New Class of Drug for Type 2 Diabetes Acts Independently of Insulin

A new first in class drug getting close to approval to treat Type 2 diabetes showed the potential to help lower blood glucose levels through a different mechanism than current treatments, according to new studies…. 

The most advanced drug in the class, dapagliflozin, is being developed by Bristol-Myers Squibb Co., and AstraZeneca PLC. The product is designed to lower blood glucose levels in patients with diabetes by increasing the amount of glucose excreted in the urine of people with diabetes.

Dapagliflozin, a new type of drug for the treatment of Type 2 diabetes, improves glycemic control independent of insulin by reducing renal glucose reabsorption, according to a new phase 3 study presented at the ADA’s 70th Scientific Sessions and published concurrently in the June 26 issue of The Lancet.

Clifford J. Bailey, PhD, from Aston University, Birmingham, United Kingdom, stated that, "Given with metformin, dapagliflozin represents a new therapeutic option for the treatment of patients with Type 2 diabetes who have inadequate glycemic control with metformin alone."

Dapagliflozin, which is a selective sodium-glucose cotransporter-2 inhibitor, works by preventing reabsorption of glucose in the kidneys and promotes the excretion of glucose in the urine. It thereby reduces high levels of blood glucose without affecting insulin-dependent systems.

Dr. Bailey stated that, "Many complications of diabetes are related to high concentrations of blood glucose, so being able to lower blood glucose is a legitimate target for new drugs for diabetes. This is a new class of agent to treat diabetes. It works in a non-insulin-dependent manner, [lowering] glucose levels by increasing the elimination of excess glucose in the urine…. Because it is a non-insulin-dependent mechanism, it should be suitable for use at any time during the duration of the disease process, and it should be compatible with an additive to any of the other therapies that we have available at the moment."

The multicenter study included 534 adults with Type 2 diabetes who were receiving at least 1500 mg of metformin per day but still had poor glycemic control. The participants were randomly assigned to receive 1 of 3 doses of dapagliflozin (2.5 mg, n = 135; 5 mg, n = 133, or 10 mg, n = 132) or placebo (n = 134) orally once daily, in addition to receiving their prestudy metformin dosing. The primary outcome measure was change from baseline in hemoglobin A1c (HbA1c) at 24 weeks.

After 24 weeks, individuals receiving dapagliflozin 2.5 mg, 5 mg and 10 mg demonstrated a statistically significant adjusted mean change in HbA1c from baseline of -0.75%, -0.82% and -0.90%, respectively, compared to -0.30% for placebo (p-value less than or equal to 0.0001 for all treatment groups).

The study also evaluated the potential impact of dapagliflozin on total body weight at week 24. At week 24, the study found that individuals treated with dapagliflozin demonstrated an adjusted mean change in total body weight: -0.98 kg for dapagliflozin 2.5 mg, -0.98 kg for dapagliflozin 5 mg and -1.67 kg for dapagliflozin 10 mg, compared to a weight gain of 0.02 kg for placebo (p-value less than or equal to 0.0001 for all treatment groups).

Individuals treated with dapagliflozin also demonstrated a reduction in daily insulin dose at week 24: -1.80 IU/d for dapagliflozin 2.5 mg, -0.61 IU/d for dapagliflozin 5 mg and -1.16 IU/d for dapagliflozin 10 mg, compared to an increase of 5.08 IU/d for placebo (p-value less than or equal to 0.0001 for all treatment groups).

Individuals treated with dapagliflozin demonstrated a reduction in FPG, a secondary endpoint, from baseline at week 24: -12.5 mg/dL for dapagliflozin 2.5 mg, -18.8 mg/dL for dapagliflozin 5 mg and -21.7 mg/dL for dapagliflozin 10 mg, compared to an increase of 3.3 mg/dL for placebo (p-value equal to 0.0008 for dapagliflozin 2.5 mg; p-value less than or equal to 0.0001 for dapagliflozin 10 mg. (Note that due to the study testing procedure, the p-value for dapagliflozin 5 mg could not be assessed.)

Generally, adverse events, serious adverse events and study discontinuations were similar across all treatment groups. The percentage of patients experiencing the most common adverse events (greater than or equal to 5%) for dapagliflozin 2.5 mg, 5 mg 10 mg, and placebo, respectively are as follows: nasopharyngitis: 13.9%, 13.7%, 8.7%, 11.2%; hypertension: 5.4%, 6.1%, 3.6%, 7.6%; headache: 4.0%, 4.2%, 1.0%, 7.1%; back pain: 4.5%, 1.9%, 4.6%, 5.1%; upper respiratory tract infection: 2.5%, 2.8%, 3.1%, 5.1%.

Reductions in blood pressure were observed without associated signs of orthostatic hypotension.

Sue Kirkman, MD, from the ADA, Alexandria, Virginia, called it an "intriguing" study and mentioned that, "It is interesting to have a drug that does not work through insulin or on insulin…. I actually was wondering as he was talking whether dapagliflozin would have any role in treating Type 1 diabetes as well."

She added that the drug appears to have a good safety profile, but that time will be the proof. "In all the studies that I’ve seen so far — including the animal studies — it looks very safe. But I think we all have concerns about long-term use. We need to make sure that it doesn’t have any bad effects on the kidney or that urinary tract infections aren’t an ongoing problem, because there definitely is a trend. People with diabetes are prone to infections and kidney problems anyway, and we certainly want to make sure that those aren’t long-term problems. But it’s certainly an interesting class of drugs and may become part of the armamentarium."

About SGLT2 Inhibition: the kidney continuously filters glucose through the glomerulus; however, nearly all of this glucose is reabsorbed. A protein called SGLT2 is responsible for the majority of glucose reabsorption and helps the body retain glucose for its energy requirements. For patients with diabetes, retention of excess glucose by this pathway contributes to persistent hyperglycemia. Suppressing the activity of SGLT2 inhibits renal-glucose reabsorption in the body, thereby leading to the excretion of glucose in the urine.

ADA 70th Scientific Sessions. Presented June 26, 2010. The Lancet. 2010;375:2223-2233.