Which of the following indicates a potential complication of diabetes mellitus?

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Hypoglycemia is the most common, life-threatening acute complication of diabetes treatment. It is characterized by multiple risk factors and complex pathophysiology (105). The brain depends on a continuous supply of glucose for energy, although it can also utilize ketone bodies. Young children and adolescents are at higher risk for hypoglycemia, and the spectrum of outcomes ranges from mild cognitive impairment to coma, seizure, and sudden death.

Missed meals, inadvertent insulin dosing error, and rapid insulin absorption due to intramuscular injection or hot shower/bath shortly after injection are common causes of hypoglycemia in insulin-treated patients. Rarely, secondary gain or suicide attempt may lead to insulin overdose. In all these situations, insulin overdose reduces hepatic glucose output. Physical activity increases glucose utilization and may lead to hypoglycemia, if not matched by lowering of insulin dose and increased carbohydrate intake. Oral hypoglycemic agents may lead to hypoglycemia by either decreasing hepatic glucose output or increasing insulin levels. In contrast, enhancers of peripheral glucose utilization (thiazolidinediones) do not cause hypoglycemia in patients with residual insulin and glucagon secretion. Release of glucagon—the major counterregulatory response to hypoglycemia in nondiabetic persons—is progressively lost within a few years after diagnosis of type 1 diabetes. Catecholamine release, the other powerful counterregulatory mechanism, is also impaired in diabetic patients, especially in those with type 1 diabetes and those on beta blocker treatment (106).

Definition

Various definitions of hypoglycemia are in use; for comparative epidemiologic studies, it is important to standardize criteria. The American Diabetes Association Workgroup on Hypoglycemia defined hypoglycemia broadly as all episodes of an abnormally low plasma glucose concentration that expose the individual to potential harm (107,108). According to the Workgroup, a hypoglycemic episode could be:

• Severe hypoglycemia: an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. The episode may lead to a significant neuroglycopenia and seizure or coma. Plasma glucose measurements may be missing during an event, but neurological recovery is sufficient evidence that the event was induced by a low plasma glucose concentration.

• Documented symptomatic hypoglycemia: an event with typical symptoms of hypoglycemia and a measured plasma glucose concentration ≤70 mg/dL (≤3.89 mmol/L).

• Asymptomatic hypoglycemia: an event with a measured plasma glucose concentration ≤70 mg/dL, but without typical symptoms of hypoglycemia.

• Probable symptomatic hypoglycemia: an event during which symptoms of hypoglycemia are not accompanied by a plasma glucose determination.

• Relative hypoglycemia: an event during which the person with diabetes reports any of the typical symptoms of hypoglycemia and interprets those as indicative of hypoglycemia, with a measured plasma glucose concentration >70 mg/dL.

The DCCT defined severe hypoglycemia as an episode in which the patient required assistance with treatment from another person to recover; blood glucose level had to be documented as <50 mg/dL (<2.78 mmol/L) and/or the clinical manifestations had to be reversed by oral carbohydrate, subcutaneous glucagon, or intravenous glucose (109). This definition is of limited value in children, particularly the youngest, as they require assistance even for mild episodes of hypoglycemia. There is lack of a uniform definition of hypoglycemia for children and adolescents with diabetes. Most experts agree that blood glucose values <60–70 mg/dL (<3.33–3.89 mmol/L) put the patient at risk for severe hypoglycemia. Those blood glucose levels lead to alterations in the counterregulatory hormones essential to the spontaneous reversal of hypoglycemia. For clinical use, the value of <65 mg/dL (<3.61 mmol/L) has been most often used as the level for defining hypoglycemia in the pediatric population. Other studies have limited the definition of severe hypoglycemia in children to episodes leading to unconsciousness or seizure (110,111).

In the ICD-9, hypoglycemic coma secondary to diabetes treatment is coded 250.3; however, this code is also used for coma with DKA. Other forms of diabetic hypoglycemia are coded 250.8. Hypoglycemia not associated with diabetes is coded 251.2. An additional E code is recommended to identify the drug that induced hypoglycemia. In the ICD-10, E1x.0 denotes coma with or without ketoacidosis, hyperosmolarity or hypoglycemia (with the x digit used to define type of diabetes), while E16.0 denotes diabetic drug-induced hypoglycemia without coma.

Incidence in Type 1 Diabetes Patients

The incidence of moderate or mild hypoglycemia is unknown; those events are frequent among patients treated with insulin and are often unrecognized or underreported. Severe hypoglycemia is more likely to be recognized. Pre-DCCT incidence rates of severe hypoglycemia varied from 3 to 86 per 100 patient-years depending on definition, age, duration of diabetes, and treatment modality (112,113,114,115,116).

Among adolescents participating in the DCCT, the incidences of hypoglycemia were 86 per 100 patient-years in intensively treated and 28 per 100 patient-years in conventionally treated participants (78). The incidences of coma and seizure in the adolescents were 27 per 100 patient-years and 10 per 100 patient-years, respectively. In all DCCT participants, intensive treatment of type 1 diabetes increased the frequency of severe hypoglycemia from two to six times that observed with conventional treatment (117).

Several studies examined the incidence rates of severe hypoglycemia in youth during the post-DCCT era. Few used a prospective design or were population based. The incidence of severe hypoglycemia of 19 per 100 patient-years was reported from a large cohort of type 1 diabetic children age 0–19 years followed by the Barbara Davis Center for Childhood Diabetes (26). A Joslin Clinic study with a similar definition found a lower rate of 8 per 100 patient-years in a cohort of older children age 7–16 years. However, this study excluded children with psychiatric disorders and difficult social situations (118). Similar rates were reported from other European, American, and Australian studies (119,120,121,122,123), with an exception of very low incidence (<4 per 100 person-years) in a study from Finland (124).

Incidence in Type 2 Diabetes Patients

Patients with type 2 diabetes treated with diet and exercise do not suffer from severe hypoglycemia. It occurs rarely in patients treated with oral hypoglycemic agents. However, the risk of hypoglycemia increases with transition to insulin-dependence. In the United Kingdom Prospective Diabetes Study (UKPDS), the risk of severe hypoglycemia was 1.0 per 100 patient-years in those intensively treated with chlorpropamide, 1.4 per 100 patient-years with glibenclamide, and 1.8 per 100 patient-years with insulin (125). Long-acting sulfonylureas confer higher risk compared to shorter-acting ones (126), particularly in older patients and those with a longer duration of diabetes, polypharmacy, and a recent hospitalization (127). One study suggested an increase in risk of hypoglycemia in patients treated with sulfonylurea and angiotensin-converting enzyme (ACE) inhibitors (128), but that finding was not confirmed in a large trial (129). Hospital admission rates for hypoglycemia in U.S. have declined since 2007; however, rates among black Medicare beneficiaries and those older than 75 years remain high (130).

Risk Factors

There is a strong relationship between severe hypoglycemia and tight glycemic control (131), especially in children and older adults (118,120,132,133,134). Age (infancy and adolescence) (120,135), male sex (26), and increased duration of diabetes (136) are the most commonly reported predictors of severe hypoglycemia in patients with type 1 diabetes. The risk of hypoglycemia increases with duration of diabetes, partially due to progressive loss of alpha cell glucagon response to hypoglycemia, and is inversely related to preservation of beta cells (137). In the DCCT, presence of residual endogenous insulin secretion predicted 65% lower risk of severe hypoglycemia (138). Sudden loss of endogenous insulin production is seen more frequently in patients with the human leukocyte antigen (HLA)-DR3/4 genotype (139,140,141) and those with multiple islet autoantibodies (140,142).

In patients with type 2 diabetes, aggressive glycemic control puts them at risk of hypoglycemia. A large, cross-sectional study of older adult patients in the Veterans Health Administration in 2009 identified patients at risk of hypoglycemia based on whether they were receiving insulin and/or sulfonylureas. Instances of overtreatment were defined as using one of these agents in patients with A1c levels below specific thresholds, such as <7.0% (<53 mmol/mol). Among patients age ≥75 years, who had a serum creatinine >2.0 mg/dL or an ICD-9-CM diagnosis of cognitive impairment or dementia (31.5% of patients), rates of overtreatment were 11.3% for those with A1c <6.0% (<42 mmol/mol), 28.6% for A1c <6.5% (<48 mmol/mol), and 50.0% for A1c <7.0%. Among patients with additional comorbidity, similar rates of overtreatment were found by A1c thresholds (134). Additional information about glycemic control and hypoglycemia risk in older adults is provided in Chapter 16 Diabetes in Older Adults.

Modifiable predictors of severe hypoglycemia include intensive insulin treatment, marked by lower A1c levels and higher insulin dose (26,119). The relation between severe hypoglycemia and tight glycemic control had been extensively explored, especially in children (118,120,132). Over 60% of the intensively treated adolescents who participated in the DCCT had coma or seizure during the trial compared to 25% of those treated conventionally (78). Intensive treatment, such as the use of insulin pumps, is beneficial in lowering A1c levels without a coincident higher risk of hypoglycemia in pediatric populations (143,144). The addition of continuous glucose monitoring to insulin pump therapy has further lowered the rates of hypoglycemia (145,146,147).

Another risk factor is the presence of hypoglycemia unawareness leading to an inability to recognize symptoms of hypoglycemia. It is present in about 10% of patients and is more common in patients with low average glucose levels (148,149). Even a single hypoglycemic episode can cause significant decrease in neurohormonal counterregulatory responses and worsen unawareness of hypoglycemia (150).

The main effect of exercise on glucose metabolism is blood glucose lowering via insulin-independent skeletal muscle uptake, which may result in hypoglycemia without modification of insulin dose and intake of carbohydrates (151).

Alcohol consumption is a significant risk factor for development of severe hypoglycemia. Alcohol suppresses gluconeogenesis and glycogenolysis and acutely improves insulin sensitivity (152,153) and may induce hypoglycemia unawareness (154). In combination with exercise, drinking alcohol can lead to severe hypoglycemia with a delay of symptoms up to 10–12 hours after alcohol consumption (155).

Family dynamics, behavioral factors, and psychiatric factors are important risk factors, particularly in the pediatric population. The DCCT showed that conventional risk factors explained only 8.5% of the variance in the occurrence of severe hypoglycemia (117). Factors such as inadequate diabetes education, low socioeconomic status, lack of insurance, unstable living conditions, behavioral factors, and psychiatric disorders affecting patients and their families have been shown to have significant influence on glycemic control and the rate of hypoglycemia. Family relationships and personality type have also had a significant effect on adaptation to illness and metabolic control among persons with diabetes (156). Presence of psychiatric disorders has a detrimental effect on metabolic control (157,158) and compliance with treatment (159). Prevalence of psychiatric disorders among patients with type 1 diabetes reached 48% by 10 years of diabetes duration and age 20 years in a small longitudinal cohort (160,161), the most prevalent being major depressive disorder (28%). Prevalence of psychiatric disorders, however, has been shown to be much lower in other studies, as discussed in Chapter 33 Psychiatric and Psychosocial Issues Among Individuals Living With Diabetes.

Coexisting autoimmune conditions, such as autoimmune thyroid, celiac, and Addison’s diseases, occurring in up to 30% of patients with type 1 diabetes, increase the risk of hypoglycemia (162,163,164,165). In pregnancy with type 1 diabetes, the incidence of mild and severe hypoglycemia is highest in early pregnancy, although metabolic control is usually tighter in the last part of pregnancy. Predictors for severe hypoglycemia are history of severe hypoglycemia and impaired awareness (166). Chronic kidney disease can be found in up to 23% of patients with diabetes. Chronic kidney disease is an independent risk factor for hypoglycemia and augments the risk already present in people with diabetes (167,168).

Morbidity and Mortality

A new analysis for Diabetes in America of the frequency of hypoglycemia (ICD-9 codes 250.8 and 251.2) as a discharge diagnosis for hospitalizations in the United States in 2001–2010 is shown in and , using data from the National Hospital Discharge Survey. Hypoglycemia was listed as an underlying cause in about 288,000 hospitalizations, which represented 5.4% of hospitalizations due to diabetes. Hospital discharges for hypoglycemia in diabetic patients occurred least often in patients age <18 years. The total number of hypoglycemic events was higher in females with diabetes compared to males, but the percentage of discharges was higher in males compared to females. The total number of hospitalizations due to hypoglycemia was greatest among whites followed by blacks, while the percentage of discharges was lower in whites than in the other race/ethnicity groups ().

TABLE 17.5

Annual Hospitalizations for Hypoglycemia, by Diabetes Status, Age, Sex, and Race, U.S., 2001–2010.

Hypoglycemia is a significant factor in excess mortality in patients with diabetes (169). Despite improvements in therapy, diabetes-related mortality among children did not decline in the time period between 1968 and 1998 (170). Sudden nocturnal death in young persons with type 1 diabetes has been described and is known as the “dead in bed” syndrome (171); it appears to be responsible for about 6% of deaths in diabetic patients age <40 years (172). In these cases, nocturnal hypoglycemia is a likely precipitant, consistent with demonstrated impairment of counterregulatory hormone response during sleep (173), as well as a high frequency of nocturnal hypoglycemia reported by the DCCT (117) and more recent studies using continuous glucose monitoring.

Hypoglycemic episodes range from mild neurogenic symptoms to coma and seizures. There is an association between hypoglycemia and a decrease in cognitive functioning in children with type 1 diabetes (174,175,176), particularly among the youngest patients (176,177). Hypoglycemic seizures lead to significant declines in verbal abilities (178), memory skills (179), and the ability to organize and recall information (180), even after mild hypoglycemia (181). Severe hypoglycemia in children may lead to persistent electroencephalographic changes (182,183,184,185). On the other hand, intensive insulin treatment in the DCCT cohort (age 13–39 years at baseline), while increasing the incidence of hypoglycemia, did not lead to a significant worsening of neuropsychological or cognitive functioning during the trial (186,187), as well as 18 years after entry into the trial (188). However, risk of hypoglycemia should be balanced by emerging data on a detrimental effect of hyperglycemia on the development of a normal brain (189).

Cost

In a study among youth with diabetes, the predicted mean annual total medical expenditures were $12,850 and $8,970 for youth with and without severe hypoglycemia, respectively. The excess of expenditures was greater among those with more than one episode ($5,929) than among those with only one ($2,888) (63). A study from Germany, Spain, and the United Kingdom showed that hospital treatment of severe hypoglycemia was a major contributor to its high cost. Average severe hypoglycemia event treatment costs were higher for patients with type 2 diabetes (Germany, €533; Spain, €691; U.K., €537) than those with type 1 diabetes (€441, €577, and €236, respectively) (190). Reliable data are not available concerning the cost of hypoglycemia in adults with diabetes in the United States.

The personal, family, and societal cost of trauma of loss of consciousness, seizure, long-term disability, and fears are harder to measure. Further studies are needed to update these figures and to estimate, in addition, indirect costs (e.g., lost productivity and diminished quality of life).

Prevention

Improved insulin delivery and technological advances provide new opportunities to improve glycemic control with decreased risk of severe hypoglycemia, but they require intensified teaching and compliance (136,191,192). Intensive insulin therapy using insulin pumps, multiple daily injections, and new insulin analogues has been found effective in lowering A1c levels, but there is less evidence for a beneficial effect on the risk of hypoglycemia. Insulin pump treatment may lower A1c levels and improve quality of life compared to multiple daily injections of insulin and, of importance, reduce the rate of severe hypoglycemia (193,194).

The introduction of rapid-acting insulin analogues (e.g., lispro, aspart) has made insulin treatment more efficient and potentially less likely to induce hypoglycemia. An ecologic analysis explored the effects of the DCCT report in 1993 and that of the introduction of a rapid-acting insulin analogue (lispro) in 1996 on the risk of severe hypoglycemia in type 1 diabetic patients (195). A1c levels declined significantly during 1993–1996 (p<0.001), following the DCCT report, but the number of severe hypoglycemic events increased (p<0.001) during that time frame. A further decline in A1c levels was observed after the introduction of lispro insulin in 1996 (p<0.001), however, without a concomitant change in the incidence of severe hypoglycemia. The introduction of long-acting insulin analogues in 2003 also suggests a potential for improving glycemic control without an increased risk of hypoglycemia (196,197,198).

Continuous Glucose Monitoring

Frequent self-blood glucose monitoring has been found to be an important factor in attaining better glucose control for the intensively treated participants in the DCCT and the UKPDS. However, many patients do not accept frequent blood glucose monitoring, mainly because of pain and inconvenience. The results also give data valid for only a discrete point in time, without any information on glucose trends before or after the glucose value. In addition, patients infrequently measure blood glucose levels during the night, although >50% of severe hypoglycemic events occur during sleep (113,117).

Continuous glucose monitoring holds great promise for prevention of hypoglycemia. Clinical trials of continuous glucose monitoring have given reason to believe that tighter glycemic control may not necessarily lead to increased risk of hypoglycemia (199,200,201,202,203,204,205). The main goal of research on devices for diabetes management is the development of automatic glucose sensing and insulin delivery without patient intervention (206). Studies evaluating closed-loop insulin delivery suggest improved glucose control and a decreased risk of hypoglycemia (207,208). Data from the Automation to Simulate Pancreatic Insulin REsponse (ASPIRE) study confirmed that use of sensor-augmented insulin pump therapy with the threshold-suspend feature reduced nocturnal hypoglycemia, without increasing A1c values (209).

Behavioral Interventions

Behavioral interventions, including intensive diabetes education, good access to care, and psychosocial support, including treatment of psychiatric disorders, lower the risk of hypoglycemia (210,211).

Treatment

The goal of treatment of hypoglycemia is to immediately increase the blood glucose approximately 3–4 mmol/L (~55–70 mg/dL). This can be accomplished by giving glucose tablets or sweetened fluids, such as juice, glucagon injection in unconscious patients, or dextrose infusion in a hospital setting.

What is the main complication of diabetes mellitus?

Which of the following is a potential acute complication of diabetes?

What are the most common acute complications of diabetes mellitus?

What are the early complications of diabetes mellitus?