Diabetes mellitus (DM) was the third most common medical diagnosis in 2016.1 Uncontrolled DM can lead to cardiovascular disease, nephropathy, neuropathy, and retinopathy. It is estimated that only 52.5% of patients with DM have achieved their goal hemoglobin A1c (HbA1c) level. The 2018 American Diabetes Association (ADA) clinical guidelines lack strong recommendations on sequential therapy for patients who have received a diagnosis of type 2 diabetes mellitus (T2DM) and have been unable to achieve their goal HbA1c level with lifestyle changes and maximum-dose metformin.2 Although those guidelines support treatment intensification with a glucagon-like peptide 1 receptor agonist (GLP-1 RA), prescribing patterns for T2DM most commonly include adding insulin to try to control blood glucose and reduce long-term comorbidities.2,3
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Insulin therapy is known for its ability to effectively lower blood glucose and HbA1c levels but comes with many limitations. Mealtime insulin has the highest risk of hypoglycemia, causes significant weight gain, requires several additional injections per day, and additional monitoring of blood glucose.4,5 The 2018 ADA guidelines state that hypoglycemia is the major limiting factor in the management of insulin-treated T2DM.2
Compared with mealtime insulin, GLP-1 RAs have the benefit of reducing the risk of hypoglycemia, weight gain, and number of daily injections.5 In addition, compared with insulin alone, GLP-1 RAs have the advantage of reducing glycemic variability.6 These advantages are especially attractive in the treatment of geriatric patients. Given its mechanism of action, liraglutide is expected to have an effect on both fasting and postprandial blood glucose. There are no recommendations on how to empirically reduce the dose of insulin when starting liraglutide.7
Background
GLP-1 is an incretin hormone that is secreted in response to meal ingestion. GLP-1 stimulates insulin release, suppresses elevated glucagon levels, and delays gastric emptying. Patients with a DM diagnosis have impaired secretion of GLP-1.8
The GLP-1 RA liraglutide was approved by the FDA in January 2010 as a once-daily injection for patients with uncontrolled T2DM despite lifestyle changes and metformin monotherapy. Because of its intermediate half-life, liraglutide has an effect on both fasting and postprandial blood glucose.7 GLP-1 RAs are associated with reduced hypoglycemic episodes—an association attributable to the mechanism of action and potentially to improved pancreatic α-cell function.3,4 In July 2016, results of the LEADER trial showed that liraglutide therapy had a cardiovascular benefit in high-risk patients.8 In October 2017, liraglutide was FDAapproved for reducing 3-point major adverse cardiac events.7
Xultophy (Novo Nordisk, Plainsboro, NJ) is a fixed-dose medication combining degludec, a long-acting basal insulin analog, with liraglutide. As seen in the DUAL trials, Xultophy was more beneficial in reducing HbA1c levels than each component alone, and minimized hypoglycemic events, weight gain, and complexity of insulin treatment intensification.9-11 Therapy that combines basal insulin and a GLP-1 RA may be more effective than either agent as monotherapy and may have a significant impact on cardiovascular risk because of the synergistic vasodilatory, anti-inflammatory, and antioxidant properties of insulin and GLP-1 RA.6 In addition, combination therapy offers many benefits over traditional basal and bolus insulin regimens. These benefits include fewer daily injections, additional weight reduction resulting from the reduced insulin requirement, and fewer episodes of hypoglycemia. Reported gastrointestinal adverse effects have been transient and were not augmented when a GLP-1 RA was used in combination with basal insulin.11