Applicability of FDC of Linagliptin and Dapagliflozin in T2DM: EVERGREEN Case Report Summaries

The EVERGREEN webinar, designed to guide physicians regarding the care of people with diabetes, highlighted the clinical applicability of a combination of Linagliptin and Dapagliflozin in real-world clinical scenarios of type 2 diabetes and comorbidities. Dr. V Mohan described multiple case scenarios to help clinicians understand the therapeutic scope of this fixed-dose combination. A summary of two cases, which includes the use in newly diagnosed type 2 diabetes and in type 2 diabetes, uncontrolled with metformin are presented in this article.

Dr. V. Mohan, M.D., FRCP (London, Edinburgh, Glasgow & Ireland), Ph.D., D.Sc. D.Sc (Hon. Causa), FNASc, FASc, FNA, FACE, FACP, FTWAS, MACP, FRSE. Dr. V. Mohan is a Padma Shri Awardee and is the Chairman, of Dr. Mohan’s Diabetes Specialities Centre in Chennai, South India, an IDF Centre of Excellence in Diabetes Care and Madras Diabetes Research Foundation, Asia’s largest stand-alone diabetes research centre.

Case-1: Newly Diagnosed Type 2 Diabetes:

Case History:

A 30-year-old female presented in the outpatient department with complaints of polyuria and polydipsia for the last one month. Her mother had hypertension and no other significant history was noted. On clinical examination, Her height was 165cm, weight was 75 kg, BMI-27 kg/m2, blood pressure was slightly elevated for her age (134/84 mm Hg), and the random blood glucose (RBG) level was 205 mg/dl, which indicated Diabetes. Her waist circumference was 84 cm, indicating abdominal obesity. Physical examination was unremarkable.

Further investigations showed her HbA1c was 9.2%, and fasting and postprandial blood glucose was 212 mg/dl and 330 mg/dl respectively. Liver function tests showed grossly elevated levels of AST and ALT indicative of fatty liver disease, specifically non-alcoholic fatty liver disease (NAFLD). Elevated free fatty acid levels were also observed, suggesting a likelihood of impending triglyceride elevation. These findings collectively pointed towards features of metabolic syndrome in the patient.

Treatment Approach:

A fixed-dose combination of dipeptidyl-peptidase 4 inhibitors (DPP-4i) [Linagliptin] and Sodium-glucose cotransporter-2 inhibitors (SGLT2i) [Dapagliflozin] was prescribed in this case. Let’s discuss the fixed-dose combination of dipeptidyl-peptidase 4 inhibitors (DPP-4i) and Sodium-glucose cotransporter-2 inhibitors (SGLT2i) in the management of type 2 diabetes:

DPP-4 Inhibitors (DPP-4i): DPP-4 inhibitors, such as Linagliptin, have an incretin effect and act by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4), which degrades incretin hormones. By inhibiting DPP-4, these drugs increase the levels of two important incretin hormones:

• GLP-1 (glucagon-like peptide-1): GLP-1 stimulates insulin secretion from beta cells in the pancreas and suppresses glucagon release from alpha cells, leading to better blood sugar control.
• GIP (gastric inhibitory polypeptide): GIP also enhances insulin secretion and helps regulate blood glucose levels. Importantly, DPP-4 inhibitors are weight-neutral.

SGLT2 Inhibitors (SGLT2i): SGLT2 inhibitors, such as Dapagliflozin, act by inhibiting the sodium-glucose cotransporter-2 (SGLT2) in the kidneys, reducing glucose reabsorption and leading to an increased glycosuria. SGLT2 inhibitors are associated with several weight reduction benefits, blood pressure lowering, and cardiovascular benefits.

Combination Therapy:

Combining DPP-4 inhibitors (DPP-4i) and SGLT2 inhibitors (SGLT2i) can effectively manage type 2 diabetes.

These drugs have complementary mechanisms of action: DPP-4 inhibitors enhance incretin hormones (GLP-1 and GIP) & SGLT2 inhibitors increase glycosuria and provide additional benefits.

As Diabetes is a multifactorial disease, the drugs act on multiple pathophysiological defects controlling glycemia.

Dual therapy or adding these agents to metformin can be considered at any stage of diabetes.

For a 30-year-old individual, the aim should be to achieve an HbA1c goal of 6.5% or even lower. This can help prevent or reduce the risk of microvascular (e.g., retinopathy, neuropathy) and macrovascular (e.g., heart disease, stroke) complications.

Considering the HbA1c of 9.2% in this patient, metformin monotherapy may not suffice. A fixed-dose combination of Linagliptin and Dapagliflozin, in addition to metformin, will help achieve blood glucose control.

Follow-up: At follow-up after 2 weeks, FPG was 118 mg/dl and 2 hr-PPG was 148 mg/dl. No hypoglycemia was reported. At the end of 3 months, the patient achieved the required HbA1c 6.9%. Weight was reduced by about 3 kgs.

Case 2: Type 2 Diabetes, uncontrolled on Metformin

Case History:

A 45-year-old male presented to the outpatient department for a regular health checkup. He had a history of type 2 diabetes for the past two years and was on metformin 1g per day, with an HbA1c of 8.4%, which kept increasing. Further attempts at lifestyle changes were unsuccessful. He also had a history of hypertension, which was controlled with a combination of telmisartan and chlorthalidone.

On examination, his weight was 98 kg, BMI was 32.5 kg/m2, and blood pressure was 138/96 mmHg. Physical examination was unremarkable, and his ECG was normal.

Further investigations showed that fasting and postprandial blood glucose were 195 mg/dl and 294 mg/dl respectively. The lipid profile was normal and within limits.

Treatment Approach & Discussion:

A fixed-dose combination of Linagliptin and Dapagliflozin was used in this case of uncontrolled Type 2 Diabetes.

If Linagliptin or Dapagliflozin alone is prescribed as an addition to metformin, this patient’s HbA1c of 8.4% will probably decrease by about 0.5% to 1.0% but this will not achieve normal glycemia or attain the target glycemic goal of less than 6.5% or probably even reach 7%

Effect on HbA1c:

Studies have shown Linagliptin results in 0.9% reduction of A1c when added to metformin, whereas, the fixed-dose combination of Dapagliflozin 10mg and Linagliptin 5mg, achieves an average HbA1c reduction of 1.36%

Studies have also shown that the percentage of patients achieving HbA1c less than 7% with a single drug, linagliptin, is 26%, whereas, when combined with dapagliflozin, it is 49%.

Effect on FPG & 2h-PPG:

Linagliptin, when combined with metformin, results in 22 mg/dl reduction in fasting blood glucose and a more significant reduction of 25 mg/dl is achieved when Linagliptin is combined in a fixed-dose combination with Dapagliflozin and added to Metformin.

The combination of linagliptin and dapagliflozin also yields a more substantial effect on 2-hour PPG, with a 52 mg/dL reduction.

Effect on Weight

The fixed-dose combination of dapagliflozin and linagliptin can produce a 1kg reduction in body weight. Therefore, for weight reduction, when a combination of Linagliptin and Dapagliflozin is prescribed, better results are achieved than with either linagliptin or dapagliflozin alone.

In summary, combining Linagliptin or Dapagliflozin with metformin can lead to improved glycemic control and weight reduction with minimal risk of hypoglycemia. It remains an effective strategy for managing T2D while considering individual patient factors.

Follow-up: At follow-up after 2 weeks, the FPG was 92 mg/dl and 2-h PPG was 139 mg/dl. No hypoglycemia was reported. At the end of 3 months, the patient achieved a HbA1c of 6.8%. Weight was reduced by about 2 kgs.

The combination of Linagliptin and Dapagliflozin may be useful, acting as an “Evergreen Duo” in newly diagnosed and uncontrolled type 2 diabetes patients.

Reference:

1. Dr V Mohan, EVERGREEN Webinar Presentation.