Interventions to Reduce SH Risk
Any intervention that reduces the frequency of hypoglycemia and/or improves timely detection and treatment of episodes will be effective in reducing SH risk. Also, interventions that reduce the frequency of hypoglycemia and SH typically reduce FOH. The essential foundation for reducing SH risk is adequate diabetes education to provide patients with an understanding of how imbalances in insulin, food, and physical activity occur, and ways to avoid such imbalances. This type of patient education and training (especially educating patients regarding HA) may not be implemented because of limited personnel resources, despite being part of recommended diabetes self-management education (DSME). Some authors have even suggested that inadequate patient education is a major reason why patients experience increased hypoglycemia when they transition to intensive insulin therapies (Mühlhauser 1993). In addition to hypoglycemia prevention, patients need education on the appropriate treatment of episodes and the importance of responding immediately and appropriately to avoid SH. Such education should include training in hypoglycemic symptomatology, including the physiological basis of symptoms and their impact on the ability to adequately self-treat.
When an individual presents with problems with SH, the first target of intervention is often the insulin regimen. Numerous studies show that long-lasting insulin analogs decrease the occurrence of both diurnal and nocturnal hypoglycemia in people with T1D and T2D (Brunelle 1998, Ratner 2000, Yki-Jarvinen 2000, Davis 2004, Home 2004, Alemzadeh 2005, Rosenstock 2005). Many studies have also demonstrated that continuous subcutaneous insulin infusion (CSII) therapy or insulin pump therapy significantly reduces the frequency of hypoglycemia and SH risk in both adults and children (Boland 1999, Bode 2002, Linkeschova 2002, Litton 2002, Rami 2003, Bulsara 2004, Colquitt 2004). However, two recent meta-analyses of this literature point out that CSII does not always reduce hypoglycemia (Weissberg-Benchell 2003, Hirsch 2005). Other changes in insulin may also be indicated; for example, discontinuing basal insulin doses during exercise may significantly decrease hypoglycemia in children (Tansey 2006). For patients who have tried a variety of different insulin regimens but continue to have serious problems with SH, transplant surgery may be considered. However, there are significant surgical and postoperative complications, and islet cell transplant does not result in long-term insulin independence for the majority of patients (Shapiro 2006, Meloche 2007). And, although glycemic thresholds for counterregulation and symptoms improve after islet cell transplant, the magnitude of the epinephrine response (signaling hypoglycemia) may remain impaired (Rickels 2007).
In addition to reducing episode frequency, interventions can focus on improving the ability to detect hypoglycemia when it occurs. There is research aimed at developing pharmacological agents that increase hypoglycemic awareness (Heller 2008), but these agents are not yet available. Several studies have found that, if patients can rigorously avoid BG levels <70 mg/dl (3.9 mmol/l) for just a few weeks, timely hormonal counterregulation and adrenergic warning symptoms are restored (Cranston 1994, Fanelli 1994). Unfortunately, there have been no large-scale clinical trials evaluating this intervention to determine what proportion of patients might respond to treatment or what types of support programs are needed for patient success. In addition, only one long-term follow-up study has investigated whether a single course of treatment (3-month physician-supervised avoidance of hypoglycemia) produces long-lasting results (Dagogo-Jack 1999).
With recent technological advances in diabetes management, continuous glucose monitoring (CGM) has been increasingly used in the detection and reduction of hypoglycemia. CGM can provide patients with warnings when BG trends indicate that hypoglycemia is imminent (Boland 2001, Chico 2003, Jeha 2004). An early randomized trial (Garg 2006) showed that patients with T1D and insulin-requiring T2D who wore continuous glucose monitors for three consecutive 72-hour periods experienced significant improvements in glycemic excursions compared with patients using traditional BG monitoring. Specifically, those using continuous glucose monitors spent 21% less time in hypoglycemia and 26% more time within BG target range. More recent clinical trials have focused on the impact of longer-duration use of continuous glucose monitors on hypoglycemic risk. In a recent study of both adults and youth with T1D who did CGM for 26 weeks, time spent in hypoglycemia was significantly shorter and time spent in euglycemia (normal glucose content) was significantly longer compared with control subjects using self-monitoring of blood glucose (SMBG) (Battelino 2011). Though these results are promising, other findings suggest that CGM may not effectively reduce hypoglycemia for all patients. Results from the Juvenile Diabetes Research Foundation (JDRF) trial did not find a statistically significant difference in time spent in hypoglycemia or in the frequency of SH over 6 months of CGM as compared with SMBG for any age-group (JDRF Continuous Glucose Monitoring Study Group 2008). However, adults in this study were able to achieve better glycemic control without increasing hypoglycemic risk.
Sensor-augmented pump (SAP) therapy, which integrates CGM use and insulin pump therapy, is a first step toward the development of a closed-loop control system (or “artificial pancreas”) and one of the newest diabetes technologies aimed at reducing hyperglycemia while preventing hypoglycemia. A number of studies, including two large clinical trials (Sensor-Augmented Pump Therapy for A1C Reduction [STAR 3]; Sensing With Insulin Pump Therapy to Control HbA1c [SWITCH]), are underway to evaluate the feasibility and efficacy of SAP therapy with adults and, most recently, youth with T1D (Fisher 2006, Kordonouri 2010, Conget 2011, Scaramuzza 2011). Early findings have indicated beneficial effects on metabolic control in both adults and children, including improved A1C (Hermanides 2011, Scaramuzza 2011), without increasing hypoglycemia (Buse 2011, Slover 2011). A possible negative effect on diabetes management is overtreating hypoglycemia due to delays in glucose feedback (Wolpert 2007, Block 2008). When this technology is introduced, however, this time lag should be addressed in the context of its use (see Chapter 11).
Because diabetes management behaviors play a critical role in hypoglycemia and SH, it is not surprising that behavioral interventions are effective in reducing risk. The behavioral intervention receiving the most scientific study is Blood Glucose Awareness Training (BGAT), designed to improve patients’ ability to recognize symptoms and other cues that signal low BG and to anticipate the effect of treatment factors such as insulin, food, and physical activity on glucose levels (Cox 1989, Gonder-Frederick 2000, Cox 2006a, Cox 2008). BGAT is a structured, manualized training program that integrates diabetes didactics, self-monitoring and self-assessment strategies, and evaluation of personal diabetes management behaviors. A recent article reviewed 15 studies of BGAT in the U.S. and Europe showing that the intervention can have numerous treatment benefits, such as improved hypoglycemia detection, decreased frequency of low BG and SH, and reduced FOH (Cox 2006a). Patients who complete BGAT after initiating intensive insulin therapy have been shown to maintain integrity of counterregulation and avoid the typical increase in frequency of hypoglycemia with improved diabetes control (Kinsley 1999).
Despite evidence for its effectiveness, BGAT is not widely disseminated. It is an intensive and demanding training program, there are reimbursement issues, and there are not enough trained and experienced health care professionals to offer BGAT. To make it more widely available, BGAT has been translated for Internet delivery as BGATHome, and the initial tests are encouraging (Cox 2008). A similar psychobehavioral intervention, also using strategies such as BG symptom diaries and BG estimation with accuracy evaluation, has been developed and tested in controlled trials in Germany (Kubiak 2006, Hermanns 2010). Long-term follow-up after this intervention found significantly lower rates of SH in the experimental group with no increase in A1C.
There is also compelling evidence that less-intensive behavioral interventions may be effective, suggesting that more effort should be directed at developing, testing, and disseminating these types of programs. For example, structured outpatient education specifically designed to teach patients about the causes, effects, and treatment of hypoglycemia may prevent the increased risk associated with intensive insulin regimens (Plank 2004, Samann 2005). Another