Glycemic control in newly insulin-initiated patients with type 2 diabetes mellitus: A retrospective follow-up study at a university hospital in Ethiopia.

BACKGROUND: Though many trials had examined the effectiveness of taking insulin with or without oral agents, there are limited real-world data, particularly among patients with type 2 diabetes mellitus (T2DM) in the resource limited settings. This study aimed to examine level of glycemic control among patients with T2DM after initiation of insulin and factors associated with poor glycemic control.
METHODS: An analysis of retrospective medical records of patients with T2DM who initiated insulin due to uncontrolled hyperglycemia by oral agents was conducted from 2015-2020 in the University of Gondar Comprehensive Specialized Hospital. Difference in median fasting plasma glucose (FPG) before and after insulin initiations was examined by a Wilcoxon signed-rank test. Kruskal Wallis test was performed to explore difference in the median level of FPG among treatment groups. A logistic regression model was also used to identify associated factors of poor glycemic control after insulin initiation. Statistical significance was declared at p < 0.05.
RESULTS: Of 424 enrolled patients with T2DM, 54.7% were males and the mean age was 59.3±9.3 years. A Wilcoxon signed-rank test showed that there was significant deference in FPG before and after insulin initiation (P < 0.001). A declining trend of blood glucose was observed during the 1-year follow-up period of post-initiation. However, majority of the participants did not achieve target glucose levels. Participants who had higher FPG and systolic blood pressure (SBP) before insulin initiation were found more likely to have poor glycemic control after insulin initiation. Similarly, patients who received atorvastatin compared with simvastatin were found to have poor glycemic control in the post-period of initiation (P = 0.04). Premixed insulin was associated with a lower likelihood of poor glycemic control than neutral protamine Hagedorn (NPH) insulin (P < 0.001).
CONCLUSION: Following insulin initiation, a significant change in glycemic level and declining trend of FPG was observed during a 1-year follow-up period. However, the majority of patients still had a poorly controlled glycemic level. Appropriate management focusing on predictors of glycemic control would be of a great benefit to achieve glycemic control.

Introduction

Diabetes continues to be one of the most common non-communicable chronic diseases, and described by elevated blood glucose levels [1,2]. Type 2 Diabetes Mellitus (T2DM) is the main type of diabetes in adults, which is characterized by a gradual deterioration of glycemic control due to progressive pancreatic beta-cell dysfunction of insulin secretion on the background of increasing of insulin resistance [3-5]. In long term, uncontrolled hyperglycemia leads to complications of cardiovascular diseases (CVDs) and microvascular complications like damages of eyes, kidneys and nerves, and finally, leads for death [1]. In addition to these common macrovascular and microvascular complications, diabetes has been associated with another important complications like cochlear dysfunction [6], and sexual dysfunction and fracture [7,8].

The International Diabetes Federation (IDF) diabetes Atlas reported in 2021 that the prevalence of diabetes in adults was 10.5% (537 million) and estimated to be 12.2% (783 million) in 2045 worldwide, while in Africa it was 4.5% (24 million) in 2021 and projected to be 5.2% (55 million) in 2045. This demonstrates diabetes has become a major public health problem particularly in under developed countries with a significant social and financial implications [9]. In Ethiopia, the prevalence of diabetes was estimated as high as 6.5% [10]; and it makes one of the largest diabetes population in the sub-Saharan Africa.

The main goal of T2DM treatment is to safely achieve and maintain glycemic control to reduce risk of diabetes related microvascular and macrovascular complications, and in the long run, diabetes related mortality. With this regard, the American Diabetes Association (ADA) recommends glycemic targets of glycosylated hemoglobin (HbA1c) values to be <7% and fasting plasma glucose (FPG) levels of 70 to 130 mg/dl [11]. Even though patients with T2DM may initially attain glycemic control with oral antidiabetics (OADs), achieving a target glycemic level becomes increasingly difficult due to disease progression, and most patients ultimately require multidrug regimens and insulin initiation [12-14].

Evidences has shown that insulin therapy improves diabetes symptoms and delay of insulin initiation may lead to significant number of diabetes related complications [15,16]. Although timely initiation of insulin for T2DM has been recommended to prevent diabetes related complications by early establishment of strict glycemic control and pancreatic beta-cell protection [17], greater proportion of patients with suboptimal glucose level tend to delay insulin therapy [18] due to fear of hypoglycemia and weight gain [19,20]. In some case, patients may not take medications intentionally, driven by their emotions they may conceal it and become nonadherence to the recommended medication, which in turn lead to potential diabetes related complications and dire consequences [21], therefore, the need to educate patients about management practices and lifestyle modifications to achieve good treatment outcome could be mandatory [22]. Healthcare providers-patient relationship is also very crucial in the treatment intensification and medication adherence. Moreover, the physician himself may also denote a risk factor for poor glycemic control due to the fear of potential drug’s adverse effect and not providing appropriate patient’s counseling [23,24]. On the other hand, the majority of patients with T2DM who initiate insulin therapy are also unable to achieve the target glycemic levels [25,26]. As a result, T2DM treatment guidelines have acknowledged a variety of factors can affect an individual’s ability to reach the standardized glycemic goal and promote patient-centered management, and health service providers also request more and real-world data on which particular patient characteristics determines glycemic outcomes [27-29].

Though many studies had examined the effectiveness of taking insulin with or without oral agents [30-32], there are limited real-world data, particularly among patients with T2DM in resource limited-countries. To the best of our literature search, a single article that examine level of glycemic control in patients with T2DM after insulin initiation has not been published in low-income settings like Ethiopia, particularly in the study area. Identification of the factors associated with poor glycemic control by using data from routine clinical care settings and characterize the level of glycemic control is important. This will help to institute appropriate measure to improve glycemic control, and prevent long-term complications and organ damages related with diabetes [33]. Therefore, this study aimed to examine level of glycemic control in patients with T2DM after initiation of insulin and associated factors for poor glycemic control at the University of Gondar Comprehensive Specialized Hospital (UoGCSH), Northwest Ethiopia. This real-world data may help to understand the trends of glycemic control and factors associated with poor glycemic control in T2DM patients initiated with insulin in the resource limited settings.

Methods and materials

Study design and participants

Retrospective follow-up study was conducted from 2015 to 2020 using medical records of patients with T2DM at UoGCSH. Patients with age 18 years and above who initiated insulin due to inadequate glycemic control by OADs were recruited and then followed 1-year pre and post initiation. To be selected in the study, patients were required to be treated with insulin therapy during the indexed period of 2015–2020. The date that the first prescription with insulin identified was taken as index date. Patients should have available data for 1 year before and after the index date, received OADs before the index date and insulin after the index date. Patients were excluded in the study if they received a diagnosis of gestational diabetes or type I diabetes over the indexed period. Patients with incomplete medical records were also excluded from the study.

Sampling size determination and sampling technique

The sample size was determined by using a single population proportion formula:

n = Z2 p (1-p)/W, Where, n = sample size required, W = marginal error of 5% (w = 0.05), Z = the degree of accuracy required (95% level of significance = 1.96), P = the proportion of poor glycemic control in patients with T2DM treated with insulin-based therapy assumed to be 0.5(50%), this is because no appropriate prior study was conducted in the study setting and other areas with similar population background. Considering the possible incomplete patient records to be 10%, 424 patient records were enrolled in the final study and selected using systematic random sampling technique from the list of all eligible study population. Simple random sampling technique using lottery method was also used to select the first participant to be the starting point. Then using the sampling interval with coding of their medical records, participants were enrolled until the required sample size was fulfilled.

Operational definitions

Macrovascular complications: diabetes associated complications related to cardiovascular outcomes such as stroke, ischemic heart disease, heart failure, coronary artery disease, peripheral vascular disease.

Microvascular complications: diabetes associated complications related to kidney (diabetic nephropathy), nerves (peripheral neuropathy) and eye problems (diabetic retinopathy)

Renal problems: include comorbidities diagnosed as acute and/or chronic kidney disease on the patients’ physical medical records

Data collection instruments and procedures

The data extraction tools were prepared by reviewing different literatures and amendments were made considering the setting and nature of patient medical records. The data collection tool had four parts. The first consisted socio-demographic characteristics of patients and the rest were clinical characteristics and medications before insulin initiation, during initiation and after initiation. A socio-demographic characteristic of the patients includes; age, gender, residency, and duration of T2DM since diagnosis, duration of treatment with OADs. Whereas clinical characteristics includes laboratory results, physicians and nurse notes, prescribed and dispensed medications, diagnosis and procedures other details of patients visit to the hospital during the follow-up periods. Medications also includes types of diabetic medications, antihypertensive agents, lipid-lowering agents and other medications used for the treatment of presented comorbidities and complications of patients. A 2-year data (1 year before and 1 year after the indexed date) were recorded every three months from stored physical medical records of the patients, and printed laboratory results were also checked for some laboratory tests like FPG, serum creatinine (Scr.) and lipid profiles such as total cholesterol (TCL) and triglycerides (TG). Metformin with or without glibenclamide was used in in pre-period of initiation and then insulin (NPH or premixed) was initiated. Treatment intensification including dosing titration and frequency were modified based on the ADA recommendations.

Data quality management and statistical analysis

The data collectors and supervisor were trained before the actual data collection. Pretest was done on 10% of sample size and some amendments was done. Once the medical record identification numbers were entered to the Microsoft excel 2016 and checked for repetition, the data was extracted. The supervisor has explicitly followed the data collection closely. Both the data collectors and supervisor checked the data for its completeness and missing information at each point before analysis. After checking the data completeness and cleanness, then coded and entered to Epi Info version 7 and exported to SPSS Version 26 for analysis.

Descriptive statistics such as frequencies and percentage were used for categorical variables and mean with standard deviation were used for continuous variables. Non-normality of the data for FPG, systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid profiles and SCr. was examined by Q-Q plot and histogram, and median with an inter-quartile range (IQR) was used to measure their levels.

A Wilcoxon signed-rank test was used to examine the median score difference between paired FPG after and before insulin initiation. Median score difference in FPG between treatment groups (insulin alone Vs insulin plus metformin Vs insulin plus metformin plus glibenclamide) was explored by Kruskal-Wallis test. The Post-hoc test using a Pairwise Multiple-comparative analysis was also used to compare the glycemic difference between all paired treatment groups. The logistic regression model was fitted to assess variables associated with poor glycemic control after insulin-initiation. Variables, with P ≤ 0.25 in the bivariable analysis, were entered for multivariable logistic regression analysis. Finally, the adjusted odds ratio (AOR) with 95% confidence interval (CI) was reported, and a P-value < 0.05 was statistically significant.

Glycemic outcome measurements

The glycemic outcome following insulin initiation in this study was examined by using level of FPG due to non-availability of HbA1c. The American diabetes association categorized glycemic control as good glycemic control: FPG levels of 70 to 130 mg/dl and poor glycemic control: FPG level of either <70mg/dl or FPG >130 mg/dl [11].

Ethical considerations

The study was approved by the ethics approval committee of the University of Gondar with reference number of Sop/037/2020. The need for informed consent was waived by the ethics committee of the University of Gondar because the study did not directly involve the patients. Privacy and confidentiality were kept, and all methods were carried out in accordance with relevant guidelines and regulations.

Results

Socio-demographic and baseline clinical characteristics

From a total of 937 eligible patients with T2DM, 424 study subjects were included in the study. More than half of the analyzed subjects were male (54.7% and urban residents (59.9%). Most of study participants had hypertension (67%) along with diabetes, and patients were most commonly received metformin plus glibenclamide combination therapy prior to insulin initiation. Enalapril (59%) was also the most frequently prescribed cardiovascular medication. The median (IQR) of FPG level at the index date was 350 (179–401) mg/dl, Tables 1 and 2.

Table 1

Socio-demographic and baseline clinical characteristics of newly insulin-initiated patients with T2DM having follow-up at UoGCSH from 2015–2020 (N = 424).

Characteristics		Frequency (%)	Mean ± SD or Median (IQR)
Sex	Male	232 (54.7)
	Female	192 (45.3)
Age (years)	Mean ± SD	-	59.3± 9.3
Weight (Kg)	Mean ± SD	-	65.7± 8.2
Residency	Urban	254 (59.9)
	Rural	17 (40.1)
Clinical characteristics
Years since T2DM diagnosis.	Mean ±SD	-	13.4±4.0
Years since OADs started	Mean ±SD	-	12.9± 3.8
Comorbidities and Complications	Hypertension	284 (67.0)
	Dyslipidemia	151 (35.6)
	Macrovascular Complications	66 (15.6)
	Bacterial infection	27 (6.4)
	Microvascular Complications	25 (5.9)
	Diabetic Keto-acidosis (DKA)	22 (5.2)
	Renal problems (AKI and CKD)	15 (3.5)
	Retroviral infection	12 (2.8)
	Bronchial asthma	6 (1.4)
	Thyrotoxicosis	5 (1.2)
Laboratory Parameters
	FPG (mg/dl) at 12th month before the index date	-	188(166–209)
	FPG (mg/dl) at the index date	-	350(179–401)
	SBP (mmHG) at 12th month before the index date	-	130(130–140)
	DBP (mmHG) at 12th month before the index date	-	70(70–80)
	SBP (mmHG) at the index date	-	140(130–140)
	DBP (mmHG) at the index date	-	80.00(71.25–90)
	Creatinine (mg/dl) at 12th month before the index date	-	0.88(0.81–1.13)
	Creatinine (mg/dl) at the index date	-	0.89(0.81–1.06)
	Total cholesterol(mg/dl) at 12th month before the index date	-	178.12(125.5–196.25)
	Total cholesterol at the index date	-	179(165.755–216.75)
	Total triglyceride (mg/dl) at 12th month before the index date	-	161(140.01–210)
	Total triglyceride (mg/dl) at the index date	-	154(140.25–190.75)

AKI, Acute kidney injury; CKD, Chronic kidney disease; SD, Standard deviation; IQR, Inter quartile range.

Table 2

Distribution of baseline medications used to treat study participants (N = 424).

Medications			Frequency	Percent
OADs	Before insulin initiation	Metformin	62	14.6
		Metformin plus Glibenclamide	362	85.4
	During insulin initiation	Metformin	56	13.2
		Metformin plus Glibenclamide	368	86.8
Antihypertensive agents	Enalapril		251	59.0
	Amlodipine		25	5.9
	Hydrochlorothiazide		77	18.2
	Atenolol		15	5.3
	Metoprolol		12	2.8
	Nifedipine		14	3.3
	Furosemide		4	0.9
Lipid lowering agent	Atorvastatin		103	24.3
	Simvastatin		79	18.6
Aspirin (ASA)			61	14.4
Amitriptyline			19	4.5
Antibiotics	Ceftriaxone		23	5.4
	Metronidazole		7	1.7
	Vancomycin		4	0.9
Gastrointestinal	Omeprazole		14	3.3
Anti-Retroviral Therapy	TDF/3TC/DTG		10	2.4
	AZT/3TC/DTG		2	0.5
Anti-asthmatic	Salbutamol		6	1.4
	Beclomethasone		6	1.4
Anticoagulant	Warfarin		6	1.4
Anti-thyroid	Propyl thiouracil		5	1.2

TDF, Tenofovir disoproxil fumarate; 3TC, Lamivudine; DTG, Dolutegravir; AZT, Zidovudine.

Patterns of medication and level of glucose during the follow-up period

The majority of patients had received a combination of metformin and glibenclamide therapy in all follow-up periods prior to insulin initiation, and nearly more than two-thirds of patients were received a combination of insulin and metformin during post-initiation periods (S1 Fig). Furthermore, the median FPG level was lower among patients treated by metformin than patients treated by a combination of metformin plus glibenclamide in all follow-up periods. Similarly, the median FPG level was also lower among patients received triple therapy (insulin plus metformin plus glibenclamide) compared with patients on dual therapy of insulin plus metformin and insulin single therapy in the post- initiation periods (S2 Fig). Among the types of insulins, significant number of patients had received NPH insulin-based therapy. However, frequency of clinical hypoglycemia was recorded more among patients treated with premixed insulin-based regimen than patients treated by NPH insulin-based therapy.

Glycemic control following insulin initiation and trends of glucose level

The level of blood glucose was compared before and after insulin initiation. On average, the study participants had worse before (Mdn = 350) than after insulin initiation (Mdn = 175.5) at the 3rd month of post-initiation period, and gradual declining of FPG level in a 1-year follow-up period was also observed. A Wilcoxon signed-rank test indicated that this difference was statistically significantly, T = 90,100, Z = -17.84, P < 0.001. However, significant number patients did not achieve a target glycemic level after insulin initiation, three-fourths (75%) and 61.3% of the study participants did not achieve the target FPG level at 3rd and 12th month of post-initiation periods, respectively (Fig 1). The study participants achieved target blood glucose level with an average time of 6.7±3.4 months during the 1–year follow-up period after insulin initiation. As shown in the Fig 2, the level of FPG was increased since 12th month of pre-period of initiation until the index date but a sharp decreasing in FPG initially followed by gradual decline was observed through a one-year follow-up period in the post-insulin initiation time.

Fig 1

Proportion of participants to level of glycemic control after insulin initiation (N = 424).

Fig 2

Trend of fasting blood glucose levels of participants during the 2-years of follow-up periods.

Difference in blood glucose between treatment groups after insulin initiation

A significantly reduced level of FPG after insulin initiation was recorded with the overall median (IQR) score of 175.5 (135–209) mg/dl at the 3rd month of post-initiation period. However, patients who were treated by triple therapy of insulin plus metformin plus glibenclamide had worse glycemic level (Mdn = 200) than patients treated by combination therapy of insulin plus metformin (Mdn = 170) and insulin alone (Mdn = 170.5). A Kruskal-Walli’s test revealed that the deference in level of FPG among treatment groups was statistically significant, H (2) = 19.51, P < 0.001. The Post-hoc tests using a Pairwise Multiple-comparative analysis showed that there was a statistically significant difference in level of FPG between a combination therapy of insulin plus metformin (Mdn = 170) vs insulin plus metformin plus glibenclamide triple treatment groups (Mdn = 200), P < of 0.001. There was also a difference in proportion of patients achieving glycemic control among these treatment groups. One-third of patients (33.3%) from insulin treated group, 29.8% from insulin plus metformin and 15.2% from insulin plus metformin plus glibenclamide treatment groups achieved the target FPG level.

However, significant difference in level of FPG among treatment groups was not observed at the 12th month of post-initiation period, and the overall median (IQR) of FPG was 139 (114–159.75). A Kruskal-Wallis test also showed that the difference in level of median FPG among treatment groups was not statistically significant, H (2) = 3.27, P = 0.195. Nearly two–fifths of patients had achieved target FPG level among all treatment groups, 40.7% from insulin, 38.2% from insulin plus metformin and 38% from insulin plus metformin plus glibenclamide treatment groups.

Determinants of glycemic control after insulin initiation

The multivariable logistics regression model showed an association between post-initiation period of poor glycemic control and higher FPG and SBP levels during the index date, and use of atorvastatin compared to simvastatin was also associated with poor glycemic control in the post period of insulin initiation. Higher FPG and SBP levels during insulin initiation were significantly associated with poor glycemic control after 3rd month of insulin initiation, [AOR: 1.018(1.009–1.028); P < 0.001] and [AOR: 1.074(1.028–1.127); P = 0.004], respectively. Similarly, patients who were treated with atorvastatin were found more likely to have poor glycemic control than patients who were treated by simvastatin at the 3rd month of post-initiation, [AOR: 2.573 (1.046–6.328); P = 0.04]. On the other hand, premixed insulin was associated with a lower likelihood of poor glycemic control as compared with NPH insulin, [AOR: 0.147(0.056–0.368); P ≤ 0.001], Table 3.

Table 3

Association of variables with poor glycemic control after insulin initiation.

Variables		Glycemic control		COR (95% CI)	P-value	AOR (95% CI)	P-value
		Poor        Good
Duration in years since T2DM diagnosis (mean ± SD)		13.6±4	12.8±3.8	1.052(0.993–1.114)	0.086	0.567(0.306–1.048)	0.07
Duration in years since OADs initiation (mean ± SD)		13.1±3.9	12.2±3.5	1.062(1.000–1.127)	0.049	1.777(0.940–3.356)	0.077
FPG at the index date (Median (IQR)		365 (326–406)	323 (306–349)	1.014 (1.009–1.018)	0.000	1.018(1.009–1.028)	0.000*
SBP at the index date (Median (IQR)		140(130–140)	130(130–140)	1.037(1.014–1.061)	0.002	1.074(1.028–1.127)	0.004*
Residency	UrbanRural	180138	7432	0.564 (0.352–0.903)1	0.017	0.586(0.225–1.525)1	0.273
OADs during insulin initiation	Metformin plus glibenclamideMetformin	28038	8818	1.507 (0.819–2.773)1	0.187	0.724 (0.218–2.046)1	0.598
Hypertension	YesNo	23385	7135	1.351(0.840–2.1731	0.214	0.517 (0.172–1.556)1	0.241
Furosemide after insulin initiation	YesNo	1317	6100	0.053(0.006–0.442)1	0.007	0.157 (0.015–1663)1	0.124
Lipid lowering agents	AtorvastatinSimvastatin	11832	3019	2.335 (1.166–4.679)1	0.017	2.573(1.046–6.328)1	0.04*
ASA after insulin initiation	YesNo	49269	2284	0.696 (0.397–1.217)1	0.203	1.160 (0.469–2.867)1	0.748
Diabetes medications	Insulin plus metforminInsulin plus metformin plus glibenclamideInsulin	17912616	78228	1.187 (0.487–2.891)2.696 (1.034–7.028)1	0.0060.7060.043	0.770 (0.125–4.741)0.568 (0.076–4.219)1	0.8010.7780.58
Type of insulin	PremixedNPH	41277	4561	0.201(0.121–0.333)1	000	0.147 (0.059–0.368)1	0.000*

ASA, Aspirin; COR, Crude odds ratio; AOR, Adjusted odds ratio; IQR, inter-quartile range; P-value * indicates the statistically significant variables at P < 0.05.

Discussion

This is an institutional based retrospective follow-up study focused on examining glycemic control in insulin-initiated patients with T2DM due to inadequate glycemic control by OADs alone. The results highlight that level of glycemic control differ meaningfully from more strictly controlled trials [34,35]. Thus, in order to identify which specific patient factors affect glycemic outcomes, generating data from a real-world clinical setting was as such important.

The current study revealed that the initiation of insulin in patients with T2DM resulted in a significant decreasing level of glucose after insulin initiation. Consistent to the previous studies assessing glycemic control in patients with T2DM after initiation of insulin therapy [25,26,36-39], the current result showed that a lower proportion of patients achieved target FPG level during the 1-year follow-up period. This indicate that the current target blood glucose goal may be unachievable for many patients with T2DM even after insulin initiation. However, this result is inconsistent with findings from clinical trials [34,35]; a significant number of patients achieving glycemic control. But it would be recognized that these clinical trials may not indicate the real life of clinical care due to nature of its’ design with treat to target trail, narrow inclusion criteria, close monitoring and regular follow-up during the study. Furthermore, it would be noted that vast majority of patients in the current study did not have a regular HbA1c test as ADA recommendations. Consequently, this used FPG to examine glycemic control, and it might have different result as compared with clinical trials using HbA1c. Therefore, to obtain better glycemic outcome in the real-world clinical settings, insulin intensification and titration could be based on the actual specific patients’ characteristics which potentially affect glycemic control. However, the treatment might not have been intensified and titrated effectively because of fear of adverse effects like hypoglycemia, and the need to educate patients about insulin administration and adverse effects would be mandatory. Patient educational on lifestyle modification and management practices could be also an important component to achieve better treatment outcome [22], and as a result patients and healthcare providers would give an equal attention to patient education as equal as medication management.

Consistent with previous studies [40-42], the blood glucose level at 3rd month of insulin initiation was significantly different among treatment groups. The results may be explained by patients who have worse glycemic level may require a combination of oral medications besides insulin to achieve their target glucose levels. The current study also disclosed that initial oral medications were continued or added in the regimen for patients with worse glycemic level following insulin initiation. In contrast, nearly equivalent glycemic levels were achieved at the 12th month of insulin initiation in all treatment groups, in consistent with the previous study [43]. This might be achieved because of increased treatment titration and treatment modifications for patients those with poor glycemic level in the early period of insulin initiation. However, regardless of differences in the level of blood glucose throughout the follow-up periods, improved change in glycemic levels after insulin initiation was observed in all treatment groups. This is in agreement with previous studies conducted across the globe [36,44-46], which shows significant change in blood glucose level after insulin initiation in patients with T2DM who were initially treated with OADs. Moreover, this study also showed that during a one-year follow-up period of post-insulin initiation, a continual declining in blood glucose level was observed from the insulin initiation to the end of follow-up period.

The current study also demonstrated about factors affecting glycemic control in insulin-initiated patients with T2DM. Similar to other studies [47-50], the current finding showed that higher baseline blood glucose level was significantly associated with poor glycemic outcome in post-initiation period. This suggests that patients with good baseline glycemic control have minimal deterioration of glycemic level after insulin initiation and the probability of achieving the target glycemic level may strongly associated with the baseline level of glucose. Thus, early insulin initiation in patients having indication might be important to achieve the target blood glucose goals and to prevent the deterioration by early establishment of strict glycemic control. The strict glycemic control also activates anti-inflammatory, anti-apoptotic and anti-oxidative stress mechanisms, as well as increases endothelium protection, reduces free fatty acid, presents an anti-glucotoxic effect, and also improves both insulin resistance and cardiac fuel metabolisms, which are vital in pancreatic beta-cell protection and reducing of complications onset. All these mechanisms are involved in pancreatic beta-cell preservation and reduced onset of complications [51,52]. In this study, the poor glycemic control following insulin initiation was also significantly increased with a clinically relevant unit increasing of SBP before insulin initiation. This indicates that the target blood glucose level may be difficult to achieve in patients with higher blood pressure even with insulin initiation. This finding might explain that uncontrolled blood pressure could result in poor glycemic control because patients with higher blood pressure sustain a resistance to insulin which decreases insulin uptake and altering delivery of insulin and finally result in impaired glucose uptake [53]. Blood pressure control is so important in patients with T2DM to curb the worse progress of glycemic level.

In the current study, patients who were treated by atorvastatin were found more likely to have poor glycemic control compared with patients treated with simvastatin following insulin initiation. This is consistent with previous studies, which demonstrated that high intensity dose of atorvastatin was associated with the worsening and deterioration of glycemic level compared with moderate intensity statins [54-56]. The finding may prove that statin treatment has a role of downregulation of glucose transporter in adipocytes, which may result in insulin resistance and glycemic deterioration in patients with diabetes especially with high intensity statin therapy. Another study showed that there is no significant changes in glycemic level between atorvastatin and other treatment groups [57], but it was a study with very small number of study participants and unknown dose of atorvastatin used; the average dose of atorvastatin in the current study was in the range of high intensity with 40 mg/day. Moreover, in consistent with the previous study [58], the finding from the current study revealed that premixed insulin-based regimen was found significantly associated with a lower likelihood of poor glycemic control compared with NPH insulin-based regimen. The finding may suggest that patients treated with premixed insulin-based regimen may have a better glycemic outcome than patients treated with NPH insulin. It might be because of that the premixed inulin has two types of insulin in the preparation which can be important to adjust both the postprandial and the basal blood glucose levels. However, frequent episode of hypoglycemia was observed in patients treated with the premixed insulin-based therapy compared with patients treated by NPH insulin-based therapy. Thus, frequent and close monitoring of hypoglycemia is required when patients initiated with premixed insulin-based therapy. Generally, in patients with type 2 diabetes glycemic control needs multifactorial interventions and appropriate management which have been proved to be vital not only to optimize a good glycemic profile, but also to reduce complications onset, in particular cardiovascular ones, and should represent the gold standard for this subset of patients’ treatment [59].

Our study has strengths and some limitations. The study is the first to explore glycemic control and determinants in newly insulin-initiated patients with T2DM who failed to achieve glycemic control by OADs in the study area. It may be used as a benchmark for clinicians and future researchers to examine glycemic control and predictors in post- insulin initiations further with prospective and larger populations. This retrospective study was conducted in preexisting patients’ medical records and some variables like AKI and CKD, macro and micro complications may not be consistent throughout the patients’ physical medical records. Besides, HbA1c, which reflects the average blood glucose level over the past three months, was not used because of non-availability. Instead, fasting plasma glucose, which shows a short-term glycemic index, was used to determine glycemic control.

Conclusion

The initiation of insulin to the therapeutic regimen of insulin naive T2DM patients brought a significant change in glycemic level and a declining trend of FPG during a 1year post-initiation follow-up period. However, a significant proportion of patients had poor level of glycemic control even after insulin initiation. Patients who had higher level of FPG and SBP before insulin initiation, and patients treated with atorvastatin were found more likely to have poor glycemic control in the post-initiation period. Similarly, premixed insulin-based therapy was associated with a lower likelihood of poor glycemic control as compared to NPH insulin-based therapy. Therefore, appropriate management of patients focusing on independent predictors of glycemic control would be of a great benefit to achieve glycemic target.

Proportion of the study subjects with respective medications during the 2-years follow-up period (N = 424).

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Fasting blood glucose level with respective medications during the 2-years follow-up period.

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Dataset.

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20 Apr 2022

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PLOS ONE

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Additional Editor Comments:

Three external peer reviewers carefully reviewed the manuscript. In this version, the paper cannot be accepted for publication in Plos One. The main issue concerns the originality of the manuscript.

If the authors are able to adequately address the issues raised by the reviewers they can resubmit a revised version of the manuscript.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

**********

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The paper “Glycemic control in patients with type 2 diabetes who initiate insulin: a retrospective follow-up study at a university hospital in Ethiopia" by Sendekie et al. deals with a very important topic and provides data of high clinical interest, especially for low-income countries.

The article is well written and only minor spell check is necessary. The paper has a good design. The article is logically divided into sections and subsections. The work has a good degree of novelty and of good interest to the readers. The introduction and discussion should be revised.

Comments:

1) Introduction, line 7: Type 2 diabetes may be accompanied by several complications as the author have stated. In my opinion it should also be reported another important and not well-known complication, which is the cochlear dysfunction (doi: 10.1016/s0026-0495(99)90141-5).

2) Introduction, line 24-25: patient’s nonadherence to pharmacological treatment is often patients’ intentional choice, and, driven by their emotions they may conceal it, which may in turn lead to potentially dire consequences (doi: 10.26355/eurrev_202202_28093). Doctor-patient relationship is fundamental in drug adherence. Moreover, the physician himself may also represent a risk factor for low glycaemic control due to the fear of potential drug’s adverse effect and not appropriate patient’s education (doi: 10.1097/01.hjh.0000239303.93872.31; doi: 10.1001/jama.2019.11489).

3) Discussion: the authors have reported an improved glycaemic control in patient with a better blood pressure monitoring and statin use. The role of multifactorial intervention in type 2 diabetes has been proved to be fundamental not only to reach a good glycaemic profile, but also to reduce complications onset, in particular cardiovascular ones, and should represent the gold standard for this subset of patients’ treatment (doi: 10.1186/s12933-021-01343-1).

4) Discussion, page 14, line 16-18: the strict glycaemic control also activates anti-inflammatory, anti-apoptotic and anti-oxidative stress mechanisms, as well as increases endothelium protection, reduces free fatty acid, presents an anti-glucotoxic effect, and also improves both insulin resistance and cardiac fuel metabolisms. All these mechanisms are involved in pancreatic beta-cell protection and reduced complications onset (doi: 10.1016/j.diabres.2021.108959; doi: 10.1155/2018/3106056)

Reviewer #2: This is an interesting update about glycemic control in patients with type 2 diabetes who initiate insulin in Ethiopia. Anyway, I have some comments and suggestions for the authors.

Abstract

- see better acronym for Type 2 diabetes.

Introduction

- please, about complications includes erectile dysfunction and fracture (see these ref: doi: 10.1002/dmrr.3494; doi: 10.2337/dc18-1965).

- please, update your ref about IDF Atlas ADA standard with the latest.

- after ref 15,16, about the need to educate patients, you can use ref DOI: 10.1007/s42000-018-0005-9.

Material and methods

- have you used any glucometro in particular?

Results

- have you data about HbA1c?

- have you data about the different type of anti hyperglycemic drugs used?

Discussion

- about appropriate management, could be important to emphasize thew role of educational therapy (see ref. DOI: 10.1007/s42000-018-0005-9)

Reviewer #3: In the current article the authors investigated the effectiveness of taking insulin with or without oral agents among patients with type 2 diabetes mellitus (T2DM) in the resource limited-countries like Ethiopia. Thus, in analysis of retrospective medical records of patients with T2DM who initiated insulin due to uncontrolled hyperglycemia of 424 enrolled patients with T2DM, there was significant deference in FPG before and after insulin initiation (P < 0.001), and a declining trend of blood glucose during a 1-year follow-up period of post-initiation was observed. However, majority of the participants did not achieve target glucose levels. Participants who had higher FPG and systolic blood pressure (SBP) before insulin initiation were found more likely to have poor glycemic control after insulin initiation. Similarly, patients who received atorvastatin than simvastatin were found to have poor glycemic control in the post-period of initiation (P =0.04), whereas premixed insulin was associated with a lower likelihood of poor glycemic control than neutral protamine Hagedorn (NPH) insulin (P < 0.001).

Therefore, they concluded that following insulin initiation, a significant change in glycemic level and declining trend of FPG during a 1-year post-initiation period was established. However, the majority of patients were under poor level of glycemic control. Appropriate management focusing on predictors of glycemic control would be of great benefit to achieve glycemic control.

The article looks as other just published articles on the same theme. However, my question is: what is new from the current article? What is the current article adding to the current literature on the topic of glycemic control in the diagnosis and treatment of the patients with type diabetes? It is well known that the insulin therapy could be used with higher success rate to achieve the best glycemic control in patients with type 2 diabetes. In my opinion we cannot publish this article.

**********

6. 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.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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2 May 2022

Responses to the review’s comments

Dear PLOS ONE Academic Editor

We would like to thank you for your crucial comments on our paper (Manuscript Number: PONE-D-22-08211). We have tried to address all the suggested comments, which we believe it could strengthen our paper. We hope this render our paper to be considered for publication in your reputed journal.

We, the authors would like to let you know that we made our best changes given by both reviewers and the editor point by points to the raised comments and recommendations. In addition, throughout our revision we made some corrections too. All the manuscript changes notified using tracking changes.

Comments from the editor:

1#....Journal requirements:

When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming

Author reply: Thank you for your recommendations to assure adherence to the Manuscript Template requirements of the journal. Considering to your recommendation, we have adjusted it accordingly.

2#.....Additional Editor Comments:

Three external peer reviewers carefully reviewed the manuscript. In this version, the paper cannot be accepted for publication in Plos One. The main issue concerns the originality of the manuscript.

If the authors are able to adequately address the issues raised by the reviewers they can resubmit a revised version of the manuscript.

Author reply: Thank you very much for your recommendations to improve the whole manuscript of our work. With reminding the given recommendations and comments we rewrite the corrected parts with point-by-point and indicated with track changes.

Response to Reviewers’ comments:

Reviewer #1

The paper “Glycemic control in patients with type 2 diabetes who initiate insulin: a retrospective follow-up study at a university hospital in Ethiopia" by Sendekie et al. deals with a very important topic and provides data of high clinical interest, especially for low-income countries.

The article is well written and only minor spell check is necessary. The paper has a good design. The article is logically divided into sections and subsections. The work has a good degree of novelty and of good interest to the readers. The introduction and discussion should be revised.

Comments:

Introduction

1#... Introduction, line 7: Type 2 diabetes may be accompanied by several complications as the author have stated. In my opinion it should also be reported another important and not well-known complication, which is the cochlear dysfunction (doi: 10.1016/s0026-0495(99)90141-5).

Author reply: We would like say thank you to the suggestion and the recommendations on this section to add important points. We actually accepted your suggestions and recommendations and it has been shown with track changes in the manuscript (page 3, lines 8-10).

2#... Introduction, line 24-25: patient’s nonadherence to pharmacological treatment is often patients’ intentional choice, and, driven by their emotions they may conceal it, which may in turn lead to potentially dire consequences (doi:10.26355/eurrev_202202_28093). Doctor-patient relationship is fundamental in drug adherence. Moreover, the physician himself may also represent a risk factor for low glycemic control due to the fear of potential drug’s adverse effect and not appropriate patient’s education (doi:10.1097/01.hjh.0000239303.93872.31;doi: 10.1001/jama.2019.11489).

Author reply: Thank you for the given suggestions and based on the raised points we had corrected and revised the manuscript accordingly (page 4, lines 1-9).

Discussion

#3… Discussion: the authors have reported an improved glycemic control in patient with a better blood pressure monitoring and statin use. The role of multifactorial intervention in type 2 diabetes has been proved to be fundamental not only to reach a good glycemic profile, but also to reduce complications onset, in particular cardiovascular ones, and should represent the gold standard for this subset of patients’ treatment (doi: 10.1186/s12933-021-01343-1).

Author reply: Thank you, such evidences will improve the manuscript quality further. Regarding this we included the recommended evidence in the revised manuscript (page 15, lines 23-26).

#4…Discussion, page 14, line 16-18: the strict glycaemic control also activates anti-inflammatory, anti-apoptotic and anti-oxidative stress mechanisms, as well as increases endothelium protection, reduces free fatty acid, presents an anti-glucotoxic effect, and also improves both insulin resistance and cardiac fuel metabolisms. All these mechanisms are involved in pancreatic beta-cell protection and reduced complications onset (doi: 10.1016/j.diabres.2021.108959; doi: 10.1155/2018/3106056).

Authors reply: We are grateful for the important evidence which can strength the discussion. Thus, we included the recommended evidence and indicated with track changes in the main document (page 14, lines 21-26).

Reviewer #2

This is an interesting update about glycemic control in patients with type 2 diabetes who initiate insulin in Ethiopia. Anyway, I have some comments and suggestions for the authors.

Comments:

Abstract

#1…see better acronym for Type 2 diabetes

Authors reply: Thank you very much for your suggestion. We used the acronym T2DM to accommodate the word “mellitus” of course many literatures and guidelines also used it. But considering your suggestions and comments we have searched further and T2DM was still found better acronym to type 2 diabetes mellitus.

Introduction

#1… please, about complications includes erectile dysfunction and fracture (see these ref: doi: 10.1002/dmrr.3494; doi: 10.2337/dc18-1965).

Authors reply: We are thankful for your suggestions to include the most important complications of diabetes. By taking your recommendations, we incorporated it in the manuscript (page 3, lines 8-10).

#2… please, update your ref about IDF Atlas ADA standard with the latest.

Authors reply: Thank you for this important reminder to use the latest version. We revised with latest version of IDF diabetes Atlas (page 3, lines 11-16).

#3… after ref 15, 16, about the need to educate patients, you can use ref DOI: 10.1007/s42000-018-0005-9.

Author reply: It is important evidence which further improve the statements and support the arguments. By considering your constructive recommendation, we revised accordingly (page 4, lines 4-5).

Material and methods

#1…have you used any glucometro in particular?

Author reply: Thank you for the question you raised. Physicians advice their patients how regularly the blood sugar should be monitored either at the health facility (the hospital) by healthcare providers or at home. We have no any data about a particular glucometer used to monitor at home. We used the data from patients’ medical records in the health facility, which is recorded and measured in the hospital setting.

Results

#1…have you data about HbA1c?

Author reply: Thank you for your comments and questions to give clarification about HbA1c. As we mentioned in the limitation section of the current study, HbA1c was not used to determine glycemic level since it is not available in the study setting and included subjects. Even though it was not consistent, a limited number of subjects had monitored using HbA1c (they have been used it occasionally in private healthcare facilities for some patients who have appointments with their private endocrinologists). It may present for one time monitoring then missed for the next and the rest follow-up periods. Therefore, we examined glycemic control using fasting blood glucose and we have no data about HbA1c.

#2…have you data about the different type of anti hyperglycemic drugs used?

Author reply: As we mentioned in the data collection instruments and procedures section (page 6, lines 20-22), in this study patients with type 2 diabetes had treated by Metformin with or without glibenclamide in pre-period of initiation and then insulin (NPH or premixed) was initiated. After insulin initiation, insulin based therapy was continued either alone or with a single or the two oral agents (metformin and glibenclamide). We also provided in the result section of medication patterns and respective proportion of patients (page 10, lines 1-4) in the 2-year follow-up periods (look at S1 fig.). Therefore, the data about anti hyperglycaemic drugs used is available there.

Discussion

#1…about appropriate management, could be important to emphasize the role of educational therapy (see ref. DOI: 10.1007/s42000-018-0005-9)

Author reply: Thank you very much for this important suggestion. By considering your feedback, we revised the manuscript by incorporating the recommended evidence (page, 13 lines 24-27).

Reviewer #3

In the current article the authors investigated the effectiveness of taking insulin with or without oral agents among patients with type 2 diabetes mellitus (T2DM) in the resource limited-countries like Ethiopia. Thus, in analysis of retrospective medical records of patients with T2DM who initiated insulin due to uncontrolled hyperglycemia of 424 enrolled patients with T2DM, there was significant deference in FPG before and after insulin initiation (P < 0.001), and a declining trend of blood glucose during a 1-year follow-up period of post-initiation was observed. However, majority of the participants did not achieve target glucose levels. Participants who had higher FPG and systolic blood pressure (SBP) before insulin initiation were found more likely to have poor glycemic control after insulin initiation. Similarly, patients who received atorvastatin than simvastatin were found to have poor glycemic control in the post-period of initiation (P =0.04), whereas premixed insulin was associated with a lower likelihood of poor glycemic control than neutral protamine Hagedorn (NPH) insulin (P < 0.001).

Therefore, they concluded that following insulin initiation, a significant change in glycemic level and declining trend of FPG during a 1-year post-initiation period was established. However, the majority of patients were under poor level of glycemic control. Appropriate management focusing on predictors of glycemic control would be of great benefit to achieve glycemic control.

The article looks as other just published articles on the same theme. However, my question is: what is new from the current article? What is the current article adding to the current literature on the topic of glycemic control in the diagnosis and treatment of the patients with type diabetes? It is well known that the insulin therapy could be used with higher success rate to achieve the best glycemic control in patients with type 2 diabetes. In my opinion we cannot publish this article

Author reply: Dear reviewer, we appreciate your time to review our manuscript. Despite we share some of your concern, we hope that the finding from the current paper showed the real world practices in the low-income counties like Ethiopia which there no prior evidence in such settings. Furthermore, we also believe that the findings were not duplication of a published literature everywhere as trials and guidelines recommendations vary in different settings due to different reasons.

Though guidelines and trails have acknowledged that initiation of insulin can improve glycemic level of patients with type 2 diabetes but as evidences revealed, it is not easy to achieve the target levels of glycemic control in the real practice settings. Level of glycemic achievement is also different across different study settings due to various reasons from patient’s side or related to management and monitoring practices, and the setting itself. The problem requires real world evidence in particular with low income countries.

Most importantly, in the current paper we had examined factors associated with glycemic control positively or negatively. As literatures showed there are different factors of glycemic control across the globe, which are ranged from sociodemographic characteristics up to clinical and management related variables. So, exploring these factors with real world data could be important to tailor evidence based intervention accordingly. Particularly, in Ethiopia, which is one of the largest diabetes population countries in the sab-Saharan Africa, determining level of glycemic control and analysing the factors of poor glycemic control in new insulin-initiated patients with type 2 diabetes who failed to achieve glucose targets by OADs alone has a lot of implications. The study was carried out using real world data from the tertiary setting by incorporating all available and necessary information from the patients’ side and management practice of the setting. As a result, we have found important contributory factors associated with glycemic control. It can help to intervene the management practice accordingly and a benchmark for further investigation in the study setting. Generally, the current research highlighted the general image of glycemic level and potential factors of glycemic control in insulin initiated patients with type 2 diabetes in the study area, which are important to consider in managing of insulin initiated patients with type 2 diabetes.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

4 May 2022

Glycemic control in newly insulin initiated patients with type 2 diabetes mellitus: A retrospective follow-up study at a university hospital in Ethiopia

PONE-D-22-08211R1

Dear Dr.  Ashenafi Kibret Sendekie

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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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,

Ferdinando Carlo Sasso, PhD, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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 #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The author answered appropriately to all my queries. The manuscript has much improved and, in my opinion, can be further processed for publication.

Reviewer #2: Please, insert all the part not present in the manuscript, underlined by reviewers (as the lack of evaluatoion of HbA1c or data of a type of glucometer) in the text.

**********

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.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

18 May 2022

PONE-D-22-08211R1

Glycemic control in newly insulin-initiated patients with type 2 diabetes mellitus: A retrospective follow-up study at a university hospital in Ethiopia

Dear Dr. Sendekie:

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

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.

If we can help with anything else, please email us at plosone@plos.org.

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

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Ferdinando Carlo Sasso

Academic Editor

PLOS ONE