Pharmacologic Therapy for Type 2 Diabetes: Synopsis of the 2017 American Diabetes Association Standards of Medical Care in Diabetes

The American Diabetes Association (ADA) first released its Standards of Medical Care in Diabetes for health professionals in 1989. These practice guidelines provide an extensive set of evidence-based recommendations that are updated annually for the diagnosis and management of patients with diabetes. The 2017 Standards cover all aspects of patient care (1); this guideline synopsis focuses on pharmacologic approaches for patients with type 2 diabetes. Guideline Development and Evidence Grading To develop the 2017 Standards, the ADA Professional Practice Committee, which comprises physicians, adult and pediatric endocrinologists, diabetes educators, registered dietitians, epidemiologists, and public health experts, systematically searched MEDLINE from 1 January 2016 (date of last previous search) to November 2016. The committee revised recommendations based on the new evidence or, in some cases, to clarify prior ones or match the strength of the wording to the strength of the evidence. It also solicited feedback from the larger clinical community. The recommendations are rated as A, B, C, or E. Those with an A rating are based on large, well-designed, multicenter clinical trials or high-quality meta-analyses. Recommendations with lower-quality evidence may be equally important and are based on well-conducted cohort studies (B rating) or uncontrolled studies (C rating). Those assigned an E rating are consensus recommendations for which there is no evidence from clinical trials, in which clinical trials may be impractical, or in which there is conflicting evidence. The ADA funds development of the Standards from its general revenues with no industry support or involvement. Details on the methodology, information about the committee members and their conflict-of-interest disclosures, and the complete Standards can be downloaded at professional.diabetes.org/annals. Pharmacologic Therapy for Type 2 Diabetes: Recommendations Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacologic agent for the treatment of type 2 diabetes (A rating). Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in patients treated with metformin, especially those with anemia or peripheral neuropathy (B rating). Providers should consider initiating insulin therapy (with or without additional agents) in patients with newly diagnosed type 2 diabetes who are symptomatic, have a hemoglobin A1c (HbA1c) level of 10% or greater, or have a blood glucose level of 16.7 mmol/L (300 mg/dL) or greater (E rating). If noninsulin monotherapy at the maximum tolerated dose does not achieve or maintain the HbA1c target after 3 months, adding a second oral agent, a glucagon-like peptide-1 (GLP-1)receptor agonist, or basal insulin should be considered (A rating). For patients with type 2 diabetes who are not achieving glycemic goals, insulin therapy should be instituted without delay (B rating). A patient-centered approach should be used to guide the choice of pharmacologic agents (E rating). Initial Treatment Approach: Metformin Metformin monotherapy should be initiated at the time of diagnosis of type 2 diabetes for most patients unless there are contraindications. It is effective, safe, and inexpensive and may reduce the risk for cardiovascular events and death (2). A large meta-analysis (3) supports the use of metformin monotherapy as first-line therapy. It may be safely used in patients with an estimated glomerular filtration rate as low as 30 mL/min/1.73 m2 (4); the U.S. label of metformin was recently revised to reflect its safety in patients with an estimated glomerular filtration rate of 30 mL/min/1.73 m2 or greater (5). Gastrointestinal side effects are common in patients receiving metformin. In the authors' experience, these side effects can be reduced if metformin monotherapy is started at a dose of 500 mg once or twice daily with food and titrated gradually to the maximum effective dose (2 g/d). Patients should be advised to stop taking their medication if they experience nausea, vomiting, or dehydration. The Diabetes Prevention Program Outcomes Study found that long-term users of metformin may develop vitamin B12 deficiency. Periodic testing of vitamin B12 levels should be considered in metformin users, especially those with anemia or peripheral neuropathy (6). Using Pharmacotherapies Other Than or in Addition to Metformin If the patient does not tolerate or has a contraindication to metformin, another option should be considered. The ADA/European Association for the Study of Diabetes position statement (7) recommends a patient-centered approach, including assessment of efficacy, hypoglycemia risk, effect on weight, side effects, cost, and patient preferences. A table detailing characteristics of all available glucose-lowering agents in the United States that may guide individualized treatment choices is available in section 8 of the Standards (8). Tables 1 and 2 depict the costs of antihyperglycemic agents that were extracted from the Red Book (9). With so many choices, patients and providers should be able to find a mutually agreeable treatment option. Table 1. Median Monthly Cost of Maximum Approved Daily Dose of Noninsulin Glucose-Lowering Agents in the United States* Table 2. Median Cost of Insulins in the United States, Calculated as the AWP per 1000 Units of Specified Dosage Form/Product* For patients with an HbA1c level of 9% or greater who are not acutely symptomatic, initiation of dual combination therapy (Figure 1) should be considered to more quickly achieve the target HbA1c level. If the patient has a random glucose level of 16.7 mmol/L (300 mg/dL) or greater or an HbA1c level of 10% or greater and has acute symptoms of polyuria, polydipsia, or weight loss, combination therapy that includes insulin should be considered (Figure 2). Figure 1. Antihyperglycemic therapy for type 2 diabetes: general recommendations. The order in the chart was determined by historical availability and the route of administration, with injectables to the right; it is not meant to denote any specific preference. Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, with the usual transition moving vertically from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). Adapted with permission from Inzucchi and colleagues (7). DPP-4-i= dipeptidyl peptidase-4 inhibitor; GI= gastrointestinal; GLP-1-RA= glucagon-like peptide-1receptor agonist; GU= genitourinary; HbA1c= hemoglobin A1c; HF= heart failure; SGLT-2-i= sodiumglucose contransporter-2 inhibitor. * See Dieuzeide and colleagues (21) for description of efficacy and cost categorizations. Usually a basal insulin (such as neutral protamine Hagedorn, glargine, detemir, or degludec). Figure 2. Combination injectable therapy for type 2 diabetes. Adapted with permission from Inzucchi and colleagues (7). GLP-1-RA= glucagon-like peptide-1receptor agonist; HbA1c= hemoglobin A1c; SMBG= self-monitored blood glucose. Assessing Response and Deciding to Intensify Therapy Providers should assess whether the HbA1c target has been achieved within approximately 3 months of therapy initiation (Figure 1); if it has not, therapy should be intensified (Figure 2). They should use shared decision making and a patient-centered approach when selecting a second agent. Potential combination therapies include a sulfonylurea, thiazolidinedione, dipeptidyl peptidase-4 (DPP-4) inhibitor, sodiumglucose contransporter-2 (SGLT-2) inhibitor, GLP-1receptor agonist, or basal insulin. Insulin should also be considered as part of any combination regimen for patients with severe hyperglycemia, especially if symptoms or catabolic features (such as weight loss or ketosis) are present. Patients should be reassessed within 3 months for achievement of the HbA1c target. Recent Evidence From Cardiovascular Outcomes Trials Major cardiovascular outcomes trials have studied patients with type 2 diabetes and established cardiovascular disease, including EMPA-REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) (10) and the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial (11). These 2 studies found that, compared with placebo and standard treatment, empagliflozin and liraglutide reduced composite outcomes for myocardial infarction, stroke, and cardiovascular death in populations in which most, if not all, patients had established atherosclerotic cardiovascular disease. Whether other agents in the same class as empagliflozin and liraglutide have similar benefits, and whether the treatments benefit patients at lower risk for cardiovascular disease, is unknown. Cardiovascular outcomes trial data for the DPP-4 inhibitors sitagliptin (12), saxagliptin (13), and alogliptin (14) showed no statistically significant differences in rates of major cardiovascular events between treatment and placebo groups. Recent Warnings About Pharmacotherapies In May 2015, the U.S. Food and Drug Administration (FDA) issued a warning that SGLT-2 inhibitors may lead to ketoacidosis in the absence of significant hyperglycemia (termed euglycemic diabetic ketoacidosis). Patients who develop symptoms of ketoacidosis, which may include dyspnea, nausea, vomiting, and abdominal pain, should stop taking SGLT-2 inhibitors and immediately seek medical attention (15). In April 2016, the FDA also warned that the DPP-4 inhibitors saxagliptin and alogliptin may increase the risk for heart failure, especially in patients with preexisting heart failure or renal impairment (16). Insulin Therapy Diabetes is a progressive condition, and many patients with type 2 diabetes eventually require and benefit from insulin therapy. Early patient education about expected disease progression,