The patient presented is failing basal/bolus insulin therapy that has been added to an insulin sensitizer, metformin. If we look at her insulin requirement, assuming that she very conservatively adds only 10 extra units of rapid bolus insulin to her daily prandial insulin load per her correction algorithm, she is already using about 2.2 units of insulin per kilogram. She is also obese with a BMI of over 41. In addition, she has diabetes-associated complications of retinopathy and nephropathy, which puts her at risk of coronary disease, and has hypertension with an abnormal lipids profile, both under treatment.
This patient is an excellent candidate for added GLP-1RA therapy. What would support this?
GLP-1RA Basics
Among the more recent treatment options for those with diabetes mellitus type 2 are incretin agents, a group of which are the injectable recombinant protein glucagon-like peptide-1 (GLP-1) receptor agonists (GLP1-RAs). The GLP-1RAs regulate pancreatic α- and β-cell function in a glucose-dependent response.
GLP-1RAs simultaneously suppress α-cell glucagon production, thereby decreasing resistance to insulin, and induce β-cell insulin secretion.1 GLP1-RAs also delay gastric emptying, a limiting step in postprandial glucose absorption, and decrease appetite and food intake,1 which can make these agents particularly appealing for patients struggling to lose weight as well as control their diabetes. GLP-1RAs are also thought to have a central effect in the brain, on appetite modulators.2 In addition, the improved insulin sensitivity and glucose disposal, and decreased caloric intake, is associated with a relatively low risk of hypoglycemia.
A1c and Weight Impact
To date there have been few published randomized controlled reports on the impact of adding GLP-1RA to basal/bolus insulin. However, in a 2011 randomized controlled trial, a short-acting GLP-1RA (exenatide BID) added to basal insulin (glargine) was shown to reduce A1c by 1.74% versus 1.04% for placebo added to basal insulin, decrease postprandial hyperglycemia, decrease needed insulin (by 7 units/day versus placebo), and decrease weight (by 1.8 kg versus a gain of 1.0 kg with placebo), all without any significant change in hypoglycemia. However, there was a significant side effect profile of increased nausea, emesis, and diarrhea in the GLP-1 agonist group.3
Several observational-only studies have also shown positive effects of GLP-1RA on A1c, weight, and insulin requirements. Yoon et al. reported on 188 patients on both a GLP-1RA and insulin over a 27 month period. The mean changes in A1c were: -0.66% at 0 to 6 months; -0.55% at 6 to 12 months; -0.54% at 12 to 18 months; and -0.54% at 18 to 27 months. Additionally, weight and total daily dose of insulin (primarily prandial insulin) decreased the longer a patient was on the combination. Mean weight loss was 5.5 kg.4
Sheffield et al. did a similar study with exenatide BID and insulin, with 134 patients for 1 year. Exenatide use was associated with an 0.87% reduction in A1c, 45% discontinuation of premeal insulin, a 9-unit reduction in mean premeal insulin doses, a reduction in the median number of daily insulin injections, and mean weight loss of 5.2 kg).5
Viswanathan et al. reported on 38 patients completing 26 weeks treatment with exenatide BID and insulin. Mean A1c decreased by 0.6 +/- 0.21%, insulin dosage requirement decreased for rapid-acting and mixed insulins, and mean body weight decreased by 6.46 +/- 0.8 kg.6 An additional observational study by Balena et al. over a 12 month period showed that adding exenatide BID to patients continuing on insulin resulted in a mean A1c level reduction of 0.51%, weight reduction of 5.8 kg, and an insulin dose reduction of 42 units/day, with 16.6% of patients stopping insulin use altogether.7
Finally, in a report retrospectively looking at the addition of once daily GLP-1RA in insulin-resistant patients (defined as requiring 200 or more units of insulin daily), A1c dropped to an average of 7.6% (range 5.6 to 9.0%) from a mean starting A1c of 8.9% (range 5.7 to 11.1%) (p=0.0159). Mean weight loss in the 10 out of 14 individuals who lost weight was 4.5kg. Interestingly, there was no correlation between weight loss and change in A1c. Patients were on an average of 2.3 units/kg of insulin (range 1.2-6.6 units/kg) prior to initiating GLP-1RA. On follow-up, this insulin dosage decreased to an average of 1.6 units/kg (range 0.8-2.6 units/kg). Daily insulin dose specifically decreased in 7 patients, and the decreases were significant, ranging from 11 to 60 units.8
Non-Glycemic Effects
Another consideration for this patient is her significant risk of either already having cardiovascular disease, or developing it. One exciting feature of GLP-1RAs is their potential to slow the development of cardiovascular disease. Although a number of randomized control prospective studies are still in progress, GLP-1RAs have already been shown to decrease blood pressure, both systolic and diastolic, as well as to have a beneficial effects on lipids, thought to be independent of weight loss.9 There also appear to be a number of pleiotropic effects that may reduce potential for cardiovascular disease,10 although whether these translate into fewer actual cardiovascular events in humans needs to be demonstrated.
Potential Concerns
Gastrointestinal side effects of nausea, emesis, and diarrhea associated with GLP-1RAs can be challenging, although starting at a low dose and titrating as tolerated is helpful. Additionally, the concern of pancreatitis risk, or pancreatic cancer has been addressed in a previous blog. There has also been a concern of a light increase in heart rate associated with GLP-1RAs, the significance of which, if any, remains unclear.