Breay W. Paty, MD, FRCPC (biography and disclosures)
What I did before
Until recently, the standard approach to managing type 2 diabetes consisted of “lifestyle” (diet and exercise) therapy, along with metformin, followed by either sulfonylurea (glyburide or gliclazide), or TZD (rosiglitazone or pioglitazone), and eventually insulin, depending on the circumstance (1). In the last few years, the use of TZDs has declined; mostly reflecting the recognition of potential side effects, such as weight gain, edema, and possible cardiovascular effects of rosiglitazone (2). At the same time, a new class of agents, incretins, has emerged, with both real and potential advantages over previous agents (3). However, as with any new class of agents, long term follow-up will be required before we can fully understand the role (including risks and benefits) of these new agents.
What changed my practice
Incretins utilize the physiologic effects of a gut hormone, Glucagon-like peptide-1 (GLP-1), to augment pancreatic insulin secretion, thereby lowering blood glucose. One group of agents [DPP-4 inhibitors: sitagliptin (Januvia®), saxagliptin (Onglyza®), linagliptin (Trajenta®)], blocks the rapid breakdown of natural GLP-1, by inhibiting the enzyme DPP-4. These oral agents, administered once daily, augment endogenous GLP-1, resulting in an A1C reduction of 0.5 – 0.9%. Since GLP-1 does not directly stimulate insulin, they have the advantage of not promoting hypoglycemia or weight gain. Another approach uses peptides with similar effects as GLP-1, but which are not degraded as quickly. These so called “incretin mimetics” include liraglutide (Victoza®) and exenatide (Byetta®) and are administered by subcutaneous injection, once or twice daily, respectively. In addition to augmenting insulin secretion, the incretin mimetics can slow gastric emptying, reduce appetite and promote weight loss, which can further improve metabolic control (approximate A1C reduction: 1 – 1.5%). For individuals in whom weight gain is a particular concern, these added benefits can outweigh the disadvantages of injection therapy. There may be additional effects, including improving surrogate markers of CV risk such as blood pressure, and lipids, but it is not clear whether these effects are clinically significant. The primary dose-limiting side effect of the incretin mimetics is nausea, which often improves with time. Other possible (though rare and not proven) side effects include risks of pancreatitis and thyroid c-cell hyperplasia observed in rodents, but is not clear whether these occur more frequently in humans (4).
What I do now
Since the advent of incretin therapy, my approach to the management of type 2 diabetes has become more nuanced, tailoring therapy for each patient, rather than “one size fits all”. After lifestyle and metformin, the choice of a 2nd line agent should be based on the:
a) Amount of A1C lowering desired
If the desired A1C lowering exceeds the demonstrated ability of an agent to achieve, then it should not be used. For example, a DPP-4 inhibitor may be a reasonable choice for an A1C between 7.0 – 8.5% (A1C lowering ~ 1%), but would not be a good choice if the A1C exceeded this range. If the desired A1C lowering exceeds 1.0 – 1.5% and hypoglycemia or weight gain is not of particular concern, a sulfonylurea or even pioglitazone (in selected patients) may be more effective.
b) Potential for side effects
If weight gain or hypoglycemia is of concern, then an incretin agent would be advantageous over a sulfonylurea, such as glyburide. If weight loss is desired, then only the injectable incretin mimetics have been demonstrated to achieve this. If the relative lack of data regarding possible long-term side effects is concerning, then using more established agents may be more appropriate until more long-term data is available.
Before initiating any new agent, it is important to establish whether the patient has extended (private) medical coverage. If no extended medical coverage is available to help defray the higher cost of these new agents, then less expensive agents may be satisfactory, unless side effects preclude their use.
Type 2 diabetes is a complex metabolic condition with many variables influencing its presentation, progression, risk of complications and metabolic control. The more therapeutic options available, the more challenging it can be for prescribers to choose the right therapy. Incretin agents offer additional options to address some of this complexity and improve the ability to tailor therapy for individual patients. If used properly, in the right patient, under the right circumstance, incretin agents can improve glycemic control and offer additional benefits, while avoiding some common side effects of more traditional agents.
References (Note: Article requests require a login ID with CPSBC or UBC)
- Canadian Diabetes Association 2008 Clinical Practice Guidelines for the prevention and management of diabetes in Canada. Pharmacologic management of type 2 diabetes. Canadian Journal of Diabetes 2008; 32(1): S53 – S61. (View article)
- Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 2007 Sep; 370: 1129-36 (View article with CPSBC or UBC)
- Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006; 368: 1696-705. (View article with CPSBC or UBC)
- Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA 2007; 298: 194-206. (View article with CPSBC or UBC)