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Hypoglycemia

      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.
      • Frier B.M.
      How hypoglycaemia can affect the life of a person with diabetes.
      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).
      • Seaquist E.R.
      • Anderson J.
      • Childs B.
      • et al.
      Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society.
      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).
      • Seaquist E.R.
      • Anderson J.
      • Childs B.
      • et al.
      Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society.
      As Seaquist et al
      • Seaquist E.R.
      • Anderson J.
      • Childs B.
      • et al.
      Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society.
      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
      • Seaquist E.R.
      • Anderson J.
      • Childs B.
      • et al.
      Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society.
      Severe HypoglycemiaDocumented Symptomatic HypoglycemiaAsymptomatic (Documented) HypoglycemiaProbable Symptomatic HypoglycemiaPseudo-hypoglycemia
      Requires assistance of a third party and is ameliorated by normalization of plasma glucoseTypical symptoms accompanied by measured plasma glucose ≤70 mg/dLMeasured plasma glucose ≤70 mg/dL but without typical symptomsTypical symptoms responding to self-treatment but not confirmed by biochemical documentation but presumably caused by plasma glucose ≤70 mg/dLTypical 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.
      • Frier B.M.
      Defining hypoglycaemia: what level has clinical relevance?.
      With respect to symptomatic definitions, hypoglycemia may be self-treated (mild) or severe/major (ie, requiring assistance of a third party).
      • Seaquist E.R.
      • Anderson J.
      • Childs B.
      • et al.
      Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society.
      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).
      • Graveling A.J.
      • Frier B.M.
      Hypoglycaemia: an overview.
      • Henderson J.N.
      • Allen K.V.
      • Deary I.J.
      • Frier B.M.
      Hypoglycaemia in insulin-treated Type 2 diabetes: frequency, symptoms and impaired awareness.
      Unfortunately, the symptoms experienced are inconsistent between individuals, which complicates our efforts in identifying hypoglycemia and in counseling patients who experience these symptoms.
      • Zammitt N.N.
      • Streftaris G.
      • Gibson G.J.
      • et al.
      Modeling the consistency of hypoglycemic symptoms: high variability in diabetes.
      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.
      • El Khoury M.
      • Yousuf F.
      • Martin V.
      • Cohen R.M.
      Pseudohypoglycemia: a cause for unreliable finger-stick glucose measurements.
      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 diabetes
      • Guillod L.
      • Comte-Perret S.
      • Monbaron D.
      • et al.
      Nocturnal hypoglycaemias in type 1 diabetic patients: what can we learn with continuous glucose monitoring?.
      and type 2 diabetes.
      • Weber K.K.
      • Lohmann T.
      • Busch K.
      • et al.
      High frequency of unrecognized hypoglycaemias in patients with type 2 diabetes is discovered by continuous glucose monitoring.

      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).
      • Donnelly L.A.
      • Morris A.D.
      • Frier B.M.
      • et al.
      Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2 diabetes: a population-based study.
      Another review estimated that 7% to 25% of patients with type 2 diabetes using insulin experience at least 1 severe episode annually.
      • Graveling A.J.
      • Frier B.M.
      Hypoglycaemia: an overview.
      Hypoglycemia also is commonly reported in people with type 2 diabetes using oral medications.
      • Graveling A.J.
      • Frier B.M.
      Hypoglycaemia: an overview.
      • Zoungas S.
      • Patel A.
      • Chalmers J.
      • et al.
      Severe hypoglycemia and risks of vascular events and death.
      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.
      • Pedersen-Bjergaard U.
      • Pramming S.
      • Heller S.R.
      • et al.
      Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection.
      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.
      • Bonds D.E.
      • Miller M.E.
      • Dudl J.
      • et al.
      Severe hypoglycemia symptoms, antecedent behaviors, immediate consequences and association with glycemia medication usage: Secondary analysis of the ACCORD clinical trial data.
      • Inkster B.
      • Zammitt N.N.
      • Frier B.M.
      Drug-induced hypoglycaemia in type 2 diabetes.
      • Phung O.J.
      • Scholle J.M.
      • Talwar M.
      • Coleman C.I.
      Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes.
      • Tschöpe D.
      • Bramlage P.
      • Binz C.
      • et al.
      Incidence and predictors of hypoglycaemia in type 2 diabetes - an analysis of the prospective DiaRegis registry.
      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).
      • Phung O.J.
      • Scholle J.M.
      • Talwar M.
      • Coleman C.I.
      Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes.
      Table 2Results of Two Methods of Meta-analysis Comparing Noninsulin Antidiabetic Drugs with Placebo on Overall Hypoglycemia
      • Phung O.J.
      • Scholle J.M.
      • Talwar M.
      • Coleman C.I.
      Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes.
      No. of TrialsRisk of Overall Hypoglycemia
      Traditional Meta-analysisMixed-Treatment Meta-analysis
      Relative Risk95% CIRelative Risk95% Credible Interval
      Sulfonylureas32.630.76-9.13
      I2 ≥ 75% (significant statistical heterogeneity present).
      4.572.11-11.45
      Glinides27.921.45-43.217.502.12-41.52
      Thiazolidinediones22.040.50-8.230.560.19-1.69
      AGIs20.600.08-4.550.420.01-9.00
      DPP4-inhibitors80.670.30-1.500.630.26-1.71
      GLP-1 analogs20.940.42-2.120.890.22-3.96
      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).
      • Donnelly L.A.
      • Morris A.D.
      • Frier B.M.
      • et al.
      Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2 diabetes: a population-based study.
      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).
      • Tschöpe D.
      • Bramlage P.
      • Binz C.
      • et al.
      Incidence and predictors of hypoglycaemia in type 2 diabetes - an analysis of the prospective DiaRegis registry.
      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.
      • Bonds D.E.
      • Miller M.E.
      • Dudl J.
      • et al.
      Severe hypoglycemia symptoms, antecedent behaviors, immediate consequences and association with glycemia medication usage: Secondary analysis of the ACCORD clinical trial data.
      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.
      • Watson J.M.
      • Jenkins E.J.
      • Hamilton P.
      • et al.
      Influence of caffeine on the frequency and perception of hypoglycemia in free-living patients with type 1 diabetes.

      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).
      • Moen M.F.
      • Zhan M.
      • Hsu V.D.
      • et al.
      Frequency of hypoglycemia and its significance in chronic kidney disease.
      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.
      • Moen M.F.
      • Zhan M.
      • Hsu V.D.
      • et al.
      Frequency of hypoglycemia and its significance in chronic kidney disease.

      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.
      • Ligthelm R.J.
      • Kaiser M.
      • Vora J.
      • Yale J.F.
      Insulin use in elderly adults: risk of hypoglycemia and strategies for care.
      This elevated risk compared with nonelderly individuals persists even at comparable glycemic control.
      • Bramlage P.
      • Gitt A.K.
      • Binz C.
      • et al.
      Oral antidiabetic treatment in type-2 diabetes in the elderly: balancing the need for glucose control and the risk of hypoglycemia.
      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.
      • Bramlage P.
      • Gitt A.K.
      • Binz C.
      • et al.
      Oral antidiabetic treatment in type-2 diabetes in the elderly: balancing the need for glucose control and the risk of hypoglycemia.
      • Zammitt N.N.
      • Frier B.M.
      Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities.
      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.
      • Lin C.H.
      • Sheu W.H.
      Hypoglycaemic episodes and risk of dementia in diabetes mellitus: 7-year follow-up study.
      • Strachan M.W.
      • Reynolds R.M.
      • Marioni R.E.
      • Price J.F.
      Cognitive function, dementia and type 2 diabetes mellitus in the elderly.
      The joint occurrence of hypoglycemia unawareness and deteriorated cognitive function is a critical factor to be carefully considered in the treatment of older patients.
      • Bremer J.P.
      • Jauch-Chara K.
      • Hallschmid M.
      • et al.
      Hypoglycemia unawareness in older compared with middle-aged patients with type 2 diabetes.
      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.
      • Munshi M.N.
      • Segal A.R.
      • Suhl E.
      • et al.
      Frequent hypoglycemia among elderly patients with poor glycemic control.
      Thus, expert guidelines recognize that it may be prudent to strive for less ambitious targets in many elderly patients.
      • 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).

      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.
      • Bakatselos S.O.
      Hypoglycemia unawareness.
      • Unger J.
      • Parkin C.
      Recognition, prevention, and proactive management of hypoglycemia in patients with type 1 diabetes mellitus.
      Affected individuals have loss of forewarning symptoms of hypoglycemia and decreased response to those symptoms, and thus are at increased risk of hypoglycemia.
      • Bakatselos S.O.
      Hypoglycemia unawareness.
      • Unger J.
      • Parkin C.
      Recognition, prevention, and proactive management of hypoglycemia in patients with type 1 diabetes mellitus.
      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).
      • Schopman J.E.
      • Geddes J.
      • Frier B.M.
      Frequency of symptomatic and asymptomatic hypoglycaemia in type 1 diabetes: effect of impaired awareness of hypoglycaemia.
      Annual prevalence of severe hypoglycemia was 53% in people with type 1 diabetes and impaired awareness compared with 5% for people with normal awareness.
      • Schopman J.E.
      • Geddes J.
      • Frier B.M.
      Frequency of symptomatic and asymptomatic hypoglycaemia in type 1 diabetes: effect of impaired awareness of hypoglycaemia.
      During sleep, physiologic defenses may be further compromised, making it less likely that a person will awaken because of hypoglycemia.
      • Banarer S.
      • Cryer P.E.
      Sleep-related hypoglycemia-associated autonomic failure in type 1 diabetes: reduced awakening from sleep during hypoglycemia.
      • Jones T.W.
      • Porter P.
      • Sherwin R.S.
      • et al.
      Decreased epinephrine responses to hypoglycemia during sleep.

      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.
      • Seaquist E.R.
      • Anderson J.
      • Childs B.
      • et al.
      Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society.
      • Cryer P.E.
      Severe hypoglycemia predicts mortality in diabetes.
      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.
      • McCoy R.G.
      • Van Houten H.K.
      • Ziegenfuss J.Y.
      • et al.
      Increased mortality of patients with diabetes reporting severe hypoglycemia.
      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.
      • Zoungas S.
      • Patel A.
      • Chalmers J.
      • et al.
      Severe hypoglycemia and risks of vascular events and death.
      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).
      • Zoungas S.
      • Patel A.
      • Chalmers J.
      • et al.
      Severe hypoglycemia and risks of vascular events and death.
      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.
      • Johnston S.S.
      • Conner C.
      • Aagren M.
      • et al.
      Evidence linking hypoglycemic events to an increased risk of acute cardiovascular events in patients with type 2 diabetes.
      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.
      • Gimenéz M.
      • Gilabert R.
      • Monteagudo J.
      • et al.
      Repeated episodes of hypoglycemia as a potential aggravating factor for preclinical atherosclerosis in subjects with type 1 diabetes.
      • Gogitidze Joy N.
      • Hedrington M.S.
      • Briscoe V.J.
      • et al.
      Effects of acute hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with type 1 diabetes and healthy individuals.
      • Wright R.J.
      • Newby D.E.
      • Stirling D.
      • et al.
      Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes.
      • Snell-Bergeon J.K.
      • Wadwa R.P.
      Hypoglycemia, diabetes, and cardiovascular disease.
      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.
      • Laitinen T.
      • Lyyra-Laitinen T.
      • Huopio H.
      • et al.
      Electrocardiographic alterations during hyperinsulinemic hypoglycemia in healthy subjects.
      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.
      • Christensen T.F.
      • Lewinski I.
      • Kristensen L.E.
      • et al.
      QT interval prolongation during rapid fall in blood glucose in type 1 diabetes.
      Severe hypoglycemia may permanently impair cognitive function in the young and in older adults.
      • Asvold B.O.
      • Sand T.
      • Hestad K.
      • Bjorgaas M.R.
      Cognitive function in type 1 diabetic adults with early exposure to severe hypoglycemia: a 16-year follow-up study.
      • Whitmer R.A.
      • Karter A.J.
      • Yaffe K.
      • et al.
      Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus.
      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.
      • Strachan M.W.
      • Reynolds R.M.
      • Marioni R.E.
      • Price J.F.
      Cognitive function, dementia and type 2 diabetes mellitus in the elderly.
      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).
      • Whitmer R.A.
      • Karter A.J.
      • Yaffe K.
      • et al.
      Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus.

      Economic Consequences

      Hypoglycemia poses significant burdens to the healthcare system, for both emergency services
      • Budnitz D.S.
      • Lovegrove M.C.
      • Shehab N.
      • Richards C.L.
      Emergency hospitalizations for adverse drug events in older Americans.
      • Parsaik A.K.
      • Carter R.E.
      • Myers L.A.
      • et al.
      Population-based study of hypoglycemia in patients with type 1 diabetes mellitus requiring emergency medical services.
      • Parsaik A.K.
      • Carter R.E.
      • Myers L.A.
      • et al.
      Hypoglycemia requiring ambulance services in patients with type 2 diabetes is associated with increased long-term mortality.
      and increased use of primary care resources.
      • Davis R.E.
      • Morrissey M.
      • Peters J.R.
      • et al.
      Impact of hypoglycaemia on quality of life and productivity in type 1 and type 2 diabetes.
      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).
      • Bullano M.F.
      • Al-Zakwani I.S.
      • Fisher M.D.
      • et al.
      Differences in hypoglycemia event rates and associated cost-consequence in patients initiated on long-acting and intermediate-acting insulin products.
      An increase in diabetes-related or all cause–related costs has been reported in other studies comparing patients with and without hypoglycemia.
      • Bron M.
      • Marynchenko M.
      • Yang H.
      • et al.
      Hypoglycemia, treatment discontinuation, and costs in patients with type 2 diabetes mellitus on oral antidiabetic drugs.
      • Williams S.A.
      • Pollack M.F.
      • Dibonaventura M.
      Effects of hypoglycemia on health-related quality of life, treatment satisfaction and healthcare resource utilization in patients with type 2 diabetes mellitus.
      • Williams S.A.
      • Shi L.
      • Brenneman S.K.
      • et al.
      The burden of hypoglycemia on healthcare utilization, costs, and quality of life among type 2 diabetes mellitus patients.
      Furthermore, patients may incur out-of-pocket costs for managing hypoglycemic events.
      • Harris S.B.
      • Leiter L.A.
      • Yale J.F.
      • et al.
      Out-of-pocket costs of managing hyperglycemia and hypoglycemia in patients with type 1 diabetes and insulin-treated type 2 diabetes.
      Hypoglycemia can affect next-day functioning, particularly after nocturnal events, and therefore affect productivity in the workplace.
      • Allen K.V.
      • Frier B.M.
      Nocturnal hypoglycemia: clinical manifestations and therapeutic strategies toward prevention.
      • Brod M.
      • Christensen T.
      • Bushnell D.M.
      Impact of nocturnal hypoglycemic events on diabetes management, sleep quality, and next-day function: results from a four-country survey.
      • Brod M.
      • Pohlman B.
      • Wolden M.
      • Christensen T.
      Non-severe nocturnal hypoglycemic events: experience and impacts on patient functioning and well-being.
      It may take, on average, half a day to return to functioning at a normal level after a nonsevere hypoglycemic event.
      • Brod M.
      • Christensen T.
      • Bushnell D.M.
      The impact of non-severe hypoglycemic events on daytime function and diabetes management among adults with type 1 and type 2 diabetes.
      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.
      • Brod M.
      • Christensen T.
      • Thomsen T.L.
      • Bushnell D.M.
      The impact of non-severe hypoglycemic events on work productivity and diabetes management.
      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.
      • 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.
      • Alvarez-Guisasola F.
      • Yin D.D.
      • Nocea G.
      • et al.
      Association of hypoglycemic symptoms with patients’ rating of their health-related quality of life state: a cross sectional study.
      • Green A.J.
      • Fox K.M.
      • Grandy S.
      Self-reported hypoglycemia and impact on quality of life and depression among adults with type 2 diabetes mellitus.
      • Lundkvist J.
      • Berne C.
      • Bolinder B.
      • Jonsson L.
      The economic and quality of life impact of hypoglycemia.
      • Marrett E.
      • Stargardt T.
      • Mavros P.
      • Alexander C.M.
      Patient-reported outcomes in a survey of patients treated with oral antihyperglycaemic medications: associations with hypoglycaemia and weight gain.
      • Sheu W.H.
      • Ji L.N.
      • Nitiyanant W.
      • et al.
      Hypoglycemia is associated with increased worry and lower quality of life among patients with type 2 diabetes treated with oral antihyperglycemic agents in the Asia-Pacific region.
      • Vexiau P.
      • Mavros P.
      • Krishnarajah G.
      • et al.
      Hypoglycaemia in patients with type 2 diabetes treated with a combination of metformin and sulphonylurea therapy in France.
      There may be changes in the behavior of patients and health care providers, which are reviewed by Edelman and Pettus
      • Edelman S.
      • Pettus J.
      Challenges associated with insulin therapy in type 2 diabetes mellitus.
      in this supplement.

      Health Care Reform Issues

      Diabetes remains an important target for pay for performance programs, such as the Physician Quality Reporting System

      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.

      and the Healthcare Effectiveness Data and Information Set.

      National Committee for Quality Assurance. Last updated 2013. HEDIS & Performance Measurement. Available at: http://www.ncqa.org/HEDISQualityMeasurement.aspx. Accessed December 2013.

      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.

      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.
      • Lawton J.
      • Rankin D.
      • Cooke D.D.
      • et al.
      Self-treating hypoglycaemia: a longitudinal qualitative investigation of the experiences and views of people with Type 1 diabetes.
      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.
      • Tan P.
      • Chen H.C.
      • Taylor B.
      • Hegney D.
      Experience of hypoglycaemia and strategies used for its management by community-dwelling adults with diabetes mellitus: a systematic review.
      Coexisting clinical depression may complicate, or result from, diabetes, so it is important that clinicians screen for this condition routinely.
      • Hermanns N.
      • Caputo S.
      • Dzida G.
      • et al.
      Screening, evaluation and management of depression in people with diabetes in primary care.
      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.
      • Vindedzis S.
      • Marsh B.
      • Sherriff J.
      • et al.
      Dietary treatment of hypoglycaemia: should the Australian recommendation be increased?.
      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.
      • Husband A.C.
      • Crawford S.
      • McCoy L.A.
      • Pacaud D.
      The effectiveness of glucose, sucrose, and fructose in treating hypoglycemia in children with type 1 diabetes.
      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.
      • Cryer P.E.
      Hypoglycemia in type 1 diabetes mellitus.
      A structured educational program can improve impaired hypoglycemia awareness and patients' self-treatment abilities while reducing the incidence of hypoglycemia.
      • Cox D.J.
      • Gonder-Frederick L.
      • Polonsky W.
      • et al.
      Blood glucose awareness training (BGAT-2): long-term benefits.
      • Hermanns N.
      • Kulzer B.
      • Kubiak T.
      • et al.
      The effect of an education programme (HyPOS) to treat hypoglycaemia problems in patients with type 1 diabetes.
      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.
      • Hermanns N.
      • Kulzer B.
      • Krichbaum M.
      • et al.
      Long-term effect of an education program (HyPOS) on the incidence of severe hypoglycemia in patients with type 1 diabetes.

      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).
      • 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).
      For patients with type 2 diabetes, incretin-based therapies have a low risk of hypoglycemia, in some studies comparable to placebo.
      • Deacon C.F.
      • Mannucci E.
      • Ahren B.
      Glycaemic efficacy of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors as add-on therapy to metformin in subjects with type 2 diabetes-a review and meta analysis.
      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.
      • Heise T.
      • Hermanski L.
      • Nosek L.
      • et al.
      Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes.
      • Little S.
      • Shaw J.
      • Home P.
      Hypoglycemia rates with basal insulin analogs.
      • Tibaldi J.M.
      Evolution of insulin development: focus on key parameters.
      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.
      • Heise T.
      • Pieber T.R.
      Towards peakless, reproducible and long-acting insulins. An assessment of the basal analogues based on isoglycaemic clamp studies.
      • Heise T.
      • Nosek L.
      • Bottcher S.G.
      • et al.
      Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes.
      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
      • Monami M.
      • Marchionni N.
      • Mannucci E.
      Long-acting insulin analogues vs. NPH human insulin in type 1 diabetes. A meta-analysis.
      and a 54% reduction in nocturnal hypoglycemia and 31% reduction in symptomatic hypoglycemia in type 2 diabetes.
      • Monami M.
      • Marchionni N.
      • Mannucci E.
      Long-acting insulin analogues versus NPH human insulin in type 2 diabetes: a meta-analysis.
      Thus, they are recommended over neutral protamine Hagedorn in the American Association of Clinical Endocrinologists Guidelines.
      • Rodbard H.W.
      • Jellinger P.S.
      • Davidson J.A.
      • et al.
      Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control.
      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).
      • Ratner R.
      • Gough S.C.
      • Mathieu C.
      • et al.
      Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials.
      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.
      • Qu Y.
      • Jacober S.J.
      • Zhang Q.
      • et al.
      Rate of hypoglycemia in insulin-treated patients with type 2 diabetes can be predicted from glycemic variability data.
      In a study on type 2 diabetes,
      • Monnier L.
      • Wojtusciszyn A.
      • Colette C.
      • Owens D.
      The contribution of glucose variability to asymptomatic hypoglycemia in persons with type 2 diabetes.
      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.
      • Cox D.J.
      • Gonder-Frederick L.
      • Ritterband L.
      • et al.
      Prediction of severe hypoglycemia.
      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.
      • Vora J.
      • Bain S.C.
      • Damci T.
      • et al.
      Incretin-based therapy in combination with basal insulin: a promising tactic for the treatment of type 2 diabetes.

      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 .

      References

        • Frier B.M.
        How hypoglycaemia can affect the life of a person with diabetes.
        Diabetes Metab Res Rev. 2008; 24: 87-92
        • Seaquist E.R.
        • Anderson J.
        • Childs B.
        • et al.
        Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society.
        Diabetes Care. 2013; 36: 1384-1395
        • Frier B.M.
        Defining hypoglycaemia: what level has clinical relevance?.
        Diabetologia. 2009; 52: 31-34
        • Graveling A.J.
        • Frier B.M.
        Hypoglycaemia: an overview.
        Prim Care Diabetes. 2009; 3: 131-139
        • Henderson J.N.
        • Allen K.V.
        • Deary I.J.
        • Frier B.M.
        Hypoglycaemia in insulin-treated Type 2 diabetes: frequency, symptoms and impaired awareness.
        Diabet Med. 2003; 20: 1016-1021
        • Zammitt N.N.
        • Streftaris G.
        • Gibson G.J.
        • et al.
        Modeling the consistency of hypoglycemic symptoms: high variability in diabetes.
        Diabetes Technol Ther. 2011; 13: 571-578
        • El Khoury M.
        • Yousuf F.
        • Martin V.
        • Cohen R.M.
        Pseudohypoglycemia: a cause for unreliable finger-stick glucose measurements.
        Endocr Pract. 2008; 14: 337-339
        • Guillod L.
        • Comte-Perret S.
        • Monbaron D.
        • et al.
        Nocturnal hypoglycaemias in type 1 diabetic patients: what can we learn with continuous glucose monitoring?.
        Diabetes Metab. 2007; 33: 360-365
        • Weber K.K.
        • Lohmann T.
        • Busch K.
        • et al.
        High frequency of unrecognized hypoglycaemias in patients with type 2 diabetes is discovered by continuous glucose monitoring.
        Exp Clin Endocrinol Diabetes. 2007; 115: 491-494
        • Donnelly L.A.
        • Morris A.D.
        • Frier B.M.
        • et al.
        Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2 diabetes: a population-based study.
        Diabet Med. 2005; 22: 749-755
        • Zoungas S.
        • Patel A.
        • Chalmers J.
        • et al.
        Severe hypoglycemia and risks of vascular events and death.
        N Engl J Med. 2010; 363: 1410-1418
        • Pedersen-Bjergaard U.
        • Pramming S.
        • Heller S.R.
        • et al.
        Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection.
        Diabetes Metab Res Rev. 2004; 20: 479-486
        • Bonds D.E.
        • Miller M.E.
        • Dudl J.
        • et al.
        Severe hypoglycemia symptoms, antecedent behaviors, immediate consequences and association with glycemia medication usage: Secondary analysis of the ACCORD clinical trial data.
        BMC Endocr Disord. 2012; 12: 5
        • Inkster B.
        • Zammitt N.N.
        • Frier B.M.
        Drug-induced hypoglycaemia in type 2 diabetes.
        Expert Opin Drug Saf. 2012; 11: 597-614
        • Phung O.J.
        • Scholle J.M.
        • Talwar M.
        • Coleman C.I.
        Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes.
        JAMA. 2010; 303: 1410-1418
        • Tschöpe D.
        • Bramlage P.
        • Binz C.
        • et al.
        Incidence and predictors of hypoglycaemia in type 2 diabetes - an analysis of the prospective DiaRegis registry.
        BMC Endocr Disord. 2012; 12: 23
        • Watson J.M.
        • Jenkins E.J.
        • Hamilton P.
        • et al.
        Influence of caffeine on the frequency and perception of hypoglycemia in free-living patients with type 1 diabetes.
        Diabetes Care. 2000; 23: 455-459
        • Moen M.F.
        • Zhan M.
        • Hsu V.D.
        • et al.
        Frequency of hypoglycemia and its significance in chronic kidney disease.
        Clin J Am Soc Nephrol. 2009; 4: 1121-1127
        • Ligthelm R.J.
        • Kaiser M.
        • Vora J.
        • Yale J.F.
        Insulin use in elderly adults: risk of hypoglycemia and strategies for care.
        J Am Geriatr Soc. 2012; 60: 1564-1570
        • Bramlage P.
        • Gitt A.K.
        • Binz C.
        • et al.
        Oral antidiabetic treatment in type-2 diabetes in the elderly: balancing the need for glucose control and the risk of hypoglycemia.
        Cardiovasc Diabetol. 2012; 11: 122
        • Zammitt N.N.
        • Frier B.M.
        Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities.
        Diabetes Care. 2005; 28: 2948-2961
        • Lin C.H.
        • Sheu W.H.
        Hypoglycaemic episodes and risk of dementia in diabetes mellitus: 7-year follow-up study.
        J Intern Med. 2013; 273: 102-110
        • Strachan M.W.
        • Reynolds R.M.
        • Marioni R.E.
        • Price J.F.
        Cognitive function, dementia and type 2 diabetes mellitus in the elderly.
        Nat Rev Endocrinol. 2011; 7: 108-114
        • Bremer J.P.
        • Jauch-Chara K.
        • Hallschmid M.
        • et al.
        Hypoglycemia unawareness in older compared with middle-aged patients with type 2 diabetes.
        Diabetes Care. 2009; 32: 1513-1517
        • Munshi M.N.
        • Segal A.R.
        • Suhl E.
        • et al.
        Frequent hypoglycemia among elderly patients with poor glycemic control.
        Arch Intern Med. 2011; 171: 362-364
        • 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
        • Bakatselos S.O.
        Hypoglycemia unawareness.
        Diabetes Res Clin Pract. 2011; 93: S92-S96
        • Unger J.
        • Parkin C.
        Recognition, prevention, and proactive management of hypoglycemia in patients with type 1 diabetes mellitus.
        Postgrad Med. 2011; 123: 71-80
        • Schopman J.E.
        • Geddes J.
        • Frier B.M.
        Frequency of symptomatic and asymptomatic hypoglycaemia in type 1 diabetes: effect of impaired awareness of hypoglycaemia.
        Diabet Med. 2011; 28: 352-355
        • Banarer S.
        • Cryer P.E.
        Sleep-related hypoglycemia-associated autonomic failure in type 1 diabetes: reduced awakening from sleep during hypoglycemia.
        Diabetes. 2003; 52: 1195-1203
        • Jones T.W.
        • Porter P.
        • Sherwin R.S.
        • et al.
        Decreased epinephrine responses to hypoglycemia during sleep.
        N Engl J Med. 1998; 338: 1657-1662
        • Cryer P.E.
        Severe hypoglycemia predicts mortality in diabetes.
        Diabetes Care. 2012; 35: 1814-1816
        • McCoy R.G.
        • Van Houten H.K.
        • Ziegenfuss J.Y.
        • et al.
        Increased mortality of patients with diabetes reporting severe hypoglycemia.
        Diabetes Care. 2012; 35: 1897-1901
        • Johnston S.S.
        • Conner C.
        • Aagren M.
        • et al.
        Evidence linking hypoglycemic events to an increased risk of acute cardiovascular events in patients with type 2 diabetes.
        Diabetes Care. 2011; 34: 1164-1170
        • Gimenéz M.
        • Gilabert R.
        • Monteagudo J.
        • et al.
        Repeated episodes of hypoglycemia as a potential aggravating factor for preclinical atherosclerosis in subjects with type 1 diabetes.
        Diabetes Care. 2011; 34: 198-203
        • Gogitidze Joy N.
        • Hedrington M.S.
        • Briscoe V.J.
        • et al.
        Effects of acute hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with type 1 diabetes and healthy individuals.
        Diabetes Care. 2010; 33: 1529-1535
        • Wright R.J.
        • Newby D.E.
        • Stirling D.
        • et al.
        Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes.
        Diabetes Care. 2010; 33: 1591-1597
        • Snell-Bergeon J.K.
        • Wadwa R.P.
        Hypoglycemia, diabetes, and cardiovascular disease.
        Diabetes Technol Ther. 2012; 14: S51-S58
        • Laitinen T.
        • Lyyra-Laitinen T.
        • Huopio H.
        • et al.
        Electrocardiographic alterations during hyperinsulinemic hypoglycemia in healthy subjects.
        Ann Noninvasive Electrocardiol. 2008; 13: 97-105
        • Christensen T.F.
        • Lewinski I.
        • Kristensen L.E.
        • et al.
        QT interval prolongation during rapid fall in blood glucose in type 1 diabetes.
        Comput Cardiol. 2007; 34: 345-348
        • Asvold B.O.
        • Sand T.
        • Hestad K.
        • Bjorgaas M.R.
        Cognitive function in type 1 diabetic adults with early exposure to severe hypoglycemia: a 16-year follow-up study.
        Diabetes Care. 2010; 33: 1945-1947
        • Whitmer R.A.
        • Karter A.J.
        • Yaffe K.
        • et al.
        Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus.
        JAMA. 2009; 301: 1565-1572
        • Budnitz D.S.
        • Lovegrove M.C.
        • Shehab N.
        • Richards C.L.
        Emergency hospitalizations for adverse drug events in older Americans.
        N Engl J Med. 2011; 365: 2002-2012
        • Parsaik A.K.
        • Carter R.E.
        • Myers L.A.
        • et al.
        Population-based study of hypoglycemia in patients with type 1 diabetes mellitus requiring emergency medical services.
        Endocr Pract. 2012; 18: 834-841
        • Parsaik A.K.
        • Carter R.E.
        • Myers L.A.
        • et al.
        Hypoglycemia requiring ambulance services in patients with type 2 diabetes is associated with increased long-term mortality.
        Endocr Pract. 2013; 19: 29-35
        • Davis R.E.
        • Morrissey M.
        • Peters J.R.
        • et al.
        Impact of hypoglycaemia on quality of life and productivity in type 1 and type 2 diabetes.
        Curr Med Res Opin. 2005; 21: 1477-1483
        • Bullano M.F.
        • Al-Zakwani I.S.
        • Fisher M.D.
        • et al.
        Differences in hypoglycemia event rates and associated cost-consequence in patients initiated on long-acting and intermediate-acting insulin products.
        Curr Med Res Opin. 2005; 21: 291-298
        • Bron M.
        • Marynchenko M.
        • Yang H.
        • et al.
        Hypoglycemia, treatment discontinuation, and costs in patients with type 2 diabetes mellitus on oral antidiabetic drugs.
        Postgrad Med. 2012; 124: 124-132
        • Williams S.A.
        • Pollack M.F.
        • Dibonaventura M.
        Effects of hypoglycemia on health-related quality of life, treatment satisfaction and healthcare resource utilization in patients with type 2 diabetes mellitus.
        Diabetes Res Clin Pract. 2011; 91: 363-370
        • Williams S.A.
        • Shi L.
        • Brenneman S.K.
        • et al.
        The burden of hypoglycemia on healthcare utilization, costs, and quality of life among type 2 diabetes mellitus patients.
        J Diabetes Complications. 2012; 26: 399-406
        • Harris S.B.
        • Leiter L.A.
        • Yale J.F.
        • et al.
        Out-of-pocket costs of managing hyperglycemia and hypoglycemia in patients with type 1 diabetes and insulin-treated type 2 diabetes.
        Can J Diabetes. 2007; 31: 25-33
        • Allen K.V.
        • Frier B.M.
        Nocturnal hypoglycemia: clinical manifestations and therapeutic strategies toward prevention.
        Endocr Pract. 2003; 9: 530-543
        • Brod M.
        • Christensen T.
        • Bushnell D.M.
        Impact of nocturnal hypoglycemic events on diabetes management, sleep quality, and next-day function: results from a four-country survey.
        J Med Econ. 2012; 15: 77-86
        • Brod M.
        • Pohlman B.
        • Wolden M.
        • Christensen T.
        Non-severe nocturnal hypoglycemic events: experience and impacts on patient functioning and well-being.
        Qual Life Res. 2013; 22: 997-1004
        • Brod M.
        • Christensen T.
        • Bushnell D.M.
        The impact of non-severe hypoglycemic events on daytime function and diabetes management among adults with type 1 and type 2 diabetes.
        J Med Econ. 2012; 15: 869-877
        • Brod M.
        • Christensen T.
        • Thomsen T.L.
        • Bushnell D.M.
        The impact of non-severe hypoglycemic events on work productivity and diabetes management.
        Value Health. 2011; 14: 665-671
        • 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
        • Alvarez-Guisasola F.
        • Yin D.D.
        • Nocea G.
        • et al.
        Association of hypoglycemic symptoms with patients’ rating of their health-related quality of life state: a cross sectional study.
        Health Qual Life Outcomes. 2010; 8: 86
        • Green A.J.
        • Fox K.M.
        • Grandy S.
        Self-reported hypoglycemia and impact on quality of life and depression among adults with type 2 diabetes mellitus.
        Diabetes Res Clin Pract. 2012; 96: 313-318
        • Lundkvist J.
        • Berne C.
        • Bolinder B.
        • Jonsson L.
        The economic and quality of life impact of hypoglycemia.
        Eur J Health Econ. 2005; 6: 197-202
        • Marrett E.
        • Stargardt T.
        • Mavros P.
        • Alexander C.M.
        Patient-reported outcomes in a survey of patients treated with oral antihyperglycaemic medications: associations with hypoglycaemia and weight gain.
        Diabetes Obes Metab. 2009; 11: 1138-1144
        • Sheu W.H.
        • Ji L.N.
        • Nitiyanant W.
        • et al.
        Hypoglycemia is associated with increased worry and lower quality of life among patients with type 2 diabetes treated with oral antihyperglycemic agents in the Asia-Pacific region.
        Diabetes Res Clin Pract. 2012; 96: 141-148
        • Vexiau P.
        • Mavros P.
        • Krishnarajah G.
        • et al.
        Hypoglycaemia in patients with type 2 diabetes treated with a combination of metformin and sulphonylurea therapy in France.
        Diabetes Obes Metab. 2008; 10: 16-24
        • Edelman S.
        • Pettus J.
        Challenges associated with insulin therapy in type 2 diabetes mellitus.
        Am J Med. 2013; 127: S11-S16
      1. 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.

      2. National Committee for Quality Assurance. Last updated 2013. HEDIS & Performance Measurement. Available at: http://www.ncqa.org/HEDISQualityMeasurement.aspx. Accessed December 2013.

      3. 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.

        • Lawton J.
        • Rankin D.
        • Cooke D.D.
        • et al.
        Self-treating hypoglycaemia: a longitudinal qualitative investigation of the experiences and views of people with Type 1 diabetes.
        Diabet Med. 2013; 30: 209-215
        • Tan P.
        • Chen H.C.
        • Taylor B.
        • Hegney D.
        Experience of hypoglycaemia and strategies used for its management by community-dwelling adults with diabetes mellitus: a systematic review.
        Int J Evid Based Healthc. 2012; 10: 169-180
        • Hermanns N.
        • Caputo S.
        • Dzida G.
        • et al.
        Screening, evaluation and management of depression in people with diabetes in primary care.
        Prim Care Diabetes. 2013; 7: 1-10
        • Vindedzis S.
        • Marsh B.
        • Sherriff J.
        • et al.
        Dietary treatment of hypoglycaemia: should the Australian recommendation be increased?.
        Intern Med J. 2012; 42: 830-833
        • Husband A.C.
        • Crawford S.
        • McCoy L.A.
        • Pacaud D.
        The effectiveness of glucose, sucrose, and fructose in treating hypoglycemia in children with type 1 diabetes.
        Pediatr Diabetes. 2010; 11: 154-158
        • Cryer P.E.
        Hypoglycemia in type 1 diabetes mellitus.
        Endocrinol Metab Clin North Am. 2010; 39: 641-654
        • Cox D.J.
        • Gonder-Frederick L.
        • Polonsky W.
        • et al.
        Blood glucose awareness training (BGAT-2): long-term benefits.
        Diabetes Care. 2001; 24: 637-642
        • Hermanns N.
        • Kulzer B.
        • Kubiak T.
        • et al.
        The effect of an education programme (HyPOS) to treat hypoglycaemia problems in patients with type 1 diabetes.
        Diabetes Metab Res Rev. 2007; 23: 528-538
        • Hermanns N.
        • Kulzer B.
        • Krichbaum M.
        • et al.
        Long-term effect of an education program (HyPOS) on the incidence of severe hypoglycemia in patients with type 1 diabetes.
        Diabetes Care. 2010; 33: e36
        • Deacon C.F.
        • Mannucci E.
        • Ahren B.
        Glycaemic efficacy of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors as add-on therapy to metformin in subjects with type 2 diabetes-a review and meta analysis.
        Diabetes Obes Metab. 2012; 14: 762-767
        • Heise T.
        • Hermanski L.
        • Nosek L.
        • et al.
        Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes.
        Diabetes Obes Metab. 2012; 14: 859-864
        • Little S.
        • Shaw J.
        • Home P.
        Hypoglycemia rates with basal insulin analogs.
        Diabetes Technol Ther. 2011; 13: S53-S64
        • Tibaldi J.M.
        Evolution of insulin development: focus on key parameters.
        Adv Ther. 2012; 29: 590-619
        • Heise T.
        • Pieber T.R.
        Towards peakless, reproducible and long-acting insulins. An assessment of the basal analogues based on isoglycaemic clamp studies.
        Diabetes Obes Metab. 2007; 9: 648-659
        • Heise T.
        • Nosek L.
        • Bottcher S.G.
        • et al.
        Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes.
        Diabetes Obes Metab. 2012; 14: 944-950
        • Monami M.
        • Marchionni N.
        • Mannucci E.
        Long-acting insulin analogues vs. NPH human insulin in type 1 diabetes. A meta-analysis.
        Diabetes Obes Metab. 2009; 11: 372-378
        • Monami M.
        • Marchionni N.
        • Mannucci E.
        Long-acting insulin analogues versus NPH human insulin in type 2 diabetes: a meta-analysis.
        Diabetes Res Clin Pract. 2008; 81: 184-189
        • Rodbard H.W.
        • Jellinger P.S.
        • Davidson J.A.
        • et al.
        Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control.
        Endocr Pract. 2009; 15: 540-559
        • Ratner R.
        • Gough S.C.
        • Mathieu C.
        • et al.
        Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials.
        Diabetes Obes Metab. 2013; 15: 175-184
        • Qu Y.
        • Jacober S.J.
        • Zhang Q.
        • et al.
        Rate of hypoglycemia in insulin-treated patients with type 2 diabetes can be predicted from glycemic variability data.
        Diabetes Technol Ther. 2012; 14: 1008-1012
        • Monnier L.
        • Wojtusciszyn A.
        • Colette C.
        • Owens D.
        The contribution of glucose variability to asymptomatic hypoglycemia in persons with type 2 diabetes.
        Diabetes Technol Ther. 2011; 13: 813-818
        • Cox D.J.
        • Gonder-Frederick L.
        • Ritterband L.
        • et al.
        Prediction of severe hypoglycemia.
        Diabetes Care. 2007; 30: 1370-1373
        • Vora J.
        • Bain S.C.
        • Damci T.
        • et al.
        Incretin-based therapy in combination with basal insulin: a promising tactic for the treatment of type 2 diabetes.
        Diabetes Metab. 2013; 39: 6-15