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The 70th Scientific Sessions of the American Diabetes Association was attended by 13,500 health care professionals and 17,000 individuals from June 25 to 29, 2010, in Orlando, Florida. This article reviews two sessions showing improved glycemic control with sitagliptin (Januvia and Janumet), a subset analysis of the TRINITY trial looking into hypertension in diabetes, and research on an investigational agent (GFT505) used to treat prediabetic patients with metabolic disorders.
Initial treatment combining sitagliptin and metformin (Janumet, Merck) produced significantly greater improvement in glycemic control and weight loss when compared with initial pioglitazone (Actos, Takeda/Lilly) in patients with type-2 diabetes mellitus. The finding comes from a study of 517 patients who were randomly assigned to receive sitagliptin/metformin, with the dose titrated upward over four weeks to 50/1,000 mg twice daily (n = 261), or pioglitazone, with the dose titrated upward over four weeks to 45 mg once daily (n = 256).
At baseline, subjects’ glycosylated hemoglobin (HbA1c) levels were between 7.5% and 12% (mean 9% for sitagliptin/metformin and 8.9% for pioglitazone); mean fasting plasma glucose (FPG) was 190.6 mg/dL for the sitagliptin/metformin group and 188.9 mg/dL for those receiving pioglitazone.
At week 32, the decrease in HbA1c was −1.9% with sitagliptin/metformin and −1.4% with pioglitazone (P < 0.001). In addition, a significantly greater proportion of patients in the sitagliptin/metformin group achieved HbA1c below 7%, compared with the pioglitazone group (57% vs. 43%; P < 0.001).
FPG was reduced by 56 mg/dL with the combination therapy, compared with a reduction of 44 mg/dL with pioglitazone (P < 0.001). Two-hour postprandial glucose reductions were higher for sitagliptin/metformin (−102.2 mg/dL) than for pioglitazone (−82 mg/dL) (P < 0.001).
Although mean weight loss was 1.4 kg (about 3 pounds) among patients receiving sitagliptin/metformin, the pioglitazone group had a mean weight gain of 3 kg (P < 0.001).
Diarrhea occurred more frequently in patients receiving sitagliptin/metformin (15.3% vs. 4.3%; P < 0.001), as did nausea (4.6% vs. 1.2%; P = 0.02) and vomiting (1.9% vs. 0.0%; P = 0.026); however, edema was lower with the combination (1.1%) than with pioglitazone (7%) (P < 0.001). The incidence of hypoglycemia was similar in the two study groups.
Dr. Katz concluded, “These findings are highly clinically meaningful, since managing blood glucose and weight are critical in clinicians’ decisions about treatment.”
In a clinical trial of 1,072 patients with type-2 diabetes mellitus, glycemic control was similar between those receiving either sitagliptin (Januvia, Merck) or the sulfonylurea glipizide (Glucotrol, Pfizer); however, more patients receiving sitagliptin had HbA1c reductions of greater than 0.5% without experiencing hypoglycemia or weight gain.
All patients were receiving metformin (Glucophage, Bristol-Myers Squibb) monotherapy at baseline and had inadequate glycemic control (HbA1c between 6.5% and 10%). They were randomly assigned to receive add-on sitagliptin 100 mg/day (n = 588) or add-on glipizide 5 mg/day, with the dose titrated upward to 20 mg/day, as needed (n = 584), for 104 weeks.
At the 52-week analysis, Dr. Seck reported, sitagliptin was non-inferior to glipizide in mean HbA1c reductions (0.7% for both). However, a significantly higher proportion of patients in the sitagliptin group (38.1% of 388 evaluable patients) achieved the primary composite endpoint of glycemic improvement (more than 0.5%) without weight gain or hypoglycemia, compared with patients receiving adjunctive glipizide (11.8% of 415 evaluable patients). The relative difference between the cohorts was 26.3%, and the odds ratio for achieving the composite endpoint was 5.43 with sitagliptin compared with glipizide.
In addition, significantly more patients in the sitagliptin cohort, with HbA1c baseline levels either above 8% or below 8%, achieved the composite endpoint (55.8% and 31.7%, respectively), compared with these same subgroups in the glipizide cohort (20.9% and 8.3%, respectively).
Dr. Seck concluded, “The odds of achieving a composite endpoint of HbA1c reduction from baseline of more than 0.5% without hypoglycemia and weight gain were more than five times higher with sitagliptin than with glipizide.”
Results from the subset of patients with hypertension and diabetes mellitus in the TRINITY (Triple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients) study show greater blood pressure (BP) reductions with three drugs in combination—olmesartan medoxomil (OM)/hydrochlorothiazide (HCTZ) plus amlodipine besylate (AML)—than with all dual combinations of the same drugs. Because of the strong linkage between cardiovascular disease, stroke, renal disease progression, and diabetic retinopathy, Dr. Oparil said that hypertension concomitant with diabetes was an important medical concern.
The phase 3, multicenter, 12-week TRINITY study (with a 40-week open-label extension period) included patients with a mean BP of between 140/100 and 160/90 mm Hg with diabetes, chronic renal disease, or cardiovascular disease. The diabetes subset analysis was prespecified.
Dual-combination treatment was given to participants for two weeks except those with newly diagnosed disease or those new to treatment; these latter two groups of patients received placebo for two weeks (n = 36). The placebo patients were then switched to dual-combination therapy. This regimen was continued for all patients from week 2 to week 4. The dual therapies were OM/HCTZ for 99 patients with diabetes and for 538 patients without diabetes, AML/HCTZ for 92 patients with diabetes and 508 without, and OM/AML for 100 patients with diabetes and 528 without.
Triple antihypertensive therapy (OM 40 mg/AML 10 mg/HCTZ 25 mg) was initiated at week 4 among a subset of patients (96 patients with diabetes and 531 patients without) from each of the three dual-combination groups and was continued for 12 weeks. The 12-week double-blind treatment period was followed by a 40-week open-label treatment period.
From baseline to week 12, patients with and without diabetes in all treatment groups experienced statistically significant reductions in diastolic BP (P < 0.0001) and systolic BP (P < 0.0001). Mean reductions in diastolic BP (P ≤ 0.0013) and systolic BP (P < 0.0001) were significantly greater for triple antihypertensive therapy than for the dual combination. With triple therapy, 68% of patients achieved their goal, compared with 39% to 52.8 % in the dual-combination therapy groups (P < 0.0001). Triple therapy also resulted in greater least-squares mean reductions in systolic and diastolic BP in the non-diabetes cohort, compared with dual-combination therapy (38.5/21.5 mm Hg vs. 28.9–31.9/14.7 to 17.8 mm Hg, respectively; P < 0.0001).
Treatment-emergent adverse events were mostly mild or moderate and were comparable between subgroups.
On July 26, 2010, Daiichi Sankyo announced that the FDA had approved Tribenzor (OM/AML/HCTZ) once daily for patients with hypertension who were not achieving adequate BP control with any of the following antihypertensive drug classes: angiotensin-receptor blockers, calcium-channel blockers, and diuretics.
An earlier discussion of TRINITY was published in the Meeting Highlights report in the June issue of P&T.
GFT505 (Genfit, Lille and Cambridge, Mass.) is an investigational dual-peroxisome proliferator–activated receptor beta/delta (PPAR-β/δ) agonist. It is currently undergoing testing for the management of metabolic disorders, including atherogenic dyslipidemia associated with metabolic syndrome and type-2 diabetes (defined by the simultaneous presence of impaired glucose tolerance and increased fasting plasma glucose [FPG]). In two studies, GFT505 was effective and safe in treating signs and symptoms of prediabetes.
“We saw a significant decrease in fasting plasma glucose in prediabetic patients and a significant improvement in HOMA–IR [homeostasis model of insulin resistance],” Dr. Staels said. The finding, he added, indicates that the drug is acting on parameters of glucose metabolism.
In the first trial, 47 patients with prediabetes, all with elevated FPG levels, impaired glucose tolerance, and abdominal obesity, were randomly assigned to receive double-blinded therapy with GFT505 80 mg/day (n = 23) or placebo (n = 24) for 28 days. Those receiving GFT505 experienced a significant reduction in FPG (−5%), compared with the placebo patients (P = 0.03), and a reduction in fasting plasma insulin (−25%), compared with those receiving placebo (P = 0.009). This translated into a treatment-related decreased HOMA–IR index of −31%, compared with placebo (P = 0.0027).
When compared with placebo, treatment with GFT505 resulted in significantly reduced levels of both low-density lipoprotein-cholesterol (LDL-C) and triglycerides (P = 0.005 and P < 0.001, respectively) and in significantly increased levels of high-density lipoprotein-cholesterol (HDL-C) (P = 0.003).
In the second study, 98 patients with atherogenic dyslipidemia were randomly assigned to receive double-blinded treatment with GFT505 80 mg/day (n = 63, evaluable) or placebo (n = 31, evaluable) for 28 days. After 28 days, researchers found a significant (P = 0.0027 vs. placebo) 21% reduction in triglyceride levels and a significant 9% increase in HDL-C levels.
GFT505 therapy also lowered two indicators of liver dysfunction: alanine aminotransferase (ALT, SGPT) by15% and gamma glutamyl transpeptidase (GGT) by 20%, compared with placebo. Aspartate aminotransferase (AST, SGOT) levels were not affected. Other benefits of GFT505, revealed in both studies, included significant anti-inflammatory effects and reductions in plasma fibrinogen and haptoglobin levels.
The fact that GFT505 is excreted in feces rather than through the kidney, Dr. Staels commented further, could be beneficial for patients with chronic kidney disease for whom fenofibrate presents risks.