Treating the Obese Diabetic

Julia Kenkre; Tricia Tan; Stephen Bloom

Disclosures

Expert Rev Clin Pharmacol. 2013;6(2):171-183. 

In This Article

GLP-1 Analogues

GLP-1 is a 30 amino acid peptide produced and secreted by the L cells of the intestinal mucosa in response to ingestion of carbohydrates and lipids.[26,27] It stimulates β-cell activity via its Gs-coupled receptor, leading to stimulation of β-cell proliferation and differentiation, insulin gene expression and insulin secretion. Importantly, GLP-1 enhances insulin release in a glucose-dependent manner and therefore has less risk of causing hypoglycemia. The 'incretin effect' is the augmentation of postprandial insulin secretion due to intestinal hormones; GLP-1 accounts for more than 80% of this effect.[28,29] Apart from its role in insulin secretion, GLP-1 acts to suppress glucagon secretion, reduces gastric motility promoting early satiety[30] and reduces the rate of gastric acid production. Our group showed that GLP-1 treatment was able to improve acute glycemic control in Type 2 diabetics.[31]

GLP-1 itself cannot practically be used as a treatment: it has a plasma half-life less than a few minutes as it is degraded to its inactive form, GLP-1(9–36) by DPP-IV[32] and therefore requires multiple subcutaneous injections. GLP-1 analogues have therefore been developed to produce a longer terminal elimination half-life, and these have been shown to cause weight loss and improvement in glycemia in the diabetic population. A meta-analysis of GLP-1 analogues showed that these were able to reduce HbA1c by 0.97% (95% CI: 1.13–0.81%).[33] It has been postulated that shorter acting GLP-1 analogues (exenatide and lixisenatide) reduce hyperglycemia primarily by slowing gastric emptying, whereas longer acting GLP-1 analogues (liraglutide, exenatide long-acting release, albiglutide and dulaglutide) predominantly lower postprandial glucose levels by insulinotropy and glucagon inhibition.[34] Another recent meta-analysis including 25 trials involving exenatide twice daily, exenatide once weekly and liraglutide given for at least 20 weeks in both diabetics and nondiabetics found patients treated with GLP-1 analogues achieved a greater weight loss than control groups (weighted mean difference: 2.9 kg; 95% CI: 3.6–2.2 kg). Additionally, benefits were seen in terms of lowering systolic blood pressure, cholesterol and glycemia.[14] GLP-1 is thought to promote weight loss by central suppression of feeding[35] and via delayed gastric emptying promoting early satiety.[36] While rodent studies have found a favorable effect of GLP-1 analogues on β-cell mass, raising the possibility of a disease-modifying effect, it is probably premature to assume the same will happen in humans, despite some positive studies.[37]

Since insulin use is generally associated with weight gain and GLP-1 analogues with weight reduction, their combination would be expected to be beneficial or at least neutral in terms of bodyweight. A UK-wide audit found that those patients who had exenatide added to insulin therapy obtained a reduction in HbA1c of 0.51% and weight reduction of 5.8 kg along with a decrease in insulin requirements.[38] Randomized clinical trials (RCTs) assessing the addition of insulin to pre-existing GLP-1 analogue treatment found improvement in glycemic control with no weight gain or minimal loss.[39,40]

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