Evaluating Various Treatment Options for Type 2 Diabetes

San Francisco—The ADA and American Association of Clinical Endocrinologists (AACE) guidelines recommend patients with type 2 diabetes begin treatment with metformin and lifestyle modifications. If this treatment plan fails, they then have more than a dozen choices of second- and third-line medications.

During a satellite symposium at the ADA meeting, speakers discussed and compared the numerous
options and emphasized the need for individualized attention to patients. Patients should also understand the benefits and risks of the drugs, according to the healthcare professionals who spoke at the session.

Zachary Bloomgarden, MD, professor, Mount Sinai School of Medicine, said treating type 2 diabetes is associated with microvascular and macrovascular benefits. However, he also noted that some medications are associated with weight gain.

He mentioned that in the ACCORD [Action to Control Cardiovascular Risk in Diabetes] trial, patients who started metformin did not gain weight, but those who began using insulin or thiazolidinediones saw an increase in weight. The ACCORD study took place in 77 sites in the United States and Canada and included 10,251 adults with type 2 diabetes who were at a high risk for cardiovascular events and had a hemoglobin A1c (HbA1c) level >8.5%.

Goals & Guidelines
Hypoglycemia is another concern associated with diabetes medications, according to Dr. Bloomgarden. Patients with hypoglycemia have abnormally low blood glucose, usually <70 mg/dL.

Yehuda Handelsman, MD, medical director, principal investigator, Metabolic Institute of America, said the ADA and AACE have various goals for HbA1c levels. Most people are recommended to have an HbA1c level between 6.5% and 7%, although young, healthy people can have HbA1c levels <6.5%. He mentioned that people with multiple comorbidities and a short life expectancy could have HbA1c levels >7%.

Dr. Handelsman said there are several noninsulin agents available to treat type 2 diabetes, including metformin and newer medications such as dipeptidyl peptidase-4 (DPP-4) inhibitors (eg, alogliptin, linagliptin, saxagliptin, and sitagliptin), glucagon-like peptide-1 (GLP-1) receptor agonists (eg, exenatide and liraglutide), and sodium-glucose cotransporter-2 (SGLT-2) inhibitors (eg, canagliflozin and dapagliflozin). There are also basal, prandial, and premixed insulins.

In 2012, the ADA and European Association for the Study of Diabetes released a position statement on managing hyperglycemia (high blood glucose levels) and suggested a patient-centered approach, according to Dr. Handelsman. He defined a patient-centered approach as providing care that is respectful and responsive to individual patient preferences, needs, and values, ensuring that patient values guide all clinical decisions.

The position statement also recommended patients begin using monotherapies before advancing to dual or triple combination therapies and possibly insulin. Dr. Handelsman noted that the strategy depends on numerous factors, including age; weight; sex; racial, ethnic, or genetic differences; and comorbidities, such as coronary artery disease, heart failure, chronic kidney disease, liver dysfunction, and hypoglycemia.

Last year, the ADA and AACE released its principles and algorithms for glycemic control. The authors suggested a comprehensive approach addressing all cardiovascular risk factors, minimizing the risk of hypoglycemia and weight gain, individualizing and personalizing the management of diabetes, considering fasting and postprandial glucose levels, and accounting for the total cost of therapy, including the acquisition cost of the drug and costs associated with hypoglycemic events, drug-related adverse events, treatments of complications from adherence, and additional laboratory tests. They also recommended healthcare professionals and patients consider all major classes of FDA-approved drugs and select therapies based on their potential to lower HbA1c levels.

GLP-1 Receptor Agonists, DPP-4 Inhibitors, Thiazolidinediones, and SGLT-2 Inhibitors
Ralph DeFronzo, MD, professor of medicine, chief of diabetes division, University of Health Science
Center, San Antonio, Texas, provided an overview of the GLP-1 receptor agonists and DPP-4 inhibitors.

According to Dr. DeFronzo, studies have shown exenatide and liraglutide are effective at reducing HbA1c levels, preserving beta-cell function, and promoting weight loss. He added that the drugs do not cause hypoglycemia and have an excellent safety profile.

In several trials, patients who received 1.8 mg liraglutide per day had a mean decrease in HbA1c level between 1% and 1.5%, while 42% to 54% of patients had an HbA1c level <7%.

Meanwhile, patients who received saxagliptin had a significant decrease in HbA1c level. The mean decrease in HbA1c level was 0.63% for drug-naïve patients, 0.76% for patients who received saxagliptin and glyburide, 0.83% for patients who received saxagliptin and metformin, and 0.64% for patients who received saxagliptin and pioglitazone or rosiglitazone.

Dr. DeFronzo also mentioned that studies have proven thiazolidinediones have a durable reduction in HbA1c level, insulin sensitivity, insulin secretion, lipotoxicity, dyslipidemia, atherosclerotic cardiovascular disease, nonalcoholic steatohepatitis, and nephropathy.

Robert Henry, MD, chief of diabetes and endocrinology, Veterans Affairs San Diego Healthcare System, mentioned numerous companies are developing SGLT-2 inhibitors. Canagliflozin, dapagliflozin, and  empagliflozin are FDA-approved SGLT-2 inhibitors; other SGLT-2 inhibitors that are in late-stage development include ertugliflozin and luseogliflozin.

Canagliflozin is approved in 100 mg and 300 mg once-daily doses, although Dr. Henry said patients should initiate treatment at the lower dose and can titrate up if they require better glycemic control, tolerate the drug, and have an estimated glomerular filtration rate (GFR) <60 mL/min/1.73 m². If patients have an estimated GFR <45 mL/min/1.73 m², they should not start or continue taking canagliflozin.

Dr. Henry said dapagliflozin is approved in 5 mg and 10 mg once-daily doses. Patients should in-
itiate treatment at the lower dose and can increase the dose if they require better glycemic control and tolerate the drug. If patients have an estimated GFR <60 mL/min/1.73 m², they should not start or continue taking dapagliflozin.

Insulins
Vivian Fonseca, MD, chief of endocrinology, professor of medicine and pharmacology, Tulane University, said there are numerous insulins that are used to effectively treat type 2 diabetes. He mentioned that all insulins lower glucose and HbA1c levels but are associated with weight gain and risk of hypoglycemia.

Larger doses and more aggressive titrations lead to lower HbA1c levels, although they are also often associated with an increased risk of adverse events, according to Dr. Fonseca. He added that long-
acting insulin analogs reduce the incidence of overnight hypoglycemia, while rapid-acting insulin analogs reduce postprandial glucose excursions but are associated with more hypoglycemia and weight gain.

Dr. Fonseca also discussed the DAWN [Diabetes Attitudes Wishes & Needs] survey of 2681 physicians and 2061 patients. Most of the physicians indicated that they preferred to delay insulin until it was
absolutely necessary and admitted they used insulin as a threat to most patients. Meanwhile, most patients said they believed that needing insulin was a sign that they failed to follow the treatment recommendations.—Tim Casey