Incretin based treatment
The incretin-based therapies were developed as a consequence of painstaking investigation of two unsolved problems in diabetes. The first was the nature of the incretin effect, whereby oral glucose stimulates a greater insulin response than intravenous glucose, and the second was the function of various glucagon-like molecules secreted by cells lining the intestine. This led to the discovery that the gut peptides GLP-1 and GIP are released in response to oral nutrients and promote insulin secretion by the pancreas, thus accounting for the incretin effect. GLP-1 levels are deficient in type 2 diabetes, suggesting therapeutic possibilities; the main obstacle was that GLP-1 has a very short (1-2 minute) survival in the circulation. Two strategies have been used to overcome this. The first is development of GLP-1 receptor agonists which are resistant to degradation, and the second is inhibition of the DPP4 enzymes which degrade GLP-1, thereby enhancing delivery of the naturally-produced hormone. Both GLP-1 agonists and DPP4 inhibitors are in wide use, but concerns have been raised as to the pleiotropic effects of GLP-1, whose actions on the exocrine pancreas might for example explain why there have been safety alerts for acute pancreatitis for many agents in this class.
The "incretin effect" describes a long-recognised phenomenon whereby oral glucose provokes a greater insulin secretory response than the same amount of glucose injected into a vein. This strongly suggested a mediating factor(s) which augments insulin secretion, but the nature of the stimulus was unknown.
It was also known that administration of an extract from the upper intestine could produce a fall in blood glucose, and In 1932 La Barre proposed the name "incretin" for the presumed hormone. Here matters rested until the identification of the gut peptides in the 1960s. Glucagon itself stimulates insulin secretion, but the role of a family of immunoreactive glucagon-related peptides in cells lining the intestine remained conjectural.
This family of glucagon-related molecules includes the 69 amino-acid glicentin and a truncated form known as oxyntomodulin. Gastric inhibitory peptide, identified in 1970, was renamed glucose-dependent insulinotrophic peptide (also GIP) when its ability to stimulate insulin was demonstrated, but evidence emerged that GIP alone could not be wholly responsible for the incretin effect.
Proglucagon was cloned and sequenced in 1983, with the surprising information that the molecule contained two additional glucagon-like sequences, coding for two glucagon-like peptides, subsequently known as GLP-1 and GLP-2. GLP-2 is an important gastrointestinal growth factor, and the 7-37 sequence within GLP-1 was found to be the most powerful insulinotropic agent yet known , thus explaining the incretin effect .
GLP-1 as a therapy
Several investigators then undertook the experiment of infusing GLP-1 into volunteers. High infusion rates induced nausea and vomiting, but lower rates reduced glucose effectively with minimal side effects for up to 6 weeks of therapy. Studies published in 1992 confirmed efficacy in volunteer patients with type 2 diabetes. Long term IV administration is clearly impractical, but these studies provided proof of concept for the development of stable analogues for clinical use.
Development of GLP-1 receptor agonists.
The short-half-life of GLP-1 in the circulation (1-2 minutes) is due to its speedy inactivation by the enzyme Dipeptidyl Peptidase 4 (DPP4). Amino-acid substitution overcame this problem but did not greatly prolong the half-life of some analogues since native GLP-1 is actively eliminated by the kidney.
Figure 1. The Gila Monster A number of biologically active peptides were discovered by analysis of substances secreted by amphibians in their skin or saliva. These included peptides closely related to GLP-1, notably Exendin-4, which is present in the saliva of the Gila monster, Heloderma suspectum (figure 1). Exendin-4 is resistant to degradation by DPP4 and is not actively excreted by the kidney. This, under the name exenatide (Byetta), was approved by the FDA in April 2005, and became the first clinically useful GLP-1 receptor agonist. Exenatide has a plasma half-life of 30 minutes, and can therefore be administered by twice daily injection. A very long-acting variant (Bydureon) permitting once-weekly injection was subsequently developed.
A second GLP-1 receptor agonist named liraglutide (Victoza) is resistant to DPP4 inactivation and renal elimination by virtue of a short fatty acid chain attached to the molecule, and has a plasma half-life of 12 hours, allowing once daily injection. Other GLP-1 analogues are in various stages of development.
Efficacy and Safety
The GLP-1 agonists are very effective in selected patients since they target both blood glucose and body weight. This is achieved by a combination of actions, including stimulation of insulin secretion, delayed gastric emptying (thus slowing post-prandial glucose rises), inhibition of glucagon secretion, and central effects upon appetite. Earlier hopes that they might also promote beta cell regeneration were not fulfilled: this effect is only seen in immature rodents.
GLP-1 is a pleiotropic agent which has many biological effects other than those related to its therapeutic action, and its receptors are widely distributed in tissues such as elements of the vascular system, thyroid, kidney and exocrine pancreas. Described effects upon the thyroid and exocrine pancreas have prompted particular concern. Rare C-cell thyroid tumours have been reported in rodents, as has a gain in pancreatic weight and other morphological changes. Subclinical increases in pancreatic enzymes are relatively frequent, although their clinical significance remains uncertain, and acute pancreatitis has been reported in association with both exenatide and liraglutide. Acute renal failure sometimes requiring dialysis and transplantation is well recognised, and a signal for carcinoma of the pancreas has also been noted in two regulatory databases(see GLP-1 based therapies and cancer).
The DPP4 Inhibitors
By 1993, in vitro studies had shown that both GIP and GLP-1 are N-terminally degraded to an inactive metabolite by DPP4, and the same phenomenon was soon documented in vivo. DPP4 is widely distributed in the capillary endothelium, renal tubules and hepatocytes, and its location in the endothelium of capillaries adjacent to the GLP-1 containing L cells of the intestine showed that a proportion of the secreted peptide is degraded before it even reaches the circulation. By 1995 DPP4 inhibition was already under consideration for the treatment of diabetes.
Efficacy and Safety
Although technically non-inferior to metformin, the DPP4 drugs are generally considered less potent in lowering blood glucose, and their main selling points have been their novel mode of action and apparent safety. Similarly, they appear less potent than the GLP-1 agonists and do not induce weight loss. Reported side effects do however include acute pancreatitis, warnings for which have been issued for every widely-used agent in the class, and acute renal failure sometimes requiring dialysis. Animal studies suggest the potential to induce growth and proliferation of pancreatic exocrine tissue, although human studies are lacking. DPP4 inhibition is not restricted to GLP-1 and GIP, and effects upon other regulatory systems are not known. DPP4 is a tumour suppressor, and its inhibition might theoretically enhance growth of some types of cancer.
Agents in the Class
Sitagliptin (Januvia) FDA approved October 2006, marketed by Merck.
Vildagliptin (Galvus) not approved by FDA, marketed in EU by Novartis. Vildagliptin is named for the chemist Edwin B. Villhauer, and did not receive FDA approval because of blistering skin lesions in non-human primates.
Saxagliptin (Onglyza), FDA approved July 2009, marketed by Bristol-Myers-Squibb
Linagliptin (Trajenta), FDA approved May 2011, marketed by Boehringer Ingelheim and Lilly
Alogliptin (Nesina) Approval stalled by FDA since the application was submitted in December 2007, for reasons which are unclear, but licensed in Japan. FDA approval finally granted January 25th 2013.
Lixisenatide (Lyxumia), marketed by Sanofi. Outline approval granted in Europe (November 2012), Application filed in USA (January 2013).
The GLP-1 based therapies have been well received and are widely used. There is as yet no evidence that they influence hard outcomes in diabetes, however, and their long term cardiovascular risks and benefits are unknown. Finally, and although conclusive evidence of harm is still lacking, there is a disturbing potential for off-target effects with all these agents which requires ongoing scrutiny.
^ Holst JJ. Glucagon-like peptide 1: from extract to agent. The Claude Bernard Lecture 2005. Diabetologia 2006;
^ Gutniak M et al. Antidiabetogenic effect of glucagon-like peptide -1 (7-37) amide in normal subjects and patients with diabetes mellitus. N Engl J Med 1992;326:1316-22
^ Nathan DM et al. Insulinotropic action of glucagonlike peptide-1 (7-37) in diabetic and non-diabetic subjects. Diabetes Care 1992;15:270-6
^ Deacon CF, Holst JJ. Dipeptidyl peptidase IV inhibition as an approach to the treatment and prevention of type 2 diabetes: a historical perspective. BBRC 2002;294:1-4