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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

2nd International Congress on Prediabetes and the Metabolic Syndrome

Barcelona, Spain / April 25-28, 2007

In the next 25 years, the number of people with type 2 diabetes mellitus (T2DM) is expected to double from 150 million to 300 million, because of increasingly sedentary lifestyles and poor diets. Such an increase would place a huge burden on health services, so prevention is clearly important.

A Precursor to Clinically Manifest Disease

A key aspect of any prevention strategy would be to identify individuals at risk of developing T2DM. Prof. Sir George Alberti, Imperial College, London, UK, and long-standing member of the World Health Organization Expert Advisory Panel on Diabetes, explained that the current concept of prediabetes was formulated in 2002 when the American Diabetes Association (ADA) was concerned about the impact of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), but decided that these terms “didn’t have any punch to them.” Importantly, though this definition does not include all people at risk: “If you have a first-degree relative with diabetes, you have a 40% lifetime chance of diabetes, which is higher than if you have got IFG, for example,” explained Prof. Alberti. Another problem with this definition is that two different entities such as IFG and IGT are grouped together, even though there is solid evidence to suggest that IGT is associated with increased risk of macrovascular disease whereas such a link is much more tenuous in the case of IFG.

Lifestyle Modifications

It is only useful to define a concept such as prediabetes if interventions are possible. In the opinion of Dr. Stefano del Prato, University of Pisa, Italy, “Diabetes is spreading because of lifestyle changes… therefore we could try and reverse these lifestyles.” General health education programs should be aimed particularly at young people. Dr. del Prato commented on the prevalence of aggressive antismoking campaigns while a healthy diet and physical activity is less strongly promoted, even though the consequences of an unhealthy lifestyle can be serious. In individuals already considered prediabetic, the Finnish Diabetes Prevention Study showed that a lifestyle intervention could reduce the incidence of conversion to T2DM by 58% compared to the control group (Tuomilehto et al. N Engl J Med 2001;344(18):1343-50). Furthermore, in a follow-up study, a carryover effect was observed, that is, those who had originally received counselling continued to have a lower conversion rate to T2DM.

Pharmacological Interventions

Although lifestyle interventions have been shown to be effective in clinical studies, they are often hard to apply in clinical practice. In many ways, resorting to drugs can be considered a “simpler” intervention. The Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study of adults with IFG showed that rosiglitazone was effective at preventing diabetes, but there was a significant increase in heart failure in the treatment arm (14 [0.5%] vs. two cases [0.1%] in the control group; P=0.01). “These are small numbers, so you might think that it is worthwhile to run the risk of heart failure because of the very effective prevention of diabetes,” stated Dr. del Prato, but we should also consider “how many patients amongst those who would not spontaneously convert to T2DM are at risk of heart failure.” Viewed in this way, the risk:benefit ratio of rosiglitazone as preventative therapy is less appealing.

Another point is that a pharmacological intervention should aim to modify the underlying processes, and not just treat their manifestations. Follow-up of the patients from the DREAM study after the end of treatment showed no significant difference in the rate of conversion to T2DM, that is, there was no carryover effect with rosiglitazone.

The Incretin Effect

“If we administer glucose orally and intravenously, the body ‘sees’ the same glucose, but the body’s response is different in each case, and the beta-cell response is much higher when glucose enters through the stomach,” affirmed Dr. Daniel Drucker, Mt. Sinai Hospital, Toronto, Ontario. This enhanced beta-cell response is due to substances known as incretins, in particular, glucose-dependent insulinotropic peptide (GIP) and glucogen-like peptide-1 (GLP-1), which are released in response to food. When diabetes has become clinically manifest, the incretin effect is smaller. Individuals with IGT and IFG who progress to T2DM therefore might somehow have defective incretin action. In this case, progression may be prevented by restoring incretin function.

Infusion of incretins has been tried as a therapy, but they are rapidly degraded by the dipeptidyl peptidase-4 (DPP-4) enzyme. Alternatively, levels of GIP and GLP-1 can be increased through inhibition of DPP-4. DPP-4 inhibitors (also known as incretin enhancers) such as sitagliptin and vildagliptin have been shown to improve blood glucose profiles in patients with T2DM with limited risk of hypoglycemia. An attractive feature of these inhibitors is that they do not induce weight gain. “Because these incretin-based therapies mimic the body’s physiology, they are emerging as safe therapies with a good adverse-event profile,” concluded Dr. Drucker.

Clinical Study Findings

According to researcher Dr. Gaia Panina, Basel, Switzerland, “There have been more than 5000 patients treated with vildagliptin in phase III studies for up to two years.” Studies include monotherapy vs. placebo, head-to-head vs. metformin and rosiglitazone, and as an add-on to a thiazolidinedione, metformin or insulin in patients with T2DM. In the direct- comparison studies, efficacy was generally comparable. Importantly, the adverse-event profile with the DPP-4 inhibitor appeared more favourable—the incidence of gastrointestinal events in the pooled analysis was much lower than for metformin (diarrhea: 3.1% vs. 26.2%; nausea: 2.9% vs. 10.3%; and abdominal pain: 1.2%, vs. 7.1%, respectively). Hypoglycemia was also infrequent (<1% of patients in the pooled analysis).

Dr. Panina also presented preliminary results of vildagliptin monotherapy in individuals with IGT. The decrease observed in blood glucose after a meal was not mirrored by an increase in the insulin concentration and a 20% improvement in beta-cell function was observed.

ADA Consensus Statement for Prediabetes

Dr. Julio Rosenstock, Dallas Diabetes and Endocrine Center, and Professor of Medicine, University of Texas Southwestern Medical School, presented a very recent ADA consensus statement (Nathan et al. Diabetes Care 2007;30:753-9). The statement firstly defined cutoff values of 7.8 to 11.0 mM for IGT and 5.6 to 6.9 mM for IFG. For individuals with isolated IGT or IFG, the statement recommends lifestyle interventions with a reduction of 5 to 10% in weight and moderate daily physical activity. But in those with both IGT and IFG and one of a number of other conditions (e.g. high body mass index, family history of diabetes, unfavourable lipid profile), the statement goes further and recommends metformin in addition to lifestyle modification. “For the first time, a pharmacological drug that has been with us for a long time and done very well is recommended in prevention,” remarked Dr. Rosenstock, but “I am not afraid to take a position; I don’t see this drug as a potential therapy because of the side-effect profile.” In contrast, he added, while the jury is still out on DPP-4 inhibitors, studies so far demonstrate their comparable efficacy to metformin with a more attractive adverse-event profile.

Summary

Clinicians are now in a position to think in terms of preventing T2DM. Lifestyle interventions have been shown to work and pharmacological interventions may also prove effective, although hard evidence is not yet available. In view of this, in their closing remarks, the panel concluded that now is the time to think of prevention studies.

Note: At the time of printing, sitagliptin and vildagliptin are not available in Canada.