A multifaceted approach to diabetes management


New treatment options range from novel insulin therapies to GLP-1 agonists, DPP-4 inhibitors, SGLT-2 inhibitors, and more.

Diabetes mellitus is a severe chronic disease that affects nearly 30 million Americans. Despite advances in the treatment of type 2 diabetes mellitus (T2DM), many patients still remain in suboptimal glycemic control.

Patrick Curtin“Management of T2DM usually requires a multifaceted approach, and new treatment options aim to address this growing challenge,” said Patrick Curtin, PharmD, BCPS, pharmacy clinical coordinator, Overlook Medical Center, Summit, N.J.

“A fundamental understanding of the various agents’ mechanisms to lower blood glucose and the side-effect profile is essential for a positive therapeutic outcome,” said Lisa Kroon, PharmD, CDE, professor and chair, Department of Clinical Pharmacy, University of California, San Francisco.

See also: CPE: New and emerging therapies for the treatment of diabetes

Insulin therapies

Toujeo. The newly available basal insulin glargine U300 (Toujeo; Sanofi), may offer an alternative for diabetes patients to control their blood glucose levels. Toujeo is the same type of once-daily, long-acting insulin as Sanofi’s Lantus, but a stronger version. Each milliliter of Toujeo carries 300 units of insulin (U300); Lantus carries only 100 units of insulin per mL (U100).

See also: What's on the horizon for diabetes therapy?

Toujeo’s approval was based on results from the EDITION clinical trial program, which comprised several Phase 3 studies and included 3,500 adults from diverse diabetes populations. The studies showed that Toujeo and Lantus were similarly effective in controlling overall blood glucose levels. “Of note, Toujeo showed that T2DM patients were about 30% less likely to experience nighttime hypoglycemia compared to Lantus,” said Curtin.

The most common adverse events, excluding hypoglycemia, were nasopharyngitis and upper respiratory tract infection. Toujeo is available in a disposable prefilled pen and requires one-third the injection volume to deliver the number of insulin units provided by the prefilled Lantus pen. Since Toujeo insulin requires less injection volume, Kroon believes that it may offer some advantage to patients who need larger doses of insulin, i.e., more than 100 units.

Peglispro. Eli Lilly’s new basal insulin, peglispro, differs from currently available basal insulins in its hepato-preferential action, driven by its reduced effect on peripheral tissues. It has demonstrated superior glycemic benefits, as well as significantly fewer episodes of overnight hypoglycemia and a weight advantage compared to insulin glargine in clinical studies.

Curtin believes that new basal insulin treatments may be a welcome option for patients who do not reach glycemic targets and experience nocturnal hypoglycemia. However, he cautioned, patients taking peglispro had a greater increase in alanine aminotransferase (ALT) and triglyceride levels than those taking insulin glargine.

Tresiba/Ryzodeg. In March 2015, FDA accepted class II resubmissions for Novo Nordisk’s Tresiba (insulin degludec) and Ryzodeg 70/30 (insulin degludec/insulin aspart). The manufacturer resubmitted the prespecified interim analysis data of the DEVOTE trial, an ongoing cardiovascular outcomes trial, as part of the resubmissions of the new drug applications (NDAs) for Tresiba and Ryzodeg. On September 25, FDA approved both drugs.

Oral-lyn. On the horizon is Oral-lyn (Generex), a liquid formulation of regular human insulin, which is delivered to the buccal mucosa by way of an asthma-style inhaler. The absorption of Oral-lyn is limited to the mouth, with no entry into the lungs.

“Oral-lyn may offer a new pain-free and convenient diabetes treatment alternative to prandial insulin injections for T2DM patients,” said Curtin. The efficacy of Oral-lyn has been shown in clinical studies, including rapidity of absorption and onset of action, and improved glucoses metabolism when compared to injection insulin.


GLP-1 agonists

Glucagon-like-peptide-1 (GLP-1) receptor agonists are also effective for glycemic control in diabetes patients.

Lixisenatide. Sanofi recently unveiled results of a cardiovascular outcomes trial for its investigational GLP-1 agonist, lixisenatide (Lyxumia). Presented at the American Diabetes Association (ADA) Scientific Sessions in June 2015, the results from the Phase 3b study, Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA), showed no increased risk of cardiovascular (CV) death, heart attack, stroke, unstable angina, or heart failure in patients receiving lixisenatide.

The ELIXA study was designed to satisfy FDA's 2008 requirement for cardiovascular safety studies for all new T2DM drugs. The study ran for three years, with a two-year follow-up, and involved over 6,000 patients who had recently experienced acute coronary syndrome events and were therefore at high risk for additional cardiac problems. The encouraging study results pave the way for Sanofi to resubmit lixisenatide for FDA approval. Curtin pointed out that if approved, lixisenatide would be the first GLP-1 agonist with long-term CV safety data in diabetic patients with high CV risk.

Semaglutide. Another GLP-1 agonist, semaglutide (Novo Nordisk), is also on the horizon. In its first Phase 3 study, the once-weekly GLP-1 therapy decreased HbA1c levels by 1.5%, with most patients achieving HbA1c levels of 6.5-7%. Investigators added that 74% and 73% of the people treated with 0.5-mg and 1-mg semaglutide, respectively, achieved the ADA target level, compared with 25% of those treated with placebo. Therapy with semaglutide also delivered some significant weight loss scores for patients, another key measure of success. Starting with an average weight of 92 kg, patients in the semaglutide arm lost 3.8 kg (0.5-mg dose) and 4.6 kg (1-mg dose), compared with a weight loss of 1 kg for those treated with placebo.

Fit the treatment to the patient

With the availability of various GLP-1 agonists, intended for either weekly or daily administration, Kroon advises pharmacists to recognize that “one size does not fit all.” It’s important to keep in mind the impact that a particular therapy may have on the patient’s quality of life. For example, some patients may prefer the convenience factor of taking a drug just once a week rather than every day.

Curtin recommends that pharmacists be familiar with the contraindications associated with certain GLP-1 agonists, including in those with gastroparesis or severe gastrointestinal disease, a history of pancreatitis, a personal or family history of medullary thyroid carcinoma, and multiple endocrine neoplasia syndrome type 2.

DPP-4 inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors work to prevent the breakdown of GLP-1. They enhance glucose-dependent insulin secretion, reduce hepatic glucagon production, and primarily affect gastric emptying.

Omarigliptin. Merck’s long-acting DPP-4 inhibitor omarigliptin is currently in phase 3 development. In a double-blind study, more than 600 patients were randomized to various once-weekly doses of omarigliptin or placebo. The primary efficacy end point was change from baseline in HbA1c, and secondary end points were two-hour post-meal glucose (PMG) and fasting plasma glucose (FPG). Once-weekly treatment for 12 weeks with omarigliptin provided dose-related reductions in HbA1c, two-hour PMG, and FPG. At week 12, the 25-mg dose of omarigliptin provided the greatest glycemic efficacy. The incidence of adverse events was similar across dose groups, with a low incidence of symptomatic hypoglycemia and no effect on body weight.

Kroon urges pharmacists to be aware that certain DPP-4 inhibitors, such as sitagliptin, saxagliptin, and alogliptin are renally eliminated and therefore require renal dose adjustments. On the other hand, no renal dose adjustment is necessary with linagliptin.


SGLT2 inhibitors

A novel category of diabetes therapies with an insulin-independent mechanism has recently emerged. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, unlike other available agents, promote urinary glucose excretion by inhibiting glucose reabsorption in the kidneys.

Ertugliflozin. The investigational agent ertugliflozin (Merck) has been evaluated in T2DM patients inadequately controlled on metformin. A total of 328 patients [mean T2DM duration, 6.3 years; mean HbA1c, 8.1%] were randomized to once-daily ertugliflozin, sitagliptin, or placebo for 12 weeks. Ertugliflozin (1 mg – 25 mg/day) improved glycemic control, body weight, and blood pressure in T2DM patients who were suboptimally controlled on metformin. No reductions in body weight or blood pressure were observed with sitagliptin. No dose-related increases in adverse events occurred with ertugliflozin. Hypoglycemia was reported in five (1.5%) randomized participants (all in the ertugliflozin group). The frequency of urinary tract infection was 3.2% for ertugliflozin, 1.8% for sitagliptin, and 7.4% for placebo; the frequency of genital fungal infections was 3.7% for ertugliflozin vs. 1.9% for placebo.

“It is important for pharmacists to keep abreast of post-marketing surveillance data and FDA drug safety communications associated with diabetes treatments,” said Kroon. In May 2015, FDA released a safety warning stating that the use of SGLT2 inhibitors may lead to acidosis, including diabetic ketoacidosis (DKA). According to the report, factors such as reduced insulin dose, illness, and reduced fluid intake may have contributed to the acidosis. Clinicians and patients should monitor for signs and symptoms associated with DKA, including difficulty breathing, nausea, vomiting, and abdominal pain. In patients experiencing these symptoms, SGLT2 inhibitors should be discontinued if acidosis is confirmed.

In addition, FDA recently strengthened the warning for canagliflozin (Invokana, Invokamet; Janssen) related to the increased risk of bone fractures and added new information about decreased bone mineral density. FDA is continuing to evaluate the risk of bone fracture with the other drugs in the SGLT2 inhibitor class to determine whether additional label changes or studies are required.

Fixed-dose combination therapies

Empagliflozin/linagliptin. The fixed-dose combination (FDC) tablet empagliflozin/linagliptin (Glyxambi; Boehringer Ingelheim, Eli Lilly) received FDA approval in February 2015. This combination brings together the distinct mechanisms of SGLT2 and DPP-4 inhibitors for the first time in one tablet. For patients uncontrolled on metformin, phase 3 trial results showed that Glyxambi provided significantly greater reductions in blood glucose levels compared with reductions produced by either empagliflozin or linagliptin alone.

“With Glyxambi, the dual inhibition of DPP-4 and SGLT2 provides clinicians and patients with an option to simultaneously address multiple targets to improve glycemic control,” said Curtin.

He advises pharmacists to be aware of safety concerns, including post-marketing reports of acute pancreatitis. The manufacturer advises that if pancreatitis is suspected, Glyxambi should be promptly discontinued and appropriate management should be initiated. In addition, the use of Glyxambi should be avoided by patients with severe renal impairment or end-stage renal disease, as well as those in dialysis.


Tips for pharmacists

While many oral and injectable diabetes therapies are available, both Kroon and Curtin believe that clinicians must consider patient-specific characteristics and clinical evidence when selecting treatment options.

Medication factors include ability to lower HgbA1c, ease of use, adverse event profile (i.e.. hypoglycemia potential, cardiovascular safety profile, and weight gain), and patient-specific considerations for use (i.e., renal function).

“For example, it is vital that the pharmacist, physician, and patient all be on the same page regarding the A1c goal and whether adding a second or third drug to the patient’s regimen fits into that goal. Not having a shared understanding of such key considerations can lead to confusion,” said Kroon.

Pharmacists play a vital role in drug-therapy recommendations and monitoring of medication-related issues, and patient counseling. Therefore, it is important for them to be familiar with current guidelines for diabetes management, along with emerging treatment options.

Monica Shahis a writer and hospital pharmacist in New Jersey.

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