Medical Device Dailys

With the U.S. population now obese, overweight, and normal weight at nearly equal proportions, obesity is a large market in more ways than one. As the American Diabetes Association (ADA; Alexandria, Virginia) met this week in New Orleans, a paper in the June issue of Cell Metabolism reports on a potential new target that could be harnessed to treat obesity.

In the experiments reported in Cell Metabolism, researchers from the University of California, Los Angeles, used what they termed a "molecular shunt" to protect mice from the consequences of a high-fat diet.

The authors inserted the genes for two metabolic enzymes – isocitrate lyase and malate synthase – into cultured liver cells as well as mice. These enzymes are normally part of the metabolic system of plants and bacteria, but not mammals. Expression of the enzymes increased the metabolism of fatty acids, which are used as energy sources by liver and skeletal muscles, in liver cells. Mice engineered to have the glycoxylase shunt were resistant to diet-induced obesity.

The authors write in their paper that the resistance "was accompanied by a decrease in total fat mass, circulating leptin levels, plasma triglyceride concentration, and a signaling metabolite in liver, malonyl-CoA, that inhibits fatty acid degradation."

Malonyl-CoA is part of the pathway that determines whether dietary fat will be burned or stored. Normally, Malonyl-CoA is high after eating a meal, blocking fatty acid metabolism. By lowering Malonyl-CoA levels, the shunt enables the body to keep metabolizing fatty acids in situations where they would normally be converted into body fat.

While it is unlikely that the concept of gene therapy will carry over for the treatment of obesity, the findings suggest that malonyl-CoA may be a good target for therapies aimed at ramping up fat breakdown. More generally, the authors say that "given the success in engineering synthetic phenotypes in microbes and mammalian cells, constructing non-native pathways in mammals has become increasingly attractive for understanding and identifying potential targets for treating metabolic disorders."

In other ADA-related news:

• Medtronic Diabetes (Northridge, California) reported results of a randomized, controlled trial to demonstrate the benefits of an insulin pump therapy augmented with real-time continuous glucose monitoring (Personal CGM) vs. a conventional pump and self-monitoring of blood glucose in Type 1 diabetes patients with poor metabolic control.

Study findings showed that patients who used Personal CGM more than 70% of the time achieved nearly a full percentage point reduction in A1C (average blood glucose levels).

"The REAL Trend study validates a growing body of clinical evidence that demonstrates the power of combining insulin pump therapy with Personal CGM," said Chris O'Connell, president of the Diabetes business and senior vice president at Medtronic. "As the clinical evidence continues to build, we are seeing an impressive increase in CGM adoption globally."

The six-month, multi-center REAL Trend study was designed to determine whether patients with poorly controlled A1C (about 8%) who used multiple daily injections could improve their metabolic control with the MiniMed Paradigm REAL-Time System (insulin pump augmented with Personal CGM) vs. a conventional insulin pump and self-monitoring of blood glucose levels. The study enrolled 132 patients in France, including 51 children age two and older.

"Diabetes is a complicated disease, and technologies like insulin pump therapy and Personal CGM can help patients best manage short- and long-term outcomes," said Dr. Francine Kaufman, chief medical officer of the Diabetes business at Medtronic. "This study reinforces the need for an integrated, management approach that uses multiple technologies to achieve significant results. Combining an insulin pump with Personal CGM and therapy management software are powerful tools for patients wanting to achieve optimal control."

Sensor compliance drove increased improvement of glycemic control, reflected by lower A1C results without increased hypoglycemia in the REAL Trend study. Among the compliant patient population, investigators saw a significant difference in each treatment group and between groups from baseline to study end, including an A1C reduction of 0.96% among the group fitted with the MiniMed Paradigm REAL-Time System. The conventional insulin pump arm only saw a 0.55% reduction.

• Adventist Health System (AHS; Winter Park, Florida), which operates 37 hospitals across 10 states, reported that it has achieved low systemwide hypoglycemia incidence rates comparable to those in the Normoglycemia in Intensive Care Evaluation-Survival Using Algorithm Regulation (NICE-SUGAR) trial. The NICE-SUGAR study, published in the March 26 issue of the New England Journal of Medicine, has raised the visibility of inpatient management of uncontrolled blood glucose levels.

While the study suggests that intensive blood glucose control for critical care patients with hyperglycemia (high blood glucose) does not improve outcomes, AHS data supports a system-wide effort to provide good glucose control in diabetic and non-diabetic hyperglycemic patients at its facilities.

The percentage of patients on the EndoTool glucose management system from Hospira (Lake Forest, Illinois) experiencing severe hypoglycemia (blood glucose levels ? 40 mg/dL) across AHS in medical, surgical and mixed intensive care units (ICUs) for the last quarter of 2008 was 1.8%.

Although the blood glucose treatment goals differed (100 – 150 mg/dL at AHS; 81 – 108 mg/dL for NICE-SUGAR), NICE-SUGAR reported that 6.8% of patients experienced severe hypoglycemia in the intensive control arm of the study. Adventist Health System said it believes this increased rate of hypoglycemia may be a reflection of the treatment protocol and methods used to control glucose levels.

Hospira is demonstrating EndoTool at the ADA meeting.

"Controlling glycemic, or blood glucose, levels is a major challenge in ICUs so we set out to identify a solution to reduce the incidence and thereby the impact of uncontrolled glucose," said Paul Garrett Jr., MD, medical director, evidence-based practice in the Office of Clinical Effectiveness at AHS. "We believe computer-based protocols, like EndoTool, are the future of glycemic control, replacing paper-based systems that use broad target glucose ranges, as in the NICE-SUGAR study."

EndoTool glucose management software provides a computer-based means of achieving targeted glucose control and is typically used in the ICU at AHS. The highly sophisticated glucose management system is dynamic and adaptive software, which calculates the dose of intravenous (IV) insulin needed to effectively control glycemic levels.

EndoTool can be used in other areas of the hospital with sufficiently close monitoring to treat patients with IV insulin. It identifies individual patient responses to IV insulin to help manage current and predict future dosage levels.

EndoTool software can operate on a hospital's existing computer system, and is currently available for use on stand-alone personal computers or in bedside terminal environments. Hospira also recently demonstrated a prototype of a future device with the EndoTool software integrated into the company's Symbiq intelligent infusion pump.