Linagliptin And Glimepiride Compared In Type Two Diabetes

Sulfonylureas are often added to metformin to improve glycemic control, but at the known risk of increasing hypoglycemia and weight gain. In a report published in the Lancet, more than 1,500 patients with type 2 diabetes taking metformin were randomized to the addition of either linagliptin, a dipeptidyl peptidase-4 inhibitor or the sulfonylurea glimepiride.

After two years the trial achieved the prespecified criterion for noninferiority as treatment with both drugs resulted in a similar effect on HbA1c. Both hypoglycemia and weight gain were reduced in patients taking linagliptin. There was only one case of severe hypoglycemia in the linagliptin group, compared with 12 cases in the glimepridie group. In addition, although there were only a small number of cardiovascular (CV) events, a significant reduction was observed in the linagliptin group.

  • Reduction in mean HbA1c: −0.16% for linagliptin versus −0.36% for glimepiride (difference 0.20%, CI 0.09–0.30)
  • Hypoglycemia: 7% for linagliptin versus 36% for glimepiride (p<0·0001)
  • Weight: −1.4 kg versus  +1.3 kg (p<0·0001)
  •  CV events: 12 vs 26 events, RR 0.46, CI 0.23—0.91 (p=0.0213)

The results, write the authors, “support the use of linagliptin in combination with metformin as a therapeutic option for treatment of type 2 diabetes.”

In an accompanying editorial, André Scheen and Nicolas Paquot discuss the potential benefits of linagliptin and other DPP-4 inhibitors. They note that the smaller reduction in HbA1c with linagliptin “might support the view of a slightly lower efficacy of DPP-4 inhibitors compared with sulphonylureas,” but  say that only a trial with longer followup can assess the durability of of glucose lowering with DPP-4 inhibitors. In the meantime, the effects on weight and the lower rate of hypoglycemia are “important to patients with diabetes” and can improve quality of life.

However, firm conclusions about the drugs can not be reached until long-term trials with cardiovascular outcomes are completed. These trials will “provide enough data for both efficacy (ie, effects on diabetic complications) and safety (ie, concerns about pancreatitis and pancreatic cancer) to draw firm conclusions about the real value of this new approach.”

Here is the press release from the Lancet:

New second-line drug for Type 2 diabetes results in less hypoglycaemia, less weight gain and perhaps less cardiovascular risk for patients

A new drug could offer significant advantages over existing treatments for Type 2 diabetes patients who don’t respond to metformin, the most commonly prescribed initial drug treatment for the disease. The new drug, linagliptin, results in significantly less weight gain than the most common second-line treatments currently used, and may even carry a smaller risk of cardiovascular events such as heart attack and stroke, according to an Article published Online First in The Lancet.

Diabetes is estimated to have affected around 347 million people worldwide in 2008 – almost 10% of the world’s population – and while metformin is the most commonly prescribed initial drug treatment for the disease, it can become ineffective in the long-term for many patients. There is currently a pronounced lack of evidence for which second-line drug treatments offer patients in this situation the best chances of recovering normal blood sugar levels, with the authors stating that: “When metformin and lifestyle interventions fail…in a patient with type 2 diabetes, the optimum choice for an additional pharmacotherapy is unclear.”

Usually, patients who do not respond to metformin alone are offered a class of drugs known as sulphonylureas in addition to their ongoing metformin treatment. However, sulphonylureas – which work by stimulating the cells in the pancreas to make more insulin, independently of blood glucose levels – can lead to hypoglycaemia (low blood sugar levels)* and weight gain, which put patients at increased risk of heart attack and stroke, as well as reducing their quality of life.

“Since hypoglycaemia can have substantial negative clinical consequences in terms of cognitive function, mortality, morbidity, adherence to treatment, and quality of life, its prevention is a crucial component of any diabetes management programme,” according to one of the study’s authors, Professor Baptist Gallwitz, of Tübingen University Hospital, Germany.

The new drug, linagliptin (one of a class of drugs called DPP-4 inhibitors, or “gliptins”), works in a different way to sulphonylureas, by blocking an enzyme known as dipeptidyl peptidase-4 which is involved in glucose metabolism. This allows the body to increase the amount of insulin it secretes in a glucose-dependent manner, resulting in a very low risk of hypoglycaemia. Linagliptin was licensed in 2011 but this is the first long-term study to assess its efficacy and safety.

The double-blind study, which took place over two years in sixteen different countries, examined the effects of linagliptin versus glimepiride, one of the most commonly used sulphonylureas, in more than 1,500 patients with Type 2 diabetes who had not achieved normal glucose regulation through the use of metformin alone.

While the two treatments produced comparable improvements in patients’ glucose regulation, the study showed that the side effects of linagliptin appear to be considerably less severe than those attributed to glimepiride, with just 7% of patients treated with linagliptin experiencing hypoglycaemia, compared to 38% of patients treated with glimepiride. The group treated with linagliptin also experienced fewer cardiovascular events such as heart attacks or strokes compared to those treated with glimepiride, although the authors point out that further studies will be needed to confirm this, as the study was not long enough to provide reliable evidence that linagliptin results in reduced cardiac risk compared to glimepiride.

In a linked Comment accompanying the paper, Professor Andre Scheen of Liège University Hospital, Belgium, calls for longer-term studies to assess the effectiveness of drugs like linagliptin as compared to other treatments.

“Besides [glucose regulation], other outcomes are important to patients with diabetes, such as ease of administration, weight change, and incidence of hypoglycaemia, which can all affect quality of life…The much lower risk of hypoglycaemia associated with gliptins compared with sulphonylureas might be seen as a major advantage in some patients exposed to this complication, and could affect the choice of drug to be added as second-line treatment to metformin.”

Notes to Editors:

* Hypoglycaemia (low blood sugar levels), which can occur as a result of taking sulphonyureas, is not to be confused with hyperglycaemia (elevated blood sugar levels), the main sign of untreated diabetes.


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