Determinants of hypertension among patients with type 2 diabetes mellitus on follow-up at Tikur Anbessa Specialized Hospital, Addis Ababa: A case-control study.

INTRODUCTION: Hypertension (HTN) in patients with diabetes mellitus (DM) is a common problem that increases the risk of mortality and morbidity, and lowers the quality of life. Despite the disproportionately high burden of HTN in DM patients, determinants for the comorbidity have not been sufficiently explored. Therefore, this study aimed to identify the determinants of HTN among patients with type 2 diabetes mellitus on follow-up at Tikur Anbessa Specialized Hospital. METHODS AND MATERIALS: We conducted a hospital-based unmatched case-control study at Tikur Anbessa Specialized Hospital on 386 randomly selected patients with type 2 diabetes on follow-up (200 cases and 186 controls). We collected data by using a structured interviewer-administered questionnaire and data extraction form. To identify determinants of hypertension, a multivariable binary logistic regression was fitted, and the findings are presented using adjusted odds ratio (AOR) with 95% confidence interval (CI).
RESULTS: The mean reported age (±SD) of the cases and the controls was 60.3 (±9.9) and 55.3 (±11.3) years, respectively. The eight identified independent determinants of hypertension with AOR [95% CI] were obesity: 2.82 [1.43, 5.57], sedentary activity of ≥4hrs/day: 1.75 [1.10, 2.79], higher stress score: 1.05 [1.01, 1.10], serum creatinine above 1.1 mg/dl: 2.35 [1.13, 4.91], age: 1.05 [1.02, 1.08], being government employee as compared to private workers: 2.18 [1.06, 4.50] and family history of hypertension: 2.11 [1.26, 3.54]. Further, interaction of diabetes duration with insulin use: 1.03 [1.01, 1.07] was also a significant predictor of HTN among DM patients.
CONCLUSION: The finding calls for interventions for mitigating these determinants. Further research is needed to examine the interaction between diabetes duration and insulin use.

Background

Diabetes mellitus (DM) is a chronic disease that occurs due to insufficient insulin production or ineffective insulin utilization by our body. Based on the International Diabetes Federation (IDF) 2019 estimate, globally 463 million adults were affected by DM, of whom four-fifths live in low- and middle-income countries (LMICs). The figure is further projected to increase to 578.4 million by 2030 and 700.2 million by 2045. Among its different types, type 2 diabetes is the most common, accounting for around 90% of all cases [1]. According to a recent analysis, the pooled prevalence of type 2 diabetes mellitus (T2DM) in Ethiopia is about 5% [2].

Globally, premature death attributable to diabetes and its complications is rising at an alarming rate with an estimated death exceeding four million in 2019 [1, 3, 4]. The percentage of premature deaths attributable to high blood glucose is higher in LMICs than in high-income countries (HICs) [4]. In Ethiopia, in 2019 there were about 1.7 million cases and 23,157 deaths in adults due to diabetes [1]. The DM incidence is also growing at an alarming rate [5].

Hypertension (HTN) is the most common comorbidity among people with type 2 diabetes [2]. Its prevalence in this population is sharply increasing in all regions of the world with a prevalence of 50 to 75% in most studies [6]. Even though limited studies are available in Ethiopia, a study reported a 55% prevalence of hypertension among DM patients on follow-up in a referral hospital [7].

Diabetes, HTN, or a combination of both, causes 80% of end-stage renal disease globally [1]. The combination of HTN and type 2 diabetes significantly increases the risk of cardiovascular events [8]. Besides, the comorbidity increases the risk of resistant hypertension [9], kidney disease, including nephropathy [1], diabetic peripheral neuropathy [10], retinopathy, depression, lower quality of life, and health care costs [11-13]. HTN coexistence in diabetics is a major contributor to the development and progression of micro- and macro-vascular complications [14, 15], which are the leading causes of morbidity and mortality among DM cases [16-18]. Moreover, the co-morbidity considerably impairs health-related quality of life (HRQoL) [19, 20].

For people with T2DM, comprehensive cardiovascular risk assessment, counseling and management are an essential part of diabetes management [21]. This is because the majority (>68%) of diabetic patients dies due to cardiac complications and 16% die due to stroke. In addition to the already existing excess risk of Cardiovascular disease (CVD) death in diabetic patients, HTN incurs an additional risk of CVD-related death in patients with T2DM [22]. Since HTN is one of the prominent risk factors for CVD in this population, exploring its determinants is substantive for the prevention and control of CVD and other DM complications [18].

Preventing HTN is more advantageous than treating it, particularly among DM cases [1]. HTN would lead to systemic malfunctioning which is difficult to manage [23]. The prevention also conforms with the World Health Organization (WHO) Global Action Plan, which aimed to achieve a 25% relative reduction in HTN prevalence as one of its three aims [24]. However, further evidence is required on the predictors of HTN for the successful prevention of the disease and its deleterious consequences especially among the disproportionately affected group i.e., the diabetic population, in whom the risk factors for HTN might be different from the general population.

Lowering HTN is among the recommended measures by the IDF to significantly reduce the risk of CVD outcomes and chronic kidney disease [1]. The need for a reduction of HTN burden among DM patients is extensively studied; however, the way how we reduce it in this specific population demands further evidence. Despite the disproportionately high burden of HTN, as per our knowledge, there are only three studies [7, 25, 26] conducted on this specific population. These few studies have major methodological limitations, including flawed participant population selection to explore determinant factors for the development of HTN among T2DM patients. Therefore, this study addressed the aforementioned issues and identified determinants of HTN among T2DM patients that can be used for the effective prevention and control of the condition.

Methods and materials

Study setting, design and period

This institution-based unmatched case-control study was conducted at the Diabetic clinic of Tikur Anbessa Specialized Hospital (TASH) in Addis Ababa, the capital of Ethiopia, from March 01 to June 30, 2020. TASH is a tertiary referral hospital for entire Ethiopia. It provides specialty, sub-specialty, and super-specialty health care services.

The diabetic clinic is one of the centers of the hospital, which is designated for care and follow-up of patients with diabetes. The clinic provides services for the patients on all working days of the week with a daily average of 70 to 80 clients.

Population

Cohorts of T2DM patients on follow-up in TASH diabetic clinic were used as the source population for this study. The study population were T2DM patients with follow-up appointments at the TASH diabetic clinic scheduled between March and June 2020. T2DM patients who had at least one prior visit at TASH diabetic clinic and age of 18 years and above were included in the study. Pregnant women and patients whose hypertension diagnosis precede DM diagnosis were excluded from the study.

T2DM patients with comorbid hypertension were considered as cases. On the other hand, T2DM patients with no hypertension were taken as controls.

Sample size determination and sampling procedure

The sample size was calculated using Stata version 14.1 with the assumptions of 95% confidence level, 90% power, OR &= 2.28 [7], case to control ratio of 1:1, and proportion of controls with an exposure of 70%. Considering a non-response rate of 10%, the final sample size of 202 cases and 202 controls was reached.

We used a simple random sampling technique to select participants. A digital record of the hospital, where the status and care of DM patients are regularly recorded per each visit, was used as a sampling frame and computer-generated random numbers were used to select the study participants. To illustrate, whether the patient has comorbidity including hypertension or not is recorded in the digital record, and all DM patients be screened for hypertension per each visit. As a result, those T2DM patients already recorded as hypertensive in the record were considered as list of cases, and the non-hypertensives as controls to apply the random sampling. In the process, the newly diagnosed cases were also managed accordingly.

Data collection techniques

The questionnaire was prepared in English and translated into Amharic. Finally, it was translated back to English to check its consistency. Pretest was conducted on 41 T2DM patients who were not included in the study population at TASH before actual data collection. Open Data Kit (ODK) version 1.25.2 software [https://opendatakit.org/] was used for data collection along with the KoboToolbox server to store the collected data. Four BSc nurses were recruited for the data collection. Training on how to use the software was given to the data collectors.

Data on socio-demographic and behavioral factors were collected through a face-to-face interview using “WHO STEPS Instrument for Chronic Disease Risk Factor Surveillance” [27]. To assess the stress scale, validated Cohen’s [28] 10 item perceived stress scale (PSS) [29] was adapted and used. To obtain PSS scores, the response to the four positively stated items were reverse coded and then all the scale items were summed up.

Data on clinical and laboratory profiles of the participants were obtained through a review of digital records of the participants using a data extraction tool. The biological parameters obtained through a review of digital record were fasting blood sugar (FBS), total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride, serum creatinine, hemoglobin A1c (HA1C), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Besides, anthropometric data, including BP were collected by direct measurement as described below.

Measurements

Blood pressure was measured using a mercury sphygmomanometer (adult size) following standard procedure. The sphygmomanometer was used based on the 2018 consensus document of a Universal Standard for the Validation of Blood Pressure Measuring Devices [30]. BP was taken in a sitting position from the left arm with feet on the floor and arm supported at heart level after the patient rested for at least 5 minutes. Those patients who have taken caffeine during the hour preceding the measurement and those who have smoked during the preceding 30 minutes were let to stay for at least 1 hour and 30 minutes respectively from the time of those events. To reduce within-patient variability, 2 measurements of the last consecutive visits at least 14 days apart were taken, and the average value was used for the analysis [31, 32]. Hypertension was defined as an elevated average BP of 2 measurements made at subsequent visits of at least 14 days apart (SBP ≥140 mmHg and/or DBP≥90 mmHg) or taking antihypertensive medication.

Physical activity was measured using the Global Physical Activity questionnaire included in the WHO Steps questionnaire. Exercise adherence was defined as a brisk walk for 30 to 40 minutes or more in 4 or more days of a week, and/or a minimum of 150 minutes per week of moderate-intensity and/or 90 minutes per week of vigorous cardio-respiratory exercise. Individuals were considered to have sedentary activity if they report spending ≥ 4hrs by sitting or reclining at work, home, during transportation, and or with friends but do not include the time spent by sleeping.

The weight of the participants was taken using calibrated beam balance and the scale was checked to zero before each measurement. Participants’ weight was measured after removing heavy clothes and recorded to the nearest 0.1 kg. Height was measured using the standard measuring scale and method. The occiput, shoulder, buttocks, and heels touched the measuring board, and height was recorded to the nearest 0.1cm. To compute body mass index (BMI), height and weight were automatically calculated using ODK as BMI = weight in kg/ (height in m)2.

Data quality and management

To ensure the quality of data and reduce intra and inter observation difference on the measurement of variables, a pre-test was conducted on 41 people with type 2 diabetes at TASH, and training was given to data collectors in Addis Ababa for one day before the survey. Excel template for the ODK was prepared with relevant restrictions and necessary commands and tested before actual data collection. The collected data were checked for completeness and consistency daily. Regular supervision and monitoring were made by the assigned supervisors and the principal investigator.

Data processing and analysis

The ODK collected data were validated and exported to Stata version 14.0 for analysis. The complete data set used in the analysis is provided with “S1 Dataset”. Mean, median, standard deviation, interquartile range, and proportion were used to describe the data.

To identify determinants of hypertension among people with T2DM, a binary logistic regression analysis was done. All important variables were initially analyzed using a bivariable analysis. Theoretically important confounders, irrespective of their P-value and variables with a P-value < 0.25 in a bivariable analysis were included in the multivariable model to control for confounders. Akaike’s information criteria (AIC) and Bayesian information criteria (BIC) were used to select the best-fitting model, and finally, a model with the least AIC and BIC was used as a final model. All the preliminary assumptions of the model such as multi-collinearity and model fitness were checked. Those variables showing multi-collinearity were removed from the model and the p-value of the Hosmer Lemeshow was found to be 0.25. Lastly, variables with a p-value ≤ 0.05 in the multivariable analysis were considered statistically significant, and AOR with 95% CI was estimated to measure the strength of the associations. The results are described using text, tables, and graphs, and finally interpreted into valuable information.

Ethical consideration

Ethical clearance was obtained from the Institutional Review Board of Hawassa University College of Medicine and Health Sciences. Informed verbal consent was obtained from the participants without any inducement, undue influence, or coercion. Confidentiality was maintained at all levels of the study. Besides, participants who were found to have a high BP were given education on how to control BP and linked to their care providers.

Results

Characteristics of the respondents

In this study, a total of 200 cases with both type 2 diabetes and hypertension and 186 controls with only type 2 diabetes, but no hypertension were participated. The mean (±SD) age was 60.3 (± 9.9) years for cases and 55.3 (±11.3) years for controls. Among the participants, almost half of the cases and controls (47.3%) were females, and nearly all of the respondents (96.0%) were urban residents. The median (IQR) reported duration of DM from the diagnosis was 15 (9, 20) years in cases and 10 (6, 17) years in controls. One-third of the cases and about a quarter of the controls reported a family history of HTN. Over two-thirds (68.5%) of the cases and a half (50.5%) of the controls reported using insulin. This study also revealed that there is a sedentary activity of ≥4hour/day in the majority (62.0%) of the cases and in less than half (43.0%) of the controls (Table 1). Of the study participants, 23.5% of the cases and 12.9% of the controls were obese (Fig 1).

Table 1

Characteristics of people with T2DM on follow-up at TASH hospital, Addis Ababa, Ethiopia, 2020.

Variables	Cases, no. (%)	Controls, no. (%)	Total, no. (%)
Sex (n = 386)
Male	100 (50.0%)	88 (47.3%)	188 (48.7%)
Female	100 (50.0%)	98 (52.7%)	198 (51.3%)
Residence (n = 386)
Urban	193 (96.5%)	180 (96.8%)	373 (96.6%)
Rural	7 (3.5%)	6 (3.2%)	13 (3.4%)
Current marital status (n = 386)
Single	7 (3.5%)	8 (4.3%)	15 (3.9%)
Married	136 (68.0%)	141 (75.8%)	277 (71.8%)
Divorced	24 (12.0%)	16 (8.6%)	40 (10.4%)
Widowed	33 (16.5%)	21 (11.3%)	54 (14.0%)
Educational status (n = 386)
No formal education	14 (7.0%)	14 (7.5%)	28 (7.3%)
Primary education	42 (21.0%)	45 (24.2%)	87 (22.5%)
Secondary education	64 (32.0%)	55 (29.6%)	119 (30.8%)
Above secondary education	80 (40.0%)	72 (38.7%)	152 (39.4%)
Occupation (n = 386)
Private work	33 (16.5%)	49 (26.3%)	82 (21.2%)
Government employee	36 (18.0%)	35 (18.8%)	71 (18.4%)
Housewife	68 (34.0%)	60 (32.3%)	128 (33.2%)
Unemployed	7 (3.5%)	6 (3.2%)	13 (3.4%)
Retired	56 (28.0%)	36 (19.4%)	92 (23.8%)
Household monthly income (n = 386)
</ = 1000 ETB	54 (27.0%)	42 (22.6%)	96 (24.9%)
1001–5000 ETB	114 (57.0%)	116 (62.4%)	230 (59.6%)
>5000 ETB	32 (16.0%)	28 (15.1%)	60 (15.5%)
Family history of hypertension (n = 386)
Yes	66(33.0%)	44(23.7%)	110(28.5%)
No	127(63.5%)	141(75.8%)	268(69.4%)
Ever used diabetes medication (n = 386)
Metformin	153(76.5%)	152 (81.7%)	305(79.0%)
Glibenclamide	93(46.5%)	76(40.9%)	169(43.8%)
Insulin	137(68.5%)	94(50.5%)	231(59.8%)
Missed dose in the last month (n = 386)
No	181(90.5%)	161(85.6%)	342(88.6%)
1–2	12(6%)	10(5.4%)	22(5.7%)
≥3	7(3.5%)	15(8.1%)	22(5.7%)
Ever visited traditional healers (n = 386)
Yes	6(3.0%)	10(5.4%)	16(4.1%)
No	194(97.0%)	176(94.6%)	370(95.9%)
Current herbal medicine use (n = 16)
Yes	2(33.3%)	7(70.0%)	9(56.3%)
No	4(66.7%)	3(30.0%)	7(43.8%)
Attend health education on Diabetes
Yes	143(71.5%)	127(68.3%)	270(69.9%)
No	57(28.5%)	59(31.7%)	116(30.1%)
Member of diabetes association
Yes	50(25.0%)	38(20.4%)	88(22.8%)
No	150(75.0%)	148(79.6%)	298(77.2%)
Have glucometer at home
Yes	144(72.0%)	120(64.5%)	264(68.4%)
No	56(28.0%)	66(35.5%)	122(31.6%)
Days, in which glucose was measured/wk
Not measured at all	45(22.5%)	36(19.4%)	81(21.0%)
1–2 days	99(49.5%)	111(59.7%)	210(54.4%)
3 or more days	56(28.0%)	39(21.0%)	95(24.6%)
Hemoglobin A1c (n = 195)
<7%	19 (21.3%)	23 (21.7%)	42(21.5%)
>7%	70 (78.7%)	83 (78.3%)	153 (78.5%)
Creatinine level (n = 386)
>1.1 mg/dl	97(48.5%)	103(55.4%)	200 (51.8%)
≤1.1mg/dl	39 (19.5%)	18(9.7%)	57 (14.8%)
not determined	64 (32.0%)	65(34.9%)	129 (33.4%)
Smoking
Ever smoked tobacco products (n = 386)
Yes	17(8.5%)	16 (8.6%)	33(8.5%)
No	183 (91.5%)	170(91.4%)	353(91.5%)
Alcohol consumption
Ever drunk alcoholic drinks (n = 386)	78(39.0%)	74(39.8%)	152(39.4%)
Drank alcoholic drinks at least once a month in the last year (n = 152)	12 (15.4%)	12 (16.2%)	24 (15.8%)
≥ 3 alcoholic drinks per occasion (n = 152)	17 (21.8%)	14 (18.9%)	31 (20.4%)
Vegetable consumption per week (n = 386)
<4 servings	72 (36%)	77 (41.4%)	149 (38.6)
>/ = 4 servings	128 (64.0%)	109 (58.6%)	237 (61.4)
Fruit consumption per week (n = 386)
<4 servings	156 (78.0%)	139 (74.7%)	295 (76.4%)
>/ = 4 servings	44 (22.0%)	47 (25.3%)	91 (23.6%)
Type of oils (n = 386)
Vegetable oil	194(97.0%)	174(93.5%)	368(95.3%)
Cholesterol oil and others	6(3%)	12(6.5%)	18(4.7%)
Salt consumption after diabetes (n = 386)
No change from predictable period	16(8.0%)	40(21.5%)	56(14.5%)
Minimally decreased	48(24.0%)	41(22.0%)	89(23.1%)
Substantially decreased	101(50.5%)	86(46.2%)	187(48.4%)
Stopped at all	35(17.5%)	19(10.2%)	54(14.0%)
Sleeping duration per day (n = 386)
<7hrs	45(22.5%)	43(23.1%)	88(22.8%)
≥7hrs	155(77.5%)	143(76.9%)	298(77.2%)
Moderate intensity exercise (at recreation or work) (n = 386)
No	185(92.5%)	159(85.5%)	344(89.1%)
Yes	15(7.5%)	27(14.5%)	42(10.9%)
Vigorous intensity exercise (at recreation or work) (n = 386)
No	182(91.0%)	160(86.0%)	342(88.6%)
Yes	18(9.0%)	26(14.0%)	44(11.4%)
Doing Moderate and/or vigorous exercise (n = 386)
Neither	171(85.6%)	143(76.9%)	314(81.3%)
Either	25(12.5%)	33(17.7%)	58(15.0%)
Both	4(2.0%)	10(5.4%)	14(3.6%)
Walking or use of bicycle (minutes/week) (n = 386)
≤120	81 (40.5%)	86 (46.2%)	167(43.3%)
>120	119 (59.5%)	100(53.6%)	219(56.7%)
Sedentary activity (hrs/day) (n = 386)
<4	76(38.0%)	106(57.0%)	182(47.2%)
≥4	124(62.0%)	80(43.0%)	204(52.8%)

Fig 1

Distribution of hypertensions by BMI status among people with T2DM on follow-up at TASH hospital, Addis Ababa, Ethiopia, 2020.

Metabolic risk factors of hypertension

The median SBP (Q1, Q3) and DBP (Q1, Q3) of the cases were 135 (126, 145) mmHg and 80 (75, 85) mmHg, respectively. However, the median SBP (Q1, Q3) and DBP (Q1, Q3) of the controls were 125 mmHg (120, 132) and 80 (70, 80) mmHg, respectively. (Table 2)

Table 2

Metabolic factors of people with T2DM on follow-up at TASH hospital, Addis Ababa, Ethiopia, 2020.

Variables	Cases		Controls
	Median	IQR (Q1, Q3)	Median	IQR (Q1, Q3)
Mean FBS in mg/dl (n = 386)	145.5	126, 170	150	129, 176
Total cholesterol in mg/dl (n = 212)	164.5	128, 212	177	141, 216
LDL cholesterol in mg/dl (n = 213)	106.0	79.0, 135	111	82, 139
HDL cholesterol in mg/dl (n = 213)	41.0	33, 51	42	36, 49
Triglyceride in mg/dl (n = 215)	144.0	112, 200	150	106, 193
Creatinine in mg/dl (n = 257)	0.9	0.7, 1.2	0.8	0.6, 1.1
Hemoglobin A1c % (n = 195)	8.5	7.3, 10.1	8.6	7.2, 10.0
Mean SBP in mmHg (n = 386)	135	126, 145	125	120, 132
Mean DBP in mmHg (386)	80	70, 80	80	70, 80

Key: FBS = Fasting blood sugar, LDL = Low density lipoprotein, HDL = High density lipoprotein

Determinants of hypertension among people with T2DM

Based on the p-value of the bivariable analyses, sixteen variables were identified as candidate variables for the multivariable model. These were age, occupation, duration of DM since diagnosis, diabetes medication, the interaction of duration of DM with insulin, having glucometer, family history of hypertension, visiting traditional healer, adherence to exercise, sedentary activity, stress score, BMI, retinopathy, nephropathy, serum creatinine level, and smoking status. Diabetes medications and duration of DM were excluded from the final model due to multi-collinearity.

The result of the multivariable analysis identified obesity, sedentary activity, stress scores, the interaction of diabetes duration with insulin use, serum creatinine of >1.1 mg/dl, age, government employee, and family history of hypertension as independent determinants of hypertension among people with T2DM. (Table 3).

Table 3

Bivariable and multivariable logistic regression analyses results of factors associated with hypertension among people with T2DM on follow-up at TASH hospital, Addis Ababa, Ethiopia, 2020.

Explanatory Variables	Cases	Controls	COR 95% CI	AOR 95% CI
Age	60.3±9.9€	55.0±11.3€	1.05(1.03, 1.07)	1.05(1.02,1.08)*
Occupation
Private work	33 (16.5)	49 (26.3)	1	1
Government employee	36 (18.0)	35 (18.8)	1.53(0.80,2.90)	2.18(1.06,4.50)*
Housewife	68 (34.0)	60 (32.3)	1.68(0.96,2.95)	1.27(0.65,2.46)
Unemployed	7 (3.5)	6 (3.2)	1.73(0.53,5.61)	1.76(0.44,7.00)
Retired	56 (28.0)	36 (19.4)	2.31(1.26,4.24)	1.22(0.57,2.60)
Having Glucometer
Yes	144(72.0)	120(64.5)	1	1
No	56(28.0)	66(35.5)	0.71(0.46,1.09)	0.85(0.52, 1.40)
DM duration * DM drug #
Metformin alone	#	#	1.01(0.95,1.06)	1.00 (0.94, 1.06)
Glibenclamide	#	#	1.03(0.99,1.07)	1.01(0.97, 1.05)
Insulin	#	#	1.05(1.03,1.09)	1.03(1.01, 1.07)*
Family history of HTN
Yes	66(33.0)	44(23.7)	1.59 (1.01,2.49)	2.11(1.26,3.54)*
No	127(63.5)	141(75.8)	1	1
Ever visited traditional healers
Yes	6(3.0)	10(5.4)	1	1
No	194(97.0)	176(94.6)	1.84(0.64,5.16)	2.23(0.64,7.75)
Exercise adherence
Yes	122(61.0)	113(60.7)	1.01(0.67,1.52)	1.20(0.74,1.93)
No	78(39.0)	73(39.3)	1	1
Sedentary activity
<4hour/day	76(38.0)	106(57.0)	1	1
≥4hour/day	124(62.0)	80(43.0)	2.16(1.44,3.25)	1.75(1.10,2.79)*
Stress score	17±4.8€	16.6±6.0€	1.03 (0.99,1.07)	1.05(1.01,1.10)*
BMI
<25kg/m2	77(38.5)	92(49.5)	1	1
25–29.9kg/m2	76(38.0)	70(37.6)	1.30 (0.83,2.02)	1.32(0.79,2.19)
≥30kg/m2	47(23.5)	24(12.9)	2.34 (1.31,4.17)	2.82 (1.43,5.57)*
Retinopathy
Yes	22(11.0)	8(4.3)	2.75(1.20,6.34)	1.83(0.71,4.68)
No	178(89.0)	178(95.7)	1	1
Nephropathy
Yes	22(11.0)	14(7.5)	1.52 (0.75,3.06)	0.79(0.34,1.82)
No	178(89.0)	172(92.5)	1	1
Serum Creatinine
≤1.1 mg/dl	97(48.5)	103(55.4)	1	1
>1.1 mg/dl	39 (19.5)	18(9.7)	2.30(1.23,4.29)	2.35(1.13,4.97)*
not determined	64 (32.0)	65(34.9)	1.05 (0.67,1.62)	0.92(0.56,1.52)
Cigarette smoking
Yes	17(8.5)	16(8.6)	0.98(0.48,2.01)	1.04(0.44,2.45)
No	183(91.5)	170(91.4)	1	1

* Statistically significant at p value ≤ 0.05

# Interaction term

¥ Median with (Q1, Q3)

€ Mean ± SD

Discussion

Obesity was identified as one of the significant determinants of hypertension in people with T2DM. The odds of being obese (BMI > 30 kg/m2) rather than normal (BMI <25/m2) was about 3 times higher among cases than the controls. This is in line with cross-sectional studies conducted in Botswana [33], United Arab Emirates [34], Benghazi [35], Morocco [36], and Hossana, Ethiopia [26]. The association of obesity with hypertension might be due to adipocytes in obese individuals leading to the activation of the angiotensinogen which again increases sodium reabsorption and volume overload in the renal system [37]. The other mechanism by which adiposity in obese individuals leads to hypertension is due to the increased free fatty acids, which can cause HTN either through its effect on the renal system or through causing inflammation. The inflammation again causes endothelial dysfunction leading to arterial stiffness and vasoconstriction which can cause hypertension [37, 38].

The sedentary activity state was also identified as an independent determinant of hypertension among people with T2DM. The odds that the cases stay for 4 or more hours per day in a sedentary state was about 2 times higher than that of the controls. The finding is supported by the SUN cohort [39] and a cross-sectional study conducted at Hossana NEMM hospital [26]. It also supports the country’s NSAP for the prevention of NCD, which prioritized health promotion and disease prevention targeting behavioral risk factors. Therefore, it implies that this effort still needs to be strengthened and continued [40]. The possible justification for the association of sedentary activity with hypertension might be the fact that people who stay in a sedentary state have less physical activity level, which exposes them to unhealthy weight gain which leads to hypertension [39].

This study detected an interaction of diabetes duration with insulin use to be associated with hypertension among people with T2DM. The percent odds for each 5-year increase in the duration of DM when they use insulin was about 18% higher for cases than the controls. It suggests that insulin use alone might not be associated with hypertension, but depends on the duration of diabetes as well. Though this interaction needs further investigation, it may be partly explained by the fact that type 2 diabetic patients who were on insulin might have experienced poor glycemic control probably due to insulin resistance [41]. The synergistic effect of insulin resistance, insulin-induced weight gain, and increased diabetic duration might have contributed to the development of hypertension in this population. It might also be explained by the already established risk among the insulin users just before the initiation of insulin other than the metformin users because both the patients and the physicians are not eager to start insulin on time [42]. They are, therefore, more likely to start insulin after the treatment failure [43]. The duration of treatment failure is even more pronounced in resource-limited countries such as Ethiopia due to poor health system that leads to long follow up intervals and delay with the treatment failure.

Stress score was also positively associated with hypertension in the study population. For each one-unit increase in the stress score, the risk of being hypertensive increases by 5%. The finding is supported by the study conducted to assess the role of stress in newly diagnosed T2DM and HTN by Kaur et al, who reported a positive linear trend between hypertension and stress [44]. The various hormone release during the stressful condition increases the BP subsequently leading to hypertension. The stimulation of the nervous system during stress produces large amounts of vasoconstricting hormones that increase BP. Moreover, the coupling of one risk factor with other stress-producing factors multiplies the effect on BP [45].

The other significant determinant of hypertension was occupational status. The odds of being hypertensive was 2 times higher among government employees than among private workers. This might reflect an indirect difference in the lifestyle and other risk factors of HTN between the two groups [39]. This finding is discordant with the studies conducted in Benghazi [35], Debre Tabor general hospital [46], and Hosanna NEMM hospital in Ethiopia [7, 26]. The reason for the disagreement might be the difference in the characteristics of the study population, small sample size, and failure to control for the confounding effect of stress in the previous studies which might have masked the association.

Likewise, age was identified as one of the independent risk factors contributing to the development of hypertension among people with T2DM. For each one-year increase in age, the percent odds that the patient develops hypertension increases by 5%. This is in agreement with the studies conducted in the United Arab Emirates [34], Benghazi [35], Botswana [33], Morocco [36], and Jordan [47]. Similarly, it agrees with the previous studies conducted at Hawassa University Comprehensive and Specialized Hospital [48] and two cross-sectional studies conducted in Hossana NEMM hospital, Southern Ethiopia [7, 26]. The association of age with hypertension could be due to age-induced changes in arterial and arteriolar stiffness. Large artery stiffness (LAS) is mainly due to arteriosclerotic structural alterations and calcification [49-51].

Serum creatinine level of >1.1 mg/dl was the other associated factor, which increased the risk of HTN by 2 folds among cases compared to controls. The elevation of creatinine level is an indicator of renal dysfunction leading to increased sodium reabsorption. Thus, the sodium loading may increase BP only when renal sodium excretion is constrained by ablation of 70% of renal mass or administration of angiotensin or aldosterone. Consequently, the expansion of the extracellular fluid volume initially mediates the rise in BP, despite the reduction in total peripheral resistance, leading predominantly to systolic hypertension [52]. Conversely, the association also might be due to the bidirectional nature of the relationship between creatinine and hypertension [53].

Finally, a family history of hypertension was also independently associated with hypertension among people with T2DM. The odds of cases having a family history of hypertension was about 2 times higher than their counterparts. The finding is concordant with the study conducted in Hossana NEMM hospital [26]. This is supported by the contribution of the genetic factors in the development of hypertension [54].

The use of a relatively large sample size and exhaustive inclusion of potential confounders in the model are among the strengths of this study. Further, to the best of our knowledge, this is the first study in Ethiopia to examine the association of stress and hypertension among people with T2DM. In contrast, the major limitations of this study were recall biases and chicken egg dilemma though considerable efforts were made to limit them. There might be bias towards the null and the odds ratio for the identified determinants might be underestimated. For example, patients with hypertension might have started to exercise more than those with no hypertension, which can underestimate the existing association between exercise and hypertension. The study might have also lacked power to detect an association between hypertension and rare exposures like a history of smoking.

Conclusion

In this study, obesity, sedentary activity, stress score, the interaction of diabetes duration with insulin use, serum creatinine level, age, occupation, and family history of hypertension were identified as independent determinants of hypertension among people with T2DM. On the other hand, adherence to physical exercise, glycemic control, smoking, alcoholic drink consumption, dietary habits, self-monitoring of blood glucose, adherence with diabetes medication, diabetic education, and marital status were not associated. These findings call for the interventional strategies targeting the aforementioned determinants and suggest the clinicians be curious while deciding diabetes medications for their patients who are on follow-up. It suggests that patients with a longer duration of diabetes need more frequent and focused follow-up to prevent delay in diagnosis of a treatment failure. It also connotes further researches to examine and explain the interaction of diabetes duration with insulin use. Moreover, higher officials of the government are recommended to take interventions at governmental institutions to increase the physical activity level of the employees, and the respective patients are also recommended to compensate for reclining in sitting due to the nature of most of the governmental occupations.

“Dataset of the study”.

(XLS)

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(DOCX)

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12 May 2021

PONE-D-21-08688

Determinants of hypertension among patients with type 2 diabetes on follow-up at Tikur Anbessa Specialized Hospital, Addis Ababa: a case control study

PLOS ONE

Dear Dr. Kotiso,

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Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: No

Reviewer #2: Yes

**********

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Reviewer #2: Yes

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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: This paper was a case-control study in diabetes patients in Ethiopia. The determinants of hypertension with T2DM were not physical exercise, glycemic control, smoking, alcohol intake, and education but obesity, activity, stress, duration of insulin, age, occupation, and family history of hypertension. The sample size is not so large and there was a selection bias between cases and controls. This manuscript is potentially interesting. However, there are some concerns in it.

Major comments

1) The most serious concern is a selection bias in two groups between cases and controls, I suspected that. Authors need to analysis t-test and chi-square test, and address p value in tables.

2) The second concern is not a large sample size. Authors need to mention in the section of limitation.

3) This study insisted many variables are determinants of hypertension among diabetes. What variable is the strongest or most independent factor for hypertension with diabetes? If authors insist that there was an independent association, they would need to use multiple stepwise regression analyses.

Minor comments

1) Table 1, 2, 3, and 4 were showed characteristics of patients in case and control. This manuscript have to put these tables in one.

2) There was no units for variables and no abbreviations lists in footnotes in Table 5.

3) LDL or HDL were LDL-cholesterole or HDL-cholesterol.

4) Tables were showed controls in left and cases in right. Table 6 was showed cases in left and controls in right. Tables were unified the writing.

Reviewer #2: Thank you for the opportunity to review this manuscript. The authors provided an original article assessing the determinants of hypertension in patients with diabetes mellitus at TASH. They presented the article in a meaningful way, however, the following issues need to be fixed/ clarified to make it easier for the reader to follow, and make it methodologically sound.

1) Title: please specify the type of diabetes mellitus considered in the cohort (type 2 DM as indicated in the subsequent sections), including an addition of ‘mellitus’ in the phrase. Also, use a hyphen in ‘case control’.

2) Abstract: the phrase ‘type 2 diabetic patients’ needs revision, such as ‘patients with T2DM’.

3) Introduction: line 34: check, and revise references 23 and 24.

Line 36: write the full form of WHO

4) Methods and materials: there is an inconsistency in the use of the terms; T2DM and/or type 2 DM. Please revise and apply one uniformly across the manuscript.

The specific scheduled date of study period needs to be defined.

The sample size estimation is barely defined which requires major revision. It is difficult to follow authors’ assumption (reference) of exposure variables among the cases and controls considered in the computation. As both groups emerge from a DM cohort, and that DM cannot, independently, predict hypertension among the cases only, the figure (OR=2.28) in line70, and how they came up with the stated sample size is still unclear.

Sampling method of this study is not clear. For example, in lines 45-47, of the introduction summary, the authors indicated that participant selection flaws were a problem in earlier studies. As cases and controls are not apparent to researchers from the outset, using simple random sampling simply cannot be possible. It is imperative that authors clearly indicate the procedure showing how cases and controls were recruited.

5) Results: in line 155; ‘two-thirds’ for 62.4% appears unsound, and needs revision.

Please check and revise table 5.

Lines 203-204: the term ‘diabetic medications’, also requires to be rephrased.

6) Discussion: well discussed, however, the use of abbreviations for the first time should be avoided.

Generally, the authors used some abbreviations throughout the paper without first presenting the full form. Authors are advised to have a look at on this terms, and fix for clarity.

**********

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Reviewer #1: No

Reviewer #2: No

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14 Jul 2021

Dear reviewers and editor,

Thank you for your review and important issues you raised in the paper.

We have read the reviewer's comments carefully and hope that the revised version now submitted will be regarded as having enhanced the previous version. The authors very welcome the reviewer's comments and suggestions. These contributions have appreciably improved the final paper quality. Hereunder, kindly get the responses to the points raised under each point.

Response to editor

We've checked your submission and before we can proceed, we need you to address the following issues:

- Please include a legend for figure 1.

BMI in the figure 1. was written in full in the revised figure, and the title of the figure was also included in the manuscript to locate the position of the figure.

Response to reviewers

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

________________________________________

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

Reviewer #1: No

Reviewer #2: Yes

________________________________________

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

________________________________________

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

________________________________________

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: This paper was a case-control study in diabetes patients in Ethiopia. The determinants of hypertension with T2DM were not physical exercise, glycemic control, smoking, alcohol intake, and education but obesity, activity, stress, duration of insulin, age, occupation, and family history of hypertension. The sample size is not so large and there was a selection bias between cases and controls. This manuscript is potentially interesting. However, there are some concerns in it.

Major comments

1) The most serious concern is a selection bias in two groups between cases and controls, I suspected that. Authors need to analysis t-test and chi-square test, and address p value in tables.

Comment: The detail procedures of selecting the participants were added in the revised manuscript based on the reviewer’s comment.

To eliminate selection bias, we randomly selected both the cases and controls using the digital record of the hospital, where the status and care of DM patients are regularly recorded. Because of the availability of digital record in the hospital, where the status and care of DM patients are regularly recorded per each visit to the diabetic clinic, we were able to generate sample frame from it for both cases and controls. For e.g. whether the patient has comorbidity including hypertension or not is recorded in the digital record, and all DM patients be screened for hypertension per each visit. As a result, those T2DM patients already recorded as hypertensive in the record were considered as list of cases, and the non-hypertensives as controls. In the process, the newly diagnosed cases were also managed accordingly.

Comment: Bivariable binary logistic regression analysis was conducted instead of t-test and chi-square test for each variable (since the model can handle both continuous and categorical variables), and variables with a p-value of <0.25 were presented in table.

2) The second concern is not a large sample size. Authors need to mention in the section of limitation.

Comment: Thank you for the issue you raised associated with the sample size. We stated under limitation that “The study might have also lacked power to detect an association between hypertension and rare exposures like a history of smoking.” to address the issue raised by the reviewer.

3) This study insisted many variables are determinants of hypertension among diabetes. What variable is the strongest or most independent factor for hypertension with diabetes? If authors insist that there was an independent association, they would need to use multiple stepwise regression analyses.

Comment: In terms of measures of association (Odds ratio), obesity was the strongest independent factor of hypertension. However, it’s not to mean that variables (particularly the countinous one, such as age and stress score) with the least odds ratio are the weakest independent factor, because the odds ratio for these variables is difficult to be compared with the categorical variables for they have different interpretation. On another note, we have used enter method rather than the stepwise method for the analysis both because of the limitations associated with stepwise (as supposed by different statisticians) and the AIC signified the enter method as a best fitting model for our data as stated under “Data processing and analysis”

Minor comments

1) Table 1, 2, 3, and 4 were showed characteristics of patients in case and control. This manuscript have to put these tables in one.

Comment: Amendments were made based on the reviewer’s comment.

2) There was no units for variables and no abbreviations lists in footnotes in Table 5.

Comment: Units were added, and abbreviation lists were put in footnotes in the revised manuscript.

3) LDL or HDL were LDL-cholesterole or HDL-cholesterol.

Comment: Corrected based on the comment.

4) Tables were showed controls in left and cases in right. Table 6 was showed cases in left and controls in right. Tables were unified the writing.

Comment: Corrected according to the comment.

Reviewer #2: Thank you for the opportunity to review this manuscript. The authors provided an original article assessing the determinants of hypertension in patients with diabetes mellitus at TASH. They presented the article in a meaningful way, however, the following issues need to be fixed/ clarified to make it easier for the reader to follow, and make it methodologically sound.

1) Title: please specify the type of diabetes mellitus considered in the cohort (type 2 DM as indicated in the subsequent sections), including an addition of ‘mellitus’ in the phrase. Also, use a hyphen in ‘case control’.

Comment: Corrected based on the comment.

2) Abstract: the phrase ‘type 2 diabetic patients’ needs revision, such as ‘patients with T2DM’.

Comment: Revised based on the comment.

3) Introduction: line 34: check, and revise references 23 and 24.

Comment: Checked and revised based on the reviewer’s comment.

Line 36: write the full form of WHO

Comment: WHO was written in full in the revised manuscript based on the reviewer’s comment.

4) Methods and materials: there is an inconsistency in the use of the terms; T2DM and/or type 2 DM. Please revise and apply one uniformly across the manuscript.

Comment: Revised based on the comment

The specific scheduled date of study period needs to be defined.

Comment: The specific scheduled date was stated in the revised manuscript.

The sample size estimation is barely defined which requires major revision. It is difficult to follow authors’ assumption (reference) of exposure variables among the cases and controls considered in the computation. As both groups emerge from a DM cohort, and that DM cannot, independently, predict hypertension among the cases only, the figure (OR=2.28) in line70, and how they came up with the stated sample size is still unclear.

Comment: Sorry for the mistake made while editing for language. It was mistakenly written as “Proportion of controls” but now corrected as “proportion of controls with exposure.” The command that we used in stata to compute our sample size was “power twoproportions (0.4 (0.025)0.7), test(lrchi2) oratio(2.28) power(0.9) table.” To obtain larger sample size, we used a range for the proportion of controls with exposure ranging from 0.4 to 0.7, based on the pre-study estimate of 0.56. Finally, the proportion we used to estimate the sample size was 0.7 because of yielding the largest sample size.

Sampling method of this study is not clear. For example, in lines 45-47, of the introduction summary, the authors indicated that participant selection flaws were a problem in earlier studies. As cases and controls are not apparent to researchers from the outset, using simple random sampling simply cannot be possible. It is imperative that authors clearly indicate the procedure showing how cases and controls were recruited.

Comment: Flawed participant population selection was stated in the introduction summary to explain limitations of the previous studies due to the type of population participated in the studies which might bias and or confound the results (population selection rather than the sampling technique). To mention some of the major limitations, participants in whom HTN diagnosis precedes DM diagnosis were not excluded in the previous studies (Tadesse, Amare et al. 2018, Kotiso, Mekebo et al. 2020) regardless of the fact that this might contaminate the results by mixing-up factors determining for the development of DM in HTN patients (in whom the risk factors for HTN might be similar with that of the general population) rather than HTN in DM. Besides, the other study (Mariye, Girmay et al. 2019) included all DM patients which might also bias and confound the results unless properly controlled because of similarity in the pathophysiology of T2DM with that of HTN, and T2DM accounting the vast majority of DM population. Thus, this study tried to address the aforementioned issues to provide more meaningful and valid information.

Because of the availability of digital record in the hospital, where the status and care of DM patients are regularly recorded per each visit to the diabetic clinic, we were able to generate sample frame from it for both cases and controls. For e.g. whether the patient has comorbidity including hypertension or not is recorded in the digital record, and all DM patients be screened for hypertension per each visit. As a result, those T2DM patients already recorded as hypertensive in the record were considered as list of cases, and the non-hypertensives as controls. In the process, the newly diagnosed cases were also managed accordingly.

The detail procedures of sampling were added in the revised manuscript based on the reviewer’s comment.

5) Results: in line 155; ‘two-thirds’ for 62.4% appears unsound, and needs revision.

Comment: It was addressed in the revised manuscript.

Please check and revise table 5.

Comment: table 5 was revised.

Lines 203-204: the term ‘diabetic medications’, also requires to be rephrased.

Comment: The phrase diabetic medication was rephrased as diabetes medication.

6) Discussion: well discussed, however, the use of abbreviations for the first time should be avoided.

Generally, the authors used some abbreviations throughout the paper without first presenting the full form. Authors are advised to have a look at on this terms, and fix for clarity.

Comment: All the abbreviation issues are fixed in the revised manuscript.

Thank you for your consideration. We look forward to hearing from you.

Sincerely,

The authors

Submitted filename: Rebuttal Letter.docx

Click here for additional data file.

31 Jul 2021

PONE-D-21-08688R1

Determinants of hypertension among patients with type 2 diabetes mellitus on follow-up at Tikur Anbessa Specialized Hospital, Addis Ababa: a case-control study

PLOS ONE

Dear Dr. Kotiso,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Sep 14 2021 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.

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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'.

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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Yoshihiro Fukumoto

Academic Editor

PLOS ONE

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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: (No Response)

Reviewer #2: Yes

**********

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

Reviewer #1: (No Response)

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: (No Response)

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: (No Response)

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: In table 2, units of mean SBP and DBP were mm Hg. This units need no space between mm and Hg. 'mmHg'

In table 3, AOR in DM duration was 1.035(1.01, 1.07). AOR was needed to unified two alignment.

Reviewer #2: Thank you again for presenting the revised form of your work. The authors have revised the manuscript incorporating comments suggested. I advise the inclusion of 'materials' in the methods sub-section of the abstract. Also please check the acknowledgement section for patients, while offering their full consent and participation, should have been acknowledged, or if that has been addressed elsewhere.

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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 #1: No

Reviewer #2: No

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31 Jul 2021

Dear reviewers,

Thank you for your review and important issues you raised in the paper.

We have read the reviewer's comments carefully and hope that the revised version now submitted will be regarded as having enhanced the previous version. The authors very welcome the reviewer's comments and suggestions. These contributions have appreciably improved the final paper quality. Hereunder, kindly get the responses to the points raised under each point.

Response to reviewer #1:

Review Comments to the Author

Reviewer #1: In table 2, units of mean SBP and DBP were mm Hg. This units need no space between mm and Hg. 'mmHg'

Comment: the spaces were removed and corrected as mmHG based on the reviewer’s comment.

In table 3, AOR in DM duration was 1.035(1.01, 1.07). AOR was needed to unified two alignment.

Comment: the decimal place was rounded to two places based on the reviewer’s comment.

Response to Reviewer #2:

Reviewer #2: Thank you again for presenting the revised form of your work. The authors have revised the manuscript incorporating comments suggested. I advise the inclusion of 'materials' in the methods sub-section of the abstract. Also please check the acknowledgement section for patients, while offering their full consent and participation, should have been acknowledged, or if that has been addressed elsewhere.

Comment: materials was now included in the abstract subsection methods, and the study participants were also acknowledged in the revised version based on the reviewer’s comment.

Thank you for your consideration. We look forward to hearing from you.

Sincerely,

The corresponding author

Submitted filename: Rebuttal Letter2.docx

Click here for additional data file.

6 Aug 2021

Determinants of hypertension among patients with type 2 diabetes mellitus on follow-up at Tikur Anbessa Specialized Hospital, Addis Ababa: a case-control study

PONE-D-21-08688R2

Dear Dr. Kotiso,

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.

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Kind regards,

Yoshihiro Fukumoto

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

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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

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

Reviewer #1: Yes

Reviewer #2: Yes

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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

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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

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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: (No Response)

Reviewer #2: I have found the paper meaningful and with potential contribution to practice. I have no objection to its present form thus far.

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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

13 Aug 2021

PONE-D-21-08688R2

Determinants of hypertension among patients with type 2 diabetes mellitus on follow-up at Tikur Anbessa Specialized Hospital, Addis Ababa: a case-control study

Dear Dr. Kotiso:

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

Dr. Yoshihiro Fukumoto

Academic Editor

PLOS ONE