bias either state for sure if the outcome can be attributed to the procedure. Some other points need to be clarified, mainly related to the methods.

#1 In the abstract, some methods are described in the results.

Response: Thank you for the correction, suggested changes are done in the manuscript.

Response: Thank you for the comment, the inclusion criteria comprised of patients who were on full doses of sitagliptin+ metformin as a first line therapy and their diabetes was uncontrolled based on HbA1c values. The suggested changes have been done.

#3Page 5-6, Table 1: I would not expect that Table 1 shows the baseline treatment; all patients in group 1 were already on a 3-drug regimen. Was that a mistake?

Response: Thank you for the highlight this issue. This was a mistake which was overlooked at time of submission. The correction has been made in the manuscript and the details are removed from Table 1 to avoid confusion to readers. The details of group 1 and group 2 are given in text after table 1.

#4 In the results, it would be helpful to include, if available, the data on dropouts or compliance with the treatment.

Response: Thank you for comment, the compliance was ensured by principal author as the medication were given to patients free of cost and on monthly basis the patients were instructed to meet the principal author to get the next month free doses of their medication. This also help to avoid the drop out of the patients in the study.

#5 From page 10 to the end, the lines are not numbered

Response: Thank you for comment, the line numbers are assigned to the whole manuscript as suggested.

#6 Page 11, in the discussion, what do you mean by...' despite aggressive regimens?

Response: Thank you for comment and highlighting this word, to avoid confusion to readers this has been changes to “triple OHAs regimen”.

Response: Thank you for comment, the statement has been modified and updated to “Similarly, in Group 1 the weight reduction may be attributed to empagliflozin as 20% of the patients were using empagliflozin as a third OHAs, which are consistent with findings of another study [51]”.

#8 The manuscript needs corrections in the grammar and punctuation.

Response: Thank you for comment, the whole manuscript has been thoroughly edited by native English speaker.

Reviewer #2:

Response: Thank you for comment, the title is shorten as suggested to “Comparing Dual Oral Agents Plus Insulin vs. Triple Oral Agents in Uncontrolled Type II Diabetes: A Pilot Study” and the “type 2 Diabetes Mellitus” is replaced by “type II Diabetes Mellitus” in the manuscript. We included “pilot study” in title as it is suggested by one of the reviewers.

2. On the abstract: The abstract lacks clarity and logical presentation E.g., the type of study design and analysis is missed. The result and the conclusion are inconsistent.

Response: Thank you for the correction, suggested changes are done in the manuscript. The results and conclusion were rewritten again as suggested.

Response: Thank you for comment, the background section has been updated as suggested.

Response: Thank you for comment, the method section has been updated as suggested. However, the ethics approval details are not mentioned as the journal requested us to remove these details at the time of peer-review process.

5. On the result: it lacks logical flow and brief presentation including lack of self-explanatory of tables.

Response: Thank you for the comment, the result section is rewritten again to avoid confusion to the readers.

6. The discussion is inadequate and needs rich explanation.

Response: Thank you for the comment, the discussion section is updated as suggested.

7. Others: In addition, lacks consistency E.g., you have used inclusion criteria in line 105-109 and ‘illegibility criteria’ in line 115.

Response: Thank you for the highlight, the correction is done in manuscript as suggested.

Reviewer #3:

Thank you, Editor, for inviting me to review this research paper. Authors, your research paper provides valuable insights in the field. However, some aspects need clarification and additional details to enhance the comprehensibility and robustness of your work. Below are my comments and suggestions:

Abstract:

1. Aim: Please rewrite the aim of the study to be clearer.

Response: Thank you for comment, the aim is rewritten again as suggested.

2. Glycemic Episodes: In the results section of the abstract, add the p-value (p=0.004) at the end of the sentence discussing glycemic episodes for better clarity.

Response: Thank you for comment, the suggested changes has been done.

Introduction:

3. Line 71: It would be interesting to include the prevalence of glycemic episodes among men and women in Pakistan to provide context and relevance to your study.

Response: Thank you for comment, the suggested changes has been done.

Methods:

Response: Thank you for comment, the laboratory standard use in this study showed a HbA1c range: Normal: 4-6.5, Pre-diabetes: 6.6-7, diabetes: >7.1-8.0. we used this criterion and this was the rationale behind this choice.

5. Participant Assignment: Clarify how participants were assigned to group 1 and group 2. Were they randomly allocated? This information is crucial for assessing the validity of your study design.

Response: Thank you for comment, the statement is updated in the manuscript as below: “After meeting the inclusion criteria, the patients were randomly assigned into two groups”.

6. Study Awareness: Describe how patients were informed about the study. This could include recruitment strategies.

Response: Thank you for comment, the statement is updated in the manuscript as below: “The patients were approached and the purpose of the study was explained to them in Prescence of consultant endocrinologist. Those who were willing to participate an informed written consent was obtained from them”.

7. Literature Support: Include literature that supports the notion that three months is a sufficient period to observe changes in patients' HBA1c levels.

Response: Thank you for comment, the suggested changes has been done. “HbA1c is a marker of the average glucose levels spread over a two- to three-month period [25]”.

8. Data Distribution: Indicate whether your data were normally distributed. This affects the choice of statistical tests and the interpretation of results.

Response: Thank you for comment, the normality of the data was checked by using Shapiro-Wilk Test and the data showed normal distribution. Keeping in mind the normality of data, the data was presented as mean and SD. Parametric test were performed in this study as data was normally distributed.

Results:

Response: Thank you for comment, the result section is rewritten again to avoid confusion to readers.

10. Follow-Up: Specify if there were any losses to follow-up. If yes, provide the number of patients lost and discuss the potential impact on your results.

Response: Thank you for comment, there was no drop out in this study. The principal author was responsible for giving medication free of cost to the patients and on monthly basis the patients were instructed to meet the principal author to get the next month free doses of their medication. This also help to avoid the drop out of the patients in the study.

Response: Thank you for comment, the principal author was responsible for giving medication free of cost to the patients and on monthly basis the patients were instructed to meet the principal author to get the next month free doses of their medication. This also helped in compliance of the patients toward their medication. However, no specific scale/instrument was utilized for evaluation of the adherence to therapy that’s why this was included as a limitation in limitation section.

12. Group Allocation: Reiterate how patients were allocated to each group. This should be clear and transparent to readers.

Response: Thank you for comment, the statement is incorporated in the manuscript as: “After meeting the inclusion criteria, the patients were randomly assigned into two groups”

13. Rationale for Grouping: Explain the rationale behind your age groups, weight, and BMI categories. Providing a justification for these groupings would help in understanding your results.

Response: Thank you for comment, the age and weight were categorized based on the distribution of patient keeping in mind a comparable number of patients in each category. However, for the BMI, WHO classification was used.

14. Table 1: The oral glycemic agents in Table 1 are confusing. Please present this information more clearly.

Response: Thank you for comment, the details are removed from table 1 and explained at end of table 1 as below:

“All the included patients in this study were on dual OHAs i.e. Sitagliptin + Metformin. The patients were assigned into two groups. In group 1, the patients were started with additional third OHA i.e. Empagliflozin or Gliclazide or Glimepiride by their consultant endocrinologist. While for the group 2 patients were started with insulin in addition to their dual OHAs i.e. Sitagliptin + Metformin”.

Discussion:

15. HbA1c Values: Refer to HbA1c as a value and not a percentage.

Response: Thank you for comment, the HbA1c are generally presented as percentages rather than value. That is why they are presented in percentages.

Response: Thank you for comment, the suggested changes has been done.

Again, thank you for your time and valuable feedback. We believe that the revisions have significantly improved the manuscript and hope that it is now suitable for publication.

Regard’s

Corresponding author

Attachment

Submitted filename: Rebuttal for comments.docx

pone.0311435.s001.docx^{(20.3KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0311435.r003

Decision Letter 1

Nimesh Lageju

9 Sep 2024

PONE-D-24-14159R1Comparing Dual Oral Agents Plus Insulin vs. Triple Oral Agents in Uncontrolled Type II Diabetes: A Pilot StudyPLOS ONE

Dear Dr. Rehman,

Please submit your revised manuscript by Oct 24 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Nimesh Lageju

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #4: All comments have been addressed

Reviewer #5: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #4: Yes

Reviewer #5: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #4: Yes

Reviewer #5: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #4: Yes

Reviewer #5: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #4: Yes

Reviewer #5: Yes

**********

6. Review Comments to the Author

Reviewer #4: This study has some limitations, which I think authors have already acknowledged in the discussion section. The authors have also addressed the majority of the other reviewers' comments. However, I have the following additional comments/suggestions to authors:

1. For ease of understanding, authors should consider including a flow chart that shows the number of participants evaluated for potential enrolment into the trial and the number excluded because they did not meet the inclusion criteria or declined to participate.

2. Authors should also include information on the time of the day when treatment was given to participants, as well as whether the drugs were given before or after a meal. This information can be added to the methods/results section.

3. Figure legends should be expanded to include brief descriptions of the plots depicted.

Reviewer #5: Thank you for offering me an invitation to be the reviewer of this manuscript “Comparing Dual Oral Agents Plus Insulin vs. Triple Oral Agents in Uncontrolled Type II Diabetes: A Pilot Study”

The authors had submitted a manuscript comparing dual OHA’s with Insulin and triple OHA’s in uncontrolled Type II diabetes. The selected topic becomes increasingly significant given the burden of diabetes in Asian countries.

I am giving my observations and comments for the authors to consider:

I observe the corresponding author in the first page is different from the one mentioned in page 1 line 18-24

Introduction: The introduction effectively justifies the chosen topic and the methods with convincing arguments supported by relevant references, as required.

Line 41: Insulin (please maintain the Case)

Page line 62-63: Type 1 DM increases Type 2 DM prevalence? May be rewritten as “There is an increasing trend in Type 1 DM worldwide as well”.

Line 66-67: Repeat info, may be removed

Line 70-71 Ref 16 – IDF Diabetes Atlas 10th edition may be a better reference for this information

Line 79 - Instead of “ T2DM” uncontrolled T2 DM may be used

Line 81-82: mention as “Disease” rather than “Damage”

Line 78-85: May be made briefer and to the point using scientific terms

Line 94-98 may be moved down after discussion on preferred dual therapy.

Justification may be given for choosing patients on Sitagliptin & Metformin combination, is that the preferred dual therapy in the geographical area?

Inclusion/Exclusion Criteria: It will be helpful to know if patients who are exposed to multiple drug combination before, are also excluded.

Study Procedure:

Line 138: Term “renal functioning test” may be removed

Line 141: It will be good to know how the third drug is chosen between the three choices

Line 147: Grp 2: Please mention the type of Insulin added - analogs, rapid or long acting or mix, etc

Results:

Table1: The information regarding drug regimen is missing. This information may help to explain the weight gain and glycemic control results. Suggesting to add.

Data on diabetes age of the patients if available will be significant to interpret the results considering the fact that grp 2 patients are significantly older.

Figure 1:

Group1 showed 20% improvement in glycemic control while in Group 2, 30 % of participants showed improvement. The reduction in HbA1c depends on the baseline level. Since number of patients with HbA1c more than 10 are considerable in both the groups, data of ‘more than 8’ may be further grouped and analysed.

Line 220-221: Higher the HDL is a positive outcome. Suggested to rewrite the sentence

Line 240-241: Is this an error? that patients prefer Insulin over OHA? If it is an error, please correct.

The limitations of the study are well-documented and enumerated.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #4: Yes: Suhail A. Ansari

Reviewer #5: No

**********

PLoS One. 2024 Nov 21;19(11):e0311435. doi: 10.1371/journal.pone.0311435.r004

Author response to Decision Letter 1

16 Sep 2024

Dear Editor and Reviewers,

Reply to comments

Reviewer #4

This study has some limitations, which I think authors have already acknowledged in the discussion section. The authors have also addressed the majority of the other reviewers' comments. However, I have the following additional comments/suggestions to authors:

Comment: 1. For ease of understanding, authors should consider including a flow chart that shows the number of participants evaluated for potential enrolment into the trial and the number excluded because they did not meet the inclusion criteria or declined to participate.

Response: Thank you for your comment, the flowchart is added to the manuscript as Figure 1.

Comment: 2. Authors should also include information on the time of the day when treatment was given to participants, as well as whether the drugs were given before or after a meal. This information can be added to the methods/results section.

Response: Thank you for your comment. Patients were advised to take the Sitagliptin + Metformin combination tablet twice a day, either with a meal or right after eating. Empagliflozin should be taken once in the morning, along with breakfast. Glimepiride is also to be taken once daily, with breakfast. Similarly, Gliclazide is taken once daily in the morning, with a meal.

Comment: 3. Figure legends should be expanded to include brief descriptions of the plots depicted.

Response: Thank you for your comment, the suggested changes have been incorporated in the manuscript.

Reviewer #5

Thank you for offering me an invitation to be the reviewer of this manuscript “Comparing Dual Oral Agents Plus Insulin vs. Triple Oral Agents in Uncontrolled Type II Diabetes: A Pilot Study”. The authors had submitted a manuscript comparing dual OHA’s with Insulin and triple OHA’s in uncontrolled Type II diabetes. The selected topic becomes increasingly significant given the burden of diabetes in Asian countries.

I am giving my observations and comments for the authors to consider:

Comment: I observe the corresponding author in the first page is different from the one mentioned in page 1 line 18-24.

Response: Thank you for your constructive comment, the corresponding author in the manuscript is to be considered while ignoring the submission author.

Introduction: The introduction effectively justifies the chosen topic and the methods with convincing arguments supported by relevant references, as required.

Comment: Line 41: Insulin (please maintain the Case)

Response: Thank you for your comment, the suggested changes have been made to the manuscript.

Comment: Page line 62-63: Type 1 DM increases Type 2 DM prevalence? May be rewritten as “There is an increasing trend in Type 1 DM worldwide as well”.

Response: Thank you for your comment, the suggested changes have been made to the manuscript.

Comment: Line 66-67: Repeat info, may be removed

Response: Thank you for your comment, the suggested changes have been made to the manuscript.

Comment: Line 70-71 Ref 16 – IDF Diabetes Atlas 10th edition may be a better reference for this information

Response: Thank you for your comment, the suggested changes have been made in the manuscript to IDF Diabetes Atlas 10th Edition in Reference 16.

Comment: Line 79 - Instead of “T2DM” uncontrolled T2 DM may be used

Response: Thank you for your comment, the suggested changes have been made to the manuscript as per the below comment to make it concise using scientific terms.

Comment: Line 81-82: mention as “Disease” rather than “Damage”

Response: Thank you for your comment, the suggested changes have been made to the manuscript.

Comment: Line 78-85: May be made briefer and to the point using scientific terms

Response: Thank you for your comment, the suggested changes have been made to the manuscript.

Comment: Line 94-98 may be moved down after discussion on preferred dual therapy.

Response: Thank you for the comment, the section is moved to page no 8, discussion section after the preferred dual therapy as suggested.

Comment: Justification may be given for choosing patients on Sitagliptin & Metformin combination, is that the preferred dual therapy in the geographical area?

Response: Thank you for your comment, Sitagliptin & Metformin combination is the preferred dual therapy is the preferred choice by endocrinologists in our geographic location.

Comment: Inclusion/Exclusion Criteria: It will be helpful to know if patients who are exposed to multiple drug combination before, are also excluded.

Response: Thank you for your comment, the suggested changes have been made to the relevant section i.e. inclusion/exclusion criteria in the manuscript.

Study Procedure:

Comment: Line 138: Term “renal functioning test” may be removed

Response: Thank you for your comment, the suggested text is removed from the manuscript.

Comment: Line 141: It will be good to know how the third drug is chosen between the three choices.

Response: Thank you for your comment, Empagliflozin and Gliclazide were added to the other two oral anti-diabetic medications because both offer cardiovascular benefits. Empagliflozin also has kidney-protective effects, which is important since many patients in Group 1 had high blood pressure and heart disease. Similarly, Glimepiride was chosen for its ability to slow the progression of diabetes and reduce the need for insulin, while also being cost-effective. The choice of a third medication to add to the existing two was based on the patient's overall health, including comorbid conditions, and sometimes the endocrinologist's preference for a specific medication.

Comment: Line 147: Grp 2: Please mention the type of Insulin added - analogs, rapid or long acting or mix, etc.

Response: Thank you for your comment, the Insulin used in our study was pre-mixed Insulin (70/30), and the same has been added in the method section under the section Group 2 heading.

Results:

Comment: Table1: The information regarding drug regimen is missing. This information may help to explain the weight gain and glycemic control results. Suggesting to add.

Response: Thank you for highlighting this; to avoid confusion, a footnote is added at the end of table 1 showing Group 1 and Group 2 along with details of the treatment regimen.

Comment: Data on diabetes age of the patients if available will be significant to interpret the results considering the fact that grp 2 patients are significantly older.

Response: Thank you for highlighting this point, the data on how long patients had diabetes was not collected and this could be a possible limitation of this study which is added to the limitation section of the manuscript.

Comment: Figure 1: Group1 showed 20% improvement in glycemic control while in Group 2, 30 % of participants showed improvement. The reduction in HbA1c depends on the baseline level. Since number of patients with HbA1c more than 10 are considerable in both the groups, data of ‘more than 8’ may be further grouped and analysed.

Response: Thank you for your comment, the patients recruited in the study were having HbA1c > 7% for the last year or more despite using dual OHAs (full doses of Sitagliptin and Metformin). As suggested the data was checked again for further analysis while grouping them in having HbA1c more than 8, the data revealed that only 1 participant/patient in each group was having HbA1c less than 8 i.e. 7.9 in both groups. Due to this further group and analysis will have no impact on the findings. I am hopeful that the honorable reviewer will agree with our point of view.

Comment: Line 220-221: Higher the HDL is a positive outcome. Suggested to rewrite the sentence

Response: Thank you for your comment, the suggested changes have been made to the manuscript.

Comment: Line 240-241: Is this an error? that patients prefer Insulin over OHA? If it is an error, please correct.

Response: Thank you for the comment, that was a typo and is removed from the manuscript to avoid confusion to the readers.

Comment: The limitations of the study are well-documented and enumerated.

Response: Thank you for your comment, we are thankful for sparing time for a thorough review of the manuscript.

Again, thank you for your time and valuable feedback. We believe that the revisions have significantly improved the manuscript and hope that it is now suitable for publication.

Regards

Corresponding author

Attachment

Submitted filename: Rebuttal to reviewers comments.docx

pone.0311435.s002.docx^{(22KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0311435.r005

Decision Letter 2

Nimesh Lageju

20 Sep 2024

Comparing Dual Oral Agents Plus Insulin vs. Triple Oral Agents in Uncontrolled Type II Diabetes: A Pilot Study

PONE-D-24-14159R2

Dear Dr. Rehman,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Nimesh Lageju

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0311435.r006

Acceptance letter

Nimesh Lageju

12 Nov 2024

PONE-D-24-14159R2

PLOS ONE

Dear Dr. Rehman,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

* All relevant supporting information is included in the manuscript submission,

* There are no issues that prevent the paper from being properly typeset

If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps.

Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

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on behalf of

Dr. Nimesh Lageju

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Attachment

Submitted filename: Rebuttal for comments.docx

pone.0311435.s001.docx^{(20.3KB, docx)}

Attachment

Submitted filename: Rebuttal to reviewers comments.docx

pone.0311435.s002.docx^{(22KB, docx)}

Data Availability Statement

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PERMALINK

Comparing dual oral agents plus insulin vs. Triple oral agents in uncontrolled type II diabetes: A pilot study

Nadia Gul

Inayat Ur Rehman

Yasar shah

Arbab Muhammad Ali

Zahid Ali

Omer Shehzad

Khang Wen Goh

Long Chiau Ming

Amal K Suleiman

Roles

Abstract

Introduction

Aim

Method

Results

Conclusion

Introduction

Method

Study design and setting

Inclusion/exclusion criteria

Process of measurement

Study procedure

Group 1

Group 2

Ethics and dissemination

Sample size

Statistical analysis

Results

Fig 1. Flow chart of patient’s recruitment and participation.

Table 1. Demographics and baseline characteristics of patients.

Table 2. Comparison of study groups based on patients’ variables before and after administration of study drugs.

Fig 2. Impact of group 1 and group 2 drugs on hyperglycemia based on HbA1c levels before and after 3 months of administration.

Table 3. Comparative analyses of group 1 vs group 2 based on various patient characteristics.

Fig 3. Frequency of hypoglycemic episodes in group 1 vs group 2.

Discussion

Conclusion

Data Availability

Funding Statement

References

Decision Letter 0

Nimesh Lageju

Roles

Author response to Decision Letter 0

Decision Letter 1

Nimesh Lageju

Roles

Author response to Decision Letter 1

Decision Letter 2

Nimesh Lageju

Roles

Acceptance letter

Nimesh Lageju

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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