Dapagliflozin Glimepiride Metformin FDC in Uncontrolled T2DM with HbA1c >9 %

Introduction

India has the second highest rate of diabetes in the world. (1) According to the ICMR-INDIAB-17 study, the prevalence of diabetes in India is 11.4% affecting 101 million people. (2) A recent retrospective study in India across 4793 clinics with 6,722,173 patients diagnosed with coexistent T2DM with hypertension, and dyslipidemia demonstrated that 74% of patients had HbA1c > 7%. (3)

Diabetes is a progressive disease, often requiring multiple medications that can act in a complementary manner. Many patients will require combination treatment. The American Association of Clinical Endocrinology (AACE) 2023 Consensus advises initial combination treatment for HbA1c > 7.5%, whereas the ADA suggests beginning combination treatment for patients with HbA1c 1.5-2% above their glycemic target. These guidelines are among the many clinical practice guidelines that advocate for early combination treatment for those with elevated glycated hemoglobin (HbA1c) levels. (4)

This article summarizes the case-based approach, highlighting the clinical applicability of a combination of Dapagliflozin, Glimepiride, and Metformin FDC in real-world clinical scenarios of uncontrolled type 2 diabetes patients.

Case History:

A 45-year-old male with T2D for the past 6 years came to OPD for a regular follow-up visit for his T2D. His blood tests had indicated to him that his blood sugar level was uncontrolled this time. The patient is also a K/C/O hypertension for 2 years. The patient recently reported a high level of work-related stress. On enquiry, the patient mentioned that his smoking has increased in the past few months, and leads a sedentary lifestyle, with irregular eating habits and sleep difficulty. He already brings along a family history of T2DM and atherosclerotic cardiovascular disease (ASCVD), as his father suffered a myocardial infarction (MI).

On clinical examination, blood pressure was elevated (148/92 mmHg), pulse rate 92 bpm, BMI 28.2 kg/m2. His HbA1c was 9.1%, fasting blood sugar (FBS) 161 mg/dl, post lunch blood sugar (PLBS) 234 mg/dl, S. Creatinine: 0.8 mg/dl, Lipid Profile: LDL- 108 mg/dl, TG: 185 mg/dl, S. Uric Acid: 8.1mg/dl.

The liver function test and ECG were within normal limits. Ultrasound sonography indicated the early stages of MASLD.

He has been on Metformin 500 mg b.i.d, Glimepiride 1 mg once daily before breakfast. In addition, the patient was on telmisartan 40mg for his high blood pressure.

Treatment Approach:

The treatment approach needs to integrate lifestyle interventions and pharmacological management. The following treatment approach was considered.

• Non-Pharmacological: Brisk walking 45 minutes daily, Regular balanced meal as per Nutritionist’s advice. Counseling to abstain from smoking was done.
• Pharmacological: Dapagliflozin 10 mg + Glimepiride 1 mg + Metformin 1000 mg FDC Once daily was added. Telmisartan 40 mg + Amlodipine 5mg OD was added for the management of hypertension. He was also added 10 mg Atorvastatin in view of High LDL & 40 mg Febuxostat.

Considering Dapagliflozin, Glimepiride Metformin: Evidence Snapshot:

This case demonstrates a clinical scenario of young uncontrolled T2DM with HbA1c >9%. Such patients may need a treatment approach that addresses multiple complementary mechanisms of diabetes pathophysiology, and help in robust glucose control. Also, this patient has intermediate CV risk factors like hypertension and hyperuricemia, along with F/H of ASCVD, which needs to be factored.

Dapagliflozin inhibits SGLT2 in the kidneys, reducing glucose reabsorption and leading to increased glycosuria. It also has the potential to reduce blood pressure and uric acid levels (5) Glimepiride has a robust hypoglycaemic efficacy, relatively low risk of hypoglycemia, convenient once daily use, and good cardiovascular safety. (6) Metformin has been used as first-line therapy for treating T2D for nearly two decades in the light of robust evidence that supports improved cardiovascular outcomes, reduction in HbA1c, weight neutrality, and overall safety profile. (7)

Dapagliflozin + Glimepiride + Metformin FDC Benefits T2DM Patient with HbA1c >9%: Indian Experience

A subgroup analysis of a phase 3, open-label, four-arm, active-controlled study assessed the efficacy and safety of triple-drug FDC [dapagliflozin (D)+Glimepiride (G)+Metformin (M)] vs two-drug combination (Glimepiride (G)+ metformin (M)] in Indian T2DM patients (HbA1c 9%- 11%). The adjusted mean change in HbA1c in patients aged <45 and the proportion of patients achieving HbA1c <7% were significantly higher in the triple combination group in 16 weeks [74.5% in triple FDC D (5mg)+G (1mg)+M (500mg), 85.5% in triple FDC D (5mg)+G (1mg)+M (1000mg) Versus 46.9% in two-drug combination G(1mg)+ M (1 tablet 500mg), and 58.1% in two-drug combination G(1mg)+ M (2 tablet 500mg) achieved HbA1c <7%]. (8)

Follow Up:

At follow-up after 4 weeks, FBG was 104 mg/dl, and PPG was 146 mg/dl. No hypoglycemia was reported. After 3 months, the patient achieved the required HbA1c of 6.9%, and no hypoglycemia or weight gain was reported. Improvement in lipid and metabolic parameters such as TG: 145 mg/dl and S. Uric Acid: 6.8 mg/dl were observed.

The patient returned highly satisfied after 3 months achieving target glycemic control and lipid goals. The patient also admitted that he felt relieved with the improvement in blood glucose control without the increase in pill burden or any side effects.

The patient continued to maintain glycemic and lipid goals effectively and safely at every follow-up; which was recorded consistently for 1 year until the time of writing this case report. His blood pressure control also improved based on his regular HBPM recordings. He expressed he was mentally relived with his healthy blood tests, which probably helped his blood pressure. All this improvement in treatment outcomes motivated the patient further lead and maintain a healthier lifestyle.

Take Home Messages for Clinicians

• This case study describes the pervasive issue of uncontrolled T2DM in middle-aged adult Indian population.
• When target blood glucose control is not achieved using two-agents, adding a third glucose lowering agent may be necessary in such cases of uncontrolled T2DM
• The choice of glucose-lowering agents in such cases needs to be based on their complementary mechanisms of action tackling comprehensive defects of T2DM pathophysiology.
• The CV benefit and CV safety of selected molecules are important for beyond glycemic benefits and improving long-term outcomes.
• The convenience of minimal pill burden is practically advantageous as it improves medication adherence and long-term treatment compliance.
• Clinical Evidence indicates that a fixed-dose combination of Dapagliflozin, Glimepiride, and Metformin provides significant glycemic control and less frequent treatment failure.
• This case study demonstrated that a fixed-dose combination of Dapagliflozin, Glimepiride, and Metformin may be useful consideration and beneficial in uncontrolled T2D patients with HbA1c >9% when appropriately indicated.

References:

1. Maiti, S., Akhtar, S., Upadhyay, A.K. et al. 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 13, 2971 (2023). https://doi.org/10.1038/s41598-023-29978-y

2. Anjana, Ranjit Mohan et al. “Metabolic non-communicable disease health report of India: the ICMR-INDIAB national cross-sectional study (ICMR-INDIAB-17).” The lancet. Diabetes & endocrinology vol. 11,7 (2023): 474-489. doi:10.1016/S2213-8587(23)00119-5

3. Dalal J, Chandra P, Chawla R, et al. Clinical and Demographic Characteristics of Patients with Coexistent Hypertension, Type 2 Diabetes Mellitus, and Dyslipidemia: A Retrospective Study from India. Drugs Real World Outcomes. 2024;11(1):167-176. doi:10.1007/s40801-023-00400-3

4. Schroeder EB. Management of Type 2 Diabetes: Selecting Amongst Available Pharmacological Agents. [Updated 2022 Jul 28]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK425702/

5. Fatima A, Rasool S, Devi S, et al. Exploring the Cardiovascular Benefits of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors: Expanding Horizons Beyond Diabetes Management. Cureus. 2023;15(9):e46243. Published 2023 Sep 30. doi:10.7759/cureus.46243

6. Basit A, Riaz M, Fawwad A. Glimepiride: evidence-based facts, trends, and observations (GIFTS). [corrected] [published correction appears in Vasc Health Risk Manag. 2013;9:1]. Vasc Health Risk Manag. 2012;8:463-472. doi:10.2147/HIV.S33194

7. Andraos, J., Smith, S.R., Tran, A. et al. Narrative review of data supporting alternate first-line therapies over metformin in type 2 diabetes. J Diabetes MetabDisord23, 385–394 (2024). https://doi.org/10.1007/s40200-024-01406-6

8. Prakash Kurmi, Manish Singh, Vishal Gupta, ChikkalingaiahSiddegowda, Jitendra Shukla, Sandip Gofne, Nilesh Lomte, Kaustubh Shendkar, Dinesh Gangwani, Surendra Kumar, Sandeep Gupta, Nagarajaiah Aravind G, Amit Bhaskar, Prabhat Sharma, Arjun Baidya, Animesh Maiti, Ambana Gowda, Jayesh Ambaliya, K Balachandra Giriappa, Sunil Mahavar, Hemant Gupta, Rajurkar Dr Mandodari, Supriya Sonowal, Piyush Patel, Dipak Patil, Lalit Lakhwani, Pravin Ghadge, Suyog Mehta, Sadhna Jogleka. Subgroup analysis of phase 3 study of fixed-dose combination of dapagliflozin, glimepiride, and metformin IR in type 2 diabetes mellitus patients with HbA1c 9%-11%. Article in Endocrine Abstracts, published May 2024