Novel, Incretin-based Oral Combination Therapy: A Possible Replacement for Insulin as First-line Therapy in Newly Diagnosed Type 2 Diabetes Patients

Can a new class of novel, orally available incretin-based therapies replace insulin as first-line therapy in severely hyperglycemic patients newly diagnosed with type 2 diabetes? Study results presented during a session Sunday at the American Diabetes Association’s 74th Scientific Sessions, held June 13-17, 2014, in San Francisco, CA, offered a tantalizing glimpse at this possibility.

Stuart A Ross, MD, CHB, Clinical Professor in the Faculty of Medicine at the University of Calgary, Alberta, presented results from a sub-analysis of a major clinical trial for a novel combination therapy to treat newly diagnosed type 2 diabetes.

Such patients commonly present with marked hyperglycemia and therefore insulin is often the preferred starting therapy, with the result that novel oral anti-diabetic drugs (OADs) have only rarely been studied for their effect on this population.The study explored combining metformin, the first-line OAD of choice for the treatment of type 2 diabetes, with an incretin-based therapy of linagliptin, an inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4).

Ross said the objective of the trial was “to take the patients who were assessed with extreme hyperglycemia, HbA1c over 9.8%, which is certainly very high. We wanted to look at specific sub-analyses because this was a multi-center, multi-national trial and we thought that there might be instructive variations in the data. We looked specifically at baseline HbA1c, we looked at age, we looked at renal function, race, and ethnicity to try and tease out information regarding differences among the different groups that could guide us clinically.”

Incretins are a group of gastrointestinal hormones that stimulate a decrease in blood glucose levels by raising the amount of insulin released from beta cells and by inhibiting glucagon release from alpha cells. Incretins can also slow the rate of absorption of nutrients into the bloodstream by reducing gastric emptying. The two best-known incretins -- glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP) -- are rapidly inactivated by DPP-4. Linagliptin, a drug from a class of OADs that inhibits the enzymatic activity of DPP-4, is therefore able to prevent inactivation of GLP-1 and GIP, thereby increasing levels of insulin and reducing blood glucose.

Because metformin exerts its effect by suppressing production of glucose from three-carbon molecules (such as pyruvate) in the liver, it was thought that the complementary mechanisms of action of the two OADs would not only prove effective but also serve to reduce the risk of hypoglycemia, the main factor limiting insulin treatment.

The effect of this oral, glucose-lowering combination therapy was explored in a randomized, double-blind, two-arm study comparing linagliptin plus metformin (Lina+Met) with linagliptin alone in more than 300 patients newly diagnosed (≤12 months) with type 2 diabetes who showed marked hyperglycemia. The primary endpoint was HbA1c change from baseline to week 24. Mean age was 48.8 years with standard deviation (SD) of ±11.0 and mean baseline HbA1c was 9.8% (SD±1.1%).

Results demonstrated a mean HbA1c reduction of -3.4% with a standard error (SE) of ±0.2% for Lina+Met compared with -2.5% (SE ±0.2%)with linagliptin alone in patients with baseline HbA1c ≥9.5%. For patients with baseline HbA1c <9.5%, results were -2.1% (SE ±0.2%) for Lina+Met and -1.4% (SE ±0.2%) for linagliptin alone. Similar reductions in HbA1c were observed in all subgroups of age, body mass index, renal function, race, and ethnicity. Incidences of hypoglycemia were rare, occurring in 1.9% of the high HbA1c patients and in 3.2% of the group with baseline HbA1c <9.5%, with no severe episodes in either group.

Ross summarized the results, saying, “In the analysis of newly diagnosed type 2 diabetes patients presenting with marked hyperglycemia, initial Lina+Met treatment delivered consistent HbA1c reductions across different subgroups. Oral glucose-lowering combination therapy may be a viable initial alternative to insulin for effective treatment of these patients.”

Addressing concerns of hypoglycemia specifically arising from treating newly diagnosed type 2 diabetes patients with insulin, Ross said, “Overall, we feel that we have achieved results that allow us to consider therapies other than insulin as first-line therapy.”

The study was sponsored by Boehringer Ingelheim.