Closing the loop   (February 7, 2010)

For years, the dream of "closing the loop" -- developing an algorithm that would allow a glucose-sensing device to control an insulin-delivery device -- has been an elusive dream. There have been many clues that it should be possible to figure out a program whereby either high or low blood sugar levels would be interpreted by a computer, which in turn would adjust an insulin pump's rate of delivery of insulin.

Indeed, back in the 1970's, a very expensive device called a "Biostator" was developed which did just that. It measured blood glucose, which it withdrew at the rate of 70cc/24 hours (roughly 2 tablespoons/day), and it changed the rate of insulin delivery -- the insulin was administered intravenously. It was the size of a "small refrigerator" and required a technician baby-sitting it full-time to avoid the risk of it going haywire (described scientifically as having "technical difficulties"). It was used occasionally in hospital settings, such as during surgical procedures, but clearly it wasn't practical for everyday use, and it soon became a dream that faded with the light of day.

But the dream of closing the loop continues, and is being pursued by several insulin pump companies. Ideally, a continuous glucose monitoring (CGM) device would sample blood or interstitial fluid glucose levels, then a computer algorithm would compare the glucose level to where it should be, and how fast it's changing, and then instruct an insulin pump to adjust the rate of delivery of insulin to keep the blood glucose levels normal around-the-clock (day and night, after meals, and after exercise).

That's a very tall order, however. As one researcher in the field points out: "It will need to work, meaning it will need to control ones diabetes better than people with diabetes self-manage. It will need to be safe, which is critical. As you appreciate, too much insulin at the wrong time is dangerous and an artificial pancreas will need to have safety mechanisms built in that will eliminate technical failure. It will need to be easy enough to use in everyday life for the majority of people with diabetes. I don't plan to carry a refrigerator around with me and I'm sure you don't want to either!"

The simplest example that is practical at this time would be a scenario in which a CGM device identifies a low interstitial fluid glucose level, which shuts down an insulin pump's delivery of insulin. Medtronic has such a device in Europe: "The Paradigm Veo is the world's first insulin pump equipped with a Low Glucose Suspend (LGS) function, offering automatic protection from severe hypoglycaemia."

This past week, a publication in The Lancet, Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomised crossover trial seems to have taken another small step towards the dream of closing the loop. There's been a lot of hype about this publication, such as a press release from the JDRF, Early Artificial Pancreas Trials Show Benefits for Kids, Teenagers with Diabetes While Sleeping Overnight which called it "a landmark study". But, in truth, it was a small and preliminary series of three studies - which failed to meet their primary endpoints. Even worse, in my opinion, is a comment buried in the abstract: "During closed-loop nights, glucose measurements were fed every 15 min into a control algorithm calculating rate of insulin infusion, and a nurse adjusted the insulin pump" (emphasis added). In other words, it's another Biostator all over again, if the researchers didn't trust their gadgets to automatically adjust insulin delivery.

There was some favorable data dredged out of these failed trials: A secondary analysis of pooled data documented increased time in the target range (60% vs 40%) and reduced time for which glucose concentrations were 3·90 mmol/L or lower (2·1% vs 4·1%). No events with plasma glucose concentration lower than 3·0 mmol/L were recorded during closed-loop delivery, compared with nine events during standard treatment. But if a study fails its primary endpoints, it's not a landmark study: it's a failed study.

The dream continues.