Just Accepted by Current Medical Research & Opinion BRIEF REVIEW Single-pill combination therapy for type 2 diabetes mellitus: linagliptin plus empagliflozin Ronnie Aronson doi: 10.1185/03007995.2015.1027185 Abstract
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
Background Treatment of type 2 diabetes mellitus invariably requires the use of multiple daily medications which can impact negatively on patient adherence. As a result, there is growing interest in the use of single-pill combinations that can reduce the pill burden. Many such formulations incorporate metformin, although this agent is not suitable for all patients. The single-pill combination of the dipeptidyl peptidase-4 inhibitor linagliptin with the sodium glucose co-transporter 2 inhibitor empagliflozin offers a new and attractive option, given their complementary mechanisms of action. Scope Publications with titles containing the keywords ‘linagliptin’ or ‘empagliflozin’ were identified from a nonsystematic search of PubMed without date restrictions, together with abstracts presented at the annual meetings of the American Diabetes Association and the European Association for the Study of Diabetes 2012–2014. ClinicalTrials.gov was searched for entries containing these two keywords. Additional references known to the author were included. Findings The efficacy and safety of linagliptin and empagliflozin as monotherapy or in combination with other oral antidiabetic drugs has been established through extensive clinical trial programs. Studies specifically evaluating the efficacy/safety of a dipeptidyl peptidase-4 inhibitor/sodium glucose co-transporter 2 inhibitor in combination are limited, but do include two studies of linagliptin/empagliflozin of up to 52 weeks in duration. These studies show that the single-pill combination of linagliptin and empagliflozin produced clinical improvements in glycemic control that were generally superior to the improvements seen with linagliptin and empagliflozin alone, but with a safety profile comparable to that of the individual constituents. Conclusions The single-pill combination of linagliptin and empagliflozin, with their complementary mechanisms of action, is a promising treatment option for patients with type 2 diabetes mellitus. It would reduce the daily pill burden in this population, potentially improving adherence to, and optimizing the benefits of, treatment of diabetes mellitus.
© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
BRIEF REVIEW
Single-pill combination therapy for type 2 diabetes mellitus: linagliptin plus empagliflozin
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
Ronnie Aronson LMC Diabetes & Endocrinology, Toronto, Ontario, Canada
Address for correspondence: Ronnie Aronson, LMC Diabetes & Endocrinology, 1929 Bayview Ave, Suite 106, Toronto, Ontario M4G 3E8, Canada Tel.: +1 416 645 2928; Fax: +1 416 645 2931; [email protected] Key words: Combination therapy — Dipeptidyl peptidase-4 inhibitor — Sodium glucose co-transporter 2 inhibitor — Type 2 diabetes mellitus [Short title: Linagliptin/empagliflozin single-pill combination]
Abstract Background Treatment of type 2 diabetes mellitus invariably requires the use of multiple daily medications which can impact negatively on patient adherence. As a result, there is growing interest in the use of single-pill combinations that can reduce the pill burden. Many such formulations incorporate metformin, although this agent is not suitable for all patients. The single-pill combination of the dipeptidyl peptidase-4 inhibitor linagliptin with the sodium glucose co-transporter 2 inhibitor empagliflozin offers a new and attractive option, given their complementary mechanisms of action. 1
Scope Publications with titles containing the keywords ‘linagliptin’ or ‘empagliflozin’ were identified from a non-systematic search of PubMed without date restrictions, together with abstracts presented at the annual meetings of the American Diabetes Association and the European Association for the Study of Diabetes 2012–2014. ClinicalTrials.gov was searched for entries containing these two keywords.
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
Additional references known to the author were included. Findings The efficacy and safety of linagliptin and empagliflozin as monotherapy or in combination with other oral antidiabetic drugs has been established through extensive clinical trial programs. Studies specifically evaluating the efficacy/safety of a dipeptidyl peptidase-4 inhibitor/sodium glucose co-transporter 2 inhibitor in combination are limited, but do include two studies of linagliptin/empagliflozin of up to 52 weeks in duration. These studies show that the single-pill combination of linagliptin and empagliflozin produced clinical improvements in glycemic control that were generally superior to the improvements seen with linagliptin and empagliflozin alone, but with a safety profile comparable to that of the individual constituents. Conclusions The single-pill combination of linagliptin and empagliflozin, with their complementary mechanisms of action, is a promising treatment option for patients with type 2 diabetes mellitus. It would reduce the daily pill burden in this population, potentially improving adherence to, and optimizing the benefits of, treatment of diabetes mellitus.
2
Introduction Type 2 diabetes mellitus (T2DM) is a chronic and progressive condition characterized by persistent hyperglycemia. Its pathophysiology is complex and involves insulin resistance, impaired insulin secretion and a deterioration of beta-cell function over time. Although our understanding of the pathophysiology of T2DM is growing and new treatment strategies continue to develop, its global prevalence is
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
increasing and the condition is placing an ever growing social and economic burden on healthcare systems worldwide1. In 2013, the International Diabetes Federation reported that an estimated 8.3% of adults worldwide – 382 million people – have diabetes, and this figure is predicted to rise to almost 600 million within a quarter of a century1. In the US alone, 24.4 million (10.9%) people have T2DM, with over 192,000 diabetes-related deaths in 20131. While metformin monotherapy is currently the recommended first-line treatment2-4, this strategy does not maintain glycemic control over time. Current diabetes guidelines encourage early adoption of oral combination therapies while simultaneously emphasizing the importance of individualized treatment2,5. There is growing interest in the premise that initiating therapy with a combination of agents offering complementary mechanisms of action may have potential benefits (such as preserving beta-cell function) over a stepwise treatment approach6. If preservation of beta-cell function was shown to occur with combination therapy, such an effect could potentially prolong the period before patients would require additional glucose-lowering therapies in order to maintain effective glycemic control, which typically occurs for most patients with long-term treatment. The addition of further glucose-lowering therapies may add to the pill burden in patients with T2DM, who may also be receiving treatment for hypertension and dyslipidemia, conditions that are highly prevalent in this patient population.
3
Studies have demonstrated that factors such as increasing numbers of tablets, multiple daily dosing schedules and the concurrent use of several types of oral antidiabetic drugs (OADs) are associated with poor adherence7-9. This awareness has led to considerable interest in the use of single-pill combinations that have the potential of reducing pill burden10-12. Until now, most single-pill formulations have incorporated metformin along with a second agent, but the use of such formulations may be limited
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
because metformin is not suitable for all patients: gastrointestinal side effects can limit its tolerability for some patients and it is contraindicated in certain patients with renal impairment. Combinations of other agents may therefore also offer potential value. This review considers the evidence for specifically combining linagliptin (a dipeptidyl peptidase-4 [DPP4] inhibitor) and empagliflozin (a sodium glucose co-transporter 2 [SGLT2] inhibitor) in a single-pill formulation. In 2014, the US Food and Drug Administration (FDA) accepted the filing of a new drug application for this combination, the first reported combination of these two drug classes13.
Methods A non-systematic search of PubMed was performed for titles containing linagliptin or empagliflozin without imposing date restrictions. ClinicalTrials.gov was searched for entries that were associated with linagliptin and empagliflozin as keywords. Additional references known to the author were included, and abstracts presented at the annual meetings of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) 2012–2014
were also searched for relevant content.
Linagliptin DPP-4 inhibitors produce their glucose-lowering effects by preventing the DPP-4-mediated degradation of GLP-1, a gut-derived incretin hormone with potent antihyperglycemic activity that induces glucose-
4
dependent insulin secretion while suppressing glucagon secretion14. The glucose-dependent nature of this system means that DPP-4 inhibitors are generally associated with a low risk of hypoglycemia15. Linagliptin was first approved in the US in 2011 as an adjunct to diet and exercise to improve glycemic control in adults with T2DM (recommended oral dose of 5 mg once daily)16, and has since gained approval around the world. The efficacy and safety of linagliptin has been assessed in patients with
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
T2DM in a large clinical trial program, both as monotherapy and in combination with other OADs17,18. Linagliptin 5 mg once daily was associated with significantly improved glycemic control when used as monotherapy19,20, as initial combination therapy with metformin21,22 or pioglitazone23, as add-on therapy to metformin and/or a sulfonylurea24,25, or as add-on therapy to basal insulin with or without other OADs26. Furthermore, the efficacy of linagliptin was maintained irrespective of patients’ renal function2729
, age30, race or ethnicity31-34, or duration of T2DM35.
The Phase 3 program also demonstrated that linagliptin treatment was weight neutral and that the rate of serious adverse events (AEs) across all trials was low17,18. The risk of hypoglycemia with linagliptin is low, except when used in combination with a sulfonylurea or insulin17,18,25. A pre-specified, prospective, adjudicated meta-analysis of Phase 3 studies indicated that linagliptin does not appear to increase the risk of cardiovascular (CV) events36. The CAROLINA (Cardiovascular Safety of Linagliptin versus Glimepiride) trial, an ongoing long-term CV outcomes study, will provide further information on the CV safety of linagliptin37. In addition, the CARMELINA (Cardiovascular safety and Renal Microvascular outcome with Linagliptin in patients with Type 2 Diabetes mellitus at high vascular risk) trial will investigate the effect of linagliptin on CV and renal microvascular outcomes in adults with T2DM at risk of CV and renal events (ClinicalTrials.gov identifier: NCT01897532).
5
Empagliflozin SGLT2 inhibitors produce their anti-hyperglycemic effect via inhibition of renal glucose re-absorption by SGLT2, thereby causing glucose to be excreted in the urine. As a result, glucose is removed from the body which, in turn, leads to a lowering of the level of hyperglycemia38. The insulin-independent mechanism of action of SGLT2 inhibitors makes them suitable for use in combination with any
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
background glucose-lowering agent, including insulin39,40. Empagliflozin was approved in the US in 2014 as an adjunct to diet and exercise to improve glycemic control in adults with T2DM41. It is available as 10 mg and 25 mg tablets; the recommended dose is 10 mg once daily, taken in the morning, with or without food, and the dose can be increased to 25 mg once daily41. Empagliflozin is being evaluated in adult patients with T2DM in a Phase 3 clinical development program that comprises more than 10 multinational clinical studies, and which has recruited over 14,500 patients42. A number of pivotal studies have been completed, and have demonstrated that empagliflozin, given either as monotherapy or as an add-on therapy to other OADs, produced statistically significant and clinically relevant improvements in glycemic control in patients with T2DM compared with placebo43-48, as determined by the change from baseline in glycated hemoglobin (HbA1c)39. Empagliflozin also produces modest reductions in both blood pressure and body weight43-49. Treatment was generally well tolerated39 although, as consistent with other SGLT2 inhibitors, an increased risk of genital infections was observed across studies43-48. Recently completed Phase 3 studies include investigations of empagliflozin in a comprehensive add-on study in Japanese patients (ClinicalTrials.gov identifier: NCT01368081) as add-on to insulin in obese patients50, and in a 52-week extension of 24-week trials as monotherapy or with different background therapies51-54. Ongoing studies include a dedicated CV outcome event trial (EMPA-REG OUTCOME ), which is expected to report results in 201555. 6
SGLT2 inhibitors and DPP-4 inhibitors in combination Studies with empagliflozin and dapagliflozin have shown improvements in beta-cell function56 and insulin sensitivity56,57. However, these studies have also reported an increase in endogenous glucose production, despite reducing fasting plasma glucose (FPG)56,57. For empagliflozin, this effect was observed acutely and appeared to be reduced after 28 days56; for dapagliflozin, endogenous glucose
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
production was observed up to study end (14 days)57.This increase in endogenous glucose production may be an equilibrating physiologic response to the SGT2-inhibitor-induced glycosuria. Merovci et al57 estimated that this increase in endogenous glucose production offsets approximately half of the glucose excreted as a result of SGLT2 inhibition with dapagliflozin. If this increase were to be prevented, the decrease in FPG caused by dapagliflozin would have approximately doubled. It would be of great interest, therefore, to examine combination therapy that would combine an SGLT2 inhibitor with an incretin mimetic that might additionally inhibit glucagon and stimulate insulin secretion57. Such agents would be anticipated to mitigate the increase in endogenous glucose production and therefore augment the glucose-lowering ability of the SGLT2 inhibitor. This effect has been reported for sitagliptin58 and for linagliptin59. Merovci et al hypothesized that combining an SGLT2 inhibitor with a DPP-4 inhibitor or GLP1 analog would produce an additive or possibly synergistic effect to improve glycemic parameters57. Several fixed-dose (i.e., single-pill) combination products utilizing SGLT2 inhibitors are currently in clinical development, including combinations with metformin39, and with other agents. Of these, a combination of canagliflozin and metformin60 and dapagliflozin and metformin61 have already been approved in the US. In addition, US approval has been granted for a fixed-dose combination of empagliflozin and linagliptin as an adjunct to diet and exercise to improve glycemic control in adults with T2DM when treatment with both empagliflozin and linagliptin is appropriate62. This approval is
7
based on a number of studies that have so far assessed the combination of an SGLT2 inhibitor and DPP-4 inhibitor. Jabbour et al investigated dapagliflozin as add-on (free combination) therapy in patients with T2DM who were inadequately controlled with the DPP-4 inhibitor sitagliptin ± metformin63. This study demonstrated that dapagliflozin treatment in dual combination with sitagliptin, or in triple combination
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
with sitagliptin plus metformin, was well tolerated and was associated with improvements in glycemic parameters and body weight that were sustained through 48 weeks of treatment63. Rosenstock et al have recently reported the findings of a 24-week, multicenter, randomized, doubleblind, active-controlled, parallel-group Phase 3 study comparing the efficacy and safety of dual add-on of saxagliptin (5 mg/day) plus dapagliflozin (10 mg/day), versus both agents added on alone, in patients with T2DM inadequately controlled on metformin64. Patients were randomized to saxagliptin plus dapagliflozin (n=179) or saxagliptin and placebo (n=176) or dapagliflozin and placebo (n=179) with continuing background metformin extended release ≥1,500 mg/day. The primary endpoint (adjusted mean change from baseline in HbA1c at 24 weeks) result was –1.5% (–16.1 mmol/mol) with the triple combination versus –0.9% (–9.6 mmol/mol) with saxagliptin plus metformin (difference –0.59% [–6.4 mmol/mol], p
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
Background Treatment of type 2 diabetes mellitus invariably requires the use of multiple daily medications which can impact negatively on patient adherence. As a result, there is growing interest in the use of single-pill combinations that can reduce the pill burden. Many such formulations incorporate metformin, although this agent is not suitable for all patients. The single-pill combination of the dipeptidyl peptidase-4 inhibitor linagliptin with the sodium glucose co-transporter 2 inhibitor empagliflozin offers a new and attractive option, given their complementary mechanisms of action. Scope Publications with titles containing the keywords ‘linagliptin’ or ‘empagliflozin’ were identified from a nonsystematic search of PubMed without date restrictions, together with abstracts presented at the annual meetings of the American Diabetes Association and the European Association for the Study of Diabetes 2012–2014. ClinicalTrials.gov was searched for entries containing these two keywords. Additional references known to the author were included. Findings The efficacy and safety of linagliptin and empagliflozin as monotherapy or in combination with other oral antidiabetic drugs has been established through extensive clinical trial programs. Studies specifically evaluating the efficacy/safety of a dipeptidyl peptidase-4 inhibitor/sodium glucose co-transporter 2 inhibitor in combination are limited, but do include two studies of linagliptin/empagliflozin of up to 52 weeks in duration. These studies show that the single-pill combination of linagliptin and empagliflozin produced clinical improvements in glycemic control that were generally superior to the improvements seen with linagliptin and empagliflozin alone, but with a safety profile comparable to that of the individual constituents. Conclusions The single-pill combination of linagliptin and empagliflozin, with their complementary mechanisms of action, is a promising treatment option for patients with type 2 diabetes mellitus. It would reduce the daily pill burden in this population, potentially improving adherence to, and optimizing the benefits of, treatment of diabetes mellitus.
© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
BRIEF REVIEW
Single-pill combination therapy for type 2 diabetes mellitus: linagliptin plus empagliflozin
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
Ronnie Aronson LMC Diabetes & Endocrinology, Toronto, Ontario, Canada
Address for correspondence: Ronnie Aronson, LMC Diabetes & Endocrinology, 1929 Bayview Ave, Suite 106, Toronto, Ontario M4G 3E8, Canada Tel.: +1 416 645 2928; Fax: +1 416 645 2931; [email protected] Key words: Combination therapy — Dipeptidyl peptidase-4 inhibitor — Sodium glucose co-transporter 2 inhibitor — Type 2 diabetes mellitus [Short title: Linagliptin/empagliflozin single-pill combination]
Abstract Background Treatment of type 2 diabetes mellitus invariably requires the use of multiple daily medications which can impact negatively on patient adherence. As a result, there is growing interest in the use of single-pill combinations that can reduce the pill burden. Many such formulations incorporate metformin, although this agent is not suitable for all patients. The single-pill combination of the dipeptidyl peptidase-4 inhibitor linagliptin with the sodium glucose co-transporter 2 inhibitor empagliflozin offers a new and attractive option, given their complementary mechanisms of action. 1
Scope Publications with titles containing the keywords ‘linagliptin’ or ‘empagliflozin’ were identified from a non-systematic search of PubMed without date restrictions, together with abstracts presented at the annual meetings of the American Diabetes Association and the European Association for the Study of Diabetes 2012–2014. ClinicalTrials.gov was searched for entries containing these two keywords.
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
Additional references known to the author were included. Findings The efficacy and safety of linagliptin and empagliflozin as monotherapy or in combination with other oral antidiabetic drugs has been established through extensive clinical trial programs. Studies specifically evaluating the efficacy/safety of a dipeptidyl peptidase-4 inhibitor/sodium glucose co-transporter 2 inhibitor in combination are limited, but do include two studies of linagliptin/empagliflozin of up to 52 weeks in duration. These studies show that the single-pill combination of linagliptin and empagliflozin produced clinical improvements in glycemic control that were generally superior to the improvements seen with linagliptin and empagliflozin alone, but with a safety profile comparable to that of the individual constituents. Conclusions The single-pill combination of linagliptin and empagliflozin, with their complementary mechanisms of action, is a promising treatment option for patients with type 2 diabetes mellitus. It would reduce the daily pill burden in this population, potentially improving adherence to, and optimizing the benefits of, treatment of diabetes mellitus.
2
Introduction Type 2 diabetes mellitus (T2DM) is a chronic and progressive condition characterized by persistent hyperglycemia. Its pathophysiology is complex and involves insulin resistance, impaired insulin secretion and a deterioration of beta-cell function over time. Although our understanding of the pathophysiology of T2DM is growing and new treatment strategies continue to develop, its global prevalence is
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
increasing and the condition is placing an ever growing social and economic burden on healthcare systems worldwide1. In 2013, the International Diabetes Federation reported that an estimated 8.3% of adults worldwide – 382 million people – have diabetes, and this figure is predicted to rise to almost 600 million within a quarter of a century1. In the US alone, 24.4 million (10.9%) people have T2DM, with over 192,000 diabetes-related deaths in 20131. While metformin monotherapy is currently the recommended first-line treatment2-4, this strategy does not maintain glycemic control over time. Current diabetes guidelines encourage early adoption of oral combination therapies while simultaneously emphasizing the importance of individualized treatment2,5. There is growing interest in the premise that initiating therapy with a combination of agents offering complementary mechanisms of action may have potential benefits (such as preserving beta-cell function) over a stepwise treatment approach6. If preservation of beta-cell function was shown to occur with combination therapy, such an effect could potentially prolong the period before patients would require additional glucose-lowering therapies in order to maintain effective glycemic control, which typically occurs for most patients with long-term treatment. The addition of further glucose-lowering therapies may add to the pill burden in patients with T2DM, who may also be receiving treatment for hypertension and dyslipidemia, conditions that are highly prevalent in this patient population.
3
Studies have demonstrated that factors such as increasing numbers of tablets, multiple daily dosing schedules and the concurrent use of several types of oral antidiabetic drugs (OADs) are associated with poor adherence7-9. This awareness has led to considerable interest in the use of single-pill combinations that have the potential of reducing pill burden10-12. Until now, most single-pill formulations have incorporated metformin along with a second agent, but the use of such formulations may be limited
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
because metformin is not suitable for all patients: gastrointestinal side effects can limit its tolerability for some patients and it is contraindicated in certain patients with renal impairment. Combinations of other agents may therefore also offer potential value. This review considers the evidence for specifically combining linagliptin (a dipeptidyl peptidase-4 [DPP4] inhibitor) and empagliflozin (a sodium glucose co-transporter 2 [SGLT2] inhibitor) in a single-pill formulation. In 2014, the US Food and Drug Administration (FDA) accepted the filing of a new drug application for this combination, the first reported combination of these two drug classes13.
Methods A non-systematic search of PubMed was performed for titles containing linagliptin or empagliflozin without imposing date restrictions. ClinicalTrials.gov was searched for entries that were associated with linagliptin and empagliflozin as keywords. Additional references known to the author were included, and abstracts presented at the annual meetings of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) 2012–2014
were also searched for relevant content.
Linagliptin DPP-4 inhibitors produce their glucose-lowering effects by preventing the DPP-4-mediated degradation of GLP-1, a gut-derived incretin hormone with potent antihyperglycemic activity that induces glucose-
4
dependent insulin secretion while suppressing glucagon secretion14. The glucose-dependent nature of this system means that DPP-4 inhibitors are generally associated with a low risk of hypoglycemia15. Linagliptin was first approved in the US in 2011 as an adjunct to diet and exercise to improve glycemic control in adults with T2DM (recommended oral dose of 5 mg once daily)16, and has since gained approval around the world. The efficacy and safety of linagliptin has been assessed in patients with
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
T2DM in a large clinical trial program, both as monotherapy and in combination with other OADs17,18. Linagliptin 5 mg once daily was associated with significantly improved glycemic control when used as monotherapy19,20, as initial combination therapy with metformin21,22 or pioglitazone23, as add-on therapy to metformin and/or a sulfonylurea24,25, or as add-on therapy to basal insulin with or without other OADs26. Furthermore, the efficacy of linagliptin was maintained irrespective of patients’ renal function2729
, age30, race or ethnicity31-34, or duration of T2DM35.
The Phase 3 program also demonstrated that linagliptin treatment was weight neutral and that the rate of serious adverse events (AEs) across all trials was low17,18. The risk of hypoglycemia with linagliptin is low, except when used in combination with a sulfonylurea or insulin17,18,25. A pre-specified, prospective, adjudicated meta-analysis of Phase 3 studies indicated that linagliptin does not appear to increase the risk of cardiovascular (CV) events36. The CAROLINA (Cardiovascular Safety of Linagliptin versus Glimepiride) trial, an ongoing long-term CV outcomes study, will provide further information on the CV safety of linagliptin37. In addition, the CARMELINA (Cardiovascular safety and Renal Microvascular outcome with Linagliptin in patients with Type 2 Diabetes mellitus at high vascular risk) trial will investigate the effect of linagliptin on CV and renal microvascular outcomes in adults with T2DM at risk of CV and renal events (ClinicalTrials.gov identifier: NCT01897532).
5
Empagliflozin SGLT2 inhibitors produce their anti-hyperglycemic effect via inhibition of renal glucose re-absorption by SGLT2, thereby causing glucose to be excreted in the urine. As a result, glucose is removed from the body which, in turn, leads to a lowering of the level of hyperglycemia38. The insulin-independent mechanism of action of SGLT2 inhibitors makes them suitable for use in combination with any
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
background glucose-lowering agent, including insulin39,40. Empagliflozin was approved in the US in 2014 as an adjunct to diet and exercise to improve glycemic control in adults with T2DM41. It is available as 10 mg and 25 mg tablets; the recommended dose is 10 mg once daily, taken in the morning, with or without food, and the dose can be increased to 25 mg once daily41. Empagliflozin is being evaluated in adult patients with T2DM in a Phase 3 clinical development program that comprises more than 10 multinational clinical studies, and which has recruited over 14,500 patients42. A number of pivotal studies have been completed, and have demonstrated that empagliflozin, given either as monotherapy or as an add-on therapy to other OADs, produced statistically significant and clinically relevant improvements in glycemic control in patients with T2DM compared with placebo43-48, as determined by the change from baseline in glycated hemoglobin (HbA1c)39. Empagliflozin also produces modest reductions in both blood pressure and body weight43-49. Treatment was generally well tolerated39 although, as consistent with other SGLT2 inhibitors, an increased risk of genital infections was observed across studies43-48. Recently completed Phase 3 studies include investigations of empagliflozin in a comprehensive add-on study in Japanese patients (ClinicalTrials.gov identifier: NCT01368081) as add-on to insulin in obese patients50, and in a 52-week extension of 24-week trials as monotherapy or with different background therapies51-54. Ongoing studies include a dedicated CV outcome event trial (EMPA-REG OUTCOME ), which is expected to report results in 201555. 6
SGLT2 inhibitors and DPP-4 inhibitors in combination Studies with empagliflozin and dapagliflozin have shown improvements in beta-cell function56 and insulin sensitivity56,57. However, these studies have also reported an increase in endogenous glucose production, despite reducing fasting plasma glucose (FPG)56,57. For empagliflozin, this effect was observed acutely and appeared to be reduced after 28 days56; for dapagliflozin, endogenous glucose
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/10/15 For personal use only.
production was observed up to study end (14 days)57.This increase in endogenous glucose production may be an equilibrating physiologic response to the SGT2-inhibitor-induced glycosuria. Merovci et al57 estimated that this increase in endogenous glucose production offsets approximately half of the glucose excreted as a result of SGLT2 inhibition with dapagliflozin. If this increase were to be prevented, the decrease in FPG caused by dapagliflozin would have approximately doubled. It would be of great interest, therefore, to examine combination therapy that would combine an SGLT2 inhibitor with an incretin mimetic that might additionally inhibit glucagon and stimulate insulin secretion57. Such agents would be anticipated to mitigate the increase in endogenous glucose production and therefore augment the glucose-lowering ability of the SGLT2 inhibitor. This effect has been reported for sitagliptin58 and for linagliptin59. Merovci et al hypothesized that combining an SGLT2 inhibitor with a DPP-4 inhibitor or GLP1 analog would produce an additive or possibly synergistic effect to improve glycemic parameters57. Several fixed-dose (i.e., single-pill) combination products utilizing SGLT2 inhibitors are currently in clinical development, including combinations with metformin39, and with other agents. Of these, a combination of canagliflozin and metformin60 and dapagliflozin and metformin61 have already been approved in the US. In addition, US approval has been granted for a fixed-dose combination of empagliflozin and linagliptin as an adjunct to diet and exercise to improve glycemic control in adults with T2DM when treatment with both empagliflozin and linagliptin is appropriate62. This approval is
7
based on a number of studies that have so far assessed the combination of an SGLT2 inhibitor and DPP-4 inhibitor. Jabbour et al investigated dapagliflozin as add-on (free combination) therapy in patients with T2DM who were inadequately controlled with the DPP-4 inhibitor sitagliptin ± metformin63. This study demonstrated that dapagliflozin treatment in dual combination with sitagliptin, or in triple combination
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with sitagliptin plus metformin, was well tolerated and was associated with improvements in glycemic parameters and body weight that were sustained through 48 weeks of treatment63. Rosenstock et al have recently reported the findings of a 24-week, multicenter, randomized, doubleblind, active-controlled, parallel-group Phase 3 study comparing the efficacy and safety of dual add-on of saxagliptin (5 mg/day) plus dapagliflozin (10 mg/day), versus both agents added on alone, in patients with T2DM inadequately controlled on metformin64. Patients were randomized to saxagliptin plus dapagliflozin (n=179) or saxagliptin and placebo (n=176) or dapagliflozin and placebo (n=179) with continuing background metformin extended release ≥1,500 mg/day. The primary endpoint (adjusted mean change from baseline in HbA1c at 24 weeks) result was –1.5% (–16.1 mmol/mol) with the triple combination versus –0.9% (–9.6 mmol/mol) with saxagliptin plus metformin (difference –0.59% [–6.4 mmol/mol], p
