Anne Peters, MD, and Lori Laffel, MD, MPH, Editors
Jane Lee Chiang, MD, Managing Editor
The Diabetes Control and Complications Trial (DCCT)1 was a landmark medical study conducted by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). It was the largest clinical trial focusing exclusively on patients with type 1 diabetes (T1D) and significantly changed T1D management principles. In particular, it established targets (glucose, A1C, and frequency of blood glucose testing) and their impact on long-term complications.
The United Kingdom Prospective Diabetes Study (UKPDS) studied patients with type 2 diabetes (T2D) and helped inform standards for blood pressure and glycemic control.2 In the UKPDS, blood glucose control reduced the risk of microvascular complications, although the effect was not as pronounced as in the DCCT, and blood pressure control was clearly important. As a result of the two studies, there was a paradigm shift in the way clinicians managed patients with T1D and T2D….
In this chapter, our goals are to provide an overview of the current targets, specifically discussing the Diabetes Control and Complications Trial, present differences for those with T1D versus T2D, review relevant targets for children and adults with T1D, and conclude with recommendations for future clinical research. We hope to emphasize that targets for individuals with T1D are fundamentally different from those with T2D, particularly with respect to glucose management. We will discuss pediatrics first and then will proceed to adults.
Guidelines for glucose targets are available for diabetes in general and will be discussed later in this chapter. However, glucose targets for patients with T1D deserve separate consideration from those with T2D because T1D differs significantly from T2D in many regards:
- Prevalence of nonglycemic risk factors in complications
- Disease course
- Risk for hypoglycemia
- Disease management
- Role of glycemic control
- Labile glycemic control
The pathophysiology of the two diseases differ on a basic pathophysiologic level such that T1D is marked by insulinopenia while T2D is characterized by obesity, hyperinsulinemia, insulin resistance, and relative insulinopenia. The age of onset is typically much younger in patients with T1D, and with modern treatment, the duration of disease spans many decades, necessitating management that must be adapted to individual needs over an entire lifetime. Other than hyperglycemia, patients with T1D are less likely to have other risk factors (e.g., hypertension, dyslipidemia, and obesity) for microvascular and macrovascular complications.
In addition, the disease course differs markedly. In T2D, complications such as kidney disease3 and cardiovascular disease (CVD)4,5 are often well established at the time of diagnosis of diabetes, potentially hampering the individual effect of glycemic control. In contrast, the development of complications in T1D follows a more scripted course, developing several years after the diagnosis. Therefore, it is postulated that glycemic control may be a more important relative predictor of complications in patients with T1D compared to T2D, as suggested in a large registry study.6 These observations do not mean that management of other risk factors for microvascular and macrovascular complications, such as hypertension and hyperlipidemia, should be overlooked in patients with T1D but simply that the approach may be framed in a way that is specific to the needs of patients with T1D.
The risk of hypoglycemia and hypoglycemia unawareness differs,7 potentially raising the stakes for intensive glycemic control. Management of T1D typically involves more complex insulin regimens and more frequent glycemic monitoring, yielding more circumstances for which glycemic targets are needed and utilized. While hemoglobin A1C (A1C) alone (without glucose monitoring) could be used to manage some patients with T2D, it cannot typically be used to implement changes in therapy in T1D. T1D is associated with more labile blood glucose levels,8,9 for which targets reflecting measures of glycemia other than A1C must be considered.
Targets for glucose, blood pressure, and lipids are informed by data from adult diabetes patients and smaller studies of pediatric patients. However, since young children in particular are not included in these studies, the effects of interventions are not always clear. Where available, recommendations from professional organizations in addition to that of the ADA are summarized. In some cases, relaxed targets are recommended according to age group, but in general, targets are individualized in a particular patient according to the balance of risks and benefits. Further data are necessary.
It is important to note that young children were not included in the DCCT and therefore the long-term effects of the intervention in this age group are not known. Cognitive and behavioral problems associated with hypoglycemia volume is not reached until age 7–10 years.10 In a cohort study that enrolled 117 youths age 5–16 years and 58 nondiabetic sibling controls, verbal11 intelligence was reduced with exposure to hyperglycemia, not hypoglycemia. However, performance on spatial intelligence and delayed recall tests were reduced with repeated severe hypoglycemia (marked by seizure, loss of consciousness, or the need for assistance in treatment), particularly when it occurred before age 5 years.11 In preschool-age children with T1D, hyperglycemia was associated with lower cognitive ability, slower fine motor speed, and lower receptive language scores, but hypoglycemia was not.12 In a meta-analysis of 2,144 children, hypoglycemic seizures were associated overall with negligible or inconsistent effects on cognition.13 However the study could not rule out potential synergistic effects in children with early onset disease or poor overall glycemic control. In a 12-year follow-up of patients who were diagnosed at an average age of 8 years, severe hypoglycemia was associated with lower verbal IQ and thalamic volume on MRI.14 Another small but long-term (16-year follow-up) study demonstrated decreased problem solving, verbal function, and psycho-motor efficiency among young adults who experienced severe hypoglycemia before age 10 years.15 These risks need to be interpreted in light of additional, perhaps clearer, adverse effects of hyperglycemia16,17 or insulin deficiency18 on cognitive function.
Glucose targets (see Table 6.1).19–20 There is limited scientific evidence for age-specific glucose targets. Pediatric health care providers must individualize blood glucose targets for each child, walking the tightrope of near-term hypoglycemia risks and long-term hyperglycemic complications. In young children, higher targets are recommended, but only with some reservation. This is due to the clear risks of hyperglycemia long-term, and the concerning observation that early poor metabolic control is a predictor of continued poor control, an observation that has been termed metabolic tracking.21,22 Targets for older children, particularly adolescents, with T1D should be similar to that of adults, provided that it can be done safely (Table 6.1).
With hypertension present in up to 16% of children23 with T1D and predictive of future microalbuminuria, blood pressure should be closely monitored and controlled. In children, blood pressure targets are based on age-, sex-, and height-specific percentiles. The American Diabetes Association (ADA)19 and International Society Pediatric and Adolescent Diabetes (ISPAD) both recommend a target blood pressure of <90th percentile by age, sex, and height (Table 6.2).24 Blood pressure values that fall between the 90th and 95th percentile are classified as prehypertension. Children with blood pressure readings persistently above the 95th percentile for age, sex, and height, despite lifestyle modification and weight loss (if indicated), should be started on pharmacologic therapy based on recommendations for children without diabetes. ACE inhibitors have been safe and effective in children ages 6–16 years of age in short-term studies25,26 and are to be initiated in those with persistent hypertension with a treatment goal of blood pressure <130/80 or <90th percentile, whichever is lower.
Microalbuminuria. Based on its effectiveness in adults, ACE inhibitors are also indicated for children with persistent microalbuminuria. Angiotensin receptor blockers (ARBs) have had similar clinical benefits but have not been studied in children with hypertension and diabetes. Despite the long-term renal protective effect of ACE inhibitors seen in adults, their use in children without hypertension remains of concern given the potential adverse effects after decades of exposure. According to the ADA guidelines, annual screening for microalbuminuria should start once a child is 10 years old and has had diabetes for 5 years.19 The National Institutes of Health and Clinical Excellence (NICE) guidelines suggest measuring blood pressure and microalbumin annually starting at 12 years of age,20 while the Canadian Clinical practice guidelines recommend screening all children with T1D for hypertension at least twice annually.22
Atherosclerosis starts during childhood,27 and children with T1D who have poor glycemic control develop long-term diabetic complications sooner. As per ADA guidelines, lipid screening should be targeted at those >10 years old unless there is a family history of a cardiovascular (CV) event prior to 55 years of age.19 If so, then a fasting lipid profile should be obtained soon after diagnosis. If LDLc is abnormal or >100 mg/dl, repeat annually, otherwise, it may be repeated in five years. Short-term trials have shown statin therapy to be effective and safe in children over 10 years of age,28,29 who despite optimized glucose control and compliance with a Step 2 AHA diet30, have LDLc levels >160 mg/dl or >130 mg/dl with one or more CV risk factors. The treatment goal is an LDLc <100 mg/dl (Table 6.3).19, 31–33 No randomized trials have determined the long-term safety or CV efficacy of statin therapy in children with T1D.
Current trends. In the National Health and Nutrition Examination Survey (NHANES), the proportion of patients with diabetes with an A1C <7% has improved over time but still accounts for only 56% of patients.34 However, NHANES data do not distinguish between T1D and T2D, and only 16% of subjects received insulin therapy only. Therefore, it is possible that a smaller proportion of patients with T1D attain effective glycemic control.
The Type 1 Diabetes Exchange cohort of 7,477 U.S. adults had a mean A1C of 8.7, 8.2, 7.7, and 7.4% in subjects of age 18–20, 21–25, 26–64, and >65 years respectively.31 Lower A1C was associated with older age, non-Hispanic white race, higher income, higher education, marriage, and private insurance, and greater use of insulin pumps, sensors, and self-monitoring of blood glucose.
In a Swedish national registry of over 13,000 patients with T1D, the frequency of obtaining an A1C <7% increased only slightly from 17.4% in 1997 to 21.2% in 2004 and the mean A1C decreased from 8.2 to 8.0%.32 In a large German and Austrian database of over 30,000 children and adolescents, mean A1C improved over time from 8.7 to 8.1% and the rate of severe hypoglycemia declined (RR 0.917, 95% CI 0.885–0.950) from 1995 to 2009.33 The decline in hypoglycemia was not completely attributable to insulin modality such as the introduction of continuous subcutaneous insulin infusions. However, it may be possible that a combination of new technologies may be able to lower A1C with-out increasing the risk of hypoglycemia. In the DCCT, the initiation of intensive insulin therapy resulted in an A1C reduction that was accompanied by an increase in severe hypoglycemia. However, after the introduction of rapid-acting analogs (lispro) there was an additional reduction in A1C without further increase in frequency of hypoglycemia.35 In the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study, A1C fell only about 0.5% in 1995, approximately in concert with publication of findings from the DCCT, and after 30 years of follow-up, only 17% achieved an A1C <7%.36 Clearly, more needs to be done to ensure that targets are reached.
Association with complications: A1C. Since the DCCT did not randomize subjects to multiple A1C targets, the appropriate target for A1C is based upon epidemiologic analysis of data from the DCCT. The DCCT randomly assigned 1,441 patients to conventional (one to two injections of insulin per day with a goal of freedom from severe hyperglycemia or hypoglycemia symptoms) or intensive treatment (at least three injections per day with the goal of attaining near normoglycemia) arms.37 Over the 6.5 years of the study, there was a reduction in the risk of nephropathy, retinopathy, and neuropathy in the intensive arm. Mean A1C during the study was the dominant predictor of the development of microvascular complications,38 and although the risk was nonlinear, there was no threshold below which further reduction in risk was identified.39 In addition, the risk of microvascular complications was dependent upon the duration of diabetes, emphasizing the relevance of glycemic control at the lower end of the A1C spectrum early in the disease course in order to improve long-term complications.
Long-term epidemiologic follow-up of the DCCT, known as the Epidemiology of Diabetes Interventions and Complications (EDIC) Study, demonstrated persistent beneficial effects of the intensive therapy that were explained mostly by A1C levels during the randomized portion of the trial.40,41,42 In the EDIC cohort, emergent reduction in CV events was observed in the intensively treated group, again explained by A1C reduction during the intervention phase of the trial.43 Thus a clear legacy effect exists for multiple complications.
In the Pittsburgh EDC Study, A1C was not a predictor of long-term risk of CVD in patients with T1D.44 This finding differs from the EDIC and may be at least in part due to greater A1C reduction in the DCCT, which enrolled patients earlier in the disease course, or due to renal disease.45 However, the EDC did confirm the findings of the relationship between A1C and microvascular complications.46
The EURODIAB study was another prospective observational cohort of patients with T1D. In EURODIAB, there was an increased risk of progression of microalbuminuria in a stepwise relationship with A1C.47 In fact, no thresh-old for complications was apparent, such that each percentage increase in A1C above 5.5% was associated with increased risk, although only levels >6.5% were significantly different. Similar findings were observed for retinopathy.48 There was an association of A1C with CV events only in men.49
Data from another large national prospective observational study confirmed the strong association between A1C and microvascular complications, with no apparent threshold below which complications are avoided.50
Association with complications: Hypoglycemia. Hypoglycemia may be defined in a variety of ways in the literature, but is most concerning when it results in neurologic sequelae such as seizure, or loss of consciousness or requires the assistance of someone other than the patient for treatment. Such events are typically considered to be severe. Severe hypoglycemia is often the only presentation of hypoglycemia that is reported in the literature. Intensive insulin therapy in the DCCT was associated with a threefold increase in severe hypoglycemia,51 and as the A1C falls, the hypoglycemia risk increases exponentially.1 Severe hypoglycemia was not associated with the development of microvascular complications52 or decline in cognitive function in the overall cohort16 or in the youngest cohort age 13–19 years17 after 18 years in the study. However, severe hypoglycemia should be minimized as the acute effects are not inconsequential.53,54
Association with complications: Glucose variability. In an earlier DCCT publication, there was a difference in outcomes not explained by A1C between the two groups. This was originally attributed to glycemic excursions that might be more prevalent in the less intensive group.55 However, the same data were reanalyzed, and this finding was attributed to an artifact of the Poisson model as well as to inadequate adjustment for baseline variables.42 In addition, variability of the relationship between mean glucose and A1C may be significant, further supporting the need for A1C to be supplemented by self-monitored blood glucose readings.56 In fact, total glucose exposure (A1C and diabetes duration) only explained 11% of the total variation in retinopathy risk overall, after adjustment for treatment group in the DCCT.
Post-hoc analysis of seven-point glucose profiles (self-monitored blood glucose obtained before and after meals and at bedtime) did not demonstrate a relationship between complications and various measures of glycemic variability, except for a weak association between mean amplitude of glycemic excursion (MAGE) and retinopathy.57,58 Unfortunately, seven-point profiles are limited for capturing glycemic variability, and this question remains incompletely answered.
There is stronger evidence for the use of glycemic variability measures to identify patients at risk of severe hypoglycemia. Lower mean glucose and higher glucose variability (measured as standard deviation [SD]) further contributed each 18 mg/dl increase in SD was associated with a 1.09-fold increase in risk of severe hypoglycemia, and the association strengthened for subsequent events. SD, but not mean glucose, predicted overnight hypoglycemia. The authors suggested that optimizing glycemic variability rather than bedtime glucose might be a better way of minimizing nocturnal hypoglycemia. A similar relationship between fasting glucose variability and nocturnal hypoglycemia was reported elsewhere.60
Of more recent interest are observations that long-term glycemic variability, assessed with intrapersonal SD of A1C, has been associated with renal disease and CVD, even after adjusting for mean A1C and other known risk factors.61
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Used with permission by the American Diabetes Association. Copyright © 2013 American Diabetes Association.
Please note: We are proud to have Dr. Anne Peters as a member of our Advisory Board member for Diabetes In Control, Inc.
|If you would like to purchase the full text of The Type 1 Diabetes Sourcebook, Anne Peters, MD, and Lori Laffel, MD, MPH, editors, and Jane Lee Chiang, MD, managing editor, just follow this link.