|| Patients with type 2 diabetes frequently do not reach HbA1c targets, despite the growing arsenal of glucose lowering agents.1,2 Professional society guidelines recommend initial therapy with metformin, followed by intensification with any of several classes of agents, based on an assessment of efficacy, hypoglycemia risk, contraindications, cost, and preference.3,4 However, therapeutic inertia may occur in routine practice as treatment regimens become more complex and time-consuming.5,6 Because of the chronic, progressive nature of type 2 diabetes, many patients require insulin therapy. In this setting, GLP-1 RAs provide multiple potential advantages when combined with insulin.
GLP-1 RAs produce robust HbA1c reduction stimulating endogenous insulin secretion and inhibiting the inappropriate postmeal glucagon response in a glucose-dependent manner. These agents have a low hypoglycemia risk as a result. GLP-1 RAs promote weight loss in part through signaling in appetite centers of the hypothalamus.7,8 Five agents are currently approved by the Food and Drug Administration (FDA), and these may be categorized according to whether they activate the GLP-1 receptor intermittently (exenatide twice daily) or continually (liraglutide [daily], exenatide once weekly, albiglutide [weekly], or dulaglutide [weekly]).9-11 Another intermittent agent (lixisenatide [daily]), is expected to be submitted to the FDA within the year.10
As the HbA1c drops below 8%, postprandial glucose contributes more to HbA1c, and therefore agents that specifically target postprandial glucose may be of value.12-14 While all GLP-1 RAs lower postprandial glucose, intermittent agents may lower postprandial glucose better than continuous agents, possibly because constitutive activation of the GLP-1 receptor may lead to attenuation of the effects on gastric emptying.15 This is demonstrated directly in the reviewed article by Meier and colleagues and indirectly in the Diamant article. However, the postprandial glucose advantage is only observed at the meal immediately postdose and does not translate to better HbA1c reduction or weight loss. On the other hand, continuously activating agents tend to lower fasting glucose more than intermittently activating agents, often leading to better HbA1c reduction. Other, generally small, differences in HbA1c lowering, weight loss, tolerability, and ease of use are notable among individual agents in this class, as noted by recent reviews.
Historically, intensification of therapy after failure of basal insulin begins with the addition of prandial insulin.5,6 However, the meta-analysis by Eng and colleagues (reviewed herein) demonstrates that GLP-1 RAs may be a compelling alternative strategy by lowering HbA1c without increasing the risk of hypoglycemia or weight gain. Several studies indicate that a single injection of prandial insulin at the largest meal each day provides only marginally less HbA1c reduction than three injections per day and minimizes hypolgycemia.16-18 However, the Mathieu article demonstrates that GLP-1 RA therapy is associated with similar HbA1c reduction, with significantly fewer hypoglycemic events and less weight gain compared to a single injection of prandial insulin per day.
Moreover, GLP-1 RAs generate HbA1c reductions that are similar to or better than that produced by adding multiple injections of prandial insulin per day, as shown by the Eng, Diamant, and Rosenstock articles. These reviewed articles also report a lower risk of hypoglycemia compared to thrice daily prandial insulin when either is added to basal insulin. One potential criticism of the Rosenstock article was that prandial insulin titration was not performed optimally. However, the findings arguably still surpass the real-world setting, in which prandial insulin initiation and titration are less likely to be performed optimally.19-21 In the article by Buse and colleagues, the investigators demonstrate that even among patients who require extensive insulin titration, the HbA1c lowering capability of exenatide is retained due to additional postprandial glucose reduction. While weight loss was attenuated at higher insulin titration increments, exenatide still prevented the weight gain that was observed with glargine alone.
In clinical practice, when GLP-1 RAs are added to existing insulin therapy, it is important to reduce the daily insulin dose by 10-20%, particularly if the HbA1c is < 8.0%.22 Fixed dose combinations of basal insulin and GLP-1 RAs, as described in the Mathieu article, are in development and may reduce the number of daily injections per day.23 There are currently few data to support the combination of basal-prandial insulin with GLP-1 RAs. However, one recent trial demonstrated that the addition of dulaglutide to prandial insulin provided similar HbA1c reduction with less weight gain and nocturnal hypoglycemia compared to basal-prandial insulin.24
The drawbacks of GLP-1 RAs should be considered. Treatment does involve additional injections and prescription coverage may vary. The class of drugs causes gastrointestinal side effects in a significant number of recipients, though this adverse effect tends to resolve over time. Contraindications include advanced renal failure, gastroparesis, and pancreatitis. The drugs demonstrate a small but measurable increase in heart rate, although the clinical relevance of this remains unclear.25-27 Cardiovascular outcomes studies are under way and will provide more evidence of the long-term safety of these agents. In the first of these studies, lixisenatide demonstrated a neutral effect on major cardiovascular events and no change in the risk of heart failure.28,29
In summary, the addition of GLP-1 RAs with basal insulin is an effective glycemic control strategy which minimizes the risk of hypoglycemia and weight gain incurred by traditional basal-bolus insulin therapy.
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