Reappraisal of cardiometabolic stress in type 2 diabetes mellitus patients receiving glimepiride versus insulin under bitherapy

ABSTRACT

Background:

Metformin and glimepiride are the most common oral antidiabetic drugs in India, and are used with other oral hypoglycaemic agents either separately or in combination with insulin. The objective of the present study was to compare the differences in cardiometabolic markers between metformin-glimepiride therapy versus metformin-insulin therapy in patients with type 2 diabetes mellitus (T2D).

Materials and Methods:

We divided T2D patients into two groups. Group 1 patients were treated with metformin-glimepiride and group 2 patients were treated with metformin-insulin combination. We estimated serum insulin, hs CRP, asymmetric dimethyl arginine (ADMA), Endoglin, 8OHdG, and sEndoglin levels. Cardiac autonomic function was assessed using ECG tracings to record heart rate variability (HRV) and blood pressure variability (BPV).

Results:

The most important BPV parameter, baroreflex sensitivity (BRS) was significantly lower in Group 2. A significant decrease in time-domain indices of HRV was observed in group 2, suggesting sympathovagal imbalance in metformin-insulin-treated patients. Serum NO and TAS levels were low, while sEndoglin, 8OHdG, and PSS were high in group 2, suggesting higher oxidative stress, although the level of hsCRP, indicating inflammation, was similar in both groups.

Conclusion:

The glimepiride-metformin combination was more effective against vascular dysfunction, sympathovagal balance, metabolic stress, and inflammation. Cardiometabolic mediators of cardiovascular risk were higher in metformin-insulin-treated patients, despite achieving similar glycemic targets.

Introduction

Recently the T2D burden in India has increased rapidly. In 2019, approximately 77 million Indian citizens were diagnosed with diabetes mellitus. By 2045, this rate is predicted to rise beyond 134 million.[1] Type 2 diabetes mellitus (T2D), distinguished by the decreased response to insulin action, is linked to multi-organ complications, both microvascular and macrovascular complications, contributing to increased morbidity, premature mortality, and a significant economic burden.[1] In rural areas, the T2D prevalence is 2.4% in rural areas and approximately 11.6% in urban areas. For primary care physicians (PCPs), this escalating epidemic demands strategies that not only control hyperglycemia but also mitigate long-term complications, which often go undetected until irreversible damage occurs.

All T2D patients face high risks of cardiovascular complications and require lifelong care.[2,3,4] However, the emotional burden of chronic treatment often goes unaddressed while managing this progressive disease. Cardiovascular diseases (CVD) is a multifactorial disease arises from interconnected pathways: such as dyslipidemia, endothelial dysfunction, autonomic imbalance, oxidative stress, chronic inflammation, etc., These pathways are rarely addressed comprehensively in routine primary care, where glycemic targets often overshadow holistic cardiometabolic risk management. While lifestyle modification and oral hypoglycemic agents (OHAs) like metformin and glimepiride remain first-line therapies due to their affordability and efficacy,[5] insulin is added when OHAs fail. However, this pragmatic approach overlooks few critical questions: Do insulin-based regimens inadvertently worsen cardiovascular risk markers compared to oral combinations? Are we trading glycemic control for hidden cardiometabolic harm?

Metformin, the cornerstone of T2D therapy, improves insulin sensitivity and may protect against endothelial dysfunction, but its synergy with other agents—particularly insulin—remains unclear. For primary care, affordability and adherence matter and glimepiride a second-generation sulfonylurea, being cheaper than insulin, is more cost effective. Glimepiride, despite its potential extra-pancreatic benefits, is widely used in India but faces scepticism due to historical associations with CVD risk in older sulfonylureas.[6] For PCPs, this uncertainty complicates decision-making: Should they prioritize glimepiride’s affordability and ease of use or switch earlier to insulin, despite its higher cost, adherence challenges, and needle anxiety? Insulin, while effective for glycemic control, has mixed cardiometabolic effects. Its effect on cardiac autonomic innervation in T2D patients especially sympathetic activity is controversial.[7,8] it may exacerbate sympathetic overactivity and oxidative stress, yet its impact on autonomic function (e.g., heart rate variability [HRV]) remains poorly studied in Indians. Its effects of insulin on oxidative damage to Deoxy ribonucleic acid (DNA), inflammation, vasodilating mediators, body weight reduction, and gluconeogenesis are not consistent.[7,8,9,10] This gap is critical, as autonomic dysfunction—a predictor of silent myocardial ischemia—is often underdiagnosed in primary care. Thus, the rationale for dual therapy targets an enhanced therapeutic effect with a simultaneous reduction in side effects by lowering the dosage of each drug.[6,11]

In resource-constrained settings, dual oral therapy (e.g., metformin-glimepiride) offers practical advantages: lower cost, oral administration, and reduced monitoring needs compared to insulin. However, its vascular and autonomic effects are understudied, particularly in Indian populations with unique genetic and lifestyle risk profiles. The present study directly addresses PCPs’ dilemmas by comparing two widely used regimens—metformin-glimepiride vs. metformin-insulin—on surrogate markers of cardiometabolic risks, such as: endothelial dysfunction (NO, ADMA, sEndoglin), Autonomic imbalance (HRV, blood pressure variability [BPV]), xidative stress (8OHdG), and psychological stress.

Therefore, this study was designed to compare the metabolic effects of metformin and glimepiride therapy with metformin and insulin therapy used for the treatment of T2D patients. By linking these biomarkers to clinically actionable insights, the findings aim to guide PCPs in selecting regimens that balance glycemic control, cardiovascular protection, and patient-centric factors like cost and adherence.

Material and Methods

Study design and ethics approval

Study design and ethics approval This study was approved by the Institutional Ethical Committee of the Institute (JIP/IEC/2021/013). This was designed as a cross-sectional analytical study owing to the limited time frame allotted.

Subjects

The study consisted of T2D patients (aged 25–75 years) who visited endocrinology outpatient departments were recruited for this study. Each patient was examined and screened by the principal investigator in the presence of a physician. Patients were divided into two groups. Group 1 included T2D patients on treatment with Metformin and Glimepiride and group 2 included T2D patients on treatment with Metformin and Insulin with age and gender similar to Group 1. A total of 80 participants (40 in each group) were recruited consecutively from the Endocrinology and T2D clinic Out patient department (OPD) based on the inclusion and exclusion criteria, after obtaining written informed consent. Basal demographic data such as age, blood pressure, heart rate, and individual details of their case history were recorded using a structured proforma. Five ml of fasting blood was drawn and the serum was separated. One part was used for routine blood investigations, and the other parts of the serum were stored in different aliquots at –40°C until analysis of biochemical markers.

Anthropometric measurements

All recruited subjects reported to the autonomic function test (AFT) laboratory of the Physiology Department in fasting condition next day morning.

The basal demographic data such as age, blood pressure, heart rate, and the individual details of their case history were noted down using a structured proforma. Their Body mass index (BMI) was calculated from height and weight.

Measurements of heart rate variability and baroreceptor sensitivity

Heart rate variability analysis was performed using a BIOPAC analyzer and baroreceptor sensitivity (BRS), a major parameter of blood pressure variability analysis, was performed using a FINAPRES analyzer. For HRV parameters, we recorded the time-domain indices (SDNN, RMSSD) and frequency-domain indices (LFnu, HFnu, and TP). The subjects were advised to void before recording and were instructed to relax in the supine position. ECG electrodes and respiratory transducers were attached to the subjects and connected to a BIOPAC MP150. After 10 min of supine rest, lead II ECG was recorded for 5 min at a quiet room temperature maintained at 25°C. The subjects were instructed to minimize body movements during the ECG recording.

Estimation of biochemical parameters

Five ml of fasting blood was drawn, and serum was separated. One part was used for routine blood investigations and other part of serum was stored in different aliquots at –40°C until the analysis of the biochemical markers. Estimation of routine parameters was performed using commercial kits adapted to the Beckman Coulter AU5800 auto analyzer. Serum glucose was estimated using the hexokinase method, and total cholesterol (TC), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and VLDL cholesterol (VLDL-C) were estimated using the cholesterol oxidase peroxidase method, and triglycerides were estimated by the glycerol-3-phosphate oxidase method, using commercial diagnostic kits (Beckman Coulter AU5800, Beckman Coulter Inc., Brea, California, USA).

Serum cardiometabolic markers were analyzed using by ELISA. These were asymmetric dimethyl arginine (ADMA), nitric oxide (NO), 8-Hydroxydeoxyguanosine (8-OHdG) using Abbkine kits (Abbkine Inc., Wuhan, China). Insulin and high-sensitivity C-reactive protein (hsCRP) levels were assayed using Calbiotech kits (Calbiotech Inc., 1935 Cordell Ct., El Cajon, CA, USA). Total antioxidant (TAS) was measured using the Ferric reducing antioxidant power (FRAP) Assay method.

Assessment of psychological distress

The psychological assessment of emotional distress associated with diabetes and its treatment was performed using the Perceived stress scale – 10 (PSS). PSS is rated on a 5-point scale ranging from never (0) to almost always (4). Positively phrased items were reverse-scored, and cumulative scores were calculated, where higher totals indicate elevated perceived stress. The scale provides a global assessment of stress.[12]

Statistical analyses

The distribution of sex, a categorical variable, was expressed as frequency and compared using the Chi-Square Test. Continuous data such as age and biochemical parameters such as hsCRP, 8 hydroxy 2’ deoxy guanosine, TAS, ADMA, NO, sEndoglin, HRV, and BRS were expressed as means with standard deviations. The comparison of these parameters between the two groups was carried out using the Independent Student’s t-test/Mann Whitney U test, whichever was appropriate based on the distribution of data. The linear relationship between various independent parameters was determined using Spearman correlation analysis. All statistical analyses were performed at a 5% significance level.

Results

Eighty total with 80 diabetes mellitus were recruited between August 2021 and March 2022. The distribution of age, gender, BMI, and waist hip ratio (WHR) is shown in Table 1. No significant differences were found between the groups in terms of baseline characteristics such as age, gender, BMI, WHR, and mean duration of disease. Their basal heart rates, systolic blood pressures, and diastolic blood pressures were similar [Table 1]. Among the blood pressure variability (BVP) parameters, the BRS was significantly reduced in the group treated with metformin and insulin [Table 1]. Among the HRV indices, TP, SDNN, and RMSSD were significantly higher in T2D patients on treatment with metformin and glimepiride [Table 1]. Both LFnu and LF/HF ratio were significantly higher in the metformin-insulin-treated groups, whereas HFnu was low [Table 1]. The serum concentrations of glycemic parameters, lipid profiles, and atherogenic indices in group 2 participants are presented in Table 2. Fasting glucose and lipid profile were similar, while the mean insulin level was high in the insulin-treated group. Among the lipid risk factors, TC/HDLC, LDL-C/HDL-C, and atherogenic index of plasma (AIP) were significantly higher in Group 2 patients [Table 2]. The mean NO was low, but sEndoglin was high in group 2 patients, while there was no difference in ADMA [Table 2]. 8 Hydroxy 2 guanosine (8OHdG) and psychological stress score (PSS) were high, while the total antioxidant status (TAS) was low in this group [Table 2]. There was no difference in high sensitive CRP (hsCRP) [Table 2].

Table 1.

Comparison of demographic, anthropometric indices, basal heart rate (BHR), blood pressure (BP), heart rate variability (HRV) and blood pressure variability (BPV) parameters between diabetes mellitus (DM) patients on treatment with metformin-glimepiride versus metformin-insulin

Variables	Group 1 DM on treatment with metformin-glimepiride (n=40)	Group 2 DM on treatment with metformin-glimepiride (n=40)	P
Demographic and anthropometric parameters
Age (years)	52.87±8.93	53.17±11.70	0.250
Gender (M/F)ψ	14/26	12/28	0.812
BMI (kg/m2)	26.19±4.53	27.02±4.77	0.528
WHR	0.93±0.069	0.94±0.060	0.943
Duration of treatment (years)	4.75±1.98	5.19±1.64	0.105
BPV parameters
BHR (beats per min)	81.12±9.55	84.27±10.88	0.173
SBP (mmHg)	123.11±11.08	127.72±11.63	0.123
DBP (mmHg)	75.81±7.81	77.00±8.00	0.601
RPP (mmHg/min)	100.65±16.45	107.93±19.07	0.076
BRS (ms/mmHg)#	12.46±3.93	10.50±3.52	0.021
HRV parameters
Time domain indices
SDNN (ms)	47.85±29.08	25.88±14.81	0.002
RMSSD (ms)#	42.88±24.75	18.18±16.50	0.000
Frequency domain indices
LFnu	56.16±15.50	67.25±13.34	0.010
HFnu	43.83±15.03	32.74±15.36	0.013
LF/HF	1.28±1.03	2.05±0.86	0.002
TP (ms2)#	974.88±267.60	798.75±201.37	0.012

^ψData expressed as n (%) analyzed by Chi-square test. Rest of the values are expressed as Mean±SD. Comparison between the groups was done by unpaired Student’s t-test for parametric data and by Mann–Whitney U test for non-parametric data (#). P<0.05 was considered significant. M/F=Male/Female, BMI: Body mass index, WHR=Waist-to-hip ratio, BHR=Basal heart rate, SBP=Systolic blood pressure, DBP=Diastolic blood pressure, RPP=Rate pressure product, TP=Total power of HRV, LFnu=Normalized low-frequency power of HRV, HFnu=Normalized high-frequency power of HRV, SDNN=Standard deviation of normal to normal interval, RMSSD=Square root of the mean of the sum of the squares of the differences between adjacent NN intervals, SV=Stroke volume, BRS=Baroreflex sensitivity

Table 2.

Comparison of glycemic parameters, lipid profile, lipid risk factors, and other biochemical markers of diabetes mellitus (DM) patients on treatment with metformin-Glimepiride versus metformin-Insulin

Variables	Group 1 DM on treatment with metformin-glimepiride (n=40)	Group 2 DM on treatment with metformin-glimepiride (n=40)	P
Glycemic parameters
FSG (mg/dL)	169.92±48.41	189.58±47.29	0.070
Insulin (mU/mL)#	48.42±49.82	94.98±92.79	0.021
Lipid profile
TC (mg/dL)	166.85±53.59	175.90±47.53	0.430
HDL C (mg/dL)	42.30±9.93	39.46±8.47	0.295
LDL C (mg/dL)	108.08±37.87	116.69±33.95	0.176
TG (mg/dL)	191.48±117.36	216.69±93.44	0.291
Lipid risk factors
Non HDL-C (mg/dL)	124.55±47.12	136.44±41.51	0.238
TG/HDL- C	4.76±3.05	5.64±2.28	0.150
TC/HDL-C	3.95±0.89	4.48±0.84	0.009
LDL-C/HDL-C	2.57±0.71	2.97±0.64	0.011
AIP	0.59±0.26	0.71±0.18	0.027
Other biochemical markers
NO (mM/L)	28.92±11.39	23.32±11.96	0.036
ADMA (mM/L)	19.93±3.68	19.96±4.64	0.929
sEndoglin (ng/mL)#	5.04±0.92	6.00±1.78	0.016
8 OHdG (ng/mL)	75.05±30.99	97.71±18.69	0.000
hsCRP (mg/L)	2.60±0.97	3.08±1.31	0.067
TAS (mM/L)	449.25±143.56	357.29±153.37	0.007
Psychological score
PSS#	20.10±4.87	22.40±3.35	0.017

The values are expressed as Mean±SD for parametric data. Comparison between the groups was done by unpaired Student’s t-test for parametric data and by Mann–Whitney U test for non-parametric data (#). P<0.05 was considered significant. FSG=Fasting serum glucose, HOMA-IR=Homeostatic model assessment of insulin resistance, TC=Total cholesterol, TG=Triglyceride, HDL=High density lipoprotein, LDL=Low density lipoprotein, VLDL=Very low-density lipoprotein; Non-HDL-CNon HDL cholesterol, AIP=Atherogenic index of plasma=log₁₀[TG/HDL- C], NO- Nitric oxide, ADMA=Asymmetric dimethyl arginine, 8OHG=8 Hydroxy 2 Guanosine, hsCRP: high sensitive C reactive protein, TAS=Total antioxidant status, PSS=Perceived stress scale

Stress markers showed different correlations with different endothelial dysfunction markers. The correlation of PSS with hsCRP was significant [Table 3], while sEndoglin was correlated with ADMA and TAS in Group 1 metformin and glimepiride [Table 3]. In the metformin-insulin group, PSS was significantly associated with 8OHdG, ADMA, and hsCRP, while 8OHdG was correlated with hsCRP and sEndoglin. sEndoglin was also negatively correlated with NO in group 2 [Table 4].

Table 3.

Spearman correlation of markers of stress (PSS and TAS) with hsCRP and markers of endothelial dysfunction (ADMA, sEndoglin) in diabetes mellitus (DM) patients on treatment with metformin and glimepiride

Group 1 DM on treatment with metformin-insulin (n=40)
Variables	r	P
Parameters
PSS with hsCRP	0.451	0.003
sEndoglin with ADMA	0.432	0.007
sEndoglin with TAS	0.448	0.005

PSS=Psychological stress score, ADMA=Asymmetric dimethyl arginine, hsCRP=high sensitive C reactive protein, TAS=Total antioxidant status

Table 4.

Spearman correlation of markers of stress (PSS, TAS, 8OFdG) with hsCRP and endothelial dysfunction (ADMA) in diabetes mellitus (DM) patients on treatment with metformin-insulin

Group 2 DM on treatment with metformin-insulin (n=40)
Variables	r	P
Parameters
PSS with 8OHdG	0.349	0.029
PSS with ADMA	0.441	0.005
PSS with hsCRP	0.535	0.000
8OHdG with hsCRP	0.439	0.006
sEndoglin with 8OHdG	0.339	0.035
sEndoglin with NO	−0.356	0.024

PSS=Psychological stress score, 8OHG=8 Hydroxy 2 deoxy Guanosine, hsCRP=High sensitive C reactive protein, ADMA=ASYMMETRIC dimethyl arginine

Discussion

Cardiovascular complications like silent ischemia and arrhythmias remain leading causes of mortality in type 2 diabetes (T2D), emphasizing the need for treatments that address both glycemic control and cardiovascular risk. While insulin is often necessary for uncontrolled diabetes (HbA1c ≥9%),[13] our findings suggest metformin-glimepiride combination may offer superior cardiometabolic protection in patients where adequate control can be achieved with oral agents.

Impairment in endothelial function and autonomic function are two major aspects of cardiovascular health that can increase the long-term risk of CVD in the long run in these patients. In this study there was no difference in blood pressure and blood pressure variability parameters [Table 1], except for BRS, which was significantly lower in group 2 than in the metformin–insulin therapy group. Decreased BRS is a marker of cardiovascular morbidity and mortality as it is related to both central autonomic modulation and elastic properties of arteries.[14] LF/HF ratio indicates sympathovagal imbalance. A significant rise in this ratio in the present report suggests a rise in sympathetic activity and sympathovagal imbalance. Moreover, a decrease in TP of HRV and time-domain indices (SDNN, RMSSD) were significant in group 2. A decrease in TP is a marker of CV risks. The reduction in time-domain indices of HRV reflects the decrease in vagal drive.[15] In our report, there was a significant rise in LFnu which represents sympathetic activity in the metformin-insulin group compared with metformin-glimepiride combination. Our finding corroborates with a previous report suggesting that insulin per se increases muscle sympathetic nerve activity while metformin has no effect.[8] Therefore, together the BPV and HRV results indicate a moderate rise in sympathetic drive and a reduction in vagal activity/parasympathetic drive-in metformin insulin treated patients over the years. Thus, we may derive that the group 2 patients on metformin-insulin therapy are at a higher risk of autonomic dysfunction—a precursor to silent myocardial ischemia and arrhythmias. This finding can help the PCP to note that patients on insulin may need closer monitoring for autonomic dysfunction (e.g., orthostatic hypotension, resting tachycardia) even if glycemic targets are met.

In our report fasting glucose level was similar suggesting effective treatment in both the groups [Table 2]. While sulfonylureas like glimepiride effectively lower glucose by stimulating insulin secretion, they may carry higher cardiovascular risk than metformin.[16,17] The primary mechanisms of metformin involve suppression of hepatic glucose output and enhancement of peripheral insulin sensitivity.[18] The vascular effects of glimepiride remain uncertain,[19,20] warranting consideration of its risk-benefit ratio in high-CVD-risk patients.

In our study, we have investigated the serum level of NO, ADMA, and sEndoglin as a marker of endothelial function. Endothelial dysfunction usually precedes cardiovascular disease. NO is a major endothelium-derived vasoactive substance involved in the maintenance of endothelial homeostasis. Reduced NO levels are associated with impaired endothelial function. Both Insulin[16] and Glimepiride[21] induce the expression of eNOS, hence increase NO level. As metformin was common in both groups, it was hypothesized that there would be no difference in NO level. However, in our report, NO was significantly low in metformin-insulin treated patients suggesting a higher degree of endothelial dysfunction in this group. Asymmetric dimethylarginine (ADMA), a structural analogue of L-arginine, is a metabolite found in human circulation. Elevated level of ADMA impedes NO synthesis, and impairs endothelial function. Direct effect of Metformin and insulin treatment on ADMA in diabetes is not consistent.[22,23] Soluble endoglin (sEndoglin) also regulates the expression and activity of eNOS.[24] However, the difference in the levels of these NO-related parameters in different combinations of antiT2D therapy is not reported earlier.

In our report though NO was low and sEndoglin was high in group 2, there was no difference in the level of ADMA [Table 2]. A higher level of sEndoglin has been associated with the regulation of NO synthesis and endothelial dysfunction suggesting insulin therapy patients could be at high risk of endothelial dysfunction. Insulin therapy is known to reduce ADMA levels though this effect is linked via glucose levels. As mean glucose was similar in both the groups the combined effect of insulin therapy and relatively normalized glucose level might have resulted in no change in serum ADMA level when compared between the two treatment groups. To summarize, the metformin-glimepiride preserved nitric oxide (NO) levels better than insulin, suggesting superior endothelial protection. However, sEndoglin (a marker of endothelial stress) was elevated in insulin-treated patients, potentially increasing long-term CVD risk. This finding can help the physicians to identify patients with early vascular disease (e.g., microalbuminuria, hypertension), who may gain from additional vascular benefits by metformin- glimepiride therapy beyond its glycaemic control effect.

In our study Insulin-treated patients reported significantly higher psychological stress (PSS-10 scores). Perceived stress which is easy to administer[12] was correlated with both endothelial dysfunction (ADMA) and oxidative damage (8OHdG) [Table 4]. Potential contributors of high PSS could be burden of daily injections, injection-related anxiety and perceived disease severity and reduced self-efficacy. This may suggest that psychological stress levels also may be linked to cellular stress due to endothelial dysfunction though we cannot establish any cause-and-effect relationship from these preliminary findings. Our finding emphasizes that insulin initiation should include psychological assessment, perceived stress in such patients must be addressed proactively at regular intervals; and to consider oral combination therapy in those with high stress or poor adherence.

Serum 8- hydroxy-2’- deoxyguanosine (8OHdG) is a marker of DNA damage linked to oxidative stress.[25] We found significantly higher oxidative stress in insulin-treated patients, evidenced by elevated 8OHdG and reduced TAS [Table 2]. This contrasts with some experimental data,[26,27] suggesting that our findings might be reflecting reflect real-world complexity such as comorbidities, drug interactions, lifestyle factors, etc., Clinically, these findings suggest insulin therapy may require closer monitoring for oxidative stress-related complications.

While vascular inflammation contributes to diabetic complications, neither insulin-metformin nor glimepiride-metformin significantly reduced hsCRP in our study, consistent with previous trials.[28,29] However, insulin-treated patients showed stronger correlations between oxidative stress (8OHdG), psychological stress (PSS), [(r 0.349, P 0.029)] and also with inflammation (hsCRP), [(r 0.439, P 0.006; and r 0.539, P 0.000 respectively)] suggesting this group may benefit from closer monitoring of both cardiovascular and mental health.

Neither regimen significantly reduced hsCRP, underscoring that glycemic control alone may not resolve inflammation-driven CVD risk [Table 4]. Thus, our findings may suggest that cellular and psychological stress are linked to the underlying inflammation and endothelial dysfunction despite equal reduction in blood glucose. This suggests that the PCP have to prioritize statins, lifestyle changes, and smoking cessation to mitigate residual inflammatory risk in all T2D patients.

Conclusion

Glimepiride-metformin combination was more effective against vascular dysfunction and sympathovagal balance, metabolic stress, and inflammation. There was a persistence of cellular as well as psychological stress which can be mapped to build up of inflammation and endothelial dysfunction over the years in treated diabetes patients which needs further warrant. Metformin-glimepiride may offer autonomic and endothelial protection compared to insulin, making it a pragmatic first-line combination for many T2D patients. Also, insulin therapy, while effective for glycemic control, requires additional vigilance for CVD risk factors (autonomic dysfunction, oxidative stress) and psychological support. Our findings suggest that a balanced approach of glycemic control, cardiovascular protection, cost, and patient preferences is needed in treatment of T2D patients in our set up.

Strength of the study

PCP often face the choice of intensifying oral therapy (e.g., adding glimepiride) vs. initiating insulin. This study suggests that oral combination may have cardiometabolic advantages. The primary care physician should not just focus on HbA1c but also assess vascular health (BP variability, inflammation) when choosing therapies. Based on the findings of this study, if a patient has early autonomic dysfunction (e.g., low HRV), a Primary care physician might prefer glimepiride-metformin over early insulin initiation as part of personalized medicine. The strength of this study is carefully matched patients (age, gender, BMI, glycemic control); minimum 2 years of stable dual therapy and a comprehensive cardiometabolic profiling beyond HbA1c.

Limitation of the study

Small sample size (pilot study during COVID-19) which may have lacked power to detect subtle differences.

Conflicts of interest

The authors declare no conflicts of interest.

Funding Statement

The authors received no specific grant from any funding agency. However, We thank the intramural financial support received from our institute as part of the post graduate thesis work for the first author.