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Linagliptin as add-on therapy to insulin for patients with type 2 diabetes.

von Websky K, Reichetzeder C, Hocher B - Vasc Health Risk Manag (2013)

Bottom Line: It has been shown that linagliptin is an effective and safe add-on therapy to insulin in patients with T2DM.The efficacy and safety of this combination was also shown in vulnerable, elderly T2DM patients and in patients with T2DM and renal impairment.This review aims to present the existing clinical studies on the efficacy and safety of linagliptin as add-on therapy to insulin in patients with T2DM in the context of current literature.

View Article: PubMed Central - PubMed

Affiliation: Institute of Nutritional Science, University of Potsdam, Potsdam-Rehbrücke, Germany.

ABSTRACT
Type 2 diabetes mellitus (T2DM) is a highly prevalent, progressive disease that often is poorly controlled. The combination of an incretin-based therapy and insulin is a promising approach to optimize the management of glycemic control without hypoglycemia and weight gain. Linagliptin, a recently approved oral dipeptidyl peptidase-4 inhibitor, has a unique pharmacological profile. The convenient, once-daily dosing does not need adjustment in patients with hepatic and/or renal impairment. In clinical studies linagliptin shows an important reduction of blood glucose with an overall safety profile similar to that of placebo. So far, the combination of linagliptin and insulin has been tested in three major clinical studies in different populations. It has been shown that linagliptin is an effective and safe add-on therapy to insulin in patients with T2DM. The efficacy and safety of this combination was also shown in vulnerable, elderly T2DM patients and in patients with T2DM and renal impairment. Favorable effects regarding the counteraction of hypoglycemia make linagliptin especially interesting as an add-on therapy to insulin. This review aims to present the existing clinical studies on the efficacy and safety of linagliptin as add-on therapy to insulin in patients with T2DM in the context of current literature. Additionally, the possible advantages of linagliptin as an add-on therapy to insulin in relation to cardiovascular safety, patient-centered therapy and the prevention of hypoglycemia, are discussed.

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Mode of action of incretins according to glycemic state.Notes: DPP-4 inhibition leads to an extension of physiological increases in GLP-1 and GIP, which also affects the fasting plasma levels of these incretins. However, there is accumulating evidence that GLP-1 and GIP have different modes of action according to the glycemic state.Abbreviations: DPP, dipeptidyl peptidase; GIP, glucose-dependent insulinotropic polypeptide; GLP, glucagon-like peptide.
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f2-vhrm-9-681: Mode of action of incretins according to glycemic state.Notes: DPP-4 inhibition leads to an extension of physiological increases in GLP-1 and GIP, which also affects the fasting plasma levels of these incretins. However, there is accumulating evidence that GLP-1 and GIP have different modes of action according to the glycemic state.Abbreviations: DPP, dipeptidyl peptidase; GIP, glucose-dependent insulinotropic polypeptide; GLP, glucagon-like peptide.

Mentions: In studies where linagliptin treatment had a higher incidence of hypoglycemia, this was almost exclusively attributable to the combination with sulfonylurea.37 As add-on therapy to insulin, linagliptin has the same rates of hypoglycemia as placebo, when not combined with sulfonylurea use.92,93 Therapy with sulfonylureas carries a known risk for hypoglycemia.35 Accordingly, for the coadministration of sulfonylureas with other glucose-lowering agents, the risk for hypoglycemia is higher.79,94,95 The incidence of hypoglycemic events in patients receiving linagliptin without concomitant sulfonylurea is very low, even in vulnerable patients, such as the elderly or those with renal impairment.37 When DPP-4 inhibitors are added to sulfonylurea background therapy, a lower dose of sulfonylurea has been recommended, in order to avoid hypoglycemic events.35,96,97 In a long-term study in patients with T2DM inadequately controlled on metformin, linagliptin was noninferior to the sulfonylurea glimepiride in lowering HbA1c but was associated with significantly less hypoglycemia.77 In patients with T2DM and severe renal impairment, the observed incidence of asymptomatic hypoglycemic events was higher with linagliptin than with placebo.92 This was only the case when a dose adjustment of background therapy of sulfonylurea or insulin was not permitted. When a DPP-4 inhibitor is added to insulin, the dose of insulin should be monitored carefully. With sitagliptin added to ongoing insulin therapy, a higher proportion of patients experienced symptomatic hypoglycemia compared with placebo.41 In contrast, the addition of vildagliptin to insulin was associated with a reduced incidence of hypoglycemia relative to placebo.40 An explanation is the considerably high underlying incidence of overall hypoglycemia because of a high insulin dose and the multiple daily injections of short-acting insulin in the vildagliptin study. A following study with vildagliptin and predominantly basal insulin in a lower dose showed a smaller incidence of hypoglycemia that was comparable with that of placebo.98 For alogliptin as add-on to insulin, a study showed the incidence of hypoglycemia was comparable with that of placebo.99 Potential differences in the definition of hypoglycemic events make a comparison between different studies with various DPP-4 inhibitors complicated and may also explain the differences in hypoglycemia rates seen versus placebo between the studies. When comparing study results, one should be aware of the different background insulin therapies as well as the populations and inclusion criteria. However, the overall finding of studies with DPP-4 inhibitors has been a clinically meaningful decrease in HbA1c without increased hypoglycemia. In an exploratory analysis from two Phase 3 studies in elderly patients with long-standing T2DM treated with linagliptin and basal insulin therapy, hypoglycemia risk was explored.100 The overall and confirmed hypoglycemia risk was lower with linagliptin versus placebo, despite a significantly reduced HbA1c and no relevant on-trial insulin dose reductions (Figure 1). Interestingly, there is a possible mechanistic explanation for a protection against hypoglycemia by DPP-4 inhibition. It is suggested that DPP-4 inhibition can cause a glucagon-dependent counter-regulation of hypoglycemia by restored pancreatic alpha cell function (Figure 2). The first mechanistic study directing this question was conducted by Ahrén et al in 2009.101 The glucagon response to hypoglycemia was examined in patients with T2DM by using stepped hypoglycemic clamps. Intervention with vildagliptin resulted in a suppression of glucagon secretion following a meal test. Interestingly, vildagliptin treatment also had stimulatory effects on glucagon secretion during hypoglycemia. The authors assumed there was an improved ability of alpha cells to sense and respond to changes in plasma glucose levels − this would lead to a GLP-1-mediated decrease in glucagon secretion during hyperglycemia, and a GIP-mediated stimulation of glucagon secretion during hypoglycemia. Additionally, the glucagonostatic and insulinotropic actions of GLP-1 do not occur under hypoglycemic conditions.102 As a matter of fact, Christensen et al30 showed that in healthy humans, GIP has insulinotropic effects during hyperglycemia, while it has no effects on glucagon secretion. During fasting and hypoglycemic conditions GIP increased glucagon levels but had little or no effect on insulin secretion. This physiological bifunctional action of the hormone could, in part, explain the smaller incidence of hypoglycemia observed with DPP-4 inhibitor treatment. Since then, no further studies have addressed and evaluated the hypothesis of improved alpha cell function. Consequently, more studies are warranted to examine the effect of linagliptin on alpha cell function and to bring evidence of how linagliptin treatment relates to counter-regulatory responses to hypoglycemia.


Linagliptin as add-on therapy to insulin for patients with type 2 diabetes.

von Websky K, Reichetzeder C, Hocher B - Vasc Health Risk Manag (2013)

Mode of action of incretins according to glycemic state.Notes: DPP-4 inhibition leads to an extension of physiological increases in GLP-1 and GIP, which also affects the fasting plasma levels of these incretins. However, there is accumulating evidence that GLP-1 and GIP have different modes of action according to the glycemic state.Abbreviations: DPP, dipeptidyl peptidase; GIP, glucose-dependent insulinotropic polypeptide; GLP, glucagon-like peptide.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3818026&req=5

f2-vhrm-9-681: Mode of action of incretins according to glycemic state.Notes: DPP-4 inhibition leads to an extension of physiological increases in GLP-1 and GIP, which also affects the fasting plasma levels of these incretins. However, there is accumulating evidence that GLP-1 and GIP have different modes of action according to the glycemic state.Abbreviations: DPP, dipeptidyl peptidase; GIP, glucose-dependent insulinotropic polypeptide; GLP, glucagon-like peptide.
Mentions: In studies where linagliptin treatment had a higher incidence of hypoglycemia, this was almost exclusively attributable to the combination with sulfonylurea.37 As add-on therapy to insulin, linagliptin has the same rates of hypoglycemia as placebo, when not combined with sulfonylurea use.92,93 Therapy with sulfonylureas carries a known risk for hypoglycemia.35 Accordingly, for the coadministration of sulfonylureas with other glucose-lowering agents, the risk for hypoglycemia is higher.79,94,95 The incidence of hypoglycemic events in patients receiving linagliptin without concomitant sulfonylurea is very low, even in vulnerable patients, such as the elderly or those with renal impairment.37 When DPP-4 inhibitors are added to sulfonylurea background therapy, a lower dose of sulfonylurea has been recommended, in order to avoid hypoglycemic events.35,96,97 In a long-term study in patients with T2DM inadequately controlled on metformin, linagliptin was noninferior to the sulfonylurea glimepiride in lowering HbA1c but was associated with significantly less hypoglycemia.77 In patients with T2DM and severe renal impairment, the observed incidence of asymptomatic hypoglycemic events was higher with linagliptin than with placebo.92 This was only the case when a dose adjustment of background therapy of sulfonylurea or insulin was not permitted. When a DPP-4 inhibitor is added to insulin, the dose of insulin should be monitored carefully. With sitagliptin added to ongoing insulin therapy, a higher proportion of patients experienced symptomatic hypoglycemia compared with placebo.41 In contrast, the addition of vildagliptin to insulin was associated with a reduced incidence of hypoglycemia relative to placebo.40 An explanation is the considerably high underlying incidence of overall hypoglycemia because of a high insulin dose and the multiple daily injections of short-acting insulin in the vildagliptin study. A following study with vildagliptin and predominantly basal insulin in a lower dose showed a smaller incidence of hypoglycemia that was comparable with that of placebo.98 For alogliptin as add-on to insulin, a study showed the incidence of hypoglycemia was comparable with that of placebo.99 Potential differences in the definition of hypoglycemic events make a comparison between different studies with various DPP-4 inhibitors complicated and may also explain the differences in hypoglycemia rates seen versus placebo between the studies. When comparing study results, one should be aware of the different background insulin therapies as well as the populations and inclusion criteria. However, the overall finding of studies with DPP-4 inhibitors has been a clinically meaningful decrease in HbA1c without increased hypoglycemia. In an exploratory analysis from two Phase 3 studies in elderly patients with long-standing T2DM treated with linagliptin and basal insulin therapy, hypoglycemia risk was explored.100 The overall and confirmed hypoglycemia risk was lower with linagliptin versus placebo, despite a significantly reduced HbA1c and no relevant on-trial insulin dose reductions (Figure 1). Interestingly, there is a possible mechanistic explanation for a protection against hypoglycemia by DPP-4 inhibition. It is suggested that DPP-4 inhibition can cause a glucagon-dependent counter-regulation of hypoglycemia by restored pancreatic alpha cell function (Figure 2). The first mechanistic study directing this question was conducted by Ahrén et al in 2009.101 The glucagon response to hypoglycemia was examined in patients with T2DM by using stepped hypoglycemic clamps. Intervention with vildagliptin resulted in a suppression of glucagon secretion following a meal test. Interestingly, vildagliptin treatment also had stimulatory effects on glucagon secretion during hypoglycemia. The authors assumed there was an improved ability of alpha cells to sense and respond to changes in plasma glucose levels − this would lead to a GLP-1-mediated decrease in glucagon secretion during hyperglycemia, and a GIP-mediated stimulation of glucagon secretion during hypoglycemia. Additionally, the glucagonostatic and insulinotropic actions of GLP-1 do not occur under hypoglycemic conditions.102 As a matter of fact, Christensen et al30 showed that in healthy humans, GIP has insulinotropic effects during hyperglycemia, while it has no effects on glucagon secretion. During fasting and hypoglycemic conditions GIP increased glucagon levels but had little or no effect on insulin secretion. This physiological bifunctional action of the hormone could, in part, explain the smaller incidence of hypoglycemia observed with DPP-4 inhibitor treatment. Since then, no further studies have addressed and evaluated the hypothesis of improved alpha cell function. Consequently, more studies are warranted to examine the effect of linagliptin on alpha cell function and to bring evidence of how linagliptin treatment relates to counter-regulatory responses to hypoglycemia.

Bottom Line: It has been shown that linagliptin is an effective and safe add-on therapy to insulin in patients with T2DM.The efficacy and safety of this combination was also shown in vulnerable, elderly T2DM patients and in patients with T2DM and renal impairment.This review aims to present the existing clinical studies on the efficacy and safety of linagliptin as add-on therapy to insulin in patients with T2DM in the context of current literature.

View Article: PubMed Central - PubMed

Affiliation: Institute of Nutritional Science, University of Potsdam, Potsdam-Rehbrücke, Germany.

ABSTRACT
Type 2 diabetes mellitus (T2DM) is a highly prevalent, progressive disease that often is poorly controlled. The combination of an incretin-based therapy and insulin is a promising approach to optimize the management of glycemic control without hypoglycemia and weight gain. Linagliptin, a recently approved oral dipeptidyl peptidase-4 inhibitor, has a unique pharmacological profile. The convenient, once-daily dosing does not need adjustment in patients with hepatic and/or renal impairment. In clinical studies linagliptin shows an important reduction of blood glucose with an overall safety profile similar to that of placebo. So far, the combination of linagliptin and insulin has been tested in three major clinical studies in different populations. It has been shown that linagliptin is an effective and safe add-on therapy to insulin in patients with T2DM. The efficacy and safety of this combination was also shown in vulnerable, elderly T2DM patients and in patients with T2DM and renal impairment. Favorable effects regarding the counteraction of hypoglycemia make linagliptin especially interesting as an add-on therapy to insulin. This review aims to present the existing clinical studies on the efficacy and safety of linagliptin as add-on therapy to insulin in patients with T2DM in the context of current literature. Additionally, the possible advantages of linagliptin as an add-on therapy to insulin in relation to cardiovascular safety, patient-centered therapy and the prevention of hypoglycemia, are discussed.

Show MeSH
Related in: MedlinePlus