Late-breaking Clinical Trials

Look AHEAD: 1 Year Results

The goal of the Look AHEAD study was to test whether lifestyle intervention aimed at reducing and maintaining weight can affect cardiovascular risk in people with type 2 diabetes. Participants were randomly assigned to 1 of 2 groups: the Intensive Lifestyle Intervention (ILI) or the Diabetes Support and Education (DSE). ILI phase 1 consisted of weight loss induction for the first 6 months, with a weight loss goal of 7% of body weight. During this time, participants participated in 2 group sessions and 1 individual session per month. ILI phase 2 was geared toward weight maintenance for months 7-12. During this time, frequency of group and individual sessions was decreased.

Specific recommendations for the ILI group included:
Dietary intake: 

• 1200-1500 kcal for patients < 250 lbs
• 1500-1800 kcal for patients > 250  lbs
• Meal replacements 
• Menus provided

  Physical activity:

• Gradual increase
• 175 min/week
• 10,000 steps

Participants in the DES group attended 3-4 meetings per year. Topics covered included diet, exercise, social support, and diabetes complications. They did not receive any lifestyle intervention.

After 1 year in the program, participants in the ILI group lost 8.3 kg, with men losing more than women on average. Weight loss continued for about 8 months. In terms of fitness improvements, the ILI group improved their fitness by 20.7% compared with the 5.7% improvement seen in the DSE group. Fitness improvements were greater for patients with higher body mass index. The change in fitness seen in the ILI group remained significant, even after controlling for weight loss. Glycemic control dropped 0.64% in the ILI group, compared with a  0.14% drop in the DSE group. More people in the ILI group (26%) met their glycemic goal of A1C < 7% compared with the 5% increase in the number of patients meeting goal in the DSE group. The ILI group also had a 9% drop in medication use and significant decrease in blood pressure.

Use of Vildagliptin for Treatment of Patients With Type 2 Diabetes

Vildagliptin is a highly selective inhibitor of the protease dipeptidyl peptidase IV (DPP-IV) that is rapidly absorbed after oral administration and does not show effects on weight or gastric emptying. It has been shown to be effective for the treatment of patients with type 2 diabetes at the 100 mg dose. Because no differences have been observed between once-daily and twice-daily dosing, vildagliptin is administered as 100 mg once daily. It appears to be effective across hyperglycemic spectrum, with an average drop in A1C of 1.1%. For patients with higher A1C values, there may be a greater effect. Patients with A1C > 8% showed an average drop of 1.3%, and patients with A1C > 9% showed an average drop of 1.7%. No difference in efficacy has been observed by age or baseline weight. Vildagliptin appears to be weight-neutral, and can improve HDL cholesterol.

Vildagliptin monotherapy studies have shown a comparable glycemic improvement to rosiglitazone, but vildagliptin use resulted in a better lipid profile. When compared with metformin, vildagliptin was comparable, but was associated with superior GI tolerability. The overall adverse events profile was comparable to placebo.

In combination therapy with metformin, a 0.9% drop in A1C was observed (1.3% at higher baseline A1C levels), and no weight gain was observed. When vildagliptin was given in conjunction with pioglitazone, there was a 1.9% drop in A1C.

In short, vildagliptin has the potential to impact disease pathophysiology. It enhances GLP-1 levels, suppresses glucagon secretion, and suppresses endogenous glucose production. It has a low risk of hypoglycemia and does not interact with commonly prescribed agents.

Sitagliptin: A Novel DPP-4 Inhibitor for the Treatment of Patients With Type 2 Diabetes

The incretin hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1)  have been shown to increase insulin secretion and decrease glucagon secretion. Both hormones are rapidly degraded by DPP-IV. Sitagliptin is a potent and highly selective inhibitor of DPP-IV in development for the treatment of type 2 diabetes. No toxicity has been seen in preclinical studies of sitagliptin, and no clinically important drug-drug interactions have been observed.

In clinical studies, a single dose increased active GLP-1 and GIP over 24 hours and also increased insulin, suppressed glucagon, and reduced glucose excursion following glucose load. In monotherapy studies, a significant A1C reduction was seen at 18 weeks (0.6%) and at 24 weeks (0.8%). Greater reductions were observed in patients with higher baseline A1C values. Fasting and postprandial glucose levels also improved with sitagliptin. Additionally, sitagliptin improved ß-cell response to glucose, reduced proinsulin/insulin ratio, and increased HOMA-B.

In combination therapy studies, rapid and progressive A1C reductions were seen, with a 0.65% drop observed after 24 weeks when sitagliptin was used in conjunction with metformin. Additionally, more patients reached A1C goal with sitagliptin monotherapy and combination therapy with metformin and TZD therapy. When either sulfonylurea or sitagliptin were added to metformin, comparable glycemic reductions were seen. Safety and tolerability were similar to placebo, with very little hypoglycemia observed. Additionally, sitagliptin is weight neutral.

Sitagliptin was associated with A1C reductions that were sustained up to 1 year. It also improved ß-cell function. Compared to SU add-on therapy, sitagliptin produced the same efficacy with less hypoglycemia and weight loss.

Liraglutide Improves Beta-Cell Function and Glycemic Control in Type 2 Diabetes 

Liraglutide is a GLP-1 analog that binds to albumin in order to slow absorption from subcutaneous tissue and provide improved stability against DPP-IV and a long plasma half-life. A single injection of liraglutide provides 24-hour coverage, so it is suitable for once-daily dosing. In phase 2 studies, patients who were treated with 14 weeks of liraglutide monotherapy showed a significant decrease in A1C, a greater percentage of patients who met glycemic targets, and a decrease in weight. Hypoglycemia with liraglutide was comparable to hypoglycemic events seen with metformin.

Liraglutide also showed effects on ß-cell function, including increased ß-cell mass in rodent models of type 2 diabetes and increased  ß-cell differentiation in immature human pancreatic cells. In humans, ß-cell function can be measured in a number of ways, including tests of ß-cell sensitivity, HOMA, proinsulin:insulin ratio, first phase insulin response, and maximal insulin secretory capacity using a glucose clamp. Liraglutide restored ß-cell sensitivity after 1 dose. It has also been shown to increase HOMA measurements and improve both proinsulin:insulin ratio and first phase insulin response. Additionally, in hyperglycemic clamp studies, liraglutide increased maximal ß-cell capacity 2-fold.

In short, liraglutide improves glycemic control and ß-cell function and also promotes weight loss. It appears to be well tolerated, with a low incidence of hypoglycemia.