Clinical Context

The American Diabetes Association (ADA) has just published its standards of medical care in diabetes for 2018, and of course, it includes a discussion of glycemic targets. For most patients, the ADA is comfortable with a target glycated hemoglobin (HbA_1c) level of less than 7%. However, for younger patients without a history of significant hypoglycemia or cardiovascular disease, an HbA_1c goal of less than 6.5% may be appropriate. Conversely, more frail adults with a history of severe complications of diabetes and a high risk for hypoglycemia may be treated more effectively to a target HbA_1c level of less than 8%.

The target preprandial plasma glucose level should be 80 to 130 mg/dL for most patients, and the peak postprandial glucose level should not exceed 180 mg/dL. Many pharmacologic interventions are available to achieve these targets, but what is the best practice in choosing these agents? A significant section of the current recommendations focuses on this question.

Synopsis and Perspective

The ADA annual guidelines for 2018 include new recommendations for use of glucose-lowering drugs with proven cardiovascular benefit in type 2 diabetes, optimization of diabetes care in elderly patients, and glucose screening of high-risk adolescents.

The organization has also chosen to stick with its existing definition of hypertension in diabetes, of 140/90 mm Hg, in contrast to cardiology societies^[1] that have recently changed their guidance so that ≥130/80 mm Hg represents "stage 1 hypertension," including in diabetes.

Probably the most anticipated and impactful new recommendation from the ADA calls for use of a glucose-lowering agent with proven cardiovascular benefit^[2] -- such as the glucagonlike peptide 1 receptor agonist (GLP-1 RA) liraglutide -- and/or mortality reduction^[3] -- such as that observed with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin -- in patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD) who do not meet glycemic targets with lifestyle modification and metformin.

"We now have drugs that are not only indicated to improve glycemic control but that reduce cardiovascular risk and mortality. So, based on some of the [cardiovascular-outcomes] trials,^[4] there are new recommendations for treatment of adults with type 2 diabetes who fail metformin therapy, if there's a background of atherosclerotic cardiovascular disease," the ADA's chief scientific, medical, and mission officer, William T. Cefalu, MD, told Medscape Medical News.

A new table outlines the data from recent cardiovascular outcomes studies, and a new figure details the recommendations based on those (Section 8, page S97, Table 9.4 and page S76, Figure 8.1, respectively).

Another important chart summarizes all drug-specific and patient factors that may affect diabetes treatment and includes the most relevant considerations, such as risks for hypoglycemia, weight effects, renal effects, and costs for all preferred diabetes medications, in 1 location to guide the choice of antihyperglycemic agents "as part of patient-provider shared decision-making," notes the ADA (Section 8, page S77, Table 8.1).

"The standards of care are the primary resource for the optimal management of diabetes and include updated guidelines for diabetes diagnosis and for evidence-based prevention of diabetes and diabetes-related complications. We are especially proud of the new recommendations for patients with diabetes and cardiovascular disease," Dr Cefalu noted in an ADA statement,^[5] which summarizes the major changes to prior guidance.

The 173 pages of the ADA's Standards of Medical Care in Diabetes -- 2018 were published online December 8, 2017, and as a supplement in the January 2018 issue of Diabetes Care.^[6] The 12-member writing panel was chaired by Rita R. Kalyani, MD, MHS, of Johns Hopkins School of Medicine, Baltimore, Maryland.

Glucose Screening of Kids, HbA _1c Testing, Elderly Patients, and CGMs

Another major new recommendation calls for screening for prediabetes and type 2 diabetes in children and adolescents who are overweight or obese and who have 1 or more additional risk factors.

"Clearly, it's different from type 2 in adults. There seems to be a more rapid decrease in beta-cell function," Dr Cefalu noted.

In addition, regarding use of HbA_1c levels for screening, diagnosis, or monitoring of diabetes, there is new information in the standards on limitations of the test in people with hemoglobin variants such as sickle-cell anemia^[7] and other conditions affecting red blood cell turnover.

There is also a mention of ethnic differences^[8] in the relationship of HbA_1c levels to average levels of blood glucose.

Three new recommendations address the importance of individualizing pharmacologic therapy in older adults to reduce hypoglycemia risk, avoid overtreatment, and simplify complex regimens as much as possible while maintaining HbA_1c targets.

A chart provides guidance on individualizing targets -- ie, less than 7.5%, less than 8.0%, or less than 8.5% -- for older adults based on functional status, comorbidities, and life expectancy.

There is also guidance for expanding the use of continuous glucose monitoring (CGM), indicating that all adults 18 years and older with type 1 diabetes who do not meet glycemic targets (from the current age of 25 years and older) should use CGM, but there is no pediatric recommendation for CGM as of yet.

Moreover, there is information on the availability of a new intermittent ("flash") glucose-monitoring device recently approved in the US for adult use^[9] and the fact that some CGMs are now approved^[10] to replace finger-stick testing for making treatment decisions.

No Change in Blood Pressure Targets; Rather, the ADA Stresses Individualization

Notably, the new ADA standards do not change the association's previous hypertension definition of 140/90 mm Hg or higher recently put forth in a separate set of guidelines.^[11]

This contrasts with the recent statement^[1] from the American College of Cardiology, the American Heart Association, and other organizations deeming 130/80 mm Hg or higher as "stage 1 hypertension," including specifically for people with diabetes.

The ADA document acknowledges the difference and provides details to support the 140/90-mm Hg cutoff value for people with diabetes.

This includes the ACCORD-BP^[12] trial involving 4733 patients with type 2 diabetes, in which intensive blood pressure control targeting a systolic pressure of less than 120 mm Hg did not improve the composite primary cardiovascular endpoint, and ADVANCE BP^[13] with 11,140 patients with type 2 diabetes, in which the composite endpoint was improved but blood pressure level achieved in the intervention group was 136/73 mm Hg.

Other large trials showing benefit for more intensive blood pressure lowering, including SPRINT,^[14] did not enroll patients with diabetes.

These 3 studies, plus the HOT trial,^[15] are summarized and outlined in a new table, providing support for the existing ADA recommendations that most adults with diabetes and hypertension should have a target blood pressure of less than 140/90 mm Hg (Section 9, page S88, Table 9.1).

Also new is an algorithm illustrating the recommended approach for antihypertensive treatment of such individuals (Section 9, page S90, Figure 9.1).

However, the ADA standards also say "Intensification of antihypertensive therapy to target blood pressures lower than <140/90 mm Hg (eg, <130/80 or <120/80 mm Hg) may be beneficial for selected patients with diabetes such as those with a high risk of cardiovascular disease."

On this topic, Dr Cefalu said: "We were aware of the recommendations from other organizations, and moving forward we will consider all the additional evidence."

He stressed also that the ADA's guidelines advise individualization in blood pressure management, as in all things. "We recommend individualization of care based on the particular patient and their comorbidities. We specifically discuss how to assess risk holistically and evaluate the whole patient."

The ADA does join the American Heart Association, American College of Cardiology, and other groups in new advice that patients with diabetes and hypertension monitor their blood pressure at home in order to overcome masked or "white-coat" hypertension and improve adherence to medications.

Also new is a recommendation that all pregnant women with preexisting type 1 or type 2 diabetes consider daily low-dose aspirin starting at the end of the first trimester in order to reduce the risk for preeclampsia.

Standards of the Future Will Be in "Real Time"

Going forward, the ADA standards will be continually revised rather than published all at once at the end of each year.

"We're changing the format, based on the fact that in this day and age so much new evidence accumulates so fast. We're going to a real-time, 'living document' that is event-driven," Dr Cefalu explained.

Thus, the standards will be changed right away if a new drug is approved, gains a new indication, or any other major changes occur that represent a significant shift in clinical practice.

A new standards app will be launched in February 2018. However, for those who prefer the old-fashioned way, a hard copy will still be provided in Diabetes Care every January.

Dr Cefalu is an employee of the ADA but discloses no other relevant financial relationships. Dr Kalyani has disclosed no relevant financial relationships. Disclosures for the coauthors are listed in the original article.

Diabetes Care. 2018;41(Suppl 1).

Guideline Highlights

• Insulin therapy is usually initiated at a dose of 0.4 to 1.0 units/kg/day in the treatment of type 1 diabetes.
• Research regarding the efficacy of metformin in type 1 diabetes is mixed, but it does not appear to improve glycemic control and can lead to more gastrointestinal adverse effects.
• Metformin remains the foundational drug for the treatment of type 2 diabetes. It may be used among patients with an estimated glomerular filtration rate down to 30 mL/minute/1.73 m², provided that these patients have regular follow-up.
• Metformin can promote vitamin B₁₂ deficiency, and clinicians should consider checking vitamin B₁₂ levels among patients receiving metformin, particularly in patients with anemia or peripheral neuropathy.
• All patients should receive lifestyle management to control their diabetes. If the HbA_1c level is less than 9%, treatment may include lifestyle management plus metformin alone.
• If the HbA_1c level is between 9% and 10%, clinicians should consider metformin plus another agent:
  • If the patient has known ASCVD, clinicians should prefer drugs such as canagliflozin, empagliflozin, or liraglutide, which have proven cardiovascular benefits in treating diabetes.
  • If there is no history of ASCVD, clinicians may choose the second agent based on drug-specific effects and patient factors such as the risk for adverse effects and cost of treatment. Possible choices include sulfonylureas, a thiazolidinedione, dipeptidyl peptidase 4 (DPP-4) inhibitors, SGLT2 inhibitors, GLP-1 RAs, or basal insulin.
• If the HbA_1c level is more than 10%, or the blood glucose level is at least 300 mg/dL, injection therapy with insulin is preferred, possibly with a GLP-1 RA.
• In general, adding each new noninsulin medication to a diabetes treatment regimen will reduce HbA_1c levels by just less than 1%.
• Insulin therapy never should be used as a threat or a punishment by clinicians, nor should it be described as a sign of personal failure by a patient.
• Most patients with type 2 diabetes can initiate insulin therapy with basal insulin at a dose of 10 units/day, or 0.1 to 0.2 units/kg/day.
• GLP-1 RAs generally should be continued after addition of basal insulin. However, sulfonylureas, GLP-1 RAs, and DPP-4 inhibitors are usually stopped after the insulin regimen grows more complex with basal-bolus dosing.
• If the HbA_1c level is not controlled effectively with basal insulin alone, clinicians can add a dose of rapid-acting insulin before the biggest meal of the day. The usual start dose is 4 units, or 0.1 unit/kg, or 10% of the current basal dose.
• Other options for these patients include a GLP-1 RA and premixed insulin. Premixed insulin 3 times daily has been found to be noninferior to basal-bolus regimens for glycemic control, with similar rates of hypoglycemia.

Clinical Implications

• In its 2018 guidelines for standards of medical care for diabetes, the ADA recommends a target HbA_1c level of less than 7% for most adults with diabetes, but a goal of less than 6.5% is reasonable for healthy, younger adults. Conversely, more frail adults with a history of severe complications of diabetes and high risk for hypoglycemia may be treated more effectively to a target HbA_1c level of less than 8%.
• If lifestyle and metformin are insufficient to reduce the HbA_1c level to less than 9% among patients with known ASCVD, the ADA recommends that clinicians consider treatment with canagliflozin, empagliflozin, or liraglutide. These drugs have been demonstrated to improve cardiovascular outcomes among patients with type 2 diabetes.
• Implications for the Healthcare Team: There are many options in the pharmacologic management of diabetes. The healthcare team should practice active surveillance of these patients and advance or withdraw therapy based on drug efficacy and safety.

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