Comparing the efficacy and safety of sitagliptin versus glimepiride in combination with metformin in geriatric type 2 diabetes mellitus patients

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterised by persistent hyperglycaemia, resulting from insulin resistance and impaired pancreatic beta-cell function.^[1] It has become a major global health issue, strongly associated with ageing, sedentary lifestyles and obesity. In India, T2DM affects approximately 9.3% of the population, with prevalence rising to about 14% in individuals over 60 years of age. Globally, over 460 million people live with diabetes, and this number is expected to surpass 700 million by 2045.^[2] In India alone, nearly 77 million individuals are affected.^[3,4] As the elderly population continues to grow, the burden of T2DM in this demographic is expected to increase significantly.^[5,6]

Managing T2DM in older adults is particularly challenging due to late diagnosis, the presence of multiple comorbidities and age-related physiological changes such as reduced renal function and heightened sensitivity to medications.^[7] Treatment strategies must balance glycaemic control with the minimisation of adverse effects such as hypoglycaemia and weight gain, which are more dangerous in elderly individuals.^[8] Pathophysiologically, T2DM develops through a combination of insulin resistance and beta-cell dysfunction, with additional contributions from impaired incretin activity, notably the Glucagon-like peptide-1 (GLP-1) pathway.^[9] Chronic hyperglycaemia leads to serious complications, making early and effective treatment crucial.^[10] Metformin is the first-line therapy for T2DM due to its efficacy, affordability and safety.^[11] However, many patients require additional medications, such as sulfonylureas (e.g. glimepiride) or DPP-4 inhibitors (e.g. sitagliptin), when metformin alone is insufficient. Glimepiride stimulates insulin secretion but carries a higher risk of hypoglycaemia and weight gain, especially in elderly patients.^[12] In contrast, sitagliptin enhances incretin activity, improving glucose control with a lower risk of hypoglycaemia and weight neutrality.^[13]

Combination therapies are commonly used to enhance glycaemic control and improve adherence. While glimepiride with metformin remains effective and affordable, the risk of hypoglycaemia is a concern. Sitagliptin with metformin offers a safer alternative for elderly patients, reducing the risk of hypoglycaemia and avoiding weight gain.^[14,15] Overall, individualised treatment approaches are essential for elderly T2DM patients, prioritising both efficacy and safety. Comparative studies between glimepiride-metformin and sitagliptinmetformin combinations are vital to optimise therapeutic strategies and improve outcomes in the geriatric population.^[16]

MATERIALS AND METHODS

This is an age- and sex-matched randomised, prospective, interventional, active-controlled study with parallel group assignment. The study was started after ethical clearance from the Institutional Ethics Committee, KGMU (Ref code: XXIII– PGTSC-IIA/P13). The duration of the study was 1 Year. The work was conducted in the Department of Pharmacology and Therapeutics in collaboration with the Department of Medicine, King George’s Medical University, Lucknow. Patients registered in the outpatient department of the Department of Medicine, King George’s Medical University, Lucknow, who are diagnosed to be a case of T2DM as defined by the International Diabetes Federation (IDF).^[17]

RESULTS

This 12-week randomised controlled trial investigated the efficacy and safety of sitagliptin versus glimepiride, both in combination with metformin, in geriatric patients (≥60 years) with type 2 diabetes mellitus (T2DM). A total of 60 participants were equally randomised into two treatment groups: Sitagliptin (100 mg once daily) plus metformin (stable dose) and glimepiride (1 mg daily) plus metformin (stable dose). Baseline characteristics, including age and gender distribution, were well-matched between the two groups, ensuring a robust comparative analysis [Table 1].

Demographic characteristics

The primary efficacy outcome, HbA1c [Table 2] demonstrated a statistically significant reduction in both groups [Figure 1]; however, difference in difference analysis between groups showed that the change between groups is not significant (P = 0.7).

Table 2: HbA1c distribution across the study groups.

Characteristic	Glimepiride+ Metformin	Sitagliptin+ Metformin	P-value
Baseline	7.9±0.5	7.4±0.3	<0.001
Week 12	7.1±0.4	6.6±0.2	<0.001
Change in HbA1C	0.79±0.12	0.80±0.15	0.7

P-value was calculated using unpaired t-test and <0.05 is considered statistically significant. HbA1C: Glycated hemoglobin

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Figure 1:

HbA1c distribution. Red dot indicates outlier.

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While both groups showed a reduction in FBG [Table 3] over the study period, the differences between the groups were not statistically significant at any time point [Figure 2]. Regarding lipid profiles, no statistically significant differences were observed between the two treatment groups in total cholesterol [Figure 3 and Table 4], triglycerides, HDL-cholesterol, LDL-cholesterol (LDL-C), or VLDL-cholesterol levels throughout the 12-week study.

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Figure 2:

Fasting blood glucose (FBG) distribution.

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Figure 3:

Total cholesterol distribution. Orange dot indicates outlier.

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Table 3: Fasting blood glucose distribution.

Characteristic	Glimepiride+ Metformin	Sitagliptin+ Metformin	P-value
Baseline	126.3±30.3	125.4±16.4	0.88
Week 4	118.8±28.1	116.8±15.5	0.72
Week 8	112.4±25.2	111±14.7	0.78
Week 12	106.3±22.6	105.9±14.1	0.94

P-value was calculated using unpaired t-test and <0.05 is considered statistically significant.

Table 4: Total cholesterol distribution.

Characteristic	Glimepiride+ Metformin	Sitagliptin+ Metformin	P-value
Baseline	132.0±28.9	136.2±50.6	0.69
Week 4	131.1±28.7	130.6±45.9	0.96
Week 8	130.3±28.5	128.0±44.7	0.81
Week 12	129.2±28.6	120.9±34.4	0.31

P-value was calculated using unpaired t-test and <0.05 is considered statistically significant.

Interestingly, significant differences were observed in weight [Table 5] and BMI [Table 6]. The sitagliptin + metformin group maintained a lower mean weight and BMI throughout the study, with statistically significant differences at all time points (P < 0.001). Systolic and diastolic BP did not differ [Figures 4 and 5].

Table 5: Weight distribution.

Characteristic	Glimepiride+ Metformin	Sitagliptin+ Metformin	P-value
Baseline	75.49±5.78	66.23±9.86	<0.001
Week 4	75.86±5.78	65.61±9.56	<0.001
Week 8	76.14±5.96	65.28±9.42	<0.001
Week 12	76.45±6.07	64.95±9.30	<0.001

P-value was calculated using unpaired t-test and <0.05 is considered statistically significant.

Table 6: Body mass index distribution.

Characteristic	Glimepiride+ Metformin	Sitagliptin+ Metformin	P-value
Baseline	26.56±1.97	24.64±3.39	0.009
Week 4	26.71±1.97	24.39±3.33	0.002
Week 8	26.80±2.03	24.28±3.27	0.001
Week 12	26.93±2.08	24.16±3.26	<0.001

P-value was calculated using unpaired t-test and <0.05 is considered statistically significant.

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Figure 4:

Body weight distribution. Dots indicate outliers.

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Figure 5:

Body mass index (BMI) distribution.

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DISCUSSION

Diabetes mellitus remains a major global health issue, with India at its epicentre. Effective T2DM management requires a combination therapy targeting both insulin resistance and beta-cell dysfunction. Metformin remains the first-line agent, but when additional control is needed, sulfonylureas like glimepiride are widely used, particularly in India, despite the availability of newer agents.^[13] Our study demonstrated a reduction in HbA1c [Figure 1] with both sitagliptin + metformin and glimepiride + metformin in the geriatric population; however, there is not much difference between the groups. Furthermore, the significant results with weight and BMI align with previous studies and meta-analyses, which have shown that DPP-4 inhibitors like sitagliptin provide comparable glycaemic control to sulfonylureas but with significantly lower risks of weight gain.^[19] Trials by Arechavaleta et al. and Bourdel-Marchasson et al. also support these findings, highlighting sitagliptin’s safer profile in older adults.^[20,21] FBG changes were not significantly different between groups. Lipid profiles remained stable in both groups, consistent with the generally neutral metabolic effects of DPP-4 inhibitors and sulfonylureas.^[19] The significant difference observed in weight and BMI-favouring the sitagliptin group-is consistent with literature showing sulfonylurea-induced weight gain and the weight-neutral or modest weight loss effects associated with sitagliptin.^[21] There were no significant differences in systolic or diastolic BP between groups, aligning with the neutral cardiovascular profile typically observed with these drug classes. Sitagliptin improves glucose homeostasis by enhancing glucose-dependent insulin secretion and suppressing glucagon, leading to lower hypoglycaemia risk and better postprandial control. In contrast, glimepiride stimulates insulin release regardless of glucose levels, increasing the risk of hypoglycaemia and weight gain. Overall, our study supports the use of sitagliptin over glimepiride as a safer, effective second-line agent in combination with metformin for elderly T2DM patients, emphasising better HbA1c control, lower hypoglycaemia risk and avoidance of weight gain without significant impacts on lipid profiles or BP. Limitations of our study include the relatively short duration of 12 weeks limits the assessment of long-term efficacy and safety. The sample size of 60 due to pilot study participants may limit the statistical power to detect smaller but potentially clinically significant differences in some parameters, such as lipid profiles and BP. The study lacks detailed information on adverse events like hypoglycaemia due to shorter duration and a smaller sample size, which is crucial for a comprehensive safety comparison. A more robust study with a larger sample size may give more reliable data on the comparison of safety between the drugs in the elderly population.

CONCLUSION

Based on our study findings, we have put forth the following recommendations: Given the similar HbA1c reduction and the lack of weight gain observed in the sitagliptin + metformin group, clinicians should consider sitagliptin as a preferred second-line agent to metformin in geriatric patients with T2DM who require additional glycaemic control but are at risk of weight gain or where weight neutrality is desired. Due to the known higher risk of hypoglycaemia associated with sulphonylureas like glimepiride, its use in elderly patients should be approached with caution, particularly in those with comorbidities, polypharmacy or cognitive impairment who may be less able to recognise or manage hypoglycaemic episodes. Future research should focus on longer-term studies extending beyond 12 weeks to evaluate the sustained efficacy of sitagliptin and glimepiride in this population, including their impact on diabetes-related complications, cardiovascular outcomes and the incidence of adverse events, particularly hypoglycaemia. While this study provides valuable comparative data, treatment decisions should always be individualised based on the patient’s specific clinical profile, comorbidities, preferences and tolerance to medications. Regular monitoring of glycaemic control, weight and potential adverse effects is crucial for both treatment strategies.