Introduction

According to a Lancet Diabetes study published in 2022, India has surpassed China as the country with the largest number of people with diabetes (1). Diabetes is linked to nearly every chronic disease. There is a high prevalence of Diabetes and related non-communicable diseases (NCDs) in India, leading to a significant population at risk for cardiovascular diseases and chronic complications of diabetes, such as kidney, foot and eye diseases, according to the Indian Council of Medical Research-India Diabetes (ICMR-INDIAB) study (2,3).

Maintaining good glycaemic control is vital for preventing and delaying the progression of these complications(4). Following diet modifications and lifestyle changes, the initial recommended therapy for type 2 diabetes mellitus (T2DM) is metformin. Based on baseline HbA1c at diagnosis, there are several other alternative oral antidiabetics, which include sulfonylureas (SU), glucagon-like peptide (GLP-1), di-peptidyl peptidase-4 inhibitors (DPP-4i), sodium glucose co-transporters-2 inhibitors (SGLT2i) and alpha glucosidase inhibitors (AGIs). Despite the availability and widespread use of anti-diabetic drugs, the poor achievement of glycaemic targets suggests insufficient monitoring and follow-up. A recent study on diabetes prevalence in India, published in Diabetes Research and Clinical Practice, observed that nearly half of the tested population exhibited abnormal glucose levels when analysing their HbA1c test results(5). Regular follow-ups with healthcare providers are essential for achieving glycemic control and preventing T2DM associated complications(6). It is therefore essential to focus antidiabetic treatment approaches not only on glycemic control but also on preventing diabetes-related complications and comorbidities without triggering hypoglycaemic episodes, weight gain or cardio-renal toxicity. Two classes of oral hypoglycaemic agents that meet the above criteria are sodium-glucose cotransporters-2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP-4i)(7,8).

These newer classes of oral anti-diabetic agents SGLT2i and DPP-4i, were approved in India a decade ago. Both these classes have received much attention owing to their cardio-renal benefits, weight loss and fewer incidences of hypoglycaemic episodes unlike the traditional anti-diabetic agents(9). SGLT2i (dapagliflozin, canagliflozin, empagliflozin) block the sodium-glucose transport proteins, preventing the reabsorption of 90% of glucose in the glomerulus and increasing glucose loss through urine. While selective DPP-4i (sitagliptin, vildagliptin, linagliptin) reduce the fasting glucose and post-meal spikes by preventing the degradation of glucose-dependent insulinotropic polypeptide (GDIP) and glucagon-like peptide1(GLP-1)(4). These two newer classes of anti-diabetic agents are preferred for managing T2DM patients with complications, according to guidelines from the American Diabetes Association (ADA) and Kidney Disease Improving Global Outcomes (KDIGO) guidelines(10). Combining SGLT2i or DPP-4i with metformin is an effective strategy to improve the glucose-lowering effect. However, triple therapy with metformin, SGLT2i and DPP-4i has shown potential for significant reduction in HbA1c levels, fasting and postprandial blood glucose, body weight and blood pressure (11-13). Given the increasing impact of diabetes, positioning it as a pandemic in making, and the availability of newer anti-diabetic agents in India, there has been a significant shift in prescribing patterns of anti-diabetic drugs. This study aimed to assess the real-world prescribing trends of SGLT2i and DPP-4i stratified by their HbA1c values in T2DM patients with complications.

Materials and Methods

This was a prospective cross-sectional observational analysis of antidiabetic prescription patterns in Kerala, India, conducted between October 2023 and December 2024. Patient records of individuals diagnosed with T2DM and complications who visited a tertiary care hospital were utilised for the study. The Ethics committee of Karuna Medical College and Hospital, Palakkad, approved the study protocol. Patients aged >40 years with T2DM and associated complications, with at least 1 HbA1c laboratory result and who were prescribed antidiabetic agents between 2023 and 2024, were included. Patients with type 1 diabetes, gestational diabetes and end-stage kidney disease were excluded. Our primary objective was to compare patients who received and did not receive DPP-4i (teneligliptin, vildagliptin, sitagliptin or linagliptin) or SGLT2i (empagliflozin or dapagliflozin) treatment along with the conventional classes of antidiabetic agents (metformin, SU and Insulin) throughout the study period. A subgroup analysis was conducted, categorising patients into three distinct cohorts, stratified based on their HbA1c levels; controlled (HbA1c <7.5%), above-target (HbA1c 7.5%-9%), and elevated (HbA1c > 9%). The demographic characteristics such as age, sex, HbA1c values, diabetes-specific complications, co-morbidities and use of other antidiabetic drugs, were tabulated for these 3 cohorts. The study also examined the pattern of therapy in relation to patient’s HbA1c levels and factors associated with prescribing newer antidiabetic agents.

Statistical Analysis:

Standardized differences were used to evaluate balance across groups in terms of demographic characteristics, HbA1c levels and comorbidities and treatment-related factors such as the number of glucose-lowering drugs and the use of specific anti-diabetic agents. This approach ensured a consistent comparison of baseline characteristics and treatment patterns between patients receiving newer antidiabetic agents (SGLT2i and DPP4i) and those on traditional therapies (Metformin and Sulfonylureas) across different HbA1c categories (<7.5%, 7.5%-9%, >9%). Categorical variables, including comorbidities and prescribing patterns, were compared using chi-square tests. Statistical significance was determined at a p-value threshold of 0.05, focusing on identifying patterns in prescribing practices and glycemic control among the study population. The data was analysed using IBM SPSS 22 software.

Results

Of the 260 eligible patients (mean [SD] age, 63.7[12.4] years; 54.6% male patients) with T2DM identified, 36.5% of diabetic patients initiated treatment with newer antidiabetic agents and 84.6% initiated traditional antidiabetic agents. 49.6% had controlled HbA1c value, 33.4% above target levels and only 16.9% of patients had uncontrolled glycaemic levels. Table 1 evaluates newer (SGLT2i, DPP-4i) and traditional (Metformin, SU) antidiabetic agents across HbA1c ranges (<7.5%, 7.5%-9%, >9%), analysing demographic, clinical, and treatment-related factors through standardized differences (St. Diff). Age and HbA1c levels were well-balanced across groups (St. Diff <0.4), but gender showed a notable imbalance in the HbA1c >9% group for newer antidiabetic agents (St. Diff = 1). Male patients had a higher rate of using newer antidiabetic agents (20%) compared to female patients (16.5%). The most common comorbidities were hypertension (75.7%), coronary artery disease (46.3%) and nephropathy (46.3%). Comorbidities like nephropathy and CAD demonstrated moderate to high imbalances, particularly in the HbA1c <7.5% group (e.g., nephropathy St. Diff = -0.96, CAD St. Diff = 0.89). These complications were prevalent among individuals with HbA1c levels between 7.5% and 9%. DPP-4i was more commonly prescribed for diabetes related complications like nephropathy (60.7%), while patients with coronary artery disease were more frequently prescribed SGLT2i (66.6%). In traditional antidiabetic cohorts, hypertension in the HbA1c >9% group showed significant imbalance (St. Diff = -0.91). A higher percentage of males was prescribed with traditional agents (53.6% vs 46.3%). Nephropathy and coronary artery disease were the most prevalent diabetes-related comorbidities, with metformin being the mainstay treatment in these patients. Also, patients with HbA1c levels ranging from 7.5% to 9% frequently exhibited coronary artery disease. For these patients, SGLT2i and DPP-4i were prescribed equally as adjunct therapies alongside traditional antidiabetic agents (13.6% vs 14.5%). Treatment intensity, indicated by the number of glucose-lowering drugs, was higher in patients with HbA1c >9%, with imbalances reaching -0.93 for newer antidiabetic agents. Insulin use was more frequent in higher HbA1c groups but displayed smaller differences. Overall, newer agents were more commonly prescribed in patients with complex comorbidities and higher HbA1c levels, reflecting tailored prescribing patterns.

Utilisation percentage of newer antidiabetic medication

Figure 1 summarises the percentage usage of newer antidiabetic agents. Of the 260 prescriptions, the percentage of SGLT2i and DPP-4i prescriptions were as follows: 16.9% for Dapagliflozin, 0.38% for empagliflozin, 9.6% for linagliptin, 5% each for sitagliptin and teneligliptin and 3.4% for Vildagliptin. This distribution indicates that Dapagliflozin and Linagliptin are the most preferred agents among the newer antidiabetic drugs, likely reflecting prescribing trends influenced by efficacy, safety profiles, or patient-specific factors. The study reveals that SGLT2i and DPP-4i are not widely prescribed. Despite patients being diagnosed with T2DM and associated complications, only a few patients received these newer agents, hinting at a lack of adherence to the latest treatment guidelines as per ADA.

Figure 1: Patterns of Newer Anti-Diabetic Agents used: SGLT2i and DPP-4i distribution.

Antidiabetic treatment pattern stratified by HbA1c status

Further analysis of treatment patterns revealed diabetic patients received treatments ranging from monotherapy to quadruple therapy. Table 2 presents the distribution of patients across various antidiabetic therapy regimens and their corresponding mean HbA1c levels with 95% confidence intervals. Metformin monotherapy is the most commonly used regimen (17.69%) and is associated with the lowest mean HbA1c (6.48%), indicating better glycemic control. Patients prescribed with dual therapy of metformin and sulfonylureas shows moderate HbA1c levels (7.76%). In contrast, combination therapies, particularly triple or quadruple regimens, are less common and show higher mean HbA1c values, such as 8.81% in the metformin, sulfonylureas, and SGLT2i triple therapy group, demonstrating their preference in patients with more challenging glycemic level. The variability in HbA1c levels within regimens, as indicated by wider confidence intervals, may reflect differences in response to therapy depending upon the HbA1c status. These findings indicate that patients exhibiting higher levels of glycated haemoglobin were prescribed newer antidiabetic agents alongside traditional treatment.

Variation in prescribing pattern by age, sex and prescriber speciality

The prescribing patterns of older and newer antidiabetic drugs (SGLT2i and DPP4i) varied based on age, gender, and prescriber speciality. While patients aged ≥65 years received newer drugs more frequently (21.5%) compared to those <65 years (15%), this difference was not statistically significant (p = 0.182) (Figure 2a). Similarly, no significant gender-based difference was observed, with males (20%) and females (16.5%) receiving newer drugs at comparable rates (p = 0.9548) (Figure 2b). Prescriber speciality showed a significant impact (p = 0.00038). Endocrinologists predominantly prescribed older drugs (38.8%), while Nephrologists showed a relatively balanced pattern (18% vs. 14.6%), and Cardiologists demonstrated the highest shift toward newer drugs, with 36.5% of their prescriptions being newer agents, although older drugs remained dominant at 84.6%. These trends indicate that cardiologists were more likely to adopt newer therapies compared to endocrinologists and nephrologists, reflecting variations in prescribing practices within specialities (Figure 2c)

Fig 2a: Age wise Prescribing Patterns

Fig 2b: Gender-Wise Prescribing Patterns

Fig 2c: Prescribing Patterns among prescriber speciality

Discussion

We collected medical records between 2023 to 2024 to compare antidiabetic prescribing patterns among patients with T2DM and associated complications. Despite evidence from landmark trials demonstrating the cardiorenal benefits of SGLT2i and DPP-4i, their prescribing remained limited during our study period(14). In real-world settings, we observed DPP-4i (22.3%) and SGLT2i (16.9%), were the third and fourth most commonly prescribed anti-diabetic medication after metformin (78.4%) and SU (41.9%). A similar trend was observed by H Y. Chang et al., with SGLT2i being the fourth most commonly prescribed drug after metformin, DPP-4i and SU(15). Mahtta et al., also observed a similar trend among T2DM patients, with only 14.9% of patients receiving SGLT2i(16).

Metformin has consistently been the first-line therapy prescribed regardless of whether T2DM patients had complications or not. In line with our study, the DAPA-HF trial and ASIAN-HF registry also identified metformin as the most commonly prescribed antidiabetic agent(17,18). This preference is likely due to metformin’s well-established safety profile in T2DM patients compared to other antidiabetic agents. Despite recommendations to avoid its use in patients with severe renal insufficiency, metformin is still being prescribed to individuals with advanced chronic kidney disease (CKD) in actual clinical practice(19). Even with stringent glycemic control attained through the use of metformin and sulfonylureas, patients with T2DM remain at a significant risk of cardiovascular mortality and renal failure. As per the 2018 guidelines provided by the American Diabetes Association (ADA) and the European Association for the study of Diabetes (EASD), it is recommended to consider cardiovascular risk or presence of chronic kidney disease, following the initial treatment with metformin. Additionally, patients with heart failure or chronic kidney disease are advised to use DPP-4i and SGLT2i(12). Recent clinical trial data have also highlighted the better tolerability profiles, minimal risk of hypoglycaemia and convenient once-daily dosing, making them particularly suitable for elderly diabetic patients(20). However, there remains underutilisation of this medication class, potentially due to mixed data from clinical trials regarding their safety profile(7).

One of the main strengths of our study is the analysis of the prescribing profile of SGLT2i, DPP-4i and traditional antidiabetic agents across patients based on their HbA1c values. The findings were consistent across all HbA1c sub-cohorts, with the highest risk identified in patients with HbA1c levels between 7.5% and 9%. This subgroup exhibited the highest prevalence of diabetes-related complications, indicating a more advanced stage of diabetes compared to other subgroups. These findings align with a study by Elvira D’Andrea et al., which also reported similar results in diabetic patients with HbA1c levels ranging from 7.5% to 9%(21).

The ADA-EASD (2018) guidelines recommend the step-wise addition of antidiabetic agents based on the patient’s HbA1c values(11). Our study revealed that SGLT2i and DPP-4i were often prescribed as triple or quadruple therapy alongside metformin, sulfonylureas and insulin for patients with HbA1c levels above 8%. Most meta-analyses showed that monotherapy with SGLT2i improves HbA1c levels by 0.5-1.0%. In our study, only 3% and 5.3% of patients were initiated with SGLT2i and DPP-4i respectively as monotherapy. Additionally, combination therapy with SGLT2i or DPP-4i can provide optimal efficacy for patients receiving metformin without increasing the risk of side effects(8,22). However, there is significant geographical differences in the prescribing trend of antidiabetic medications. For instance, the Asian-HF registry, which recruited Asian diabetic patients, reported that half of the patients were on monotherapy and 37% on dual therapy(17). Our study had 31.5% receiving monotherapy and 10.7% on dual therapy.

The observed contrast in the rate of prescribing of SGLT2i and DPP-4i may be attributed to several factors. Firstly, restricted access to these medications in our settings might have led prescribers to reserve them for patients at high risk of complications. Secondly, the high cost of treatment may not be affordable for all patients. Lastly, the significant risk of genitourinary infections associated with SGLT2i, particularly in women, might have influenced prescribing decisions.

The variables that were associated with the utilisation of DPP-4i and SGLT2i in our study were patients with co-existing CVD or CKD, patients aged > 65 years and male patients with poorer glycaemic control, as well as those who had more frequent visits from nephrologist and cardiologist. Limited clinical experience, knowledge and competency gaps among providers may contribute to the restricted prescribing of these newer agents(19,23,24). In a similar study, disparities in SGLT2i prescribing were noted, with markers of poorer glycaemic control and male patients being linked to higher odds of SGLT2i prescribing. Conversely, female sex, advancing age and socioeconomic disparities were linked to lower odds of being prescribed the medication(25).

Our study reflected the real-world prescribing pattern compared to the highly selected population in clinical trials which is the strength of the study. Also, the prescribing trend of the antidiabetic agents was stratified based on their HbA1c values. The study had certain limitations. Since data were gathered from a single hospital, the population was relatively homogeneous. Therefore, the findings may not apply to the general population. Secondly, alpha glucosidase inhibitors (voglibose), GLP1-RAs (exenatide) and glitazones (pioglitazone) were excluded as their usage in the hospital was very low. Thirdly, in our study, only 16.9% exhibited uncontrolled blood sugar levels, potentially explaining the under-prescription of the newer agents.

Conclusion

The current study highlights the prescription pattern of newer versus traditional antidiabetic medications among patients with T2DM and complications. There is significant variation in prescription patterns based on age, gender and prescriber speciality. Traditional agents remain the most commonly prescribed, whereas newer antidiabetics see low prescription rates despite their benefits for T2DM patients with complications. Efforts are needed to identify the barriers to the utilisation of SGLT2i and DPP-4i among this patient population.

Acknowledgement

We thank Dr Sudha Bhanu, Medical superintendent at Karuna Medical College and Hospital, Palakkad, Kerala, India for her guidance and continuing support. We also thank the Institutional Human Ethics Committee of Karuna Medical College for timely approval of the research proposal.

Conflicts Of Interest:

The author(s) do not have any conflict of interest.

Ethics statement

Ethical clearance was granted from the Institutional Human Ethics Committee of Karuna Medical College and Hospital, Palakkad, Kerala, under the study reference number KMC/IHEC/15/2023.

Funding

Self-funded.

Informed consent statement

Written consent was obtained from all the participants using an approved and locally translated consent form. Patients were informed about the details of the study, purpose, also confidentiality was maintained through all stages.

References

1. Thacker T. India tops global diabetes list with 212 million cases in 2022: Lancet Study. The Economics Times. 2024 Nov 13;
2. Maiti S, Akhtar S, Upadhyay AK, Mohanty SK. Socioeconomic inequality in awareness, treatment and control of diabetes among adults in India: Evidence from National Family Health Survey of India (NFHS), 2019–2021. Sci Rep. 2023 Dec 1;13(1).
3. Anjana RM, Unnikrishnan R, Deepa M et al. Metabolic non-communicable disease health report of India: the ICMR-INDIAB national cross-sectional study (ICMR-INDIAB-17). Lancet Diabetes Endocrinol. 2023 Jul 1;11(7):474–89.
4. Arnouts P, Bolignano D, Nistor I et al. Glucose-lowering drugs in patients with chronic kidney disease: A narrative review on pharmacokinetic properties. Vol. 29, Nephrology Dialysis Transplantation. Oxford University Press; 2014. p. 1284–300.
5. Vora H, Kaur P. Prediabetes and diabetes in India: An HbA1c based epidemiology study. Diabetes Research and Clinical Practice.2024;217:111889
6. Anjana RM, Unnikrishnan R, Deepa M et al. Achievement of guideline recommended diabetes treatment targets and health habits in people with self-reported diabetes in India (ICMR-INDIAB-13): a national cross-sectional study. Lancet Diabetes Endocrinol. 2022 Jun 1;10(6):430–41.
7. Narasaki Y, Kovesdy CP, You AS et al. Safety of SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 receptor agonists in US veterans with and without chronic kidney disease: a population-based study. The Lancet Regional Health - Americas. 2024 Aug 1;36.
8. Ajmal M, Akhter S, Khushtar M. An Update On Fixed-Dose Combination Of Sglt-2 And Dpp-4 Inhibitors In The Management Of Type-2 Diabetes Section A-Research paper Eur. Available from: https://www.researchgate.net/publication/372892117
9. Chadha M, Das AK, Deb P et al. Expert Opinion: Optimum Clinical Approach to Combination-Use of SGLT2i + DPP4i in the Indian Diabetes Setting. Diabetes Therapy. 2022 May 1;13(5):1097–114.
10. Consensus on the use of DPP4 Inhibitors and SGLT2 Inhibitors in T2DM with Chronic Kidney Disease-from Indian Context. Diabetes Obes Int J. 2021;6(2):1–14.
11. Das AK, Gandhi P, Saboo B et al. Optimizing the treatment of newly diagnosed type 2 diabetes mellitus with combination of dipeptidyl peptidase-4 inhibitors and metformin. J Family Med Prim Care. 2021 Dec;10(12):4398–409.
12. Suto G, Molnár GA, Rokszin G et al. Risk of morbidity and mortality in patients with type 2 diabetes treated with sodium-glucose cotransporter-2 inhibitor and/or dipeptidyl peptidase-4 inhibitor: A nationwide study. BMJ Open Diabetes Res Care. 2021 Jan 20;9(1).
13. Mengdi Li. Efficacy and Safety of Triple Therapy with SGLT-2 Inhibitor, DPP-4 Inhibitor, and Metformin in Type 2 Diabetes: A Meta-Analysis. ALTERNATIVE THERAPIES. 2023 Jul;29(5):320–6.
14. Liaw J, Harhay M, Setoguchi S, Gerhard T, Dave CV. Trends in Prescribing Preferences for Antidiabetic Medications Among Patients With Type 2 Diabetes in the U.K. With and Without Chronic Kidney Disease, 2006–2020. Diabetes Care. 2022 Oct 1;45(10):2316–25.
15. Chang HY, Su YW, Feng AN et al. Prescription patterns of diabetes medications influencing clinical outcomes of heart failure patients with reduced ejection fraction. ESC Heart Fail. 2020 Apr 1;7(2):604–15.
16. Mahtta D, Ramsey DJ, Lee MT et al. Utilization Rates of SGLT2 Inhibitors and GLP-1 Receptor Agonists and Their Facility-Level Variation Among Patients With Atherosclerotic Cardiovascular Disease and Type 2 Diabetes: Insights From the Department of Veterans Affairs. Diabetes Care. 2022 Feb 1;45(2):372–80.
17. Chia YMF, Teng THK, Tay WT et al. Prescription patterns of anti-diabetic medications and clinical outcomes in Asian patients with heart failure and diabetes mellitus. European Journal of Heart Failure. 2019;21:685–8.
18. McMurray JJV, DeMets DL, Inzucchi SE et al. The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial: baseline characteristics. Eur J Heart Fail. 2019 Nov 1;21(11):1402–11.
19. Rhee JJ, Han J, Montez-Rath ME et al. Antidiabetic medication use in patients with type 2 diabetes and chronic kidney disease. J Diabetes Complications. 2019 Nov 1;33(11).
20. Du YF, Ou HY, Beverly EA, Chiu CJ. Achieving glycemic control in elderly patients with type 2 diabetes: A critical comparison of current options. Vol. 9, Clinical Interventions in Aging. Dove Medical Press Ltd.; 2014. p. 1963–80.
21. D’Andrea E, Wexler DJ, Kim SC, Paik JM, Alt E, Patorno E. Comparing Effectiveness and Safety of SGLT2 Inhibitors vs DPP-4 Inhibitors in Patients with Type 2 Diabetes and Varying Baseline HbA1cLevels. JAMA Intern Med. 2023 Mar 6;183(3):242–54.
22. Sim R, Chong CW, Loganadan NK, Adam NL, Hussein Z, Lee SWH. Factors associated with DPP4i or SGLT2i utilisation: a retrospective cohort study among people with type 2 diabetes mellitus. Journal of Pharmacy Practice and Research. 2024;
23. Harris ST, Patorno E, Zhuo M, Kim SC, Paik JM. Prescribing Trends of Antidiabetes Medications in Patients With Type 2 Diabetes and Diabetic Kidney Disease: A Cohort Study. Diabetes Care. 2021 Oct 1;44(10):2293–301.
24. Pantalone KM, Misra-Hebert AD, Hobbs TM et al. Antidiabetic treatment patterns and specialty care utilization among patients with type 2 diabetes and cardiovascular disease. Cardiovasc Diabetol. 2018 Apr 10;17(1).
25. Ozaki AF, Ko DT, Chong A et al. Prescribing patterns and factors associated with sodium–glucose cotransporter-2 inhibitor prescribing in patients with diabetes mellitus and atherosclerotic cardiovascular disease. CMAJ Open. 2023 May;11(3):E494–503.