Many new drugs are in various stages of development for the treatment of type 1 and type 2 diabetes. This article highlights some of the novel therapies that were featured at the 2011 annual meeting of the American Diabetes Association and were recently approved by the US Food and Drug Administration (FDA) or are furthest along in clinical trials.
New Drugs for Type 2 Diabetes
Dipeptidyl Peptidase-4 Inhibitors
Linagliptin (Tradjenta) belongs to the dipeptidyl peptidase (DPP)-4 inhibitor class that was recently approved by the FDA for type 2 diabetes and has the potential to replace sulfonylureas in the future, according to Baptist Gallwitz, MD, Outpatient Clinics for Endocrinology, Diabetes, and Metabolism, Eberhard Karls Universität, Tübingen, Germany. Linagliptin is not excreted renally and therefore no dose adjustments are needed in patients with renal impairment. With sulfonylureas, patients need to be taught to self-measure blood glucose, which involves substantial costs in terms of healthcare personnel time and purchasing testing strips and meters; this is not necessary with linagliptin, which could potentially result in cost-savings, according to Dr Gallwitz.
Alogliptin (Nesina) is another DPP-4 agent in late-stage development. It is already approved in Japan. Alogliptin had been submitted for approval to the FDA, but in 2008 the FDA requested additional information regarding cardiovascular safety. A clinical trial examining the cardiovascular safety profile of the drug is ongoing. On July 26, 2011, alogliptin was resubmitted to the FDA, based on interim results from the ongoing trial showing cardiovascular safety for this drug.
Glucagon-Like Peptide-1 Receptor Agonists
Exenatide is being investigated as 2 new formulations— once weekly (Bydureon) and once monthly.
The twice-daily formulation of this drug (Byetta) was approved by the FDA in 2005. Exenatide works by reducing the level of blood glucose, mimicking the effect of incretins, such as glucagon-like peptide (GLP)-1 receptor agonists. The GLP-1 agonists increase the secretion of insulin from the pancreas, slow the absorption of glucose from the gut, and reduce the action of glucagon. In addition, GLP-1 agents reduce appetite, an important quality in a disease that is often associated with being overweight. Studies have shown that the original formulation of exenatide sustains glycemic control and weight loss for up to 2 years.
At the meeting, 3-year data from Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) and 84-week data from Once-Weekly Exenatide Injection Improves Blood Sugar Control More Than Daily Oral Sitagliptin or Pioglitazone and Induces More Weight Loss (DURATION- 2) were presented. Long-term extensions of the DURATION-1 and 3 additional studies demonstrated that after 3 years, the once-weekly formulation achieved a significant 1.6% reduction from baseline in hemoglobin (Hb) A1c and weight (5.1 lb).
Cardiometabolic risk markers also improved, including systolic blood pressure (–2.1 mm Hg), total cholesterol (–9.9 mg/dL), low-density lipoprotein cholesterol (–7.0 mg/dL), and triglyceride levels (–12%). Bydureon was approved in the European Union in June 2011.
A phase 2 clinical trial showed that the oncemonthly investigational formulation of injectable exenatide achieved substantial improvements in glycemic control, including reductions in HbA1c and fasting plasma glucose and modest weight loss. The study included 121 patients given 3 different doses of once-monthly exena tide. More than 90% of the patients completed the study.
Lixisenatide (Lyxumia) achieved positive results in patients not achieving glycemic goal with oral therapies or basal insulin. In the GetGoal-X trial, once-daily lixisenatide achieved noninferiority results in HbA1c reduction versus twice-daily exenatide; both drugs were used as add-on to metformin in patients inadequately controlled with metformin.
A second study, GetGoal-L Asia, presented at the meeting showed that Asian patients with type 2 diabetes who were inadequately controlled with basal insulin with and without a sulfonylurea were significantly improved with lixisenatide once daily versus placebo at week 24, as reflected by the improvement in HbA1c level, with a target of <6.5% or <7.0%.
Sodium-Glucose Cotransporter-2 Inhibitors
Sodium-glucose cotransporter (SGLT)-2 inhibitors represent a promising new class of drugs for treatment of type 2 diabetes. These drugs work by inhibiting reabsorp-tion of endogenously produced glucose in the proximal tubules of the kidney.
Results from a phase 3 trial showed that the investigational SGLT-2 inhibitor dapagliflozin added to metformin sustained reductions in HbA1c from 52 weeks to 104 weeks in adults with type 2 diabetes compared with glipizide (a frequently used sulfonylurea) added to metformin. Adverse events were similar in frequency between the 2 treatment arms. These results are from an extension phase of the original 52-week trial. Weight reduction was sustained at 104 weeks, and hypoglycemic episodes were reported 10 times more frequently in patients treated with glipizide plus metformin (45.8% with glipizide plus metformin vs 4.2% for dapagliflozin plus metformin). Genital and urinary tract infections were more frequent with dapagliflozin than with glipizide.
A randomized, double-blind, placebo-controlled, parallel- group, multidose study showed that canagliflozin is safe and generally well-tolerated at doses up to 300 mg twice daily when added to stable doses of insulin in subjects with type 2 diabetes. The drug reduced the renal threshold for glucose excretion, improved glycemic control, and was associated with weight loss. A trend toward blood pressure reduction was observed, with no ortho - static symptoms.
Ultra–Long-Acting Insulin Degludec
Studies show promise for the investigational ultra– long-acting basal insulin, degludec. This drug’s activity lasts for up to 40 hours and may be able to reduce the frequency of insulin dosing. At the meeting, two phase 3, 52-week trials (one in type 1 diabetes and one in type 2 diabetes) showed that ultra–long-acting insulin degludec reduced the rates of hypoglycemia compared with insulin glargine.
A second late-breaking 26-week study showed that insulin degludec could be dosed at different times from day to day.
Drugs in Development for Type 1 Diabetes
In a phase 3, double-blind, multinational study, the anti-CD3 drug teplizumab (which modulates T-cells) failed to show a significant improvement over placebo on the combined goal of reducing the HbA1c level to <6.5% for patients newly diagnosed with type 1 diabetes and reducing the amount of insulin needed to <0.5 U/kg of body weight per day.
Although the study did not achieve this combined goal, 5% of the patients who received treatment with teplizumab no longer needed insulin at the end of 1 year compared with none of those who received placebo, noted lead researcher Nicole Sherry, MD, Director of the Diabetes Center at the Massachusetts General Hospital for Children in Boston.
In a post-hoc analysis, 40% of those who received a 14-day regimen of teplizumab experienced a preservation of or increase in C-peptide levels compared with 28% of those in the placebo group.
A phase 2 study looked at whether giving a second course of teplizumab intravenously a year after it was first administered could prolong its effects. Those who were given teplizumab continued to show improved beta-cell function even 2 years after diagnosis over an untreated group.
Teplizumab recipients experienced a 45% decrease in beta-cell function over 2 years compared with a 77% decrease for those in the untreated group. In addition, at 24 months, the untreated group used 57% more insulin, on average, than the group that received teplizumab.
DiaPep277 is a potential vaccine for type 1 diabetes, with the goal of preventing beta-cell destruction. During the development of type 1 diabetes, an increase in a protein in the beta-cell, called “heat shock” protein, is thought to cause beta-cell destruction through activation of destructive T-cells.
In a phase 2 study, the altered heat shock protein, given subcutaneously to 100 patients newly diagnosed with type 1 diabetes, succeeded in protecting the betacells, replicating in humans the findings in laboratory mice. Administering this vaccine also allowed beta-cells to continue to secrete insulin for up to 2 years after a type 1 diagnosis. The drug is currently in phase 3 trials in which beta-cell function, insulin use, and glucose control are being monitored.
Abatacept is being studied in a phase 2, randomized study that is comparing the effects of abatacept with those of placebo in patients newly diagnosed with type 1 diabetes. Abatacept recipients experienced a 59% increased level of C-peptide at the end of 2 years compared with the placebo group. On average, abatacept preserved beta-cell function for an additional 9.6 months.
“The problem is, despite giving the drug for 2 years, we only had a 9.6-month delay,” said Jay Skyler, MD, Chairman of the National Institutes of Health–funded Type 1 Diabetes TrialNet study group, which conducted the study. “That means that the effect over time may have been lost. It may have had an effect early on that created the delay and then may have lost further effect as time went on.”