Linagliptin and Dapagliflozin: Evidence for Robust Glycemic Control and Reaping CV-CKD Benefits in T2DM (EVERGREEN) Practice Perspective

Multi-Comorbidity Burden with Type 2 Diabetes Mellitus (T2DM)

The comorbidities and complications add to the burden of diabetes. Reportedly, 75% of patients have at least one additional comorbidity at the time of T2DM diagnosis, and 44% have at least two comorbidities. (3) Among Indian T2DM patients, high blood pressure (28.5%) is reported as a major comorbidity, followed by rheumatism (24.4%), retinopathy (21.8%), and cardiovascular diseases (19.5%). (4)

Therapeutic Approach in Type 2 Diabetes (T2DM): Overview

The latest American Diabetes Association 2023 guidelines recommend that a patient-centered approach should guide the choice of therapy. (5) Patient-related factors such as age, presence of comorbidities and cardiovascular (CV) risk, and treatment-related factors such as individualised glycemic targets, avoidance of hypoglycemia and weight gain, cardiorenal protection, minimal side effects of the medications, and treatment costs are important factors that must be considered when managing T2DM. (6)

Combination of Dipeptidyl Peptidase IV Inhibitors (DPP-4i) and Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors (SGLT2i): Opinion from the Indian Experts

Compared to monotherapy, combination therapy improves treatment adherence and tackles several pathophysiologic defects in T2DM, enabling faster blood glucose control. Evidence from several clinical trials suggests that the SGLT2i+DPP4i combination is efficient and safe in controlling glycemic parameters in T2DM patients. (7) SGLT2 inhibitors have a unique insulin-independent mechanism of action and clinically proven weight lowering, blood pressure lowering, and cardiorenal-benefits. DPP4 inhibitors are weight-neutral; neither of these drug classes induce hypoglycemia. (8)

An expert opinion published on the optimal clinical approach to the combination use of SGLT2i + DPP4i in Indian diabetes settings suggests using SGLT2i+DPP4i fixed-dose combination in uncontrolled type 2 diabetes on Metformin with HbA1c >8.5% and among treatment-naive T2DM patients with HbA1c>8% in whom Metformin may be contraindicated or not tolerated. The SGLT2i+DPP4i combination may assist weight loss while providing benefits in T2DM patients with a higher predisposition to CV events and kidney disease. (7)

Linagliptin and Dapagliflozin: Applicability Across the Continuum of T2DM Care

Linagliptin is a DPP-4 inhibitor clinically useful for improving glycemic control in adults with T2DM. It offers a lower risk of hypoglycemia than other antidiabetic therapies and is weight-neutral. Importantly, it does not require dose modifications in a broad range of patient populations. It has a reassuring safety profile with robust evidence in T2DM, especially in cases of cardiac and renal comorbidities. (6)

Dapagliflozin is a highly selective SGLT2i that induces glucosuria by inhibiting glucose reabsorption in the kidney's proximal tubule. (9) In addition to potent blood glucose lowering effects, it has clinically established benefits beyond glycemic control, including lowering the rates of serious cardiovascular events, CV death, and hospitalisation for heart failure (HF) among T2DM with high CV risk. It also reduces the progression of CKD. (10)

Linagliptin & Dapagliflozin: Robust Glycemic Benefits

Linagliptin improves glycemic control in a varied T2DM population, including Asians, as established in several clinical trials and real-world evidence. (11) Treatment with Linagliptin reduces HbA1c level by 0.94%, fasting blood glucose (FBG) by 31.81 mg/dL (12), and postprandial glucose (PPG) by 33.5 mg/dl in T2DM patients. (13) Additionally, linagliptin treatment reduces the need for other glucose-lowering therapies, including insulin addition and up-titration. (11)

Dapagliflozin reduces glycemic fluctuations without increasing hypoglycemia episodes in patients newly diagnosed with T2DM. Treatment with dapagliflozin among T2DM patients has shown a reduction in HbA1c by 1.1%, FBG by 31.6 mg/dL, and PPG by 54.9 mg/dl. (9)

Linagliptin & Dapagliflozin: Reaping CV-CKD Benefits in Type 2 Diabetes

Linagliptin: Linagliptin reduces CV risk by 6.36% (P= 0.017), lowers triglyceride by 31.70 mg/dL [P=0.009] (12) and LDL-C by 41.9 mg/dL [P<0.05] (14). Treatment with Linagliptin also reduces albuminuria by 32% [P<0.05], indicating reno-protective benefits (15)

Dapagliflozin: Treatment with Dapagliflozin reduces CV death by 45%, hospitalization for HF by 36%, and all-cause mortality by 41% among T2DM with Heart Failure with reduced Ejection Fraction (HFrEF). (10) It also reduces the risk of ventricular arrhythmia, resuscitated cardiac arrest, or sudden death by 21%, (16) atrial fibrillations and atrial flutter events by 19% [ P=0.009] (17).

Dapagliflozin reduces albuminuria by 33.2% (95% CI −45.4, −18.2) in T2DM with hypertension (18). The subanalysis of the DECLARE-TIMI 58 trial has shown positive impact of Dapagliflozin on renal outcomes with no evidence of modification of treatment effect (P=0.28 and P=0.52). (19)

Linagliptin & Dapagliflozin: Effectiveness in T2DM Across Liver & Kidney Impairment & CVD :

Liver Safety:

Linagliptin: Linagliptin can be safely used in T2DM patients with mild to moderate liver dysfunction as opined by 87% Indian HCPs in a recent position paper on Linagliptin in T2DM management. (6) A pooled analysis of 17 randomized trials (n=7009, 39% Asians) showed that the adjusted mean change in HbA1c from baseline in those with hepatic disorders (hepatic steatosis, hepatitis C) was −0.75% ± 0.05 with linagliptin and − 0.20% ± 0.08 with placebo (P<0.0001) over 24 weeks. These suggest that linagliptin is effective and safe in people with T2DM and liver disease. (20)

Dapagliflozin: Dapagliflozin is well tolerated and associated with improvements in body composition and visceral fat, as well as improvements in liver parameters (serum concentrations of aspartate aminotransferase and alanine aminotransferase) and metabolic variables such as FPG, insulin, HbA1c, HDL-C, LDL-C, and triglycerides in patients with NASH associated with T2DM. (21)

Kidney Safety:

Linagliptin: Linagliptin is the only gliptin to have renal safety evidence, with demonstrated effectiveness across the spectrum of CKD in T2DM. (6) The KDIGO (Kidney Disease: Improving Global Outcomes) 2022 guidelines noted the favourable effects of linagliptin and recommended its use as no dose modifications are required. (22)

Dapagliflozin: Dapagliflozin has renal protection function and controls the progression of diabetic nephropathy by enhancing glomerular and renal tubular function and decreasing the release of TNF- and IL-6 inflammatory factors. (23) The KDIGO 2022 guideline recommended initiation of an SGLT2i for patients with T2DM and CKD who have eGFR ≥20 mL/min/1.73 m2 (a change from ≥30 mL/min/1.73 m2 in the 2020 guideline), and the ADA has also updated this threshold to ≥20 mL/min/1.73 m2 in its Standards of Care (from ≥25 mL/min/1.73 m2 in the initial issue of the 2022 Standards of Care). (22)

CV Safety- Established in Asian T2DM Patients

Linagliptin: A subgroup analysis of the CARMELINA trial (N=6979, 8.0% Asian) assessed the CV safety of linagliptin among Asian T2DM. During a median follow-up of 2.2 years, 3-point MACE (first occurrence of CV death, non-fatal MI, or nonfatal stroke) occurred in 29/272 (10.7%) and 33/283 (11.7%) of linagliptin and placebo groups, respectively (HR]0.90 P=0.3349). This suggests the CV safety of linagliptin among Asian T2DM patients. (24)

Another subgroup analyses of the CAROLINA trial showed that linagliptin showed fewer 3P-MACE (first occurrence of CV death, non-fatal MI, or non-fatal stroke events) during 6.2 years of median follow-up (9.5% linagliptin vs 11.1% glimepiride, HR 0.85, There were no significant differences between groups for other outcomes, including CV death (HR 0.73), non-CV mortality (HR 0.76) and hospitalization for heart failure (HR 0.89). Hypoglycemia adverse events occurred in 13.1% of linagliptin patients versus 42.1% of glimepiride patients (HR 0.25; P<0.0001) despite similar glycemic control. Body weight was slightly lower with linagliptin relative to glimepiride. (25)

Dapagliflozin: Dapagliflozin is well tolerated and safe in a wide spectrum of T2DM including patients with poorly controlled diabetes, the elderly, heart failure (NYHA class II or higher), or patients with CV risk factors. It decreases body weight and SBP (systolic blood pressure) in patients with poorly managed hypertension and pre-existing CVD without affecting CV safety. (26)

Clinical Takeaways

• Diabetes is growing alarmingly, and the increasing comorbidities add to the disease burden. Glucose-lowering medications with long-term durability, as well as CV, hepatic, and renal safety, are relevant and important for streamlining T2DM management.
• Linagliptin has a reassuring safety profile with robust evidence across the T2DM continuum.
• Linagliptin has been proven efficacious in the Asian T2DM population, with demonstrated cardiovascular (CV) and renal safety, improvement in the metabolic profile, and enhanced adherence due to once-a-day dosing without the need for dose modifications.
• Dapagliflozin is effective in reducing the risk of hospitalisation for HF, CV deaths, and renal disease progression.
• Dapagliflozin is well-tolerated and safe across T2DM patient population groups, including poorly controlled diabetes with high CV risk and CKD.

The combination treatment of linagliptin and dapagliflozin may be a reasonable choice as a potential ‘evergreen duo’ for managing a wide spectrum of T2DM. This is due to their complementary actions, robust glycemic control, and the associated benefits of metabolic improvement, weight and blood pressure reduction. Moreover, this combination offers cardiovascular and renal safety and can be administered once daily without the need for dose modifications, benefiting a broad range of T2DM patients.

References:

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