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ADA/JDRF Type 1 Diabetes Sourcebook, Excerpt #13: Setting Treatment Targets, Part 2 of 2

Anne Peters, MD, and Lori Laffel, MD, MPH, Editors
Jane Lee Chiang, MD, Managing Editor


Jane Lee Chiang, MD, and Stephen E. Gitelman, MD

Current guidelines for glycemic control from select organizations worldwide are shown in Table 6.4.19-22,62 Due to the special nature of T1D, only those guidelines that are intended for T1D or that specify self-monitored blood glucose targets are included. In general, guidelines reflect glucose targets established by the DCCT. However, all guidelines recommend that targets be individualized based upon life expectancy and risk for severe hypoglycemia. Conversely, most guidelines allow lower targets for those in which it can be achieved safely, but as noted above, most patients with T1D have difficulty reaching current targets….

Interpretation of Guidelines

A1C (see Table 6.4). The current guidelines for A1C reflect the balance between the continuous benefits achieved by lowering A1C with the increased risk of hypoglycemia as A1C declines (Table 6.4).19–22,63 As the A1C falls, the hypoglycemia risk increases exponentially.1 However, since many people with T1D live beyond the duration of time captured in the DCCT, even a small increase in A1C will likely have cumulative adverse effects over time. Based upon evidence from the DCCT, an A1C <7% still appears reasonable for most. However, in select patients for whom it can be done safely, a lower target should be considered. Indeed, as technologies such as continuous glucose monitoring and closed-loop insulin pumps evolve, lower glucose targets may be achievable without increasing the risk of severe hypoglycemia. Such interventions, if successfully established, would warrant a reappraisal of the target A1C.

Glucose (see Table 6.4). Because most patients with T1D are treated with complex insulin regimens, actual insulin titration relies more upon frequent self-monitored or continuous glucose profiles than it does on A1C. Targets by various organizations generally reflect those used by the DCCT (Table 6.4).19-22,63 Post-meal targets should be considered, particularly in those patients not meeting A1C targets. Although some normative data exist for continuous glucose monitoring, there are no long-term outcomes studies to warrant the reestablishment of separate targets.64


Glycemic Variability. A measure of glycemic variability, such as SD, should be considered to guide interventions aimed at preventing severe hypoglycemia, since such episodes are preceded by periods of increased glycemic variability.65,66 This is of particular relevance in patients with prior episodes of severe hypoglycemia or with hypoglycemia unawareness. There are currently few data to support the use of one measure over another. However, SD is readily available from downloaded reports of many insulin pumps and glucose meters. Since SD is directly proportional to mean glucose (MG), it must be reported as a percent-age of mean glucose, known as the coefficient of variation (%CV). One simple approach proposes that the optimal MG/SD value should be <3, whereas a value >2 is proposed as poor.63 Further data are needed to determine whether these cut-offs are the best predictors of outcomes such as severe hypoglycemia. CGM data show that the cutoff for the interquartile range for %CV among patients with diabetes is 33.5–40.6%.67 Glycemic variability should be assessed using continuous glucose monitoring or frequent glucose measurements (minimum of every 4 h) for optimal use.68

Alternative markers. Where there are known conditions that affect the accuracy of A1C or where A1C and self-monitored blood glucoses are discrepant, alternative markers of glycemia, such as fructosamine, glycoalbumin, or 1,5-anhydroglucitol, could be considered.19 While there are insufficient data to warrant the establishment of a specific target level for alternative markers of glycemia, these markers can be used to track patients over time.69 These markers have not been studied adequately as predictors of long-term complications and it is unclear whether interventions utilizing these markers will improve outcomes over time.

Special Considerations

Severe hypoglycemia. Higher targets are reasonable in patients with severe hypoglycemia or hypoglycemia unawareness in order to restore hypoglycemia sensitivity.70 In these cases, a higher target A1C may be reasonable, but relaxed example, instead of a premeal target of 70–130 mg/dl, the premeal target would be 90–180 mg/dl. Ultimately, the degree of relaxation of glucose targets is that which eliminates hypoglycemia without causing severe hyperglycemia or ketoacidosis. Relaxation of glycemic targets for only a short period of time may restore hypoglycemia awareness, which may allow for resumption of somewhat tighter targets.

Limited life expectancy/cognitive limitations. We advise higher targets for patients with limited life expectancy and patients with cognitive limitations in which tighter glucose targets are not considered feasible or safe. These targets must be individualized for each patient and their circumstances.

Pregnancy (see Table 6.5). Targets for pregnancy are mainly derived from large randomized controlled trials of women with gestational diabetes (Table 6.5).19,22,71–72 However, some data from T1D are available. In pregnancy, women with T1D maintained with meal glucose <95 mg/dl in the second and third trimesters minimize the risk of fetal macrosomia.73 A CGM study determined that early-onset large-for-gestational-age is associated with hyperglycemia in all three trimesters.74 In another cohort study of 289 patients with T1D, A1C <7% was present in 84% but macrosomia still occurred in nearly half of pregnancies.75 A1C was a significant predictor but only explained 5% of the variance in macrosomia. This is believed to be due to a greater importance of postprandial hyperglycemia.76,77,78 In addition, suboptimal glycemic control (A1C >8.0% early pregnancy, >6.1% at 26 weeks, or >7.0% at 34 weeks) was associated with increased risk of preeclampsia.79 A randomized controlled trial demonstrated that postprandial glucose targeting reduced this risk.72 Finally, suboptimal first trimester median blood glucose >120 mg/dl80 and A1C >7%81 were associated with increased risk of congenital malformations and abortions. Both ACOG75 and ADA19 have published guidelines for specific glucose targets as well as other countries.22,76–78 Most guidelines recommend fasting glucose in the <100 mg/dl range and postprandial glucose <140 mg/dl as well as an A1C as close to 6.0% as possible during pregnancy, if it can be done without severe hypoglycemia. (See chapter 17.)

Hospitalized patients (see Table 6.6). There are no guidelines that specifically address glucose targets for patients with T1D in the hospital. Most of these recommendations are based upon extrapolation from randomized controlled trials of predominantly patients with stress hyperglycemia or T2D (Table 6.6).82

The current American Diabetes Association/American Association of Clinical Endocrinology hospital guidelines recommend a target glucose of 140–180 mg/dl in the ICU for most patients, with targets of 110–140 possible for selected patients if it can be safely attained. In non-ICU settings, recommendations are for fasting glucose <140 mg/dl and random glucose <180 mg/dl until further data are available.83 The Endocrine Society published recommendations for meal-specific targets for non–critical care settings, including a fasting glucose <140 mg/dl and postprandial target of <180 mg/dl,84 while the American College of Physicians allowed a higher range of 140–200 mg/dl.85 These targets are generally higher than that advocated for most outpatients with diabetes. The recommendations are based largely upon the NICE-SUGAR study (both T1D and T2D patients), which showed that tight glycemic control (target glucose 80–110 mg/dl) compared to standard care (target glucose 140– 180 mg/dl) resulted in DCMS158CG2

higher frequency of severe hypoglycemia and mortality in the intensively treated group.86 However, NICE-SUGAR did not address whether glycemic control targeting a more modest glucose range (110–140 mg/dl) is better. As a result, the guidelines suggest that an intermediate target glucose range between 110–140 mg/dl may be reasonable in certain populations (for example, postcardiac surgery) and institutions and patients where it can be done safely. In children, higher targets may be advised in the hospital.87 Improvements in technology, such as more precise methods of glucose monitoring and computerized (or even closed-loop) intravenous infusion algorithms are ultimately needed to determine whether achievement of normoglycemia is beneficial.87,88


Blood Pressure

Current trends. In the DCCT, 44% of patients developed incident hypertension during the 15-year follow-up, for which hyperglycemia was a major risk factor of CV events.89 Thus, hypertension is felt to be a consequence rather than a cause of nephropathy. However, patients were excluded from the DCCT if they had hypertension (defined as >140/90 mmHg) at entry. In the EDC and EURO-DIAB studies, the prevalence of treatment for hypertension was 7–10% (mean diabetes duration 14–19 years).48 In a large Swedish study of patients with T1D there was a slow improvement in blood pressure and cholesterol over time, but only 61% of patients achieved a mean blood pressure <130/80 mmHg.37 Other studies demonstrate that hypertension is suboptimally managed in patients with T1D, although this has improved over time.90,91

Association with complications. Diabetes significantly increases the prevalence of CVD, with T1D conferring an independent risk factor for premature morbidity and mortality related to its duration, control, and association with traditional CV risk factors including hypertension and hyperlipidemia.48,92

Blood pressure management was not a salient feature of the DCCT. In the UKPDS (which enrolled patients with T2D), a 10 mmHg increase in systolic blood pressure was associated with an 11% rise in myocardial infarction, a 13% rise in microvascular disease, and a 15% rise in diabetes-related mortality.93 Numerous other large trials, including the HOT trial, HOPE, LIFE, and ALLHAT studies have also shown significant improvement in CV outcomes and slowed progression of microvascular complications when aggressive blood pressure targets are achieved, albeit largely in individuals with T2D.94,95,96,97 Achievement of tighter control to <130 mmHg systolic that was examined in 6,400 patients with diabetes and CVD in the International Verapamil/Trandolapril Study (INVEST) did not reveal further improvement of CV outcomes compared with the usual 130–140 mmHg, but patients were not randomized to different targets.98 Nor was randomization to tighter blood pressure control (systolic <120 mmHg) found to be beneficial on the primary outcome in patients with T2D in the ACCORD study, although there was a statistically significant reduction in strokes, a secondary outcome.99

Guidelines. On the basis of these findings, although not specifically conducted for T1D, ADA guidelines recommend a blood pressure target of <130/80.19 The NICE guidelines recommend intervention at 135/85 mmHg unless the individual has an abnormal albumin excretion rate or at least two of the metabolic syndrome features, in which case it should be initiated at 130/80 mmHg.20

Interpretation of guidelines. Individuals should have routine blood pressure checks at diabetes visits.19 According to the ADA, those with systolic blood pressure >130 mmHg and diastolic blood pressure >80 mmHg, despite lifestyle interventions for a maximum of 3 months, should be started on a pharmacologic agent blocking the renin angiotensin system.19 Although a systolic blood pressure of >140 mmHg clearly results in worse outcomes, further evidence is needed to support targeting a systolic blood pressure significantly <130 mmHg in T1D. Some variation may be appropriate based on individual response and tolerance to therapy as well as specific characteristics.

Special circumstances: Nephropathy. In patients who develop diabetic nephropathy characterized by persistent proteinuria, optimization of blood pressure can slow the progression of renal damage. The blood pressure targets are the same for individuals with T1D with or without nephropathy per ADA,19 AACE,63 NICE,20 and Canadian22 guidelines. The Australian guidelines, however, conclude a blood pressure target <125/75 mmHg in the presence of 1 g daily or more of proteinuria.21 In addition to controlling blood pressure, ACE inhibitor therapy has decreased albuminuria and prevented worsening nephropathy while ARBs have reduced proteinuria. These renal-protective effects were demonstrated in a study of 698 microalbuminuric patients without hypertension.100 Those receiving ACE inhibitors had a reduction in progression to macroalbuminuria and an increase in regression to nonalbuminuria.101

Special circumstances: Pregnancy. In pregnant women with T1D, hypertension is more commonly associated with preeclampsia and complicates the pregnancy 40–45% of the time.102 Hypertension may result in very adverse outcomes, and thus the blood pressure target throughout the pregnancy is lower, at 110–129/65–79 mmHg, to protect maternal health and fetal growth.76 ACE inhibitors and ARBs are contraindicated during pregnancy given associated risk of increased congenital malformations. Instead, calcium channel blockers, β blockers, hydralazine, and methyldopa should be used to achieve blood pressure target goal.103 (Also see chapter 17.)

Low Density Lipoprotein Cholesterol

Current trends. While T2D most commonly presents with hypertriglyceridemia, low HDLc, and increased LDLc,104 in T1D, lipid and lipoprotein concentrations may be normal but present with impaired function and increased atherogenicity due to oxidation and glycation of lipoproteins.105,106,107 In a large Swedish national registry study, only 48% of patients receiving lipid lowering agents achieved the goal LDLc of <100 mg/dl.37 Suboptimal control has also been reported in the U.S., with only 5.5% meeting targets, particularly children.48

Association with complications. Dyslipidemia is highly prevalent in people with diabetes, further increasing the risk of microvascular complications as seen in DCCT/EDIC108 along with CVD and associated mortality. Overall, in T1D evidence indicates an effect of statin on lipids consistent with the general population. The Heart Protection Study (HPS) is one of a few studies that examined the effect of a statin in patients with T1D, and nearly 600 patients were included. The HPS found a CV risk reduction similar to that of patients with T2D.109 This study supported the reduction of baseline LDLc level by about 30–40% as an alternative therapeutic goal. A large meta-analysis of statin trials demonstrated similar CV risk reduction in patients with T1D (1,566 patients) compared to patients with T2D and patients without diabetes.110

Guidelines. According to the ADA and the National Cholesterol Education Program’s Adult Treatment Panel III, the primary goal for individuals without overt CVD is an LDL <100 mg/dl and <70 mg/dl with overt CVD or more than two major CV risk factors.19,111 However, statins should be started in individuals over the age of 40 years or with CV risk factors or overt disease, regardless of baseline lipid levels.19 The Adult Treatment Panel III guidelines were last updated in 2002 and an updated version is expected to be released soon.112 The target HDLc is >40 mg/ dl for men and >50 mg/dl for women, while that for triglycerides is <150 mg/dl.19

Interpretation of guidelines. To screen adult patients for dyslipidemia, a fasting lipid profile should be checked at least annually, and then repeated every 1–2 years. To achieve target goals for lipid measures, aggressive lifestyle and medical management of dyslipidemia is necessary.


Statins are contraindicated during pregnancy (category X) and should be stopped prior to conception.113 Thus, adequate patient education and family planning counseling are necessary for women with T1D of childbearing age.

Other Lipid Targets

Additional measures of atherogenic lipid lipoproteins have been explored. The TC/HDLc ratio (or non-HDL cholesterol) has been proposed as a specific index of CV risk and a secondary goal of therapy to <4.0 (for the ratio) or 30 mg/dl above the LDLc target for non-HDLc) is suggested.19,114 The use of apo B to predict CVD events with target of <80 mg/dl in patients with CVD and <90 mg/dl in those without has been recommended by some,115 but inadequate supporting evidence exists.

Other Metabolic Variables

Intensive glycemic control was associated with greater weight gain and risk of metabolic syndrome compared to the standard group in the DCCT.116 However, the benefits of glycemic control appear to mitigate any observed increase in risk of complications. In contrast, insulin resistance at baseline (assessed with estimated glucose disposal rate) but not metabolic syndrome or insulin dose predicted the onset of both microvascular and macrovascular complications. In another study within the DCCT, waist circumference was associated with increased risk of incident microalbuminuria but not decline in creatinine clearance.117 However, those patients in the intensive group who did not gain weight still experienced a survival benefit and lower risk of complications compared to those who gained weight.118

In EURODIAB, waist-to-hip ratio and triglycerides (as markers of insulin resistance) were independent predictors of incident retinopathy.119 Furthermore, waist-to-hip ratio and triglycerides were nearly as strong as albumin excretion rate for predicting microalbuminuria.120 Increased weight was a predictor of progression from microalbuminuria to macroalbuminuria.51

As noted above, dyslipidemia commonly associated with metabolic syndrome or T2D may be observed in patients with T1D. If low HDLc results in a persistently elevated ratio, niacin therapy may be added to statin. Niacin combined with statin was associated with >13% absolute risk reduction for CV outcomes in the HATS nondiabetic cohort.121 However, CV risk reduction was not confirmed in a large prospective study of patients with T2D who were already receiving statin therapy, and there was suggestion of increased risk of stroke.122 Fibrate therapy is recommended for individuals with significantly elevated triglyceride levels although it revealed no reduction in CV outcomes in a large trial of T2D patients unless there was dyslipidemia present at baseline.19,123 Outside of lowering triglycerides to prevent pancreatitis, further research is needed to determine the optimal role of managing dyslipidemia beyond statin therapy in patients with T1D.


There are many unanswered questions surrounding optimal targets for risk factors of microvascular and macrovascular complications. The following is a list of more urgent questions.


■ Effects of severe hypoglycemia on cognitive function in children with T1D stratified by age in order to more closely establish any threshold effect Blood pressure

■ Optimal blood pressure targets and long-term safety and efficacy of blockade of the  renin-angiotensin system LDLc

■ Optimal targets and long-term safety and efficacy of statins

Adults Glucose

■ Updated risk of complications and hypoglycemia risk at various A1C strata and duration of diabetes

■ Assessment of the long-term risk of complications using continuous glucose monitoring data, including glucose area under the curve, time spent in hyperglycemic and hypoglycemic ranges, and measures of glycemic variability

■ Robust longitudinal assessment of the prevalence of severe hypoglycemia in relationship to newer technologies, such as insulin analogues, continuous subcutaneous insulin infusion, and continuous glucose monitoring

■ Optimal targets for avoidance of hypoglycemia in hypoglycemia-associated autonomic failure

■ Utility and comparison of measures of glycemic variability for preventing severe hypoglycemia

■ Utility of alternative markers of glycemia for predicting long-term complications

Blood pressure

■ Further characterization of the relative role of blood pressure in the development of microvascular and macrovascular complications

■ Optimal target blood pressure in patients by duration of diabetes (with separate attention to essential hypertension and that presumably mediated by early nephropathy)

■ Optimal blood pressure targets in nephropathy


■ Optimal LDLc level for CV prevention in patients with T1D by age and duration of diabetes

■ Prospective studies further characterizing the role of lipids in the development of microvascular complications

■ Longitudinal studies assessing and comparing the association between various components of the lipid profile, including lipoprotein analysis on risk of CVD in patients with T1D

■ Investigation of any additive benefit of managing dyslipidemia associated with metabolic syndrome


It is clear that the optimal targets for T2D cannot always be extrapolated to patients with T1D, since the pathophysiology, disease course, and management differ so markedly. In patients with T1D, it is likely that glycemic control is even more important than for T2D, although other factors such as blood pressure and lipids play a key role. Targets should include A1C, but A1C alone has little utility for making specific adjustments in glucose-lowering therapy. Instead targets should include goals for glucose in a variety of circumstances, such as fasting, premeal and postmeal, and possibly for glycemic variability. In general, targets must be individualized to fit the specific circumstances of the patient, taking into account the risks and benefits of the intervention, particularly in the case of glucose targets. Newer technologies may allow tighter targets over time without increasing the risk of hypoglycemia. Therefore, targets should be frequently reevaluated among individuals and among the population as a whole.


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