Novartis combination therapy with Vildagliptin-Metformin shows positive results for Type 2 Diabetes

The vildagliptin and metformin dual therapy are used when the patient’s T2DM is insufficiently controlled by metformin monotherapy.

Mumbai: Novartis recently announced the key results from the Phase IV clinical study VERIFY evaluating the long-term efficacy and safety of an early combination treatment strategy with metformin plus vildagliptin (dipeptidyl peptidase-4 [DPP-4] inhibitor) compared to the traditional stepwise approach with metformin as initial therapy followed by vildagliptin, added at the time of metformin failure. The key study findings were presented today at the European Association for the Study of Diabetes (EASD) Annual Meeting and published simultaneously in The Lancet.

The combination of these two anti-diabetic agents with complementary mechanisms of action provides superior efficacy and allows patients to reach glycemic targets without increasing the risk of hypoglycemia, weight gain and other CV risk factors. Vildagliptin-metformin combination was the first single-pill dual therapy of a DPP-4 inhibitor with metformin approved in Japan and Europe. The vildagliptin and metformin dual therapy is used when the patient’s T2DM is insufficiently controlled by metformin monotherapy.

Metformin hydrochloride is a widely-used and is the recommended first-line therapy in patients with newly-diagnosed T2DM either immediately after diagnosis or in those not able to achieve glycemic targets despite diet and other lifestyle interventions.

Despite its discovery already in 1922, the exact mode of action for metformin is not yet known. However, its effect in management of diabetes is through reduction of glucose output in the liver and secondarily, through an increase of glucose uptake in the peripheral tissues. However, recent data suggest that some clinical activity may also arise from the synthesis and stimulation of intestinal release of incretin hormones.

Vildagliptin is approved as an oral treatment for adults with T2DM in more than 120 countries, including the EU, Japan, Latin America and Asia-Pacific. Vildagliptin is approved for use as monotherapy, dual therapy in combination with metformin, sulfonylurea (SU) or a thiazolidinedione, as triple oral therapy in combination with a SU and metformin or as an add-on to insulin (with or without metformin).

Vildagliptin is a selective and potent DPP-4 inhibitor that acts by preventing the usually rapid degradation of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which in turn, enhances the α- and β-cell sensitivity to glucose and inhibits glucagon secretion, thereby improving glycemic control in T2DM 7,8,9,10 . Vildagliptin has been widely studied in randomized clinical trials but it also has an extensive pool of evidence in real-world settings within diverse patient populations across the disease continuum.

VERIFY is a unique study designed to determine durability, over a pre-specified five-year follow-up of early use of combination therapy strategy with vildagliptin-metformin. The study was conducted across 254 centres in 34 countries and involved 2001 treatment-naïve diverse individuals recently diagnosed with T2DM (HbA1c between 6.5–7.5% [48–58 mmol/mol]).

In the randomized, double-blind Phase IV study (ClinicalTrials.gov Identifier: NCT01528254), early combination therapy of vildagliptin (50 mg, twice daily) and metformin (individually, 1000–2000 mg, daily) met the primary endpoint with a statistically significant 49% reduction in the relative risk for time to initial treatment failure (HbA1c ≥ 7.0% twice, consecutively, 13 weeks apart), versus metformin alone (HR: 0.51, 95% CI [0.45, 0.58]; P<0·0001).

The combination treatment strategy also showed a lower frequency of secondary failure when all patients were receiving combination therapy (HR: 0.74, 95% CI [0.63, 0.86]; P<0.0001). Furthermore, patients treated with early combination had consecutively lower HbA1c levels (below 6.0%, 6.5% or 7.0%) for 5 years versus those receiving combination therapy only after metformin monotherapy failure.

“The initial findings from the VERIFY study uniquely demonstrate that early intervention with a combination therapy strategy provides greater and durable long-term benefits for patients.

The currently recommended initial monotherapy approach with later treatment intensification in type 2 diabetes management is now shown to be an inferior strategy,” said Professor David Matthews, EASD President and Emeritus Professor of Diabetic Medicine, University of Oxford, UK.

The overall safety and tolerability profile were similar between the treatment approaches, with no unexpected or new safety finding reported “In light of the existing gaps in diabetes management in India which is home to over 72 million people living with diabetes, we continue to focus on driving science in order to improve patient outcomes. The VERIFY study is an extension of our efforts towards continuing to win for as many patients with diabetes. The positive results from the VERIFY study further affirm the importance of early treatment intensification in newly diagnosed type 2 diabetes patients,” said Sanjay Murdeshwar, Managing Director, Novartis in India.

Additional pre-defined secondary analyses of the VERIFY study results are ongoing and data will be disclosed over the coming months at international and local medical congresses and in scientific journals.

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