In studies that provided structured education or feedback in addition to technology to all participants, SH was reduced and HA status improved in all intervention arms, with technology CSII or RT-CGM having no additional benefit 59 , 60 , In the adults from Ly et al.

Despite greater frequency of visits compared with routine care, the follow-up of the participants in all of these studies did not differ between arms. Use of the HHC and predictive data were associated with reduction in SH, greater in those with hypoglycemia unawareness at baseline, with an increase in the BG estimation accuracy index.

Of studies conducting hyperinsulinemic-hypoglycemic clamps, one showed an increase in plasma metanephrine responses to hypoglycemia 59 , and two showed no significant differences in hormone responses 58 , In all studies comparing CSII with insulin analog therapy, there was no deterioration or differences in glycemic control in any of the intervention arms when compared with control despite reductions in SH and improvements in HA status.

In the Kovatchev et al. Five studies were identified, all of which were conducted more than 10 years ago. Four studies compared short-acting and long-acting analog insulin against conventional soluble SI or NPH insulin 64 — One noninsulin study was identified, investigating propranolol to restore HA There was no mention of any change in education between the arms.

SH did not occur in three of these studies 64 , 66 , 68 ; two had no statistically significant change in SH rates between study arms 65 , There was no consistent finding in changes in hypoglycemia symptom scores during hypoglycemic clamp studies between comparator arms in the insulin studies 64 — The study on propranolol reported increased sweating during hypoglycemia with propranolol There was, however, a higher peak plasma epinephrine response when NPH was delivered separately at bedtime compared with a combined SI and NPH with dinner Counterregulatory hormones were not measured in the remaining two studies 65 , There were no significant changes in glycemic control in the three lispro studies 64 , 65 , HbA 1c was lower at the end of the treatment period in the split-NPH dosing Changes in HbA 1c were not reported in the propranolol study, which lasted only 1 month.

A meta-analysis for educational interventions on change in mean SH rates per person per year was performed. We evaluated the active interventions used in the RCTs as individual before-and-after trials, because all included some educational component, a structured curriculum, and information around causes and prevention of hypoglycemia.

For Schachinger et al. Forest plot of meta-analysis of SMDs in SH rates per person per year in each study and the overall pooled estimate. The horizontal lines represent the SMD. The size of box is proportional to the weight of that study. The diamond indicates the weighted mean difference, and the lateral tips of the diamond indicate the associated SMD.

A random-effects meta-analysis revealed an effect size of a reduction in SH rates of 0. From the RCT studies Hermanns et al. Heterogeneity between studies was significant, with I 2 statistic of Most of the educational interventions were observational and mostly retrospective, with few RCTs.

The overall risk of bias is considered medium to high and the study quality moderate. Most, if not all, of the RCTs did not use double blinding and lacked information on concealment.

The strength of association of the effect of educational interventions is moderate. The ability of educational interventions to restore IAH and reduce SH is consistent and direct with educational interventions showing a largely positive outcome. There is substantial heterogeneity between studies, and the estimate is imprecise, as reflected by the large CIs.

The strength of evidence is moderate to high. There were approximately equal numbers of observational and RCTs of technological interventions. These trials were well conducted, with two RCTs of almost patients selected for hypoglycemia unawareness.

The overall risk of bias was considered low to medium, with moderate study quality. Double blinding was not possible, and there was lack of information on concealment in the RCTs.

Combining all of these studies into a single meta-analysis was not appropriate because CSII, RT-CGM, and SAP are all different categories of technological interventions, with variable reporting of outcomes in each category.

Furthermore, provision of education at baseline provides a degree of confounding. In CGM studies, the ability of CGM to reduce SH is consistent and direct, with all included studies showing a positive outcome and reduction in SH rates. The strength of evidence is thus moderate to high. However, the ability to improve or restore hypoglycemia unawareness is uncertain and the strength of evidence is low.

The strength of evidence for the ability of CSII to reduce SH and restore hypoglycemia awareness is moderate to high, with a generally positive effect of CSII. However, when patients were provided education and optimized MDI therapy, CSII appeared not to provide any additional benefit.

All of the pharmacological intervention studies were RCTs. Lack of information on concealment was present, but the overall risk of bias was considered low to medium and the study quality was high.

However, the strength of evidence for insulin analogs to reduce SH was low because SH was an exclusion criterion for many of the included studies.

The strength of evidence of insulin analogs to restore hypoglycemia awareness was low, with no consistent outcome seen. To our knowledge, this study represents the first systematic review and meta-analysis of the different interventions available for reversing IAH in T1D and includes a comprehensive and expansive literature search.

Despite this, there are still limitations. A large proportion of studies did not report the type of diabetes education subjects received before the study intervention, and it is possible that a proportion of patients would have received previous structured education and that some may have had ongoing education given the duration of diabetes in most studies.

Another limitation is study heterogeneity and the inconsistent reporting of outcome measures, in particular, in SH rates and measures of HA status, in noneducation studies, preventing a more comprehensive meta-analysis.

SH rates were reported as mean SD , median interquartile range [IQR] , odds ratios, and proportion of subjects with reduced SH. HA was reported as Gold and Clarke scores, and BG estimation accuracy and the proportion of subjects who had improved awareness was often subjectively assessed.

Some studies reported a modified Gold score with a score from 0 to 10 on a visual analog scale. In studies reporting Gold and Clarke scores, we used Clarke scores as the main reporting outcome. In studies that reported Gold scores only, we grouped the outcomes, because Gold and Clarke scores have been shown to be well correlated Even so, it was not possible to perform a meta-analysis due to study heterogeneity.

In an unselected population with no prior diabetes education, structured education or BGAT can reduce SH and improve glycemic control. There is early evidence that such programs can also achieve these outcomes when provided as reeducation some years after the initial exposure In patients with established IAH, BGAT and other psychotherapeutic programs, such as HyPOS and HAATT, are also effective.

There was no difference between structured education programs in flexible insulin therapy and programs with a psychological approach when compared head to head, and this may be because in teaching users the basics of insulin pharmacodynamics and how to adjust their insulin regimens around their lifestyles to achieve glucose targets that exclude hypoglycemia, hypoglycemia exposure is lessened.

There is perhaps a need to seek the common factors in successful programs to distill the essential elements of any new programs. Meanwhile, DAFNE-HART had a much higher baseline level of SH than any of the other studies and was the only study that took people who were IAH despite prior education.

Although a small nonrandomized study, it demonstrated that a psychobehavioral therapeutic approach can have a sustained effect on SH and nonsevere hypoglycemic episodes in people whose IAH seems resistant to other interventions Thus, in unselected populations with T1D, structured education in flexible insulin usage reduces SH and may reduce the proportion of people with IAH and SH.

In those with IAH, further education or BGAT reduces SH, with the greatest reductions seen in programs with a behavioral component. CSII can reduce SH with greater reductions in those with greater SH at baseline 52 , although there was evidence that in an unselected population, CSII and improved control may cause some deterioration of awareness In observational studies, CGM showed a reduction in SH, even in those who remained in IAH despite education and CSII A RCT of LGS compared with CSII in young people with IAH showed improved awareness and reduced SH with LGS-enabled SAP Most studies with technology, such as CSII or CGM, were done in patients who had received prior education.

Thus, in people with IAH despite prior education, CSII, CGM, and, in particular, sensor-augmented pump therapy with LGS provide additional benefits.

The HypoCOMPaSS study 63 is in keeping with earlier studies by Cranston et al. HypoCOMPaSS clearly illustrates the value of a holistic approach to the management of people with IAH, using structured education as a core foundation combined with optimized MDI and the use of CSII in selected individuals, to provide far greater advantages than one intervention alone.

We thus propose a stepped-care algorithm that may guide the health care professional in choosing the appropriate intervention when faced with a person with IAH Fig. We would argue that step one—provision of structured education in flexible insulin therapy—should be available to any person with T1D but that additional resources for individuals with higher care needs may be focused in centers where the more intensive interventions combining psychoeducational and technological interventions are available, to which people with IAH and SH posteducation can be referred.

Proposed algorithm for the selection of interventions in patients with IAH and SH. The gray shading indicates recommendation based on expert opinion, with as yet no completed evidence. For future research, we would recommend that outcome measures such as SH rates and HA scores should be reported in a standardized manner to allow future systematic reviews and meta-analyses.

Because incidence and prevalence of SH rates are not normally distributed, the median IQR SH rate may be more appropriate than the mean SD commonly used. Measures of assessment of HA should also be standardized using Gold or Clarke scores because these have been shown to correlate well with clinical and clamp findings and each other.

The proportion of patients with baseline IAH and then improved awareness should be reported as well as Gold or Clarke scores and their change. Future research may be needed to compare structured education, possibly using psychotherapeutic techniques, and optimized MDI using insulin analogs, with comparisons against new diabetes technologies such as LGS-enabled SAP.

Psychotherapeutic techniques may provide additional benefit, in particular in improving HA status, and large RCTs using this approach should be conducted. Use of technology in diabetes, either better warning systems through CGM or through improved insulin delivery via CSII, can reduce SH rates and improve HA without worsening glycemic control, but without restoring counterregulatory hormone responses.

A stepped approach is recommended in the management of people with IAH. The authors thank the authors of the original cited studies who were contacted for sharing the information required from their studies.

received fellowship funding as part of the Health Manpower Development Plan award from Khoo Teck Puat Hospital, Alexandra Health Pte, Ltd. received PhD funding as part of a Diabetes UK project grant. None of the funding or supportive agencies were involved in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.

The views expressed are those of the author s and not necessarily those of the funding agencies. Duality of Interest.

has received travel support from Roche and Lilly UK. No other potential conflicts of interest relevant to this article were reported. Author Contributions. undertook the literature search and reviewed the abstracts and full articles. wrote the manuscript. performed and supervised the statistical analysis.

conceived the idea for the review. All authors designed the study, contributed to the discussion, and critically reviewed the final manuscript. Prior Presentation. Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest.

filter your search All Content All Journals Diabetes Care. Advanced Search. User Tools Dropdown. Sign In. Skip Nav Destination Close navigation menu Article navigation. Volume 38, Issue 8. Previous Article Next Article. Research Design and Methods.

Article Information. Article Navigation. Systematic Review July 14 Interventions That Restore Awareness of Hypoglycemia in Adults With Type 1 Diabetes: A Systematic Review and Meta-analysis Ester Yeoh ; Ester Yeoh.

Corresponding author: Ester Yeoh, esteryeoh nhs. This Site. Google Scholar. Pratik Choudhary ; Pratik Choudhary. Munachiso Nwokolo ; Munachiso Nwokolo.

Salma Ayis ; Salma Ayis. Stephanie A. Amiel Stephanie A. Diabetes Care ;38 8 — Article history Received:. Get Permissions. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Figure 1. View large Download slide. Table 1 Summary of the 43 studies that were included in the final systematic review.

First author, year ref. Intervention, brief description. N ; study duration. Age years ; diabetes duration years. SH rates. HA score. HbA 1c. Mean SH Gold score from 5. Clarke score from 5.

No change in HbA 1c : baseline 7. Jordan, 4 Tayside insulin management course: Structured group education, 1 day of education per week for 4 consecutive weeks. Decrease in number of patients with HU Median HbA 1c reduction: 8. Hopkins, 21 DAFNE audit: Structured diabetes group education program, 5-day course in flexible insulin therapy.

Improved HbA 1c : 8. Hernandez, 29 Self-awareness education on body cues associated with various levels of glycemia. Eight 3-h, biweekly sessions, follow-up study of Hernandez, Improved detection of symptom cues of euglycemia and hypoglycemia.

Kubiak, 31 IG with hypoglycemia-specific education program 6 lessons, 45 min vs. Using modified Gold score: visual analog scale Improved HbA 1c in both groups; no difference between IG: 6. Broers, 22 Dutch adaptation of BGAT-III 6 weekly 1.

individual setting. Psychoeducational intervention, follow-up study to Broers, Improved recognition of hypoglycemia in both groups No change in HbA 1c : 7.

Hernandez, 30 Refer to Hernandez, No increase in ability to detect hypoglycemia but subjects could identify normal BG more accurately. No change in HbA 1c : 8. Broers, 23 Refer to Broers, Accuracy index of BG perception increased from 8. Improved autonomic and neuroglycopenic symptom scores during hypoglycemic clamp.

No change in epinephrine and norepinephrine responses. Increased HbA 1c : 6. Cox, 24 BGAT-II psychoeducational group program, follow-up study of Cox, Booster intervention did not affect these benefits.

No change in HbA 1c : Dagogo-Jack, 33 Avoidance of hypoglycemia, 3-year follow-up study of Dagogo-Jack, No report on SH. Improvement in neurogenic and neuroglycopenic symptoms score at 1 year postreversal from preintervention. Slight increase in HbA 1c : 7.

Fritsche, 25 5-day inpatient diabetes education program DTTP , 25 min lessons on flexible insulin therapy, carbohydrate counting, correction and prevention of hypo- and hyperglycemia. those with no history of SH. Improved accuracy index of BG estimation in patients with SH but no improvement in the group without SH.

Decreased HbA 1c : 8. Fanelli, 35 Avoidance of hypoglycemia for 6 months in patients with T1D 8 without diabetic autonomic neuropathy [DAN], 13 with DAN and 15 subjects without T1D.

SH did not occur. Improved autonomic and neuroglycopenic symptoms in all groups. Responses remained lower than in subjects without T1D. Increased HbA 1c in all groups but remained within therapeutic target: 6. Liu, 36 Avoidance of hypoglycemia with less strict glycemic control and higher BG targets, SMBG 4 times daily with modification of insulin doses.

Improved symptoms scores for sweating and lack of concentration. Improved GH and epinephrine responses but no changes in glucagon, norepinephrine, and cortisol.

Cox, 26 BGAT-II, refer to Cox, No report of SH. Better accuracy in detecting BG fluctuations and low BG levels.

Those with reduced HA had improved detection of low BG. Not available. Davis, 27 Conventional insulin therapy vs. intensive insulin therapy.

intensive insulin therapy was 0. Reduction in total hypoglycemia symptom scores with intensive insulin therapy, with no reversal on reinstitution of conventional therapy. Lower plasma glucose to stimulate plasma epinephrine secretion during intensive therapy compared with initial conventional therapy without complete reversal on reinstitution of conventional therapy.

HbA 1c in conventional group: 9. Dagogo-Jack, 34 Refer to Dagogo-Jack, Original group of 18 patients 6 HA, 6 HU, 6 healthy volunteers.

Increase in total neurogenic and neuroglycopenic symptoms score responses to hypoglycemia. No significant increases in neuroendocrine responses epinephrine, pancreatic polypeptide, glucagon, GH, and cortisol after intervention. Increase in HbA 1c : 7. Improved symptoms scores after 3 weeks of no hypoglycemia.

Improved glucose threshold for recognition of hypoglycemia in group A from glucose threshold of 2. Improved counterregulatory hormone adrenaline, noradrenaline, GH responses. No significant change in HbA 1c during intervention period; group A: 6. Fanelli, 38 Intensive insulin therapy physiologic insulin replacement and continuous education with avoidance of hypoglycemia.

no decrease in frequency of hypoglycemia in CG. Baseline 9 patients had at least 1 SH during the year before study to no episodes of SH during study. Improvement in autonomic symptoms in IG, glucose threshold for autonomic symptoms at baseline from 2.

No change in CG. Improved counterregulatory hormones adrenaline, cortisol, GH responses in IG maintained at 1-year follow-up, but not normalized to healthy volunteers. No changes in CG. Increased HbA 1c in IG but still within target 5. CG: HbA 1c showed no increase over 3 months.

Fanelli, 37 Avoidance of hypoglycemia with adjustment of doses of insulin aiming for higher fasting, preprandial, and bedtime BG targets.

Baseline 2 patients had at least 1 SH in the year preceding study to no SH during study. Improved neuroendocrine and symptom responses with no difference in autonomic glycemic thresholds compared with healthy volunteers. Epinephrine responses increased from baseline but still lower than in healthy volunteers.

Increased HbA 1c : 5. DTTP CG. IG: 0. Improvement in HA modified Clarke score in both groups: CG: 1. IG: 1. Improved HbA 1c in PRIMAS group: 8. no change in CG: 8. Hermanns, 43 HyPOS IG vs. standard education CG , long-term follow-up study of Hermanns, ; CG: 0.

Not reported. No difference in glycemic control: CG: 7. HyPOS: 7. Hermanns, 44 Refer to Hermanns, IG: 3. Improved detection of low BG and treatment of low BG. Increased intensity of hypoglycemia symptoms scores in HyPOS group.

HbA 1c improved in CG 7. Schachinger, 45 Randomized to BGAT—III IG vs. physician-guided self-help control intervention CG. CG: 1. Improved recognition of low, high, and overall BG in BGAT vs. Detection of low BG improved in BGAT: No change in HbA 1c : 6.

SMBG CG. No change in HbA 1c : HAATT group 8. Kinsley, 47 BGAT vs. cholesterol awareness CG in patients enrolled into an intensive diabetes treatment program. No data on SH. Increased neurogenic and neuroglycopenic symptom scores but did not differ between CG and BGAT groups before or after 4 months of intensive diabetes therapy.

Increased epinephrine response in BGAT group to hypoglycemia. Improved HbA 1c in both groups: 9. Cox, 48 Long-term follow-up of BGAT patients with a proportion of patients receiving BGAT booster training. SH not reported. BGAT patients had better estimation of BG levels than control subjects.

Improved HbA 1c over time: BGAT: Improved Clarke score, baseline 5. At baseline, 19 subjects were HU according to Clarke test, and at 24 months, 3 of 20 were HU.

Leinung, 56 Retrospective study on CGM use on HbA 1c and SH rates. Improved HbA 1c : 7. Ryan, 54 CGM use in patients with SH. Hübinger, 53 Patients started on CSII with changes in HA.

Improved HbA 1c in HU group: 8. CSII with or without RT-CGM in SH 2 × 2 factorial design. All patients received structured diabetes and hypoglycemia education, weekly telephone contact, and monthly clinic visits. Overall study population decreased Gold score: 5. CSII only in patients with HU.

Mean SH in LGS: 1. Improvement in Clarke score in both groups: CSII: 6. No difference in epinephrine response to hypoglycemia between groups.

HbA 1c was similar in both groups at baseline and did not change at end of study. CSII: 7. Leelarathna, 59 HypoCOMPaSS clamp study refer to Little, Decreased Gold scores: baseline 5.

Glucose threshold at which subjects felt hypoglycemic improved: 2. Improved autonomic and neuroglycopenic symptoms scores. Improved metanephrine response.

Kovatchev, 62 SMBG with HHC device providing feedback, randomized to different sequences: or 1: routine SMBG, 2: added estimated HbA 1c , hypoglycemia risk and glucose variability, 3: estimates of symptoms potentially related to hypoglycemia. Not reported on follow-up.

Thomas, 60 Randomized to optimized MDI preprandial insulin lispro and pre-evening meal glargine , CSII, or education. Incidence of SH was 0. No change in HbA 1c in education group: 8. improved HbA 1c in analog group: 8. improved HbA 1c in CSII: 8. Kanc, 61 Randomized crossover study to 2 groups: A bedtime NPH vs.

B nighttime CSII. SH outcome not reported. Autonomic symptoms appeared earlier at higher BG levels in CSII than in NPH group: 3. No differences between CSII and NPH for hypoglycemic thresholds for neuroglycopenic symptoms.

No differences in end HbA 1c between CSII and NPH: 7. human soluble insulin SI with NPH. Not eating enough carbs for how much insulin you take.

Timing of when you take your insulin. The amount and timing of physical activity. Drinking alcohol. How much fat, protein, and fiber are in your meal. Hot and humid weather. Unexpected changes in your schedule. Spending time at a high altitude. Going through puberty. Symptoms of Low Blood Sugar How you react to low blood sugar may not be the same as how someone else with low blood sugar reacts.

Common symptoms may include: Fast heartbeat Shaking Sweating Nervousness or anxiety Irritability or confusion Dizziness Hunger. Hypoglycemia Unawareness. This is more likely to happen if you: Have had diabetes for more than years.

Frequently have low blood sugar. Take certain medicines, such as beta blockers for high blood pressure. Types of Low Blood Sugar Nighttime low blood sugar While low blood sugar can happen at any time during the day, some people may experience low blood sugar while they sleep.

Reasons this may happen include: Having an active day. Being physically active close to bedtime. Taking too much insulin. Drinking alcohol at night. Severe low blood sugar As your low blood sugar gets worse, you may experience more serious symptoms, including: Feeling weak.

Having difficulty walking or seeing clearly. Acting strange or feeling confused. Having seizures. Manage Blood Sugar Monitoring Your Blood Sugar How To Treat Low Blood Sugar.

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