V. DIABETES CARE

Section Overview

This section provides information from the time of diagnosis through the progression of the disease. The detailed menu on the left can help guide you to the information you need to maintain good health while assessing your condition to fight the disease.

A. Initial evaluation

A complete medical evaluation should be performed to classify the diabetes, detect the presence of diabetes complications, review previous treatment and glycemic control in patients with established diabetes, assist in formulating a management plan, and provide a basis for continuing care. Laboratory tests appropriate to the evaluation of each patient's medical condition should be performed. A focus on the components of comprehensive care will assist the health care team to ensure optimal management of the patient with diabetes.

B. Management

People with diabetes should receive medical care from a physician-coordinated team. Such teams may include, but are not limited to, physicians, nurse practitioners, physician's assistants, nurses, dietitians, pharmacists, and mental health professionals with expertise and a special interest in diabetes. It is essential in this collaborative and integrated team approach that individuals with diabetes assume an active role in their care.

The management plan should be formulated as an individualized therapeutic alliance among the patient and family, the physician, and other members of the health care team. A variety of strategies and techniques should be used to provide adequate education and development of problem-solving skills in the various aspects of diabetes management. Implementation of the management plan requires that each aspect is understood and agreed on by the patient and the care providers and that the goals and treatment plan are reasonable. Any plan should recognize diabetes self-management education (DSME) as an integral component of care. In developing the plan, consideration should be given to the patient's age, school or work schedule and conditions, physical activity, eating patterns, social situation and personality, cultural factors, and presence of complications of diabetes or other medical conditions.

C. Glycemic control

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1. Assessment of glycemic control

Two primary techniques are available for health providers and patients to assess the effectiveness of the management plan on glycemic control: patient self-monitoring of blood glucose (SMBG) or of interstitial glucose and measurement of A1C.

a. Glucose monitoring

Recommendations

• SMBG should be carried out three or more times daily for patients using multiple insulin injections or insulin pump therapy.
• For patients using less frequent insulin injections, noninsulin therapies, or medical nutrition therapy (MNT) and physical activity alone, SMBG may be useful as a guide to the success of therapy.
• To achieve postprandial glucose targets, postprandial SMBG may be appropriate.
• When prescribing SMBG, ensure that patients receive initial instruction in, and routine follow-up evaluation of, SMBG technique and their ability to use data to adjust therapy. 
• Continuous glucose monitoring (CGM) in conjunction with intensive insulin regimens can be a useful tool to lower A1C in selected adults (age ≥25 years) with Type 1 diabetes.
• Although the evidence for A1C lowering is less strong in children, teens, and younger adults, CGM may be helpful in these groups. Success correlates with adherence to ongoing use of the device.
• CGM may be a supplemental tool to SMBG in those with hypoglycemia unawareness and/or frequent hypoglycemic episodes.

The ADA's consensus and position statements on SMBG provide a comprehensive review of the subject. Major clinical trials of insulin-treated patients that demonstrated the benefits of intensive glycemic control on diabetes complications have included SMBG as part of multifactorial interventions, suggesting that SMBG is a component of effective therapy. SMBG allows patients to evaluate their individual response to therapy and assess whether glycemic targets are being achieved. Results of SMBG can be useful in preventing hypoglycemia and adjusting medications (particularly prandial insulin doses), MNT, and physical activity.

The frequency and timing of SMBG should be dictated by the particular needs and goals of the patients. SMBG is especially important for patients treated with insulin to monitor for and prevent asymptomatic hypoglycemia and hyperglycemia. For most patients with Type 1 diabetes and pregnant women taking insulin, SMBG is recommended three or more times daily. For this population, significantly more frequent testing may be required to reach A1C targets safely without hypoglycemia. The optimal frequency and timing of SMBG for patients with Type 2 diabetes on noninsulin therapy is unclear. A meta-analysis of SMBG in non–insulin-treated patients with Type 2 diabetes concluded that some regimen of SMBG was associated with a reduction in A1C of ≥0.4%. However, many of the studies in this analysis also included patient education with diet and exercise counseling and, in some cases, pharmacologic intervention, making it difficult to assess the contribution of SMBG alone to improved control. Several recent trials have called into question the clinical utility and cost-effectiveness of routine SMBG in non–insulin-treated patients.

Because the accuracy of SMBG is instrument and user dependent, it is important to evaluate each patient's monitoring technique, both initially and at regular intervals thereafter. In addition, optimal use of SMBG requires proper interpretation of the data. Patients should be taught how to use the data to adjust food intake, exercise, or pharmacological therapy to achieve specific glycemic goals, and these skills should be reevaluated periodically.

CGM through the measurement of interstitial glucose (which correlates well with plasma glucose) is available. These sensors require calibration with SMBG, and the latter are still recommended for making acute treatment decisions.

CGM devices also have alarms for hypo- and hyperglycemic excursions. Small studies in selected patients with Type 1 diabetes have suggested that CGM use reduces the time spent in hypo- and hyperglycemic ranges and may modestly improve glycemic control. A larger 26-week randomized trial of 322 Type 1 patients showed that adults age 25 years and older using intensive insulin therapy and CGM experienced a 0.5% reduction in A1C (from ∼7.6 to 7.1%) compared with usual intensive insulin therapy with SMBG. Sensor use in children, teens, and adults to age 24 years did not result in significant A1C lowering, and there was no significant difference in hypoglycemia in any group. Importantly, the greatest predictor of A1C lowering in this study for all age-groups was frequency of sensor use, which was lower in younger age-groups. Although CGM is an evolving technology, emerging data suggest that, in appropriately selected patients who are motivated to wear it most of the time, it may offer benefit. CGM may be particularly useful in those with hypoglycemia unawareness and/or frequent episodes of hypoglycemia, and studies in this area are ongoing.

b. A1C

Recommendations

• Perform the A1C test at least two times a year in patients who are meeting treatment goals (and who have stable glycemic control).
• Perform the A1C test quarterly in patients whose therapy has changed or who are not meeting glycemic goals.
• Use of point-of-care testing for A1C allows for timely decisions on therapy changes, when needed.

Because A1C is thought to reflect average glycemia over several months, and has strong predictive value for diabetes complications, A1C testing should be performed routinely in all patients with diabetes at initial assessment and then as part of continuing care. Measurement approximately every 3 months determines whether a patient's glycemic targets have been reached and maintained. For any individual patient, the frequency of A1C testing should be dependent on the clinical situation, the treatment regimen used, and the judgment of the clinician. Some patients with stable glycemia well within target may do well with testing only twice per year, while unstable or highly intensively managed patients (e.g., pregnant Type 1 women) may be tested more frequently than every 3 months. The availability of the A1C result at the time that the patient is seen (point-of-care testing) has been reported to result in increased intensification of therapy and improvement in glycemic control.

The A1C test is subject to certain limitations. Conditions that affect erythrocyte turnover (hemolysis, blood loss) and hemoglobin variants must be considered, particularly when the A1C result does not correlate with the patient's clinical situation. In addition, A1C does not provide a measure of glycemic variability or hypoglycemia. For patients prone to glycemic variability (especially Type 1 patients, or Type 2 patients with severe insulin deficiency), glycemic control is best judged by the combination of results of SMBG testing and the A1C. The A1C may also serve as a check on the accuracy of the patient's meter (or the patient's reported SMBG results) and the adequacy of the SMBG testing schedule.

Table 8 contains the correlation between A1C levels and mean plasma glucose levels based on data from the international A1C-Derived Average Glucose (ADAG) trial utilizing frequent SMBG and continuous glucose monitoring in 507 adults (83% Caucasian) with Type 1, Type 2, and no diabetes The ADA and American Association of Clinical Chemists have determined that the correlation (r = 0.92) is strong enough to justify reporting both an A1C result and an estimated average glucose (eAG) result when a clinician orders the A1C test. The table in previous versions of the Standards of Medical Care in Diabetes describing the correlation between A1C and mean glucose was derived from relatively sparse data (one seven-point profile over 1 day per A1C reading) in the primarily Caucasian Type 1 participants in the Diabetes Control and Complications Trial (DCCT) trial. Clinicians should note that the numbers in the table are now different, as they are based on ∼2,800 readings per A1C in the ADAG trial.

In the ADAG study, there were no significant differences among racial and ethnic groups in the regression lines between A1C and mean glucose, although there was a trend toward a difference between African/African-American and Caucasian participants’ regression lines that might have been significant had more African/African-American participants been studied. A recent study comparing A1C to CGM data in 48 Type 1 children found a highly statistically significant correlation between A1C and mean blood glucose, although the correlation (r = 0.7) was significantly lower than in the ADAG trial. Whether there are significant differences in how A1C relates to average glucose in children or in African-American patients is an area for further study. For the time being, the question has not led to different recommendations about testing A1C or to different interpretations of the clinical meaning of given levels of A1C in those populations.

For patients in whom A1C/eAG and measured blood glucose appear discrepant, clinicians should consider the possibilities of hemoglobinopathy or altered red cell turnover and the options of more frequent and/or different timing of SMBG or use of CGM. Other measures of chronic glycemia such as fructosamine are available, but their linkage to average glucose and their prognostic significance are not as clear as is the case for A1C.

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2. Glycemic goals in adults

• Lowering A1C to below or around 7% has been shown to reduce microvascular and neuropathic complications of Type 1 and Type 2 diabetes. Therefore, for microvascular disease prevention, the A1C goal for nonpregnant adults in general is <7%. 
• In Type 1 and Type 2 diabetes, randomized controlled trials of intensive versus standard glycemic control have not shown a significant reduction in CVD outcomes during the randomized portion of the trials. Long-term follow-up of the DCCT and UK Prospective Diabetes Study (UKPDS) cohorts suggests that treatment to A1C targets below or around 7% in the years soon after the diagnosis of diabetes is associated with long-term reduction in risk of macrovascular disease. Until more evidence becomes available, the general goal of <7% appears reasonable for many adults for macrovascular risk reduction. 
• Subgroup analyses of clinical trials such as the DCCT and UKPDS and the microvascular evidence from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial suggest a small but incremental benefit in microvascular outcomes with A1C values closer to normal. Therefore, for selected individual patients, providers might reasonably suggest even lower A1C goals than the general goal of <7%, if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Such patients might include those with short duration of diabetes, long life expectancy, and no significant CVD.
• Conversely, less stringent A1C goals than the general goal of <7% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and those with longstanding diabetes in whom the general goal is difficult to attain despite DSME, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin.

Glycemic control is fundamental to the management of diabetes. The DCCT, a prospective, randomized, controlled trial of intensive versus standard glycemic control in patients with relatively recently diagnosed Type 1 diabetes, showed definitively that improved glycemic control is associated with significantly decreased rates of microvascular (retinopathy and nephropathy) as well as neuropathic complications. Follow-up of the DCCT cohorts in the Epidemiology of Diabetes Interventions and Complications (EDIC) study has shown persistence of this effect in previously intensively treated subjects, even though their glycemic control has been equivalent to that of previous standard arm subjects during follow-up.

In Type 2 diabetes, the Kumamoto study and the UKPDS demonstrated significant reductions in microvascular and neuropathic complications with intensive therapy. Similar to the DCCT-EDIC findings, long-term follow-up of the UKPDS cohort has recently demonstrated a “legacy effect” of early intensive glycemic control on long-term rates of microvascular complications, even with loss of glycemic separation between the intensive and standard cohorts after the end of the randomized controlled.

In each of these large randomized prospective clinical trials, treatment regimens that reduced average A1C to ≥7% (≥1% above the upper limits of normal) were associated with fewer long-term microvascular complications; however, intensive control was found to increase the risk of severe hypoglycemia, most notably in the DCCT, and led to weight gain.

Epidemiological analyses of the DCCT and UKPDS demonstrate a curvilinear relationship between A1C and microvascular complications. Such analyses suggest that, on a population level, the greatest number of complications will be averted by taking patients from very poor control to fair or good control. These analyses also suggest that further lowering of A1C from 7 to 6% is associated with further reduction in the risk of microvascular complications, albeit the absolute risk reductions become much smaller. Given the substantially increased risk of hypoglycemia (particularly in those with Type 1 diabetes) and the relatively much greater effort required to achieve near-normoglycemia, the risks of lower targets may outweigh the potential benefits on microvascular complications on a population level. However, selected individual patients, especially those with little comorbidity and long life expectancy (who may reap the benefits of further lowering of glycemia below 7%) may, at patient and provider judgment, adopt glycemic targets as close to normal as possible as long as significant hypoglycemia does not become a barrier.

Whereas many epidemiologic studies and meta-analyses have clearly shown a direct relationship between A1C and CVD, the potential of intensive glycemic control to reduce CVD has been less clearly defined. In the DCCT, there was a trend toward lower risk of CVD events with intensive control (risk reduction 41%, 95% CI 10–68%), but the number of events was small. However, 9-year post-DCCT follow-up of the cohort has shown that participants previously randomized to the intensive arm had a 42% reduction (P = 0.02) in CVD outcomes and a 57% reduction (P = 0.02) in the risk of nonfatal myocardial infarction (MI), stroke, or CVD death compared with those previously in the standard arm.

The UKPDS trial of Type 2 diabetes observed a 16% reduction in cardiovascular complications (combined fatal or nonfatal MI and sudden death) in the intensive glycemic control arm, although this difference was not statistically significant (P = 0.052), and there was no suggestion of benefit on other CVD outcomes such as stroke. In an epidemiologic analysis of the study cohort, a continuous association was observed, such that for every percentage point lower median on-study A1C (e.g., 8 to 7%) there was a statistically significant 18% reduction in CVD events, again with no glycemic threshold. A recent report of 10 years of follow-up of the UKPDS cohort describes, for the participants originally randomized to intensive glycemic control compared with those randomized to conventional glycemic control, long-term reductions in MI (15% with sulfonylurea or insulin as initial pharmacotherapy, 33% with metformin as initial pharmacotherapy, both statistically significant) and in all-cause mortality (13 and 27%, respectively, both statistically significant).

Because of ongoing uncertainty regarding whether intensive glycemic control can reduce the increased risk of CVD events in people with Type 2 diabetes, several large long-term trials were launched in the past decade to compare the effects of intensive versus standard glycemic control on CVD outcomes in relatively high-risk participants with established Type 2 diabetes.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study randomized 10,251 participants with either history of a CVD event (ages 40–79 years) or significant CVD risk (ages 55–79) to a strategy of intensive glycemic control (target A1C <6.0%) or standard glycemic control (A1C target 7.0–7.9%). Investigators used multiple glycemic medications in both arms. ACCORD participants were on average 62 years old and had a mean duration of diabetes of 10 years, with 35% already treated with insulin at baseline. From a baseline median A1C of 8.1%, the intensive arm reached a median A1C of 6.4% within 12 months of randomization, while the standard group reached a median A1C of 7.5%. Other risk factors were treated aggressively and equally in both groups. The intensive glycemic control group had more use of insulin in combination with multiple oral agents, significantly more weight gain, and more episodes of severe hypoglycemia than the standard group.

In February 2008, the glycemic control study of ACCORD was halted on the recommendation of the study's data safety monitoring board due to the finding of an increased rate of mortality in the intensive arm compared with the standard arm (1.41%/year vs. 1.14%/year; HR 1.22 [95% CI 1.01–1.46]), with a similar increase in cardiovascular deaths. The primary outcome of ACCORD (MI, stroke, or cardiovascular death) was lower in the intensive glycemic control group due to a reduction in nonfatal MI, although this finding was not statistically significant when the study was terminated (HR 0.90 [95% CI 0.78–1.04]; P = 0.16).

Exploratory analyses of the mortality findings of ACCORD (evaluating variables including weight gain, use of any specific drug or drug combination, and hypoglycemia) were reportedly unable to identify an explanation for the excess mortality in the intensive arm. Prespecified subset analyses showed that participants with no previous CVD event and those who had a baseline A1C <8% had a statistically significant reduction in the primary CVD outcome.

The ADVANCE study randomized 11,140 participants to a strategy of intensive glycemic control (with primary therapy being the sulfonylurea gliclizide and additional medications as needed to achieve a target A1C of ≤6.5%) or to standard therapy (in which any medication but gliclizide could be used and the glycemic target was according to “local guidelines”). ADVANCE participants (who had to be at least 55 years of age with either known vascular disease or at least one other vascular risk factor) were slightly older and of similar high CVD risk as those in ACCORD. However, they had an average duration of diabetes 2 years shorter, lower baseline A1C (median 7.2%), and almost no use of insulin at enrollment. The median A1C levels achieved in the intensive and standard arms were 6.3 and 7.0%, respectively, and maximal separation between the arms took several years to achieve. Use of other drugs that favorably impact CVD risk (aspirin, statins, ACE inhibitors) was lower in ADVANCE than in the ACCORD or Veterans Affairs Diabetes Trial (VADT).

The primary outcome of ADVANCE was a combination of microvascular events (nephropathy and retinopathy) and major adverse cardiovascular events (MI, stroke, and cardiovascular death). Intensive glycemic control significantly reduced the primary endpoint (HR 0.90 [95% CI 0.82–0.98]; P = 0.01), although this was due to a significant reduction in the microvascular outcome (0.86 [0.77–0.97], P = 0.01), primarily development of macroalbuminuria, with no significant reduction in the macrovascular outcome (0.94 [0.84–1.06]; P = 0.32). There was no difference in overall or cardiovascular mortality between the intensive and the standard glycemic control arms.

The VADT randomized 1,791 participants with Type 2 diabetes uncontrolled on insulin or maximal dose oral agents (median entry A1C 9.4%) to a strategy of intensive glycemic control (goal A1C <6.0%) or standard glycemic control, with a planned A1C separation of at least 1.5%. Medication treatment algorithms were used to achieve the specified glycemic goals, with a goal of using similar medications in both groups. Median A1C levels of 6.9 and 8.4% were achieved in the intensive and standard arms, respectively, within the first year of the study. Other CVD risk factors were treated aggressively and equally in both groups.

The primary outcome of the VADT was a composite of CVD events (MI, stroke, cardiovascular death, revascularization, hospitalization for heart failure, and amputation for ischemia). During a mean 6-year follow-up period, the cumulative primary outcome was nonsignificantly lower in the intensive arm (HR 0.87 [95% CI 0.73–1.04]; P = 0.12). There were more CVD deaths in the intensive arm than in the standard arm (40 vs. 33; sudden deaths 11 vs. 4), but the difference was not statistically significant. Post hoc subgroup analyses suggested that duration of diabetes interacted with randomization such that participants with duration of diabetes less than about 12 years appeared to have a CVD benefit of intensive glycemic control while those with longer duration of disease before study entry had a neutral or even adverse effect of intensive glycemic control. Other exploratory analyses suggested that severe hypoglycemia within the past 90 days was a strong predictor of the primary outcome and of CVD mortality.

The cause of the excess deaths in the intensive glycemic control arm of ACCORD compared with the standard arm has been difficult to pinpoint. By design of the trial, randomization to the intensive arm was associated with or led to many downstream effects, such as higher rates of severe hypoglycemia; more frequent use of insulin, TZDs, other drugs, and drug combinations; and greater weight gain. Such factors may be associated statistically with the higher mortality rate in the intensive arm but may not be causative. It is biologically plausible that severe hypoglycemia could increase the risk of cardiovascular death in participants with high underlying CVD risk. Other plausible mechanisms for the increase in mortality in ACCORD include weight gain, unmeasured drug effects or interactions, or the overall “intensity” of the ACCORD intervention (use of multiple oral glucose-lowering drugs along with multiple doses of insulin, frequent therapy adjustments to push A1C and self-monitored blood glucose to very low targets, and an intense effort to aggressively reduce A1C by ∼2% in participants entering the trial with advanced diabetes and multiple comorbidities).

Since the ADVANCE trial did not show any increase in mortality in the intensive glycemic control arm, examining the differences between ADVANCE and ACCORD supports additional hypotheses. ADVANCE participants on average appeared to have earlier or less advanced diabetes, with shorter duration by 2–3 years and lower A1C at entry despite very little use of insulin at baseline. A1C was also lowered less and more gradually in the ADVANCE trial, and there was no significant weight gain with intensive glycemic therapy. Although severe hypoglycemia was defined somewhat differently in the three trials, it appears that this occurred in fewer than 3% of intensively treated ADVANCE participants for the entire study duration (median 5 years) compared with ∼16% of intensively treated subjects in ACCORD and 21% in VADT.

It is likely that the increase in mortality in ACCORD was related to the overall treatment strategies for intensifying glycemic control in the study population, not the achieved A1C per se. The ADVANCE study achieved a median A1C in its intensive arm similar to that in the ACCORD study, with no increased mortality hazard. Thus, the ACCORD mortality findings do not imply that patients with Type 2 diabetes who can easily achieve or maintain low A1C levels with lifestyle modifications with or without pharmacotherapy are at risk and need to “raise” their A1C.

The three trials compared treatments to A1C levels in the “flatter” part of the observational glycemia-CVD risk curves (median A1C of 6.4–6.9% in the intensive arms compared with 7.0–8.4% in the standard arms). Importantly, their results should not be extrapolated to imply that there would be no cardiovascular benefit of glucose lowering from very poor control (e.g., A1C >9%) to good control (e.g., A1C <7%).

All three trials were carried out in participants with established diabetes (mean duration 8–11 years) and either known CVD or multiple risk factors suggesting the presence of established atherosclerosis. Subset analyses of the three trials suggested a significant benefit of intensive glycemic control on CVD in participants with shorter duration of diabetes, lower A1C at entry, and/or or absence of known CVD. The DCCT-EDIC study and the long-term follow-up of the UKPDS cohort both suggest that intensive glycemic control initiated soon after diagnosis of diabetes in patients with a lower level of CVD risk may impart long-term protection from CVD events. As is the case with microvascular complications, it may be that glycemic control plays a greater role before macrovascular disease is well developed and minimal or no role when it is advanced.

The benefits of intensive glycemic control on microvascular and neuropathic complications are well established for both Type 1 and Type 2 diabetes. The ADVANCE trial has added to that evidence base by demonstrating a significant reduction in the risk of new or worsening albuminuria when A1C was lowered to 6.3% compared with standard glycemic control achieving an A1C of 7.0%. The lack of significant reduction in CVD events with intensive glycemic control in ACCORD, ADVANCE, and VADT should not lead clinicians to abandon the general target of an A1C <7.0% and thereby discount the benefit of good control on what are serious and debilitating microvascular complications.

The evidence for a cardiovascular benefit of intensive glycemic control primarily rests on long-term follow-up of study cohorts treated early in the course of Type 1 and Type 2 diabetes and subset analyses of ACCORD, ADVANCE, and VADT. Conversely, the mortality findings in ACCORD suggest that the potential risks of very intensive glycemic control may outweigh its benefits in some patients, such as those with very long duration of diabetes, known history of severe hypoglycemia, advanced atherosclerosis, and advanced age/frailty. Certainly, providers should be vigilant in preventing severe hypoglycemia in patients with advanced disease and should not aggressively attempt to achieve near-normal A1C levels in patients in whom such a target cannot be reasonably easily and safely achieved.

The recommendations are based on those for A1C, with listed blood glucose levels that appear to correlate with achievement of an A1C of <7%. The issue of pre- versus postprandial SMBG targets is complex. Elevated post challenge (2-h OGTT) glucose values have been associated with increased cardiovascular risk independent of FPG in some epidemiological studies. In diabetic subjects, some surrogate measures of vascular pathology, such as endothelial dysfunction, are negatively affected by postprandial hyperglycemia. It is clear that postprandial hyperglycemia, like preprandial hyperglycemia, contributes to elevated A1C levels, with its relative contribution being higher at A1C levels that are closer to 7%. However, outcome studies have clearly shown A1C to be the primary predictor of complications, and landmark glycemic control trials such as the DCCT and UKPDS relied overwhelmingly on preprandial SMBG. Additionally, a randomized controlled trial presented at the 68th Scientific Sessions of the American Diabetes Association in June 2008 found no CVD benefit of insulin regimens targeting postprandial glucose compared with those targeting preprandial glucose. A reasonable recommendation for postprandial testing and targets is that for individuals who have premeal glucose values within target but have A1C values above target, monitoring postprandial plasma glucose (PPG) 1–2 h after the start of the meal and treatment aimed at reducing PPG values to <180 mg/dl may help lower A1C.

As noted above, less stringent treatment goals may be appropriate for adults with limited life expectancies or advanced vascular disease. Glycemic goals for children are provided in Section VII.A.1.a. Severe or frequent hypoglycemia is an absolute indication for the modification of treatment regimens, including setting higher glycemic goals.

Regarding goals for glycemic control for women with GDM, recommendations from the Fifth International Workshop-Conference on Gestational Diabetes Mellitus were to target the following maternal capillary glucose concentrations:

• preprandial: ≤95 mg/dl (5.3 mmol/l) and either 1-h postmeal: ≤140 mg/dl (7.8 mmol/l) or 2-h postmeal: ≤120 mg/dl (6.7 mmol/l)
  For women with preexisting Type 1 or Type 2 diabetes who become pregnant, a recent consensus statement recommended the following as optimal glycemic goals, if they can be achieved without excessive hypoglycemia:
• premeal, bedtime, and overnight glucose 60–99 mg/dl
• peak postprandial glucose 100–129 mg/dl
• A1C <6.0%

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3. Approach to treatment

a. Therapy for Type 1 diabetes.

The DCCT clearly showed that intensive insulin therapy (three or more injections per day of insulin or continuous subcutaneous insulin infusion (CSII, or insulin pump therapy) was a key part of improved glycemia and better outcomes. At the time of the study, therapy was carried out with short- and intermediate-acting human insulins. Despite better microvascular outcomes, intensive insulin therapy was associated with a marked increase in severe hypoglycemia (62 episodes per 100 patient-years of therapy). Since the time of the DCCT, a number of rapid-acting and long-acting insulin analogs have been developed. These analogs were designed to be more “physiological” in their pharmacokinetics and pharmacodynamics and are associated with less hypoglycemia with equal A1C lowering in Type 1 diabetes.

Therefore, recommended therapy for Type 1 diabetes consists of the following components: 1) use of multiple dose insulin injections (3–4 injections per day of basal and prandial insulin) or CSII therapy; 2) matching of prandial insulin to carbohydrate intake, premeal blood glucose, and anticipated activity; and 3) for many patients (especially if hypoglycemia is a problem), use of insulin analogs. There are excellent reviews available that guide the initiation and management of insulin therapy to achieve desired glycemic goals.

b. Therapy for Type 2 diabetes.

The ADA and the European Association for the Study of Diabetes published a consensus statement on the approach to management of hyperglycemia in individuals with Type 2 diabetes and recently published an update. Highlights of this approach are: intervention at the time of diagnosis with metformin in combination with lifestyle changes (MNT and exercise) and continuing timely augmentation of therapy with additional agents (including early initiation of insulin therapy) as a means of achieving and maintaining recommended levels of glycemic control (i.e., A1C <7% for most patients). The overall objective is to achieve and maintain glycemic control and to change interventions when therapeutic goals are not being met.

The algorithm took into account the evidence for A1C-lowering of the individual interventions, their additive effects, and their expense. The precise drugs used and their exact sequence may not be as important as achieving and maintaining glycemic targets safely. Medications not included in the consensus algorithm, owing to less glucose-lowering effectiveness, limited clinical data, and/or relative expense, still may be appropriate choices in individual patients to achieve glycemic goals. Initiation of insulin at time of diagnosis is recommended for individuals presenting with weight loss or other severe hyperglycemic symptoms or signs. For a list of currently approved diabetes medications, see http://ndep.nih.gov/diabetes/pubs/Drug_tables_supplement.pdf.

D. Medical Nutrition Therapy (MNT)

General recommendations

• Individuals who have pre-diabetes or diabetes should receive individualized MNT as needed to achieve treatment goals, preferably provided by a registered dietitian familiar with the components of diabetes MNT.
• MNT should be covered by insurance and other payers.

Energy balance, overweight, and obesity

• In overweight and obese insulin-resistant individuals, modest weight loss has been shown to reduce insulin resistance. Thus, weight loss is recommended for all overweight or obese individuals who have or are at risk for diabetes.
• For weight loss, either low-carbohydrate or low-fat calorie restricted diets may be effective in the short-term (up to 1 year).
• For patients on low-carbohydrate diets, monitor lipid profiles, renal function, and protein intake (in those with nephropathy) and adjust hypoglycemic therapy as needed.
• Physical activity and behavior modification are important components of weight loss programs and are most helpful in maintenance of weight loss.

Primary prevention of diabetes

• Among individuals at high risk for developing Type 2 diabetes, structured programs that emphasize lifestyle changes that include moderate weight loss (7% body weight) and regular physical activity (150 min/week), with dietary strategies including reduced calories and reduced intake of dietary fat, can reduce the risk for developing diabetes and are therefore recommended.
• Individuals at high risk for Type 2 diabetes should be encouraged to achieve the U.S. Department of Agriculture recommendation for dietary fiber (14 g fiber/1,000 kcal) and foods containing whole grains (one-half of grain intake). 

Dietary fat intake in diabetes management

• Saturated fat intake should be <7% of total calories.
• Intake of trans fat should be minimized.

Carbohydrate intake in diabetes management

• Monitoring carbohydrate, whether by carbohydrate counting, exchanges, or experience-based estimation, remains a key strategy in achieving glycemic control.
• For individuals with diabetes, the use of the glycemic index and glycemic load may provide a modest additional benefit for glycemic control over that observed when total carbohydrate is considered alone.
  Other nutrition recommendations
• Sugar alcohols and nonnutritive sweeteners are safe when consumed within the acceptable daily intake levels established by the Food and Drug Administration (FDA).
• If adults with diabetes choose to use alcohol, daily intake should be limited to a moderate amount (one drink per day or less for adult women and two drinks per day or less for adult men).
• Routine supplementation with antioxidants, such as vitamins E and C and carotene, is not advised because of lack of evidence of efficacy and concern related to long-term safety.
• Benefit from chromium supplementation in people with diabetes or obesity has not been conclusively demonstrated and, therefore, cannot be recommended.

MNT is an integral component of diabetes prevention, management, and self-management education. In addition to its role in preventing and controlling diabetes, ADA recognizes the importance of nutrition as an essential component of an overall healthy lifestyle. A full review of the evidence regarding nutrition in preventing and controlling diabetes and its complications and additional nutrition-related recommendations can be found in the ADA position statement “Nutrition Recommendations and Interventions for Diabetes,” published in 2007 and updated for 2008. Achieving nutrition-related goals requires a coordinated team effort that includes the active involvement of the person with pre-diabetes or diabetes. Because of the complexity of nutrition issues, it is recommended that a registered dietitian who is knowledgeable and skilled in implementing nutrition therapy into diabetes management and education be the team member who provides MNT.

Clinical trials/outcome studies of MNT have reported decreases in A1C at 3–6 months ranging from 0.25 to 2.9% with higher reductions seen in Type 2 diabetes of shorter duration. Multiple studies have demonstrated sustained improvements in A1C at 12 months and longer when a registered dietician provided follow-up visits ranging from monthly to three sessions per year. Meta-analyses of studies in nondiabetic, free-living subjects report that MNT reduces LDL cholesterol by 15–25 mg/dl or can lower LDL cholesterol by up to 16%, while clinical trials support a role for lifestyle modification in treating hypertension.

Because of the effects of obesity on insulin resistance, weight loss is an important therapeutic objective for overweight or obese individuals with pre-diabetes or diabetes. Short-term studies have demonstrated that moderate weight loss (5% of body weight) in subjects with Type 2 diabetes is associated with decreased insulin resistance, improved measures of glycemia and lipemia, and reduced blood pressure; longer-term studies (52 weeks) showed mixed effects on A1C in adults with Type 2 diabetes, and results were confounded by pharmacologic weight loss therapy. A systematic review of 80 weight loss studies of ≥1 year duration demonstrated that moderate weight loss achieved through diet alone, diet and exercise, and meal replacements can be achieved and maintained over the long term (4.8–8% weight loss at 12 months). The multifactorial intensive lifestyle intervention employed in the DPP, which included reduced intake of fat and calories, led to weight loss averaging 7% at 6 months and maintenance of 5% weight loss at 3 years, associated with a 58% reduction in incidence of Type 2 diabetes. Look AHEAD (Action for Health in Diabetes) is a large clinical trial designed to determine whether long-term weight loss will improve glycemia and prevent cardiovascular events in subjects with Type 2 diabetes. One-year results of the intensive lifestyle intervention in this trial show an average of 8.6% weight loss, significant reduction of A1C, and reduction in several CVD risk factors. When completed, the Look AHEAD trial should provide insight into the effects of long-term weight loss on important clinical outcomes.

The optimal macronutrient distribution of weight loss diets has not been established. Although low-fat diets have traditionally been promoted for weight loss, several randomized controlled trials found that subjects on low-carbohydrate diets (<130 g/day of carbohydrate) lost more weight at 6 months than subjects on low-fat diets; however, at 1 year, the difference in weight loss between the low-carbohydrate and low-fat diets was not significant, and weight loss was modest with both diets. Another study of overweight women randomized to one of four diets showed significantly more weight loss at 12 months with the Atkins low-carbohydrate diet than with higher-carbohydrate diets. Changes in serum triglyceride and HDL cholesterol were more favorable with the low-carbohydrate diets. In one study, those subjects with Type 2 diabetes demonstrated a greater decrease in A1C with a low-carbohydrate diet than with a low-fat diet. A recent meta-analysis showed that at 6 months, low-carbohydrate diets were associated with greater improvements in triglyceride and HDL cholesterol concentrations than low-fat diets; however, LDL cholesterol was significantly higher on the low-carbohydrate diets. In a 2-year dietary intervention study, Mediterranean and low-carbohydrate diets were found to be effective and safe alternatives to a low-fat diet for weight reduction in moderately obese participants.

The recommended dietary allowance for digestible carbohydrate is 130 g/day and is based on providing adequate glucose as the required fuel for the central nervous system without reliance on glucose production from ingested protein or fat. Although brain fuel needs can be met on lower carbohydrate diets, long-term metabolic effects of very-low-carbohydrate diets are unclear, and such diets eliminate many foods that are important sources of energy, fiber, vitamins, and minerals that are important in dietary palatability.

Although numerous studies have attempted to identify the optimal mix of macronutrients for meal plans of people with diabetes, it is unlikely that one such combination of macronutrients exists. The best mix of carbohydrate, protein, and fat appears to vary depending on individual circumstances. For those individuals seeking guidance as to macronutrient distribution in healthy adults, the Dietary Reference Intake (DRI) system may be helpful. It must be clearly recognized that regardless of the macronutrient mix, total caloric intake must be appropriate for the weight management goal. Further, individualization of the macronutrient composition will depend on the metabolic status of the patient (e.g., lipid profile, renal function) and/or food preferences. Individuals who choose to consume plant-based diets that are well planned and nutritionally adequate (i.e., vegetarian) may continue, as this can be done without being deleterious to metabolic control.

The primary goal with respect to dietary fat in individuals with diabetes is to limit saturated fatty acids, trans fatty acids, and cholesterol intake so as to reduce risk for CVD. Saturated and trans fatty acids are the principal dietary determinants of plasma LDL cholesterol. There is a lack of evidence on the effects of specific fatty acids on people with diabetes, so the recommended goals are consistent with those for individuals with CVD.

The FDA has approved five nonnutritive sweeteners for use in the U.S.: acesulfame potassium, aspartame, neotame, saccharin, and sucralose. Before being allowed on the market, all underwent rigorous scrutiny and were shown to be safe when consumed by the public, including people with diabetes and women during pregnancy. Reduced calorie sweeteners approved by the FDA include sugar alcohols (polyols) such as erythritol, isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol, tagatose, and hydrogenated starch hydrolysates. The use of sugar alcohols appears to be safe; however, they may cause diarrhea, especially in children.
Reimbursement for MNT

MNT, when delivered by a registered dietitian according to nutrition practice guidelines, is reimbursed as part of the Medicare program as overseen by the Centers for Medicare and Medicaid Services (CMS) (www.cms.hhs.gov/medicalnutritiontherapy)

E. Bariatric surgery

Recommendations

• Bariatric surgery should be considered for adults with BMI ≥35 kg/m2 and Type 2 diabetes, especially if the diabetes is difficult to control with lifestyle and pharmacologic therapy.
• Patients with Type 2 diabetes who have undergone bariatric surgery need life-long lifestyle support and medical monitoring.
• Although small trials have shown glycemic benefit of bariatric surgery in patients with Type 2 diabetes and BMI of 30–35 kg/m2, there is currently insufficient evidence to generally recommend surgery in patients with BMI <35 kg/m2 outside of a research protocol.
• The long-term benefits, cost-effectiveness, and risks of bariatric surgery in individuals with Type 2 diabetes should be studied in well-designed randomized controlled trials with optimal medical and lifestyle therapy as the comparator.

Gastric reduction surgery, either gastric banding or procedures that involve bypassing or transposing sections of the small intestine, when part of a comprehensive team approach, can be an effective weight loss treatment for severe obesity, and national guidelines support its consideration for people with Type 2 diabetes who have BMI at or exceeding 35 kg/m2. Bariatric surgery has been shown to lead to near or complete normalization of glycemia in ∼55–95% of patients with Type 2 diabetes, depending on the surgical procedure. A meta-analysis of studies of bariatric surgery reported that 78% of individuals with Type 2 diabetes had complete “resolution” of diabetes (normalization of blood glucose levels in the absence of medications), and that the resolution rates were sustained in studies that had follow-up exceeding 2 years. Resolution rates are lowest with procedures that only constrict the stomach and higher with those that bypass portions of the small intestine. Additionally, there is increasing evidence that intestinal bypass procedures may have glycemic effects that are independent of, and additive to, their effects on weight.

A recent randomized controlled trial compared adjustable gastric banding to “best available” medical and lifestyle therapy in subjects with Type 2 diabetes diagnosed less than 2 years before randomization and BMI 30–40 kg/m2. In this trial, 73% of surgically treated patients achieved “remission” of their diabetes, compared with 13% of those treated medically. The latter group lost only 1.7% of body weight, suggesting that their therapy was not optimal. Overall, the trial had 60 subjects, and only 13 had a BMI under 35 kg/m2, making it difficult to generalize these results widely to diabetic patients who are less severely obese or with longer duration of diabetes.

Bariatric surgery is costly in the short term and has some risks. Rates of morbidity and mortality directly related to the surgery have been reduced considerably in recent years, with 30-day mortality rates now 0.28%, similar to those of laparoscopic cholecystectomy. Longer-term concerns include vitamin and mineral deficiencies, osteoporosis, and rare but often severe hypoglycemia from insulin hypersecretion. Cohort studies attempting to match subjects suggest that the procedure may reduce longer-term mortality rates, and it is reasonable to postulate that there may be recouping of costs over the long run. However, studies of the mechanisms of glycemic improvement, long-term benefits and risks, and cost-effectiveness of bariatric surgery in individuals with Type 2 diabetes will require well-designed randomized clinical trials, with optimal medical and lifestyle therapy of diabetes and cardiovascular risk factors as the comparitor.

I. When treatment goals are not met

For a variety of reasons, some people with diabetes and their health care providers do not achieve the desired goals of treatment. Re-thinking the treatment regimen may require assessment of barriers to adherence including income, educational attainment, and competing demands, including those related to family responsibilities and family dynamics. Other strategies may include culturally appropriate and enhanced DSME, co-management with a diabetes team, referral to a medical social worker for assistance with insurance coverage or change in pharmacological therapy. Initiation of or increase in SMBG, utilization of continuous glucose monitoring, frequent contact with the patient, or referral to an endocrinologist may be useful.

J. Intercurrent illness

The stress of illness, trauma, and/or surgery frequently aggravates glycemic control and may precipitate diabetic ketoacidosis (DKA) or nonketotic hyperosmolar state, life-threatening conditions that require immediate medical care to prevent complications and death. Any condition leading to deterioration in glycemic control necessitates more frequent monitoring of blood glucose and (in ketosis-prone patients) urine or blood ketones. Marked hyperglycemia requires temporary adjustment of the treatment program and, if accompanied by ketosis, vomiting, or alteration in level of consciousness, immediate interaction with the diabetes care team. The patient treated with noninsulin therapies or MNT alone may temporarily require insulin. Adequate fluid and caloric intake must be assured. Infection or dehydration are more likely to necessitate hospitalization of the person with diabetes than the person without diabetes.

The hospitalized patient should be treated by a physician with expertise in the management of diabetes. For further information on management of patients with hyperglycemia in the hospital, see Section VIII.A. For further information on management of DKA or nonketotic hyperosmolar state, refer to the ADA position statement on hyperglycemic crises.

K. Hypoglycemia

Recommendations

• Glucose (15–20 g) is the preferred treatment for the conscious individual with hypoglycemia, although any form of carbohydrate that contains glucose may be used. If SMBG 15 min after treatment shows continued hypoglycemia, the treatment should be repeated. Once SMBG glucose returns to normal, the individual should consume a meal or snack to prevent recurrence of hypoglycemia.
• Glucagon should be prescribed for all individuals at significant risk of severe hypoglycemia, and caregivers or family members of these individuals should be instructed in its administration. Glucagon administration is not limited to health care professionals.
• Individuals with hypoglycemia unawareness or one or more episodes of severe hypoglycemia should be advised to raise their glycemic targets to strictly avoid further hypoglycemia for at least several weeks to partially reverse hypoglycemia unawareness and reduce risk of future episodes. (B)

Hypoglycemia is the leading limiting factor in the glycemic management of Type 1 and insulin-treated Type 2 diabetes. Treatment of hypoglycemia (plasma glucose <70 mg/dl) requires ingestion of glucose- or carbohydrate-containing foods. The acute glycemic response correlates better with the glucose content than with the carbohydrate content of the food. Although pure glucose is the preferred treatment, any form of carbohydrate that contains glucose will raise blood glucose. Added fat may retard and then prolong the acute glycemic response. Ongoing activity of insulin or insulin secretagogues may lead to recurrence of hypoglycemia unless further food is ingested after recovery.

Severe hypoglycemia (where the individual requires the assistance of another person and cannot be treated with oral carbohydrate due to confusion or unconsciousness) should be treated using emergency glucagon kits, which require a prescription. Those in close contact with, or having custodial care of, people with hypoglycemia-prone diabetes (family members, roommates, school personnel, child care providers, correctional institution staff, or coworkers) should be instructed in use of such kits. An individual does not need to be a health care professional to safely administer glucagon. Care should be taken to ensure that unexpired glucagon kits are available.

Prevention of hypoglycemia is a critical component of diabetes management. Teaching people with diabetes to balance insulin use, carbohydrate intake, and exercise is a necessary but not always sufficient strategy. In Type 1 diabetes and severely insulin-deficient Type 2 diabetes, the syndrome of hypoglycemia unawareness, or hypoglycemia-associated autonomic failure, can severely compromise stringent diabetes control and quality of life. The deficient counter-regulatory hormone release and autonomic responses in this syndrome are both risk factors for, and caused by, hypoglycemia. A corollary to this “vicious cycle” is that several weeks of avoidance of hypoglycemia has been demonstrated to improve counter-regulation and awareness to some extent in many patients. Hence, patients with one or more episodes of severe hypoglycemia may benefit from at least short-term relaxation of glycemic targets.

L. Immunization

Recommendations

• Annually provide an influenza vaccine to all diabetic patients ≥6 months of age. (C)

• Administer pneumococcal polysaccharide vaccine to all diabetic patients ≥2 years of age. A one-time revaccination is recommended for individuals >64 years of age previously immunized when they were <65 years of age if the vaccine was administered >5 years ago. Other indications for repeat vaccination include nephrotic syndrome, chronic renal disease, and other immuno-compromised states, such as after transplantation. (C)

Influenza and pneumonia are common, preventable infectious diseases associated with high mortality and morbidity in the elderly and in people with chronic diseases. Though there are limited studies reporting the morbidity and mortality of influenza and pneumococcal pneumonia specifically in people with diabetes, observational studies of patients with a variety of chronic illnesses, including diabetes, show that these conditions are associated with an increase in hospitalizations for influenza and its complications. People with diabetes may be at increased risk of the bacteremic form of pneumococcal infection and have been reported to have a high risk of nosocomial bacteremia, which has a mortality rate as high as 50%.

Safe and effective vaccines are available that can greatly reduce the risk of serious complications from these diseases. In a case-control series, influenza vaccine was shown to reduce diabetes-related hospital admission by as much as 79% during flu epidemics. There is sufficient evidence to support that people with diabetes have appropriate serologic and clinical responses to these vaccinations. The Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices recommends influenza and pneumococcal vaccines for all individuals with diabetes (http://www.cdc.gov/vaccines/recs/). For a complete discussion on the prevention of influenza and pneumococcal disease in people with diabetes, consult the technical review and position statement on this subject.