Sitagliptin: Riding the Tides of Diabetes Treatment
05 Aug 2024
The enormous burden of micro- and macrovascular complications of diabetes mellitus resulting from persistent hyperglycemia drove the development of several classes of anti-diabetic medication for years. But the available pharmacologic options were strongly associated with their adverse effects of weight gain and hypoglycemia, which limited their optimal use.1
A new era
The introduction of incretin-based therapies in 2005 marked a new era in antidiabetic drug development. The new incretin-based drug sitagliptin, the first dipeptidyl peptidase-4 (DPP-4) inhibitor, showed a promising efficacy and safety profile along with the benefit of weight neutrality that address the ballooning concerns over obesity as a key diabetes and cardiovascular risk factor.1
The incretin pathway consists of hormones mainly produced in the gut that leads to lowering of blood glucose levels. Glucagon-like peptide or GLP-1 is produced in the distal ileum and colon in response to meals, dietary glucose, lipids and parasympathetic stimulation. When GLP-1 binds to its receptors in the pancreas, it results in a net increase in insulin secretion which regulates blood glucose levels in a glucose-dependent manner. Dipeptidyl peptidase-4 is an enzyme that rapidly degrades the GLP-1 within 2 minutes to effectively cease the pharmacologic activity of GLP-1. The use of dipeptidyl peptidase-4 inhibitors (DPP4-i) like sitagliptin prevents the degradation of GLP-1, increasing its circulating levels for a more sustained glycemic effect.1
Efficacy and safety studies
Following its approval by the United States Food and Drug Administration (US FDA) for use in diabetes mellitus, numerous clinical trials have proven the efficacy and safety of sitagliptin as monotherapy or in combination treatment.1
Sitagliptin monotherapy showed significant placebo-subtracted HbA1c reductions of 0.79% and 0.94% after 24 weeks of 100 and 200 mg treatment, respectively. Both fasting (FPG) and post-prandial glucose (PPG) also fell significantly compared to placebo.1 Sitagliptin monotherapy was also shown to be non-inferior to metformin in terms of improving HbA1c levels after 24 weeks of treatment.2
As add-on to metformin (0.65%), pioglitazone (0.70%) and insulin (0.6%), sitagliptin significantly reduced HbA1c compared to placebo, which was associated with significant reductions in both FPG and PPG as well.1 Almost 75% of the sitagliptin + metformin study participants, 45.5% of the sitagliptin + pioglitazone participants and 13% of the sitagliptin + insulin participants achieved HbA1c of <7% during treatment.1 On the other hand, active comparison of sitagliptin + metformin against glipizide + metformin showed a 0.67% reduction of HbA1c in both groups proving non-inferiority of the anti-glycemic property of sitagliptin compared to a sulfonylurea. The study comparing the addition of sitagliptin to a metformin + sulfonylurea regimen compared to the addition of pioglitazone to the same combination, also showed the non-inferiority of the efficacy of sitagliptin.1
Meanwhile, sitagliptin showed a low incidence of hypoglycemia compared to placebo as an add-on to metformin or pioglitazone. Active comparison with glipizide and canagliflozin also showed lower incidence of hypoglycemia with sitagliptin.1 In addition, sitagliptin is weight-neutral with studies showing no significant weight change in patients taking it versus those taking placebo. Similar observations were made when placebo and sitagliptin were given and compared as add-ons to insulin + metformin.1
Cardiovascular outcome trials
After concerns about the cardiovascular safety of some glucose-lowering medications were raised, the US FDA and other regulatory agencies required new antihyperglycemic agents to show not only efficacy in glucose-lowering but also but must also show no associations with clinically significant increased risks of major adverse cardiovascular events.3
The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), was a landmark study that established the cardiovascular safety profile of sitagliptin. The randomized, double-blind study on 14,671 patients with coexisting diabetes and cardiovascular disease examined the cardiovascular outcomes following the addition of sitagliptin or placebo to their existing therapies. After a median follow-up of 3 years, sitagliptin proved to be non-inferior to placebo in terms of the occurrence of composite cardiovascular outcomes (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke of hospitalization for angina). It means risks of occurrence of major adverse cardiovascular events in patients taking sitagliptin are low and comparable to the risks when taking placebo.3
The TECOS trial also showed non-inferiority of sitagliptin in terms of hospitalization for heart failure or the occurrence of acute pancreatitis or pancreatic cancer, when compared to placebo.3
Therapeutic guidelines
With its proven efficacy and safety data and cardiovascular risk profile, sitagliptin has earned recommendations in local and international guidelines.
The Philippine Practice Guidelines on the Diagnosis and Management of Diabetes Mellitus recommends sitagliptin as an option for an add-on to metformin combination for patients who are symptomatic or with higher blood glucose (HbA1c >9%, FBS >250 mg/dL), indicated for target blood glucose lowering of 0.5-1%.4
The American Diabetes Association – Standards of Care in Diabetes – 2024 (ADA 2024) recommends DPP-4i like sitagliptin and recognizes its efficacy in glucose-lowering and for being weight-neutral. The guideline also recognizes sitagliptin’s low risk for hypoglycemia and its neutral effect on major adverse cardiovascular events and heart failure and its usefulness in patients with renal impairment with recommended dose adjustment.5
Conclusion
The robust development in our understanding of diabetes mellitus fuels the dynamism in its clinical management, especially in pharmacologic interventions. Through the years, sitagliptin has proven to be an enduring molecule whose safety, efficacy and cardiovascular profile has managed to adapt to and fill in the ever-changing pharmacologic needs of diabetes patients.
A new era
The introduction of incretin-based therapies in 2005 marked a new era in antidiabetic drug development. The new incretin-based drug sitagliptin, the first dipeptidyl peptidase-4 (DPP-4) inhibitor, showed a promising efficacy and safety profile along with the benefit of weight neutrality that address the ballooning concerns over obesity as a key diabetes and cardiovascular risk factor.1
The incretin pathway consists of hormones mainly produced in the gut that leads to lowering of blood glucose levels. Glucagon-like peptide or GLP-1 is produced in the distal ileum and colon in response to meals, dietary glucose, lipids and parasympathetic stimulation. When GLP-1 binds to its receptors in the pancreas, it results in a net increase in insulin secretion which regulates blood glucose levels in a glucose-dependent manner. Dipeptidyl peptidase-4 is an enzyme that rapidly degrades the GLP-1 within 2 minutes to effectively cease the pharmacologic activity of GLP-1. The use of dipeptidyl peptidase-4 inhibitors (DPP4-i) like sitagliptin prevents the degradation of GLP-1, increasing its circulating levels for a more sustained glycemic effect.1
Efficacy and safety studies
Following its approval by the United States Food and Drug Administration (US FDA) for use in diabetes mellitus, numerous clinical trials have proven the efficacy and safety of sitagliptin as monotherapy or in combination treatment.1
Sitagliptin monotherapy showed significant placebo-subtracted HbA1c reductions of 0.79% and 0.94% after 24 weeks of 100 and 200 mg treatment, respectively. Both fasting (FPG) and post-prandial glucose (PPG) also fell significantly compared to placebo.1 Sitagliptin monotherapy was also shown to be non-inferior to metformin in terms of improving HbA1c levels after 24 weeks of treatment.2
As add-on to metformin (0.65%), pioglitazone (0.70%) and insulin (0.6%), sitagliptin significantly reduced HbA1c compared to placebo, which was associated with significant reductions in both FPG and PPG as well.1 Almost 75% of the sitagliptin + metformin study participants, 45.5% of the sitagliptin + pioglitazone participants and 13% of the sitagliptin + insulin participants achieved HbA1c of <7% during treatment.1 On the other hand, active comparison of sitagliptin + metformin against glipizide + metformin showed a 0.67% reduction of HbA1c in both groups proving non-inferiority of the anti-glycemic property of sitagliptin compared to a sulfonylurea. The study comparing the addition of sitagliptin to a metformin + sulfonylurea regimen compared to the addition of pioglitazone to the same combination, also showed the non-inferiority of the efficacy of sitagliptin.1
Meanwhile, sitagliptin showed a low incidence of hypoglycemia compared to placebo as an add-on to metformin or pioglitazone. Active comparison with glipizide and canagliflozin also showed lower incidence of hypoglycemia with sitagliptin.1 In addition, sitagliptin is weight-neutral with studies showing no significant weight change in patients taking it versus those taking placebo. Similar observations were made when placebo and sitagliptin were given and compared as add-ons to insulin + metformin.1
Cardiovascular outcome trials
After concerns about the cardiovascular safety of some glucose-lowering medications were raised, the US FDA and other regulatory agencies required new antihyperglycemic agents to show not only efficacy in glucose-lowering but also but must also show no associations with clinically significant increased risks of major adverse cardiovascular events.3
The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), was a landmark study that established the cardiovascular safety profile of sitagliptin. The randomized, double-blind study on 14,671 patients with coexisting diabetes and cardiovascular disease examined the cardiovascular outcomes following the addition of sitagliptin or placebo to their existing therapies. After a median follow-up of 3 years, sitagliptin proved to be non-inferior to placebo in terms of the occurrence of composite cardiovascular outcomes (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke of hospitalization for angina). It means risks of occurrence of major adverse cardiovascular events in patients taking sitagliptin are low and comparable to the risks when taking placebo.3
The TECOS trial also showed non-inferiority of sitagliptin in terms of hospitalization for heart failure or the occurrence of acute pancreatitis or pancreatic cancer, when compared to placebo.3
Therapeutic guidelines
With its proven efficacy and safety data and cardiovascular risk profile, sitagliptin has earned recommendations in local and international guidelines.
The Philippine Practice Guidelines on the Diagnosis and Management of Diabetes Mellitus recommends sitagliptin as an option for an add-on to metformin combination for patients who are symptomatic or with higher blood glucose (HbA1c >9%, FBS >250 mg/dL), indicated for target blood glucose lowering of 0.5-1%.4
The American Diabetes Association – Standards of Care in Diabetes – 2024 (ADA 2024) recommends DPP-4i like sitagliptin and recognizes its efficacy in glucose-lowering and for being weight-neutral. The guideline also recognizes sitagliptin’s low risk for hypoglycemia and its neutral effect on major adverse cardiovascular events and heart failure and its usefulness in patients with renal impairment with recommended dose adjustment.5
Conclusion
The robust development in our understanding of diabetes mellitus fuels the dynamism in its clinical management, especially in pharmacologic interventions. Through the years, sitagliptin has proven to be an enduring molecule whose safety, efficacy and cardiovascular profile has managed to adapt to and fill in the ever-changing pharmacologic needs of diabetes patients.