Abstract
Hypoglycemia is a common, potentially avoidable consequence of diabetes treatment and is a major barrier to initiating or intensifying antihyperglycemic therapy in efforts to achieve better glycemic control. Therapy regimen and a history of hypoglycemia are the most important predictors of future events. Other risk factors include renal insufficiency, older age, and history of hypoglycemia-associated autonomic failure. Reported rates of hypoglycemia vary considerably among studies because of differences in study design, definitions used, and population included, among other factors. Although occurring more frequently in type 1 diabetes, hypoglycemia also is clinically important in type 2 diabetes. Symptoms experienced by patients vary among individuals, and many events remain undiagnosed. The incidence of severe events is unevenly distributed, with only a small proportion (∼5%) of individuals accounting for >50% of events. Consequently, clinicians must be conscientious in obtaining thorough patient histories, because an accurate picture of the frequency and severity of hypoglycemic events is essential for optimal diabetes management. Severe hypoglycemia in particular is associated with an increased risk of mortality, impairments in cognitive function, and adverse effects on patients' quality of life. Economically, hypoglycemia burdens the healthcare system and adversely affects workplace productivity, particularly after a nocturnal event. Ongoing healthcare reform efforts will result in even more emphasis on reducing this side effect of diabetes treatment. Therefore, improving patients' self-management skills and selecting or modifying therapy to reduce the risk of hypoglycemia will increase in importance for clinicians and patients alike.
Keywords
Hypoglycemia is a common, potentially avoidable consequence of diabetes treatment and a major barrier to better metabolic control in type 1 and type 2 diabetes. It is a significant concern of primary care practitioners and patients when it comes to initiating or intensifying antihyperglycemic therapy.
1
Hypoglycemia can be defined in several ways: by plasma glucose values (biochemical definition), by symptoms (type and severity), and by time of day in which it occurs (daytime or nocturnal).2
The literature is inconsistent in describing biochemical hypoglycemia, and these definitions may vary in clinical trials in inpatient versus outpatient settings; thus, an American Diabetes Association (ADA) workgroup has proposed 5 classifications (Table 1).2
As Seaquist et al2
have noted, the ADA standard of ≤70 mg/dL (3.9 mmol/L) is an alert value, intended to provide a margin of error for the limited accuracy of glucose monitoring devices at lower glucose levels. Because this value is above the threshold for symptoms, it allows sufficient time for corrective action to be taken.Table 1Definitions of Hypoglycemia
2
| Severe Hypoglycemia | Documented Symptomatic Hypoglycemia | Asymptomatic (Documented) Hypoglycemia | Probable Symptomatic Hypoglycemia | Pseudo-hypoglycemia |
|---|---|---|---|---|
| Requires assistance of a third party and is ameliorated by normalization of plasma glucose | Typical symptoms accompanied by measured plasma glucose ≤70 mg/dL | Measured plasma glucose ≤70 mg/dL but without typical symptoms | Typical symptoms responding to self-treatment but not confirmed by biochemical documentation but presumably caused by plasma glucose ≤70 mg/dL | Typical symptoms but with a measured plasma glucose greater than but approaching 70 mg/dL |
It has been questioned whether the ADA standard is the most appropriate cutoff point for the biochemical definition of hypoglycemia because it is based on glucose-clamp studies, which measure arterialized venous samples, whereas it is capillary glucose, which tends to be approximately 15% lower than venous samples, that is typically measured in practice. Thus, it has been argued that in the absence of symptoms, a lower level (eg, ≤63 mg/dL [3.5 mmol/L]) should be used for biochemical definition.
3
With respect to symptomatic definitions, hypoglycemia may be self-treated (mild) or severe/major (ie, requiring assistance of a third party).
2
Symptoms can be divided into 2 broad groups: autonomic (eg, sweating, heart palpitations, shaking, dizziness, hunger) and neuroglycopenic (eg, confusion, drowsiness, speech difficulty, odd behavior, incoordination).4
, 5
Unfortunately, the symptoms experienced are inconsistent between individuals, which complicates our efforts in identifying hypoglycemia and in counseling patients who experience these symptoms.6
Furthermore, symptoms are not pathognomonic and can occur while a person is biochemically normoglycemic (pseudo-hypoglycemia) or when normalizing glucose levels in those patients with prolonged hyperglycemia.7
Assessing the frequency of nocturnal hypoglycemia is challenging because of inconsistencies in defining the beginning and end of the nocturnal period in various studies. Furthermore, continuous glucose monitoring studies confirm that many episodes of hypoglycemia are not detected by patients with type 1 diabetes8
and type 2 diabetes.9
Frequency of Hypoglycemia
Data from population-based studies confirm that hypoglycemia rates are higher in patients with type 1 diabetes than in those with type 2 diabetes. For example, in a random sample of 267 insulin-treated people, 94 with type 1 diabetes had a total of 336 hypoglycemic events (42.89 events per person-year), 9 of which were severe (1.15 events per person-year). By comparison, 173 people with type 2 diabetes experienced a total of 236 hypoglycemic events (16.37 events per person-year), 5 of which were severe (0.35 events per person-year).
10
Another review estimated that 7% to 25% of patients with type 2 diabetes using insulin experience at least 1 severe episode annually.4
Hypoglycemia also is commonly reported in people with type 2 diabetes using oral medications.4
, 11
Nevertheless, it is important to recognize the limitations of making a broad generalization about the comparative incidence in type 1 diabetes versus type 2 diabetes in community populations or in randomized trials. Randomized trials may titrate patients more ambitiously, but exclude people with a high risk of severe hypoglycemia or hypoglycemia unawareness. If treated to a very tight glucose target, patients with type 2 diabetes conceivably could be at a similar risk to those with type 1 diabetes. In population statistics (in type 1 diabetes), the distribution of severe hypoglycemia is skewed, with a small proportion (5%) of individuals accounting for the majority (54%) of events.
12
It is critical that these patients be identified and case managed more proactively.Risk Factors/Behaviors Predisposing to Hypoglycemia
Antidiabetic therapies, individually and used in combination, vary substantially in their risk of hypoglycemia.
13
, 14
, 15
, 16
In one meta-analysis of intensification after failure of maximal metformin monotherapy, all noninsulin second-tier medications provided similar improvements in glycemic control, but were distinguishable by different rates of hypoglycemia (Table 2).15
Table 2Results of Two Methods of Meta-analysis Comparing Noninsulin Antidiabetic Drugs with Placebo on Overall Hypoglycemia
15
| No. of Trials | Risk of Overall Hypoglycemia | ||||
|---|---|---|---|---|---|
| Traditional Meta-analysis | Mixed-Treatment Meta-analysis | ||||
| Relative Risk | 95% CI | Relative Risk | 95% Credible Interval | ||
| Sulfonylureas | 3 | 2.63 | 0.76-9.13 | 4.57 | 2.11-11.45 |
| Glinides | 2 | 7.92 | 1.45-43.21 | 7.50 | 2.12-41.52 |
| Thiazolidinediones | 2 | 2.04 | 0.50-8.23 | 0.56 | 0.19-1.69 |
| AGIs | 2 | 0.60 | 0.08-4.55 | 0.42 | 0.01-9.00 |
| DPP4-inhibitors | 8 | 0.67 | 0.30-1.50 | 0.63 | 0.26-1.71 |
| GLP-1 analogs | 2 | 0.94 | 0.42-2.12 | 0.89 | 0.22-3.96 |
AGI = alpha-glucosidase inhibitor; CI = confidence interval; DPP4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1.
∗ I2 ≥ 75% (significant statistical heterogeneity present).
Studies have identified numerous patient-level predictors of hypoglycemia. In type 1 diabetes, these include a history of hypoglycemia (P = .006) and co-prescribing of any oral drug (P = .048), whereas in insulin-treated type 2 diabetes, predictors included a history of hypoglycemia (P < .0001) and duration of insulin treatment (P = .014).
10
In a study of patients intensifying therapy because of insufficient control on 1 or 2 oral medications, after adjustment for confounding variables, the following factors were significant predictors: prior anamnestic (remembered) hypoglycemia (odds ratio [OR], 4.05; 95% confidence interval [CI], 3.04-5.39), preexistent retinopathy (OR, 3.27; 95% CI, 1.07-30.02), preexistent clinically relevant depression (OR, 1.81; 95% CI, 1.14-2.88), insulin use starting at baseline (OR, 2.99; 95% CI, 2.27-3.95), and blood glucose self-measurement (OR, 1.72; 95% CI, 1.23-2.41).16
In type 2 diabetes, factors that have been reported to precede a severe hypoglycemic episode include a change in food intake, more vigorous exercise, increase in insulin dose, and cognitive impairment, among others.13
Caffeine is an example of a commonly ingested substance that, by virtue of its potential to produce resting tremors and tachycardia, may enhance the intensity of warning symptoms, and thus increase the number of mild episodes reported.17
Subgroups at Risk
Patients with Renal Insufficiency
Patients with diabetes who have chronic kidney disease have a higher frequency of hypoglycemia than people with diabetes who do not have chronic kidney disease. In a retrospective analysis of more than 200,000 patients cared for by the Veterans Health Administration, the rate of hypoglycemia was approximately twice as high for people with a diagnosis of diabetes having chronic kidney disease (glomerular filtration rate <60 mL/min per 1.73 m2) versus those without chronic kidney disease (glomerular filtration rate ≥60 mL/min per 1.73 m2) (10.72 vs 5.33 episodes per 100 patient-months, respectively).
18
Reasons for this increased risk include reduced insulin requirements because of decreased renal clearance of insulin, decreased degradation of insulin in peripheral tissues, reduced renal gluconeogenesis if there is a reduction in renal mass, and prolonged half-life of other drugs in chronic kidney disease.18
Elderly Patients
Elderly patients are at increased risk of hypoglycemia, partly because of factors such as deteriorating renal function affecting drug clearance, occurrence of polypharmacy making more drugs available for adverse interactions, and decreased cognitive functioning.
19
This elevated risk compared with nonelderly individuals persists even at comparable glycemic control.20
Glycemic thresholds at which counter-regulatory responses to hypoglycemia occur are lowered in elderly persons (eg, <2.0 mmol/L [36 mg/dL]), decreasing potential reaction time for corrective action and increasing the risk for asymptomatic hypoglycemia.20
, 21
Elderly patients also report different symptoms and have different responses to hypoglycemia (eg, diminished autonomic symptoms and more prominent neuroglycopenic symptoms). Thus, hypoglycemia can be misdiagnosed as delirium or neurologic events. Cognitive impairments in the elderly may contribute to the increased risk of hypoglycemia, and hypoglycemia may further worsen or increase the risk of cognitive issues.
22
, 23
The joint occurrence of hypoglycemia unawareness and deteriorated cognitive function is a critical factor to be carefully considered in the treatment of older patients.24
A recent study of 40 elderly (mean age, 75 years; 70% had type 2 diabetes), mostly insulin-using diabetic patients found that after continuous glucose monitoring for 3 days, 65% (n = 26) of patients had a blood glucose level <70 mg/dL, and 46% of those (n = 12) had an episode with blood glucose <50 mg/dL. It was worrisome that 93% (95/102) of hypoglycemic events were not detected, either by finger-stick glucose monitoring or symptoms.25
Thus, expert guidelines recognize that it may be prudent to strive for less ambitious targets in many elderly patients.26
- Inzucchi S.E.
- Bergenstal R.M.
- Buse J.B.
- et al.
Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
Diabetes Care. 2012; 35 (Erratum in Diabetes Care. 2013;36:490): 1364-1379
People with Hypoglycemia Unawareness and Hypoglycemia-Associated Autonomic Failure
Defective glucose counter-regulation and hypoglycemia unawareness constitute the syndrome of hypoglycemia-associated autonomic failure, which can occur in people with type 1 or 2 diabetes. Those with recent antecedent hypoglycemia are predisposed.
27
, 28
Affected individuals have loss of forewarning symptoms of hypoglycemia and decreased response to those symptoms, and thus are at increased risk of hypoglycemia.27
, 28
In one study, adults with type 1 diabetes and impaired awareness of hypoglycemia exhibited twice the frequency of all episodes of hypoglycemia over a 4-week monitoring period, compared with those with normal awareness (mean ± standard deviation, 7.9 ± 5.4 episodes vs 3.7 ± 3.6 episodes, P = .003).29
Annual prevalence of severe hypoglycemia was 53% in people with type 1 diabetes and impaired awareness compared with 5% for people with normal awareness.29
During sleep, physiologic defenses may be further compromised, making it less likely that a person will awaken because of hypoglycemia.30
, 31
Consequences of Hypoglycemia
Clinical Consequences
Overall, it has been estimated that 4% to 10% of deaths of patients with type 1 diabetes are associated with hypoglycemia.
2
, 32
In a sample of 1013 adults with type 1 or 2 diabetes, self-reports of severe hypoglycemia were associated with a 3.4-fold (95% CI, 1.5-7.4) higher mortality after 5 years compared with those who reported no events or mild events.33
In a study of 11,140 people with type 2 diabetes (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation trial [ADVANCE]), the mortality rate among those reporting severe hypoglycemia was 19.5%, compared with 9% for those without severe hypoglycemia, and all-cause mortality risk remained increased for 4 years after a severe hypoglycemic event.11
Much of this mortality may be mediated via increased risk of cardiovascular death. In the ADVANCE trial, severe hypoglycemia was associated with significant increases in the risk of major macrovascular events (hazard ratio [HR], 2.88; 95% CI, 2.01-4.12) and major microvascular events (HR, 1.81; 95% CI, 1.19-2.74).
11
In a large population (>860,000) of people with type 2 diabetes, those with an International Classification of Diseases 9th Revision–coded hypoglycemic outpatient event and subsequent admission for cardiovascular event had 79% higher odds of acute cardiovascular events, even after adjustment for important confounding variables.34
Hypoglycemia-related physiologic effects, which may increase cardiovascular disease risk, include higher circulating levels of inflammatory markers, vascular adhesion molecules, and markers of thrombosis and platelet activation.
35
, 36
, 37
, 38
Insulin-induced hypoglycemia also is associated with alterations in cardiac electrical function, which may be important in generating severe arrhythmias and “dead-in-bed” syndrome.39
It is interesting to note that in one study looking particularly at electrocardiographic alterations after a single bolus of insulin, QT prolongation in subjects was similar when normoglycemic 15 minutes after injection and when hypoglycemic at the blood glucose nadir (QTc prolongation of 27 ± 19 ms and 25 ± 24 ms, respectively, P = .25), indicating that hypoglycemia alone may not be responsible for these observed alterations.40
Severe hypoglycemia may permanently impair cognitive function in the young and in older adults.
41
, 42
Compared with the general population, people with type 2 diabetes and hypoglycemia have a 1.5- to 2.5-fold increased risk of developing dementia, which could be related to the development of cerebral microvascular disease or other factors that render brains of older individuals more vulnerable.23
The risk of dementia in older patients has been shown to be graded according to the frequency of severe hypoglycemia (episodes requiring a hospital visit): 1 episode (HR, 1.26; 95% CI, 1.10-1.49); 2 episodes (HR, 1.80; 95% CI, 1.37-2.36); and ≥3 episodes (HR, 1.94; 95% CI, 1.42-2.64).42
Economic Consequences
Hypoglycemia poses significant burdens to the healthcare system, for both emergency services
43
, 44
, 45
and increased use of primary care resources.46
In 1 medical claims database, the mean cost of a hypoglycemic event managed in an outpatient setting was $472 (95% CI, 270-674) and the mean attributable total cost was $1087 (95% CI, 764-1409).47
An increase in diabetes-related or all cause–related costs has been reported in other studies comparing patients with and without hypoglycemia.48
, 49
, 50
Furthermore, patients may incur out-of-pocket costs for managing hypoglycemic events.51
Hypoglycemia can affect next-day functioning, particularly after nocturnal events, and therefore affect productivity in the workplace.
52
, 53
, 54
It may take, on average, half a day to return to functioning at a normal level after a nonsevere hypoglycemic event.55
In one study, lost productivity was estimated to range from $15.26 to $93.47 (US dollars) per nonsevere hypoglycemia event, representing 8.3 to 15.9 hours of lost work time per month.56
Monthly out-of-pocket costs for test strips and lancets were estimated at $17.23 ± $19.51.Psychosocial/Quality of Life Consequences
Numerous studies document the adverse effects of hypoglycemia on health-related quality of life and treatment satisfaction, including how patients with hypoglycemia are more affected by their diabetes; report lower general health, physical health, and mental health; and are more anxious about hypoglycemia or worried than those without hypoglycemia.
57
, - Alvarez-Guisasola F.
- Tofe P.S.
- Krishnarajah G.
- et al.
Hypoglycaemic symptoms, treatment satisfaction, adherence and their associations with glycaemic goal in patients with type 2 diabetes mellitus: findings from the Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) Study.
Diabetes Obes Metab. 2008; 10: 25-32
58
, 59
, 60
, 61
, 62
, 63
There may be changes in the behavior of patients and health care providers, which are reviewed by Edelman and Pettus64
in this supplement.Health Care Reform Issues
Diabetes remains an important target for pay for performance programs, such as the Physician Quality Reporting System
65
and the Healthcare Effectiveness Data and Information Set.Centers for Medicare and Medicaid Services. Last updated 2013. Physician Quality Reporting System. Available at: http://www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/PQRS/index.html?redirect=/pqrs. Accessed December 2013.
66
Traditional metrics of glucose control (eg, achievement of HbA1c<7.0%) are now being supplemented by the healthcare reform–driven Value-Based Purchasing Modifier. This modifier will score clinicians in how well they control the entire cost of care for patients with diabetes. Patients who are admitted for uncontrolled diabetes will lead to clinicians scoring poorly in “quality.” Clinicians who have the highest quality scores and lowest cost will earn the most incentive payments. Thus, increased attention on reduction of hypoglycemic risk of patients will lead to reduced cost, better outcomes for patients, and enhanced payments for doctors.National Committee for Quality Assurance. Last updated 2013. HEDIS & Performance Measurement. Available at: http://www.ncqa.org/HEDISQualityMeasurement.aspx. Accessed December 2013.
67
Centers for Medicare and Medicaid Services. Last updated 2012. CMS Proposals for the Physician Value-Based Payment Modifier under the Medicare Physician Fee Schedule. Available at: http://www.cms.gov/Outreach-and-Education/Outreach/NPC/Downloads/8-1-12-VBPM-NPC-Presentation.pdf. Accessed December 2013.
Patient Management Issues
Improving Self-Treatment
Improving patients' ability to self-treat may mitigate some of the adverse consequences of hypoglycemia. A starting point is to assess the health literacy of patients and their support structure/resources at home. It is essential to determine whether they are able to administer medications correctly, perform self-monitoring of blood glucose, adjust insulin doses, and know when to ask for assistance. In one study, even after an educational program, people often struggled to adhere to guidelines for self-treatment of hypoglycemia.
68
Therefore, it is critically important that healthcare professionals assess patients' need for support during patient visits and follow-up to ensure that the required support is provided.69
Coexisting clinical depression may complicate, or result from, diabetes, so it is important that clinicians screen for this condition routinely.70
Major diabetes guidelines worldwide offer recommendations for dosing rescue carbohydrates (eg, 10-30 g with a wait time of 10-15 minutes if hypoglycemia persists). However, an Australian study in 92 adults using insulin has suggested that the initial amount should be 20 g with a 10-minute wait for optimal treatment.
71
Research in children has shown that readily available sucrose (Skittles) can increase blood glucose to the same extent as more expensive BD Glucose tablets (Becton Dickinson and Co, Franklin Lakes, NJ; product now discontinued), and better than fructose (Fruit to Go). Thus, Skittles may offer a more economic way to self-treat hypoglycemic events.72
Therefore, the common rule of 15s (ie, 15 M&Ms, 15 Skittles, recheck in 15 minutes) still seems sensible.Avoiding Hypoglycemia-Associated Autonomic Failure and Impaired Hypoglycemia Awareness
The mainstay of treatment of hypoglycemia-associated autonomic failure is the scrupulous avoidance of hypoglycemia.
73
A structured educational program can improve impaired hypoglycemia awareness and patients' self-treatment abilities while reducing the incidence of hypoglycemia.74
, 75
After 12 months of follow-up, one program (HyPOS) consisting of 5 weekly lessons of 90 minutes duration each and covering key aspects of hypoglycemia in diabetes reduced the incidence of severe episodes by approximately half (0.1 ± 0.2 episodes per patient-year vs 0.2 ± 0.4 episodes per patient-year, P = .04); 12.5% of patients in the treatment group versus 26.5% of patients in the control group experienced at least 1 severe episode.76
Selecting and Modifying Therapy to Reduce Risk
Lifestyle approaches are the mainstay of prevention of hypoglycemia. These include having a well-balanced diet, eating regular small meals, self-monitoring of blood glucose at appropriate frequency, carrying a source of rescue carbohydrate such as fruit or candy at all times, and avoiding defensive overeating to avert a hypoglycemic event. The importance of adhering to these basic practices cannot be overstated. However, if hypoglycemia persists despite good adherence to best practices, then modification of therapy is warranted. This may include revising glucose targets and prescribing drugs or combinations of drugs that may decrease the risk of hypoglycemia (Table 2).
26
For patients with type 2 diabetes, incretin-based therapies have a low risk of hypoglycemia, in some studies comparable to placebo.- Inzucchi S.E.
- Bergenstal R.M.
- Buse J.B.
- et al.
Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
Diabetes Care. 2012; 35 (Erratum in Diabetes Care. 2013;36:490): 1364-1379
77
The pharmacokinetic and pharmacodynamic properties of insulin can influence the risk of hypoglycemia, and therefore a formulation whose action closely mimics the pancreatic insulin profile and has a constant (less variable) glucose-lowering effect from dose to dose should be prioritized. Neutral protamine Hagedorn, a commonly prescribed intermediate-acting basal insulin, has several important drawbacks: an insufficient duration of action, a pronounced peak in action, and, because it is a suspension, careful shaking immediately before injection. Long-acting basal analogues, such as insulin glargine, insulin detemir, and insulin degludec, are formulated as solutions that do not require resuspension and have a flatter pharmacokinetic profile than neutral protamine Hagedorn, and may be associated with less variability than neutral protamine Hagedorn from injection to injection.
78
, 79
, 80
In laboratory studies, insulin glargine and insulin detemir have been shown to have less variability than neutral protamine Hagedorn, and insulin detemir and insulin degludec have been shown to have lower variability than insulin glargine.81
, 82
As the result of a more physiologic profile and lower variability compared with neutral protamine Hagedorn, the basal analogs insulin detemir and insulin glargine are associated with a 31% reduced risk of nocturnal hypoglycemia and a 27% reduced risk of severe hypoglycemia in type 1 diabetes
83
and a 54% reduction in nocturnal hypoglycemia and 31% reduction in symptomatic hypoglycemia in type 2 diabetes.84
Thus, they are recommended over neutral protamine Hagedorn in the American Association of Clinical Endocrinologists Guidelines.85
More recently, in a preplanned meta-analysis of pooled patient-level data from 7 randomized, controlled, phase 3a, treat-to-target trials comparing insulin degludec with insulin glargine, both administered once daily, there was a reduced risk of hypoglycemia in several patient populations (ie, type 1 diabetes, insulin-naïve type 2 diabetes, and insulin-experienced type 2 diabetes).86
Among insulin-naïve patients with type 2 diabetes, rates of overall confirmed hypoglycemia (rate ratio [RR], 0.83; 95% CI, 0.70-0.98), nocturnal confirmed hypoglycemia (RR, 0.64; 95% CI, 0.48-0.86), and severe hypoglycemia (RR, 0.14; 95% CI, 0.03-0.70) were lower for insulin degludec versus insulin glargine. Rates of overall confirmed hypoglycemia (RR, 0.83; 95% CI, 0.74-0.94) and nocturnal confirmed hypoglycemia (RR, 0.68; 95% CI, 0.57-0.82) were lower in the overall type 2 diabetes population. In patients with type 1 diabetes, the rate of nocturnal confirmed hypoglycemia (RR, 0.75; 95% CI, 0.60-0.94) was lower compared with insulin glargine during the maintenance period.Glycemic variability has an independent effect on risk of hypoglycemia.
87
In a study on type 2 diabetes,88
this excess risk was essentially eliminated when the standard deviation of glucose variability was <1.7 mmol/L (30.6 mg/dL) irrespective of the blood glucose level and treatment regimen. Another study using self-monitoring of blood glucose data from insulin-treated patients demonstrated that glucose fluctuations during the preceding 24 hours can predict occurrence of 58% to 75% of severe hypoglycemic episodes.89
Although not addressed by current guidelines, new products consisting of insulin formulated in combination with incretins offer the potential for an additional glucose-lowering effect without an increased risk of hypoglycemia, as well as to curtail the weight gain associated with insulin intensification that might accompany using insulin alone.
90
Conclusions
Hypoglycemia has many associated complications adversely affecting patients' longevity and is an economic burden both for individuals and for society as a whole. It is important for clinicians to pay close attention to hypoglycemia when managing patients with diabetes. Implementing appropriate glycemic targets sets the precedence for which tools will allow patients to achieve those goals. Selecting or modifying therapy to reduce hypoglycemia can take one of the variables of diabetes management and turn it into somewhat more of a constant, minimizing hypoglycemia risk.
Acknowledgments
The authors thank Gary Patronek and Gabrielle Parker of Watermeadow Medical for writing and editing assistance, supported by Novo Nordisk .
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Article Info
Footnotes
Funding: The publication of this manuscript was funded by Novo Nordisk Inc.
Conflict of Interest: JM has served on advisory boards for Novo Nordisk and Boehringer Ingelheim, and is on the speakers bureau for Novo Nordisk, Boehringer Ingelheim, Ortho Biotec, and Warner Chilcott. DS has served on advisory boards for Novo Nordisk, Janssen, and Lilly.
Authorship: The authors take full responsibility for the content of this manuscript. Writing support was provided by Watermeadow Medical.
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© 2014 The Authors. Published by Elsevier Inc. User rights governed by an Open Access license.
