Incretin Therapy

Components of Metabolic Syndrome

  • Obesity
  • Dyslipidemia (raised TG, decreased HDL)
  • Hypertension
  • Insulin resistance and raised FPG

Lifestyle Issues Contribute to Obesity and MetS in Saudi Arabia

A recent study in men indicated that waist size predicted death from heart attack or stroke better than any other traditional risk factors including hypercholestermia or smoking

Every 2 inch increase in waist size increased the risk of dying of CV disease by up to 17% in the next 10 years

Role of Incretin in Glucose Homeostasis

The concept of gastrointestinal hormones (The incretin concept)

The observation that in response to hyperglycemic stimuli, oral glucose elicits a greater insulin response than intravenous glucose, is termed, which accounts for up to 60% of postprandial insulin release in healthy people

Dipeptidyl-peptidase – 4 (DPP -IV ) enzyme*

In 1993 it was demonstrated that Dipeptidyl-peptidase – 4 (DPP -IV ) enzyme mediates the inactivation of GLP-1 and GIP by removing the two N-terminal amino acids of the hormones.

The incretin hormones and Pathophysiology of Type 2 DM

Consequently, in patients with Type 2 diabetes, the incretin effect is either abolished or severely reduced (From normal 60% to < 10%) resulting in inappropriately low insulin secretion following oral ingestion of nutrients.

Exenatide (Byetta)

  • Pen prefill- one month’s supply
  • Given bid, 30-60 minutes prior to meal
  • Nausea experienced by almost all initially, typically remits within days
  • Start at 5 mcg BID, then increase to 10 mcg BID after 1 month
  • Current indication: failing SFU, metformin, or both
  • Not FDA approved with insulin or monotherapy

What are Incretin Hormones?

Incretin History

1906:    First report of antidiabetogenic effect of extract of duodenal mucosa

1932:    Concept of incretin effect first proposed (ie. assumption that intestinal peptides are involved in regulation of postprandial insulin secretion)

1964:    Enhancement of insulin secretion by oral glucose demonstrated in man

1971:    Amino acid sequence of GIP reported

1973:    Insulinotropic effect of GIP demonstrated

1979:    Existence of second incretin hormone postulated

1983:    Proglucagon cloned – sequence of GLP-1 predicted

1986:    Insulinotropic effect of GLP-1 demonstrated

1995:    Therapeutic use of DPP-4 inhibitors first suggested

2002:    Clinical proof of concept – GLP-1 reduces HbA1c levels in T2DM

2005:    First GLP-1 analogue launched as antihyperglycaemic agent

2006:    First DPP-4 inhibitor launched as antihyperglycaemic agent

Incretin Hormones are Gastrointestinal Peptides

  • Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are the 2 major incretins in humans
  • Both are peptide hormones (30 and 42 amino acids)
  • Secreted from open-type endocrine cells (L- and K-cells, respectively) mainly in the distal (GLP-1, ileum, colon) or proximal (GIP, duodenum) small intestinal mucosa
  • Released in response to meal ingestion
  • Responsible for the incretin effect

Incretin-based therapy with GLP-1analogues or DPP4 inhibitors is now widely used; however, understanding of their long-term safety remains incomplete.

Incretin-based therapy in adults with type 2 diabetes

  • is moderately effective in improving glycemia
  • has favorable (GLP-1 analogues)or neutral (DPP4 inhibitors) effects on weight.
  • is rarely, if ever, associated with severehypoglycemia.

Patients should carefully be monitored for the development of pancreatitis after initiation or dose increases of these drugs.

What is now required is further long-term studies using different subgroups of patients.

The results of long-term studies are also required to determine adverse effects with chronic use (such as cancer) as well as outcomes for cardiovascular events and the incidence of microvascular complications.

Careful post-marketing surveillance for adverse effects, especially among the DPP4 inhibitors.