Insulin therapy makes a life-or-death difference for millions of people with Type 1 diabetes, but it can’t replace a healthy pancreas in keeping A1c levels in check. The daily variability of life means that even carefully calculated insulin dosing often won’t keep A1c levels in Type 1 patients at less than 7%. In fact, the more one tries to manage glucose tightly, the more likely one is to experience hypoglycemia. It’s a dilemma that leads many Type 1 patients to choose avoiding hypos by living with elevated glucose, rather than striving for tight control.
If more insulin isn’t the answer to better control, what might be? Some researchers believe it might be dapagliflozin, a new drug that can prevent glucose reabsorption into the kidneys, lower A1c and reduce insulin doses simultaneously, according to a recently completed pilot Phase IIa trial. If the once-a-day pill is approved by the FDA, Type 1s and their caregivers may have a new weapon in the daily battle against diabetes.
The dapagliflozin study, led by Dr. Robert Henry at the San Diego VA Medical Center and the University of California San Diego, focused on testing the drug in 70 T1 patients. Dr. Henry, a past president of medicine and science of the American Diabetes Association, believes the preliminary study results are promising for T1s who struggle to reach A1c targets.
“For those patients having trouble getting to goal with insulin therapy alone, this may be an opportunity to just take a pill once daily (along with insulin) and help reduce their A1c,” he says.
Dapagliflozin treatment partially blocks reabsorption of glucose by the kidneys, which is important because excessive glucose reabsorption stresses the kidneys; diabetes, in fact, is the #1 cause of renal failure. The drug, part of a class of drugs called SGLP-2 inhibitors, diverts glucose into the urine, where it can be safely expelled, Dr. Henry says.
While not yet sanctioned by the FDA for people with either Type 1 or Type 2 diabetes, dapagliflozin has been approved for use in treating Type 2 diabetes in some European countries for the last year. A similar drug, canagliflozin (marketed as Invokana) was approved by the FDA for T2 use in March 2013. Bristol-Myers Squibb and AstraZeneca, developers of dapagliflozin, plan to seek FDA approval of the drug for T2 therapy later this year; the FDA requested additional data after their initial application in January 2012. But unlike other SGLP-2 inhibitors, which so far have been deployed for T2 therapy, dapagliflozin may also help Type 1s.
The most recent study enrolled 70 T1 patients who had trouble reaching glucose targets on insulin therapy alone. Patients were either treated by insulin pump or by multiple insulin injections before entry into the study. All subjects spent 3 pre-trial days standardizing their diets and establishing both fasting and non-fasting glucose baselines as inpatients. Treatment was then started for 2 weeks, with participants receiving therapy as inpatients the first week and as outpatients the second. The subjects were randomly divided into 5 groups, stratified by body mass index (BMI) and method of insulin administration (daily injections or pump), receiving daily doses of either a placebo or dapagliflozin at 1mg, 2.5mg, 5mg, or 10mg doses daily for 14 days in addition to their insulin regimen.
In the study, fasting (morning) glucose decreases were most pronounced in all the dapagliflozin user groups and were greatest at the 2 higher doses. Those taking 5mg experienced on average a 42.2% decline, while those taking 10 mg experienced a 35.7% decline. Over the course of the study, insulin use also declined by 19.3% among the 5mg group and 16.2% among the 10mg group. All dapagliflozin users showed less volatile daily glucose variations, determined by daily continuous glucose monitoring devices. Hypoglycemia occurred in all treatment groups studied, including placebo users, but there was no apparent dose relationship between dapagliflozin and severity or frequency of hypoglycemia among the 70 patients.
While reduced insulin use is potentially good news on the hypoglycemia front, more studies need to be done to establish the most effective dose of dapagliflozin for Type 1 use. Researchers were conservative about asking participants to vary their insulin regimen in the interest of good glycemic control, Dr. Henry says.
“We didn’t want patients backing off their insulin too much,” he says.
However, Dr. Henry is optimistic about the drug’s ability to help reduce overall glucose levels. And that could mean that T1 patients may someday have another tool in their toolbelt for keeping A1c levels under control.
“My guess is that use of dapagliflozin in Type 1 diabetes patients for 3 months or more may be able to produce a mean decrease of 0.5% to .75% in A1c levels,” he says.
For many Type 1s who have accepted an A1c of 8 or above as the price to pay for avoiding hypos, this would be welcome news indeed.
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