Saxagliptin is a potent highly selective long-acting DPP-4 inhibitor developed by Bristol Myers Squibb, in partnership with Astra Zeneca Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes J Med Chem. 2005 Jul 28;48(15):5025-37
Saxagliptin (Onglyza)was approved for the treatment of type 2 diabetes, either as monotherapy, or add on combination therapy, in the United States on July 31 2009. Review the saxagliptin prescribing information for physicians. A brief summary of the saxagliptin prescribing information is also provided
A Phase 2 12 week dose-ranging study demonstrated the effiacy of saxagliptin, at doses ranging from 2.5-40 mg (12 weeks) or 100 mg (6 weeks, in patients with type 2 diabetes. Saxagliptin was generally well tolerated, however modest reductions in lymphocyte counts were noted, as outlined in Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes Diabetes Obes Metab. 2008 May;10(5):376-86
A Phase 3 study examined th efficacy and safety of saxagliptin when added to metformin therapy in patients with T2DM. Saxagliptin was well tolerated wjen used at doses ranging from 2.5-10 mg daily and reduced HbA1c by 0.59%. The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes on Metformin Alone Diabetes Care. 2009 Jun 23. [Epub ahead of print]
Early initial combination therapy with saxagliptin and metformin was examined in a 24 week study by Jadzinsky and colleagues. Subjects, ages 18-77 years of age, were randomized to 5 or 10 mg of saxagliptin and an initial 500 mg dose of metformin, titrated up to 2 grams daily after week 1. Mean entry HbA1c ranged from 8-12% with a mean entry A1c of ~9.5%. Combination therapy was more potent then either saxagliptin or metformin alone in regard to reduction of A1c and proportion of patients at goal. Drop out rates were surprisingly high across all arms of the study, ranging from 20-30%. The numbers and types of AEs were similar across all treatment groups, and a small absolute decrease in mean lymphocyte count was observed in saxagliptin-treated patients,however mean lymphocyte counts remained within normal limits, with no clinical sequelae attributable to changes in lymphocyte count. See Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial Diabetes Obes Metab. 2009 Jun;11(6):611-22
Saxagliptin efficacy has also been studied in combination with submaximal doses of SUs, vs. uptitration of SU alone. Patients (ages 18-77) had a mean entry HbA1c of 7.5-10% and were treated with 5 or 10 mg of s saxagliptin in combination with 7.5 mg glyburide vs. glyburide 10-20 mg alone for 24 weeks. The mean dose of gyburide alone was 15 mg daily at the end of the study. More patients (~22%) achieved a target A1c of less than 7% on combination therapy compared to SU therapy (9.1%) alone. The numbers of AEs and hypoglycemic events were comparable across treatment groups and weight gain was slightly but significantly greater in subjects treated with saxagliptin relative to SU-therapy alone(0.7 and 0.8 vs. 0.3 kg). See Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial Int J Clin Pract. 2009 Jul 15. [Epub ahead of print]
Saxagliptin in combination with pioglitazone or rosiglitazone was studied in a 24 week study; patients had a mean entry HbA1c of 7-10.5% on stable TZD therapy. Addition of saxagliptin reduced HbA1c by 0.66 (2.5 mg) or 0.94% (5 mg) from a mean baseline of 8.3%. About 40% of patients achieved a HbA1c of less than 70% on saxagliptin/TZD therapy. Body weight increased in subjects treated with saxagliptin and placebo (1.3 vs. 0.9 kg). See Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone J Clin Endocrinol Metab. 2009 Dec;94(12):4810-9. Epub 2009 Oct 28.
Linagliptin is a highly selective DPP4 inhibitor 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J Med Chem. 2007 Dec 27;50(26):6450-3. and the only clinically approved agent whose dose does not need to be adjusted in the setting of reduced GFR.
The long term safety of linagliptin is being studied in several long term outcome studies, including CAROLINA Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes
The primary outcome is the Time to first occurence of any of the following adjudicated components of the primary composite endpoint: CV death, non-fatal MI (excluding silent MI), non-fatal stroke and hospitalisation for unstable angina pectoris
Secondary Outcome Measures for CAROLINA include:
- Time to first occurrence of any of the following adjudicated components of the composite endpoint: CV death (including fatal stroke and fatal MI), non-fatal stroke, non-fatal MI (excluding silent MI)
- Proportion of patients on study treatment at study end, that at Final Visit maintain glycemic control (HbA1c <= 7.0%) without need for rescue medication, without any moderate/severe hypoglycaemic episodes and without > 2% weight gain (from V6 on)
- Occurence of any of the adjudicated components of the composite primary and composite first key secondary endpoint.
- Transitions in albuminuria classes between baseline and Final visit.
- Proportion of patients on study treatment at study end, that at Final Visit maintain glycaemic control (HbA1c <= 7.0%) without need for rescue medication and without > 2% weight gain (from V6 on)
- Occurence of and time to composite endpoint of all CEC confirmed adjudicated events
- Change from baseline to Final Visit in diabetes related laboratory parameters: HbA1c, fasting plasma glucose, Total cholesterol, LDL cholesterol, HDL cholesterol, Triglycerides, Creatinine, eGFR (MDRD formula), Albumin
CARMELINA Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus (CARMELINA). The primary outcome of CARMELINA is Time to the first occurence of any of the following adjudicated components of the primary composite endpoint: cardiovascular death, non fatal myocardial infarction, non fatal stroke and hospitalization for unstable angina pectoris. Secondary outcomes include: Time to first occurence of any of the following adjudicated components: cardiovascular death, non fatal myocardial infarction and non fatal stroke AND Time to first occurence of any of the following adjudicated composite renal endpoint: renal death, end stage renal disease and a sustained decrease of 50% or more in estimated glomerular filtration rate
The efficacy (0.71 % reduction in A1c) and safety of linagliptin in patients with renal impairment has been reported in 68 patients with an eGFR less than 30 studied for 1 year Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: a 1-year, randomized, double-blind, placebo-controlled study Diabetes Care. 2013 Feb;36(2):237-44
A dedicated study of the actions of linagliptin in patients with renal disease, MARLINA-T2D, Efficacy, Safety & Modification of Albuminuria in Type 2 Diabetes Subjects With Renal Disease With LINAgliptin is underway. MARLINA is a Phase IIIb, Multicenter, Multinational, Randomized, Double-blind, Placebo Controlled, Parallel Group Study to Evaluate the Glycemic and Renal Efficacy of Once Daily Administration of Linagliptin 5 mg for 24 Weeks in Type 2 Diabetes Patients, With Micro- or Macroalbuminuria (30-3000mg/g Creatinine) on Top of Current Treatment With Angiotensin ConvEnzyme Inhibitor or Angiotensin Receptor Blocker -the primary outcome is reduction in A1c vs. placebo, the secondary outcome is the time weighted average of percentage change from baseline in UACR
A summary of the safety of linagliptin in placebo-controlled clinical trials is provided in Safety and Tolerability of Linagliptin in Patients With Type 2 Diabetes: A Comprehensive Pooled Analysis of 22 Placebo-controlled Studies Clin Ther. 2014 Aug 1;36(8):1130-46 and in US Prescribing Information
Alogliptin is a highly selective DPP-4 inhibitor approved for the treatment of T2DM. An overview of the alogliptin clinical trial program is provided in Alogliptin: a new, highly selective dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes Expert Opin Pharmacother. 2009 Feb;10(3):503-12
In the EXAMINE (Examination of cardiovascular outcomes with alogliptin) study, 5380 patients with a recent (15-90 days) MI or unstable angina requiring hospitalization were randomized to alogliptin or placebo and followed for a median 18 months (up to 40 months). No differences in the primary endpoint (composite of death from cardiovascular causes, non-fatal MI or non fatal stroke) was observed between groups. Rates of pancreatitis, cancer, and hypoglycemia, were also similar between groups. Event rates were ~ 11% during the F/U period. Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes September 2, 2013DOI: 10.1056/NEJMoa1305889
A F/U analysis of heart failure events in the EXAMINE trial was reported Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial Lancet. 2015 May 23;385(9982):2067-76 Hospital admission for heart failure was the first event in 85 (3·1%) patients takingalogliptin compared with 79 (2·9%) taking placebo (HR 1·07, 95% CI 0·79-1·46).