New treatment strategies have focused on both dipeptidyl peptidase (DPP)-4 inhibitors, and SGLT-2’s….
DPP-4’s improve hyperglycemia by stimulating insulin secretion in a glucose-dependent fashion and suppressing glucagon secretion, and sodium-glucose co-transporter-2 (SGLT2) inhibitors, which reduce renal glucose reabsorption and induce urinary glucose excretion, thereby lowering plasma glucose.
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The potential complementary mechanism of action and good tolerance profile of these two classes of agents make them attractive treatment options for combination therapy with any of the existing glucose-lowering agents, including insulin. Together, the DPP-4 and SGLT2 inhibitors fulfill a need for treatments with mechanisms of action that can be used in combination with a low risk of adverse events, such as hypoglycemia or weight gain.
Dipeptidyl peptidase (DPP)-4 inhibitors enhance postprandial insulin secretion and suppress glucagon secretion by preventing the degradation of endogenously released incretins [glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP)], two intestinal peptides whose concentration increases after food intake, thus playing a vital role in glucose homeostasis. DPP-4 inhibitors stimulate insulin secretion in a glucose-dependent fashion and inhibit glucagon secretion, thus minimizing hypoglycemia and improving hyperglycemia. In addition, DPP-4 inhibitors are weight-neutral and have been shown to improve β-cell function in in vitro and animal studies. These characteristics may provide benefits to those people with T2DM who have impaired β-cell function, excessive hepatic glucose production, postprandial hyperglycemia and who are overweight or obese.
The kidney plays an important role in glucose homeostasis. Plasma glucose is freely filtered in the kidney glomeruli and must be returned to the circulation to prevent urinary excretion. This process is accomplished with two types of carrier proteins: the active sodium-glucose co-transporters (SGLTs) and the passive glucose transporters. The SGLT inhibitors are a family of membrane-bound transport proteins, of which SGLT type 1 (SGLT1; a low-capacity, high-affinity transporter) and SGLT type 2 (SGLT2; a high-capacity, low-affinity transporter) mediate glucose reabsorption from the glomerular filtrate independent of insulin and induce urinary glucose excretion (i.e. glucosuria). An indication of what to expect from pharmacological SGLT2 inhibition was derived from observations of individuals with familial renal glucosuria, a mutation of the SGLT2 gene that serves as a model for SGLT2 inhibition. The impaired function of SGLT2 in affected individuals can lead to daily urinary glucose excretion of up to 200 g, but most individuals are asymptomatic and do not seem to develop significant clinical problems over time .These findings suggest that pharmacologic SGLT2 inhibition could be a safe option in the attempt to reduce hyperglycemia in individuals with T2DM.
The lack of a common mechanistic pathway between SGLT2 inhibitors and other agents suggests that they can be given in combination with any of the existing therapeutic classes of glucose-lowering agents, including DPP-4 inhibitors, GLP-1 agonists and insulin. Together, the DPP-4 and SGLT2 inhibitors fulfil a need for agents with complementary mechanisms of action that can be used in combination with a low risk of adverse events, such as hypoglycemia or weight gain. The present review provides an overview of the pharmacology, pharmacokinetics, efficacy and safety of these two classes of agents and a rationale for their use as dual-combination therapy for the treatment of T2DM.
It has been more than 8 years since the first DPP-4 inhibitor, sitagliptin, was approved for the treatment of T2DM. Currently, eight DPP-4 inhibitors are available worldwide: sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, gemigliptin, anagliptin and teneligliptin. The latter three are only available in Asia.
In individuals with T2DM, the incretin effect is markedly impaired; whereas exogenously administered GLP-1 retains its effect and improves hyperglycemia, the insulinoptropic effect of GIP is lost in these individuals. New therapeutic advances have focused on the development of GLP-1 agonists that are resistant to DPP-4 inactivation as well as on inhibitors of DPP-4, in an effort to prevent incretins from degradation.
Three SGLT2 inhibitors are currently approved for the treatment of T2DM in the USA and the European Union: canagliflozin, dapagliflozin and empagliflozin. These agents cause reduced reabsorption of glucose from the glomerular filtrate and increased excretion of glucose into the urine, and cause urinary glucose excretion to occur at a lower plasma glucose concentration. SGLT2 inhibition results in the loss of ∼60–80 g of glucose in the urine per day, which helps to reduce hyperglycemia in individuals with T2DM. In addition to improvements in glycemic control, SGLT2 inhibitors provide other effects that are desirable in a T2DM agent, such as weight loss, moderate reductions in systolic blood pressure and no increase in hypoglycemia risk.
The combination of DPP-4 inhibitors and SGLT2 inhibitors also has the potential to exert beneficial effects on the kidney. Both classes have been reported to lower urinary albumin excretion, a risk factor for renal disease.
The drug–drug interactions of empagliflozin and linagliptin or sitagliptin were studied in healthy male volunteers. Both studies showed that administration of either linagliptin or sitagliptin with empagliflozin had no clinically relevant effect on the pharmacokinetics of either agent; therefore, empagliflozin can be co-administered with either linagliptin or sitagliptin without dose adjustments.
Two recent studies of the single-pill combination of empagliflozin and linagliptin assessed the Glycemic control with empagliflozin/linagliptin was maintained at week 52 with statistically significant improvements from baseline in HbA1c, and a higher proportion of individuals achieving HbA1c <7% [53 mmol/mol], in both single-pill combination groups vs the linagliptin 5 mg group, and the empagliflozin 10 mg/linagliptin 5 mg group vs empagliflozin 10 mg group, and for the empagliflozin 25 mg/linagliptin 5 mg combination vs the empagliflozin 25 mg group in the metformin add-on study. In addition, all therapies were well tolerated.
A single-pill combination of a DPP-4 inhibitor and a SGLT2 inhibitor, when available, would offer several advantages over the free combination of individual pills, including a reduced pill burden, which could possibly translate into improved compliance.
In summary, combining DPP-4 inhibitors with SGLT2 inhibitors has the potential to exert benefits beyond lowering glucose, such as beneficial effects on cardiovascular and renal risk factors, including albuminuria, and lowering body weight and systolic blood pressure.
- New combinations present new treatments.
- Studies showed that administration of either linagliptin or sitagliptin with empagliflozin had no clinically relevant effect on the pharmacokinetics of either agent.
- Combining DPP-4 inhibitors with SGLT2 inhibitors has the potential to exert benefits beyond lowering glucose.
American Diabetes Association. Diabetes statistics. Data from the National Diabetes Fact Sheet. Available from URL: http://www.diabetes.org/diabetes-basics/diabetes-statistics/. Accessed 31 October 2013. Published in Diabetes April 2015.