Insulin Plus GLP-1 Agonists: An Alternative Approach

Unlike insulin, GLP-1 agonists tend to promote weight loss.

A 66-year-old African-American woman with an 11-year history of type 2 diabetes mellitus (T2DM) comes to the clinic for follow-up. Current medications include metformin, 1000 mg twice daily, insulin glargine 60 units at bedtime, lisinopril 10mg/d, chlorthalidone 25mg/d, aspirin 81mg/d, and atorvastatin, 80 mg/d. Recent laboratory findings include: A1c, 7.8% (American Diabetes Association [ADA] goal,  <7%); all other laboratory results are within normal range. The patient reports that she has been checking her blood glucose at home for the last month (average fasting reading, 125mg/dL and average post-prandial reading, 195 mg/dL). She realizes the post-meal reading is not ideal and wants to know what she can do to gain better control. She worries about the possibility of hypoglycemia if her insulin is intensified and of gaining more weight; she has gained 10 lbs (current BMI, 32) over the last couple of years).  

Discussion

Therapy for patients with T2DM can be complex and new guidelines from the American Diabetes Association stress the importance of individualizing therapy, taking into consideration specific patient factors and needs. While therapy is most often initiated with one or more oral agents, the typical decline in beta-cell function that characterizes T2DM results in most patients eventually requiring insulin replacement therapy. Once oral agents and/or non-insulin therapies fail, once-daily basal insulin is typically added, (ie, insulin analogues glargine or detemir). If A1c and/or post-prandial targets are not met in a reasonable period of time, insulin therapy is intensified with a more complex basal-bolus regimen, which usually represents the last line in therapy. 

Basal-bolus regimens, often including a long-acting insulin analogue, taken once or twice daily, in combination with a rapid-acting insulin analogue at meals can be effective at controlling A1c and both fasting and post-prandial blood glucose target levels. Managing the multiple daily injections (MDI) of 2 different insulin formulations is complex and can be overwhelming for some patients and frustrating for both patient and physician. It is also associated with barriers that can prevent its full effectiveness in clinical practice. Reaching glycemic goals typically requires frequent dose titration based on home blood glucose readings. This is a difficult task for both patients and providers. Even when dose titration is frequent, nonadherence can limit continued glycemic control. Concerns about the increased risk of hypoglycemia as well as weight gain with the additional bolus insulin may also prevent achievement of glycemic control. 

In an ideal world
Given these limitations it would seem that an ideal regimen for patients uncontrolled on basal insulin would combine drugs that target both basal and PPG levels, without increasing the risk of hypoglycemia and/or weight gain. Simplified dosing and titration may also increase adherence and streamline the process of reaching glycemic targets. This ideal situation is difficult to achieve with any combination of basal and bolus insulins. With many new drug classes available, clinical focus has been shifting toward combining insulin with non-insulin therapies that target PPG excursions.  

One option that has promise is the combination of basal insulin with glucagon-like peptide–1 (GLP-1) agonists. These relatlively novel injectable agents are often used as second- or third-line therapy once one or more oral agents fail; however, newer guidelines also list this option as an alternative to bolus insulin for patients not at goal on basal insulin.² The combination offers many physiological advantages, including a synergistic effect where limitations of each individual agent used alone may be overcome by the other agent.

Once basal insulin alone, typically targeting fasting blood glucose, fails and PPG levels are uncontrolled, focus shifts to targeting PPG, traditionally by adding bolus insulin at mealtime. GLP-1 agonists primarily target PPG levels as they stimulate glucose-dependent insulin release. Additionally, these agents inhibit gastric emptying and suppress glucagon, further limiting PPG excursions. Thus, GLP-1 agonists are less likely than bolus insulin to cause hypoglycemia, which may ease anxiety for both patients and providers and potentially increase adherence to therapy.³

Also unlike insulin, GLP-1 agonists are associated with weight loss, a major benefit for patients with T2DM. Through multiple mechanisms, GLP-1 agonists also may allow a reduction in total insulin dosage, an effect which could further limit hypoglycemia, weight gain, and costs associated with insulin therapy.  Finally, GLP-1 agonists are typically dosed less frequently than bolus insulins and taken independent of mealtime.³

Theory put to test
These theoretical benefits of combining the two classes have been verified by several clinical trials, including most recently a systematic review and meta-analysis published by Eng and collegues.⁴  A total of fifteen studies, published between 2011 and 2014 comparing GLP-1 agonist and basal insulin to another treatment strategy (placebo or bolus insulin) and with a treatment duration of at least 8 weeks (mean duration 24 weeks) were included in this analysis.⁴  Participants had a mean baseline A1c of 8.13%, a mean body mass index (BMI) of 32.9 kg/m², and a mean duration of diabetes of 12 years.  Three of these trials compared basal insulin plus a GLP-1 agonist with intensive basal-bolus insulin regimens, which is the primary comparison when considering intensification of therapy in patients uncontrolled on basal insulin alone.⁴

In a pooled analysis, the combination of a GLP-1 agonist and basal insulin led to a mean greater reduction in A1c than any other treatment as well as a greater proportion of patients achieving an A1c of 7% at the end of the study. When compared specifically to basal-bolus insulin, the combination of basal insulin and GLP-1 agonists led to a greater reduction in A1c, although the proportion of patients achieving A1c goals was similar.⁴

The combination of GLP-1 and basal insulin showed no significant differences with regards to the risk of hypoglycemia when compared to other treatments; however, when specifically compared to basal-bolus insulin the GLP-1/insulin combination showed a significantly lower risk of hypoglycemia. The GLP-1/basal insulin combination led to a mean reduction in weight that was greater than other treatments, including basal-bolus insulin.⁴

Conclusion

The data from this analysis show that the combination of GLP-1 agonists and basal insulin can be a safe and effective alternative treatment for patients with T2DM. The combination offers several advantages over intensified, basal-bolus insulin therapy, including less frequent dosing, lower risk of hypoglycemia, and weight loss. 

More long-term data are needed in order to fully determine the long-term safety and place in therapy of this combination. More information is also needed in order to determine the best GLP-1 agonist to use and whether there are differences in safety and efficacy among the various GLP-1 agents (ie, short- vs  long-acting agents). The initial data, however, is promising and this combination can be considered as alternative when patients fail basal insulin alone. This combination may prove most effective for patients with pronounced fear of hypoglycemia and/or weight gain associated with intensified insulin therapy. The simplified regimen may prove useful in patients who have difficulty adhering to a MDI insulin regimen and frequent dose titrations. Further benefit may be seen if combination preparations of basal insulin and GLP-1 agonists become commercially available. 

In the case above, the addition of a GLP-1 agonist could be considered since the patient’s fasting blood glucose has been maintained well but PPG levels continue to be high. Additionally, she is concerned about hypoglycemia and the weight gain associated with her therapy and these concerns may prevent adherence to and achievement of glycemic control with an intensified insulin regimen. 

References:

• Inzucchi SE, Bergenstal RM, Buse JB, et al.  Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care.  2012;35:1364-1379.
• Garger AJ, Abrahamson MJ, Barzilay JI, et al.  AACE comprehensive diabetes management algorithm. Endocr Pract. 2013;19:327-336.
• Nauck MA.  Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. Am J Med. 2011;124:S3–S18.
• Eng C, Kramer CK, Zinman, B, Retnakaran R.  Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet.  Published online September 12, 2014.