Combination Treatment of SGLT2 Inhibitors and GLP-1 Receptor Agonists: Symbiotic Effects on Metabolism and Cardiorenal Risk

Combination Treatment of SGLT2 Inhibitors and GLP-1 Receptor Agonists: Symbiotic Effects on... Diabetes Ther (2018) 9:919–926 https://doi.org/10.1007/s13300-018-0420-6 REVIEW Combination Treatment of SGLT2 Inhibitors and GLP- 1 Receptor Agonists: Symbiotic Effects on Metabolism and Cardiorenal Risk Edison Goncalves David S. H. Bell Received: January 21, 2018 / Published online: April 5, 2018 The Author(s) 2018 glucose cotransporter-2 (SGLT2) inhibitor in ABSTRACT lowering glycated hemoglobin (HbA1c) level, cardiac risk, cardiac events and renal Introduction: When treating type 2 diabetes, decompensation. drugs that cause hypoglycemia and weight Results: Evidence is presented which shows gain should, if possible, be avoided. In addi- that the efficacy of combined SGLT2 inhi- tion, due to the increased incidence and bitor/GLP-1 receptor agonist therapy is addi- prevalence of cardiovascular disease, cardiac tive in lowering HbA1c level, systolic blood events and heart failure, as well as the accel- pressure and body weight. This combined erated renal decompensation that may occur therapy also has the potential to cause fur- with type 2 diabetes, hypoglycemic agents ther reductions in major cardiovascular that have the potential to lower cardiac and events and renal decompensation than those renal risk should be utilized as early as possible achieved with either drug used as in thecourseofthe disease. monotherapy or in combination with other Methods: This is a literature review of the effi- hypoglycemic agents. cacy of combined treatment with a glucagon- Conclusion: The combination of a GLP-1 like peptide 1 (GLP-1) agonist and a sodium agonist and an SGLT2-inhibitor has additive effects on lowering HbA1c and systolic blood pressure, body weight and cardiac risk and has the potential to synergistically reduce cardiovascular events and decelerate renal Enhanced content To view enhanced content for this decompensation. A large prospective study of article go to https://doi.org/10.6084/m9.figshare. this combination is needed to prove that this synergism, especially as it applies to cardiac risk factors, cardiac events and mor- E. Goncalves (&) tality and preservation of renal function, is Diabetes & Thyroid Associates, 2022 Brookwood Medical Center Dr, Birmingham 35209, AL, USA proven. e-mail: goncalves.edison@gmail.com Keywords: Canagliflozin; Empagliflozin; GLP-1 D. S. H. Bell Southside Endocrinology, Irondale, AL, USA receptor agonist; Heart failure; Liraglutide; Myocardial infarction; Renal decompensation; D. S. H. Bell SGLT2 inhibitor; Stroke; Weight loss University of Alabama at Birmingham, Birmingham, AL, USA 920 Diabetes Ther (2018) 9:919–926 INTRODUCTION RESULTS In choosing drugs to treat type 2 diabetes, We found only two prospective studies on of insulin and/or secretagogues are not a pru- the combination of an SGLT2 inhibitor and dent initial choice because of their associa- GLP-1 agonist (Table 1). In the DURATION-8 tion with hypoglycemia and weight gain [1]. study, combined therapy with dapagliflozin In addition to these limitations, drugs that given once daily and the GLP-1 receptor agonist cause weight gain have the potential to exenatide given once weekly was found to increase insulin resistance and/or cardiac reduce HbA1c by 2% accompanied by a 3.4 kg risk. Drugs that lower body weight, such as weight loss, with both targets superior to those glucagon-like peptide 1 (GLP-1) receptor achieved with monotherapy with either drug agonists and sodium glucose cotransporter-2 [4]. The reductions in systolic blood pressure (SGLT2) inhibitors should be preferred. These and fasting and post-prandial glucose were also drugs lead to significant cardiometabolic greater with the combination [4]. improvements, with a decrease in cardiac and The same combination was also studied in a skeletal muscle fat leading to improvement in small group of obese adults without diabetes, insulin sensitivity. Furthermore, with a similar effects on weight and systolic blood reductioninhepatic fatthere is improved pressure observed. Magnetic resonance imaging hepatic insulin sensitivity and a reduction in assessments in that study indicated that the hepatic glucose production. Also, with a weight reduction was mostly due to adipose decrease in beta cell fat there is a deceleration tissue reduction (subcutaneous and visceral of beta cell apoptosis that leads to improved adipose tissue equally) [5]. insulin secretion [2, 3]. Therefore, combined More recently, the AWARD-10 study [6] has treatment with a GLP-1 receptor agonist and shown a reduction in HbA1c of up to 1.34% and an SGLT2 inhibitor, with or without met- a 3.1 kg weight loss upon the addition of formin, should be the preferred initial ther- dulaglutide 1.5 mg weekly to the treatment apy for type 2 diabetes because in addition to regimen of patients being treated with an lowering glucose levels, body fat will be SGLT2 inhibitor (with or without metformin). reduced as will blood pressure and cardiac There was also a significant reduction in SBP risk. With these changes there is the poten- with dulaglutide 1.5 mg. Despite significant tial for a decrease in cardiac events, cardiac differences between these two studies, primarily and total mortality and deceleration of the simultaneous start in the DURATION-8 study decline in renal function. and sequential use in the AWARD-10 study, both support a complementary effect of this combination in terms of reductions in HbA1c, METHODS body weight and systolic blood pressure. A post hoc analysis of the CANVAS study, We conducted a Medline search of the literature which included 95 patients taking a GLP-1 using the Boolean expression GLP-1 receptor receptor agonist (74% exenatide and 26% agonist AND SGLT2 inhibitor, as well as using liraglutide), showed that with canagliflozin the individual drug names of both classes along 300 mg daily there was a further drop in systolic with the modifier AND; looking for studies blood pressure (8.0 mmHg) and a further weight showing the effects of this combination in loss (3.2%) over 18 weeks [7]. lowering glycated hemoglobin (HbA1c) level, A single case report of treatment with the body weight and cardiac risk factors. This study combination of canagliflozin and liraglutide is based on previously conducted studies and resulting in the discontinuation of insulin does not contain any studies with human par- therapy combined with a weight loss from 112 ticipants or animals performed by any of the to 100 kg included a retrospective analysis of 15 authors. subjects utilizing this combination [8]. HbA1c Diabetes Ther (2018) 9:919–926 921 Table 1 Summary of results of prospective and observational studies examining the effects of the combination of sodium glucose cotransporter-2 inhibitors and glucagon-like peptide 1 receptor agonists on glycated hemoglobin, body weight and systolic blood pressure Study DURATION-8 AWARD-10 Goncalves and Bell Goncalves and Saroka et al. characteristics study [4] study [6] [10] (simultaneous Bell [10] [9] (sequential a b c c d (simultaneous start) (sequential use) start) (sequential use) use) Duration of 7.6 9.2 11 9.3 13.8 DM (years) Duration of 28 24 62 76 45 study (weeks) Number of 231 (on 142 33 46 75 patients combination) HbA1c 9.3 8.0 9.1 8.5 7.9 (initial) (%) HbA1c change - 2.0 - 1.34 - 2.0 - 0.9 - 0.47 (%) Weight change - 3.4 - 3.1 - 10 - 4 - 5.45 (kg) SBP change - 4.2 - 4.5 - 13 - 7 - 4 (mmHg) Prospective studies Observational studies Drugs were initiated simultaneously or sequentially. In the latter case, with the sodium glucose cotransporter-2 (SGLT2) inhibitor administered first, followed by the glucagon-like peptide 1 (GLP-1) receptor agonist, or vice versa DM Diabetes mellitus, HbA1c glycated hemoglobin, SBP systolic blood pressure Exenatide LAR and dapagliflozin Dulaglutide 1.5 mg data presented (added to an SGLT2 inhibitor) SGLT2 inhibitor added to liraglutide or started simultaneously Canagliflozin added to GLP-1 receptor agonist, canagliflozin 300 mg data presented in this group dropped from 9.1% to 7.0%, and stimulated the performance of a real world ret- mean body weight was reduced from 113 to rospective study utilizing computerized records 108 kg, which is similar to the results obtained in a single large endocrine practice (Table 1). in the prospective study of dapagliflozin and Because there was a 3-year gap between the exenatide [4]. Another retrospective study on availability of liraglutide and that of the first subjects who had been on a GLP-1 receptor SGLT2 inhibitor (canagliflozin) the study was agonist for at least 1 year showed that the divided into those who received sequential addition of canagliflozin to the therapeutic therapy (n = 46) and those who received regimen resulted not only in a further small simultaneous therapy (n = 33) [10]. In the decrease in the HbA1c (0.39%) but also in a sequential group, HbA1c dropped from 8.9% to further 4.6 kg weight loss [9]. 7.6%, while in the simultaneous group the The striking outcomes of these prospective HbA1c dropped from 9.1% to 7.1%. The group and retrospective studies with these drugs treated sequentially was on liraglutide for a 922 Diabetes Ther (2018) 9:919–926 median of 141 weeks when the SGLT2 inhibitor mortality [14]. In another study, once-weekly was added to the therapy, which explains the exenatide was shown to be non-inferior to pla- lower total HbA1c reduction in that group cebo with respect to safety, but there were no compared to that of the simultaneous start significant decreases in myocardial infarction, group. In the sequential group, liraglutide sig- stroke or hospitalization for heart failure; total nificantly reduced body weight from 111 to and cardiovascular mortality were non-signifi- 105 kg and when the SGLT2 inhibitor was cantly decreased by 14 and 12%, respectively added there was a further decrease to 101 kg. [15]. Total weight loss was very similar in the simul- Two of the four currently available SGLT2 taneous group where there was also a weight inhibitors (empagliflozin and canagliflozin) are loss of 10 kg (116–106 kg). The data suggested associated with decreased cardiovascular mor- that there was a plateauing of the weight effect tality and a decreased risk of admission to hos- after about 1 year, since the weight loss was pital with heart failure and all-cause mortality similar at both 62 and 217 weeks. In addition, without a decrease in myocardial infarction or in the sequential group systolic blood pressure stroke [16, 17]. In addition, a large retrospective dropped by 6 mmHg with liraglutide and by a international database study has shown further 7 mmHg with the addition of canagli- decreases in cardiovascular events, all-cause flozin, while in the simultaneous group systolic mortality and hospitalization for heart failure in blood pressure dropped by 13 mm Hg. There patients receiving dapagliflozin [18, 19]. were no significant change in diastolic blood Prospective studies with the GLP-1 receptor pressure [10]. In contrast to the symbiotic agonist liraglutide once-daily and the GLP-1 effects on HbA1c, body weight and systolic receptor agonist semaglutide once-weekly have blood pressure, the beneficial effect of liraglu- shown decreases in non-fatal myocardial tide on total cholesterol, low-density lipopro- infarction, non-fatal stroke and cardiovascular tein (LDL) cholesterol and non-high-density and total mortality, without a decrease in lipoprotein (HDL) cholesterol was nullified by admission to hospital with heart failure [11, 12]. the addition of an SGLT2 inhibitor [10]. Possi- These GLP-1 receptor agonists are postulated to bly because of a rapid improvement in glycemic improve myocardial function through their control in the simultaneous group, but not the capacity to decrease inflammation, improve sequential group, there was a decrease in endothelial function and decelerate atheroma triglycerides and non-HDL cholesterol without formation [20]. GLP-1 agonists therefore have a change in total or LDL cholesterol [10]. With the potential to synergistically decrease major decreases in HbA1c, body weight and systolic adverse cardiovascular cardiac events, cardiac blood pressure as well as a drop in non-HDL mortality and total mortality when utilized in cholesterol and triglycerides, the combination combination with SGLT-2 inhibitors. of a GLP-1 receptor agonist and a SGLT2 inhi- SGLT2 inhibitors and GLP-1 receptor ago- bitor should result in at least a decrease in car- nists have potentially complementary effects on diac risk and potentially a decrease in cardiac renal function. Once-daily liraglutide (1.8 mg) events. and once-daily empagliflozin (10 or 25 mg) were found to reduce incident or worsening diabetic nephropathy by 22% over 3.8 years and DISCUSSION by 39% over 3.1 years, respectively [21, 22]. SGLT2 inhibitors and, to a lesser extent, GLP-1 To date positive cardiovascular outcomes have receptor agonists, decrease renal proximal only been reported with daily liraglutide and tubular sodium resorption. Sensing of the weekly semaglutide, while an outcome study increased urine sodium by the macula densa with dulaglutide is in progress [11–13]. In a results in decreased activity of the renin–an- safety study, lixisenatide was shown to have giotensin–aldosterone system. It also activates cardiac safety without an improvement in car- tubuloglomerular feedback, thereby increasing diac events, cardiac mortality or overall glomerular afferent arteriole resistance, which Diabetes Ther (2018) 9:919–926 923 in turn leads to decreased intraglomerular agonists is most likely due to direct and indirect pressure and decreased glomerular hyperfiltra- actions in multiple organs. In the heart itself, tion, resulting in decreased proteinuria and a GLP-1 receptors are expressed on both the deceleration in the decline in renal function myocardiocyte and the vascular endothelium. [23]. Reabsorption of sodium ions by the prox- Also, activation of receptors on monocytes, imal tubule accounts for most of the kidney’s macrophages and lymphocytes will likely result workload; therefore, if in addition to a in improved function, leading to decreased decreased sodium reabsorption and renal work- inflammation, improved endothelial function, load with an SGLT2 inhibition, there is also a a decrease in the formation of foam cells and change in metabolism from the use of glucose increased stability of atheromatous plaques and free fatty acids as a substrate to the use of [20, 27–31]. Therefore, the proposed cardiopro- ketone bodies, there would be a further decrease tective mechanisms of SGLT2 inhibitors and in renal workload and preservation of renal GLP-1 receptor agonists are likely to be com- function (see below). In addition, lowering of plementary. Theoretically, the combined car- HbA1c, blood pressure, body weight and uric diac and renal effect of the SGLT-2 inhibitor and acid levels could play at least a partial role in the the GLP-1 receptor agonist could be decreased deceleration of renal decline. by lowered hepatic ketone production, which is Therefore, it can be concluded that the dependent on glucagon activity that will be decreases in cardiac and total mortality seen acutely suppressed by GLP-1 receptor agonists. with SGLT inhibitors is a class effect and However, chronic treatment, at least with probably only due to a decreased incidence and liraglutide, is associated with a decrease or even frequency of heart failure. The potential causes a loss of glucagon suppression, which may for this decrease in heart failure are protean, but negate this effect [32]. a decrease in weight and blood pressure causing Despite beneficial effects on cardiovascular a decrease in the preload and afterload of the mortality noted in the EMPA-REG OUTCOME myocardium are likely hemodynamic candi- [16] and CANVAS [17], non-fatal stroke dates. However, the ability of SGLT2 inhibitors increased by 30% with empagliflozin and to shift metabolism away from the utilization of amputations increased by 97% with canagli- carbohydrate and free fatty acids to the utiliza- flozin. Ketoacidosis has been reported with all tion of ketone bodies derived from the break- SGLT2 inhibitors, although its risk may be down of fat is an attractive hypothesis, and in attenuated by combining it with a GLP-1 our opinion a more likely explanation [24, 25]. receptor agonist. Both drug classes have been Ketone bodies are likely to be avidly utilized by associated with acute renal failure, possibly due the myocardium and kidney, resulting in to fluid contraction, and the entire incre- decreases in both cardiac and renal workload. tin–mimetic class has been associated with Thus, the beneficial cardiovascular effect of pancreatitis. The most common side effects, SGLT2 inhibitors are most likely to be through a however, are gastrointestinal and genitourinary, decreased cardiac workload, leading to which tend to improve over time [33]. improvement in existing heart failure, preven- In conclusion, the SGLT2 inhibitor and GLP- tion of ‘‘denovo’’ heart failure and decreased 1 receptor agonist combination has additive cardiac and total mortality. effects on glycemic control without the incon- The effect of GLP-1 receptor agonists in car- venience and dangers of hypoglycemia. There diovascular events is far more complex and are also synergistic effects on weight loss and clearly not due to a decrease in heart failure. In blood pressure, potentially leading to lower a study utilizing GLP-1 receptor agonists in cardiovascular events, heart failure, cardiovas- patients hospitalized for heart failure with cular and total mortality, as well as a decelera- reduced left ventricular ejection fraction, the tion of renal function. However, if increased use of liraglutide did not lead to a greater post- cardiac and renal consumption of ketone bodies hospitalization clinical stability [26]. The car- is indeed the reason for improved outcomes dioprotection provided by GLP-1 receptor with SGLT2 inhibitors, then the combination 924 Diabetes Ther (2018) 9:919–926 may negate the effects of SGLT2 inhibitors on Pharmaceuticals. David S.H. Bell is on the cardiac and renal workload and decrease the Speaker’s bureau of Novo-Nordisk, AstraZeneca cardiorenal benefits. Ultimately, only a cardio- and Janssen Pharmaceuticals. vascular and renal outcomes trial with the Compliance with Ethics Guidelines. This combination would provide an answer to this article is based on previously conducted studies hypothesis. and does not contain any studies with human Despite the beneficial and symbiotic effects participants or animals performed by any of the of a combined therapeutic regimen consisting authors. of a SGLT-2 receptor inhibitor and a GLP-1 agonist, this combination is not being widely Open Access. This article is distributed utilized. Cost and formulary barriers are the under the terms of the Creative Commons probable reason for this, and in the absence of Attribution-NonCommercial 4.0 International more prospective studies, third party payers are License (http://creativecommons.org/licenses/ unlikely ‘‘to foot the bill.’’ So why have these by-nc/4.0/), which permits any non- studies not been performed? The likeliest commercial use, distribution, and reproduction explanation is the reluctance of pharmaceutical in any medium, provided you give appropriate companies to study their drugs in combination credit to the original author(s) and the source, with a non-generic drug for which they do not provide a link to the Creative Commons license, have a patent. One of the prospective random- and indicate if changes were made. ized studies was with dapagliflozin and exe- natide, and notably the patents of both drugs are held by the same company [4]. In addition, there have been no prospective cardiovascular REFERENCES or renal outcomes trials with any GLP-1 recep- tor agonist/SGLT2 inhibitor combination. The 1. Pathak RD, Schroeder EB, Seaquist ER, Zeng C, reluctance to prospectively study this combi- Lafata JE, Thomas A, et al. 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Combination Treatment of SGLT2 Inhibitors and GLP-1 Receptor Agonists: Symbiotic Effects on Metabolism and Cardiorenal Risk

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Diabetes Ther (2018) 9:919–926 https://doi.org/10.1007/s13300-018-0420-6 REVIEW Combination Treatment of SGLT2 Inhibitors and GLP- 1 Receptor Agonists: Symbiotic Effects on Metabolism and Cardiorenal Risk Edison Goncalves David S. H. Bell Received: January 21, 2018 / Published online: April 5, 2018 The Author(s) 2018 glucose cotransporter-2 (SGLT2) inhibitor in ABSTRACT lowering glycated hemoglobin (HbA1c) level, cardiac risk, cardiac events and renal Introduction: When treating type 2 diabetes, decompensation. drugs that cause hypoglycemia and weight Results: Evidence is presented which shows gain should, if possible, be avoided. In addi- that the efficacy of combined SGLT2 inhi- tion, due to the increased incidence and bitor/GLP-1 receptor agonist therapy is addi- prevalence of cardiovascular disease, cardiac tive in lowering HbA1c level, systolic blood events and heart failure, as well as the accel- pressure and body weight. This combined erated renal decompensation that may occur therapy also has the potential to cause fur- with type 2 diabetes, hypoglycemic agents ther reductions in major cardiovascular that have the potential to lower cardiac and events and renal decompensation than those renal risk should be utilized as early as possible achieved with either drug used as in thecourseofthe disease. monotherapy or in combination with other Methods: This is a literature review of the effi- hypoglycemic agents. cacy of combined treatment with a glucagon- Conclusion: The combination of a GLP-1 like peptide 1 (GLP-1) agonist and a sodium agonist and an SGLT2-inhibitor has additive effects on lowering HbA1c and systolic blood pressure, body weight and cardiac risk and has the potential to synergistically reduce cardiovascular events and decelerate renal Enhanced content To view enhanced content for this decompensation. A large prospective study of article go to https://doi.org/10.6084/m9.figshare. this combination is needed to prove that this synergism, especially as it applies to cardiac risk factors, cardiac events and mor- E. Goncalves (&) tality and preservation of renal function, is Diabetes & Thyroid Associates, 2022 Brookwood Medical Center Dr, Birmingham 35209, AL, USA proven. e-mail: goncalves.edison@gmail.com Keywords: Canagliflozin; Empagliflozin; GLP-1 D. S. H. Bell Southside Endocrinology, Irondale, AL, USA receptor agonist; Heart failure; Liraglutide; Myocardial infarction; Renal decompensation; D. S. H. Bell SGLT2 inhibitor; Stroke; Weight loss University of Alabama at Birmingham, Birmingham, AL, USA 920 Diabetes Ther (2018) 9:919–926 INTRODUCTION RESULTS In choosing drugs to treat type 2 diabetes, We found only two prospective studies on of insulin and/or secretagogues are not a pru- the combination of an SGLT2 inhibitor and dent initial choice because of their associa- GLP-1 agonist (Table 1). In the DURATION-8 tion with hypoglycemia and weight gain [1]. study, combined therapy with dapagliflozin In addition to these limitations, drugs that given once daily and the GLP-1 receptor agonist cause weight gain have the potential to exenatide given once weekly was found to increase insulin resistance and/or cardiac reduce HbA1c by 2% accompanied by a 3.4 kg risk. Drugs that lower body weight, such as weight loss, with both targets superior to those glucagon-like peptide 1 (GLP-1) receptor achieved with monotherapy with either drug agonists and sodium glucose cotransporter-2 [4]. The reductions in systolic blood pressure (SGLT2) inhibitors should be preferred. These and fasting and post-prandial glucose were also drugs lead to significant cardiometabolic greater with the combination [4]. improvements, with a decrease in cardiac and The same combination was also studied in a skeletal muscle fat leading to improvement in small group of obese adults without diabetes, insulin sensitivity. Furthermore, with a similar effects on weight and systolic blood reductioninhepatic fatthere is improved pressure observed. Magnetic resonance imaging hepatic insulin sensitivity and a reduction in assessments in that study indicated that the hepatic glucose production. Also, with a weight reduction was mostly due to adipose decrease in beta cell fat there is a deceleration tissue reduction (subcutaneous and visceral of beta cell apoptosis that leads to improved adipose tissue equally) [5]. insulin secretion [2, 3]. Therefore, combined More recently, the AWARD-10 study [6] has treatment with a GLP-1 receptor agonist and shown a reduction in HbA1c of up to 1.34% and an SGLT2 inhibitor, with or without met- a 3.1 kg weight loss upon the addition of formin, should be the preferred initial ther- dulaglutide 1.5 mg weekly to the treatment apy for type 2 diabetes because in addition to regimen of patients being treated with an lowering glucose levels, body fat will be SGLT2 inhibitor (with or without metformin). reduced as will blood pressure and cardiac There was also a significant reduction in SBP risk. With these changes there is the poten- with dulaglutide 1.5 mg. Despite significant tial for a decrease in cardiac events, cardiac differences between these two studies, primarily and total mortality and deceleration of the simultaneous start in the DURATION-8 study decline in renal function. and sequential use in the AWARD-10 study, both support a complementary effect of this combination in terms of reductions in HbA1c, METHODS body weight and systolic blood pressure. A post hoc analysis of the CANVAS study, We conducted a Medline search of the literature which included 95 patients taking a GLP-1 using the Boolean expression GLP-1 receptor receptor agonist (74% exenatide and 26% agonist AND SGLT2 inhibitor, as well as using liraglutide), showed that with canagliflozin the individual drug names of both classes along 300 mg daily there was a further drop in systolic with the modifier AND; looking for studies blood pressure (8.0 mmHg) and a further weight showing the effects of this combination in loss (3.2%) over 18 weeks [7]. lowering glycated hemoglobin (HbA1c) level, A single case report of treatment with the body weight and cardiac risk factors. This study combination of canagliflozin and liraglutide is based on previously conducted studies and resulting in the discontinuation of insulin does not contain any studies with human par- therapy combined with a weight loss from 112 ticipants or animals performed by any of the to 100 kg included a retrospective analysis of 15 authors. subjects utilizing this combination [8]. HbA1c Diabetes Ther (2018) 9:919–926 921 Table 1 Summary of results of prospective and observational studies examining the effects of the combination of sodium glucose cotransporter-2 inhibitors and glucagon-like peptide 1 receptor agonists on glycated hemoglobin, body weight and systolic blood pressure Study DURATION-8 AWARD-10 Goncalves and Bell Goncalves and Saroka et al. characteristics study [4] study [6] [10] (simultaneous Bell [10] [9] (sequential a b c c d (simultaneous start) (sequential use) start) (sequential use) use) Duration of 7.6 9.2 11 9.3 13.8 DM (years) Duration of 28 24 62 76 45 study (weeks) Number of 231 (on 142 33 46 75 patients combination) HbA1c 9.3 8.0 9.1 8.5 7.9 (initial) (%) HbA1c change - 2.0 - 1.34 - 2.0 - 0.9 - 0.47 (%) Weight change - 3.4 - 3.1 - 10 - 4 - 5.45 (kg) SBP change - 4.2 - 4.5 - 13 - 7 - 4 (mmHg) Prospective studies Observational studies Drugs were initiated simultaneously or sequentially. In the latter case, with the sodium glucose cotransporter-2 (SGLT2) inhibitor administered first, followed by the glucagon-like peptide 1 (GLP-1) receptor agonist, or vice versa DM Diabetes mellitus, HbA1c glycated hemoglobin, SBP systolic blood pressure Exenatide LAR and dapagliflozin Dulaglutide 1.5 mg data presented (added to an SGLT2 inhibitor) SGLT2 inhibitor added to liraglutide or started simultaneously Canagliflozin added to GLP-1 receptor agonist, canagliflozin 300 mg data presented in this group dropped from 9.1% to 7.0%, and stimulated the performance of a real world ret- mean body weight was reduced from 113 to rospective study utilizing computerized records 108 kg, which is similar to the results obtained in a single large endocrine practice (Table 1). in the prospective study of dapagliflozin and Because there was a 3-year gap between the exenatide [4]. Another retrospective study on availability of liraglutide and that of the first subjects who had been on a GLP-1 receptor SGLT2 inhibitor (canagliflozin) the study was agonist for at least 1 year showed that the divided into those who received sequential addition of canagliflozin to the therapeutic therapy (n = 46) and those who received regimen resulted not only in a further small simultaneous therapy (n = 33) [10]. In the decrease in the HbA1c (0.39%) but also in a sequential group, HbA1c dropped from 8.9% to further 4.6 kg weight loss [9]. 7.6%, while in the simultaneous group the The striking outcomes of these prospective HbA1c dropped from 9.1% to 7.1%. The group and retrospective studies with these drugs treated sequentially was on liraglutide for a 922 Diabetes Ther (2018) 9:919–926 median of 141 weeks when the SGLT2 inhibitor mortality [14]. In another study, once-weekly was added to the therapy, which explains the exenatide was shown to be non-inferior to pla- lower total HbA1c reduction in that group cebo with respect to safety, but there were no compared to that of the simultaneous start significant decreases in myocardial infarction, group. In the sequential group, liraglutide sig- stroke or hospitalization for heart failure; total nificantly reduced body weight from 111 to and cardiovascular mortality were non-signifi- 105 kg and when the SGLT2 inhibitor was cantly decreased by 14 and 12%, respectively added there was a further decrease to 101 kg. [15]. Total weight loss was very similar in the simul- Two of the four currently available SGLT2 taneous group where there was also a weight inhibitors (empagliflozin and canagliflozin) are loss of 10 kg (116–106 kg). The data suggested associated with decreased cardiovascular mor- that there was a plateauing of the weight effect tality and a decreased risk of admission to hos- after about 1 year, since the weight loss was pital with heart failure and all-cause mortality similar at both 62 and 217 weeks. In addition, without a decrease in myocardial infarction or in the sequential group systolic blood pressure stroke [16, 17]. In addition, a large retrospective dropped by 6 mmHg with liraglutide and by a international database study has shown further 7 mmHg with the addition of canagli- decreases in cardiovascular events, all-cause flozin, while in the simultaneous group systolic mortality and hospitalization for heart failure in blood pressure dropped by 13 mm Hg. There patients receiving dapagliflozin [18, 19]. were no significant change in diastolic blood Prospective studies with the GLP-1 receptor pressure [10]. In contrast to the symbiotic agonist liraglutide once-daily and the GLP-1 effects on HbA1c, body weight and systolic receptor agonist semaglutide once-weekly have blood pressure, the beneficial effect of liraglu- shown decreases in non-fatal myocardial tide on total cholesterol, low-density lipopro- infarction, non-fatal stroke and cardiovascular tein (LDL) cholesterol and non-high-density and total mortality, without a decrease in lipoprotein (HDL) cholesterol was nullified by admission to hospital with heart failure [11, 12]. the addition of an SGLT2 inhibitor [10]. Possi- These GLP-1 receptor agonists are postulated to bly because of a rapid improvement in glycemic improve myocardial function through their control in the simultaneous group, but not the capacity to decrease inflammation, improve sequential group, there was a decrease in endothelial function and decelerate atheroma triglycerides and non-HDL cholesterol without formation [20]. GLP-1 agonists therefore have a change in total or LDL cholesterol [10]. With the potential to synergistically decrease major decreases in HbA1c, body weight and systolic adverse cardiovascular cardiac events, cardiac blood pressure as well as a drop in non-HDL mortality and total mortality when utilized in cholesterol and triglycerides, the combination combination with SGLT-2 inhibitors. of a GLP-1 receptor agonist and a SGLT2 inhi- SGLT2 inhibitors and GLP-1 receptor ago- bitor should result in at least a decrease in car- nists have potentially complementary effects on diac risk and potentially a decrease in cardiac renal function. Once-daily liraglutide (1.8 mg) events. and once-daily empagliflozin (10 or 25 mg) were found to reduce incident or worsening diabetic nephropathy by 22% over 3.8 years and DISCUSSION by 39% over 3.1 years, respectively [21, 22]. SGLT2 inhibitors and, to a lesser extent, GLP-1 To date positive cardiovascular outcomes have receptor agonists, decrease renal proximal only been reported with daily liraglutide and tubular sodium resorption. Sensing of the weekly semaglutide, while an outcome study increased urine sodium by the macula densa with dulaglutide is in progress [11–13]. In a results in decreased activity of the renin–an- safety study, lixisenatide was shown to have giotensin–aldosterone system. It also activates cardiac safety without an improvement in car- tubuloglomerular feedback, thereby increasing diac events, cardiac mortality or overall glomerular afferent arteriole resistance, which Diabetes Ther (2018) 9:919–926 923 in turn leads to decreased intraglomerular agonists is most likely due to direct and indirect pressure and decreased glomerular hyperfiltra- actions in multiple organs. In the heart itself, tion, resulting in decreased proteinuria and a GLP-1 receptors are expressed on both the deceleration in the decline in renal function myocardiocyte and the vascular endothelium. [23]. Reabsorption of sodium ions by the prox- Also, activation of receptors on monocytes, imal tubule accounts for most of the kidney’s macrophages and lymphocytes will likely result workload; therefore, if in addition to a in improved function, leading to decreased decreased sodium reabsorption and renal work- inflammation, improved endothelial function, load with an SGLT2 inhibition, there is also a a decrease in the formation of foam cells and change in metabolism from the use of glucose increased stability of atheromatous plaques and free fatty acids as a substrate to the use of [20, 27–31]. Therefore, the proposed cardiopro- ketone bodies, there would be a further decrease tective mechanisms of SGLT2 inhibitors and in renal workload and preservation of renal GLP-1 receptor agonists are likely to be com- function (see below). In addition, lowering of plementary. Theoretically, the combined car- HbA1c, blood pressure, body weight and uric diac and renal effect of the SGLT-2 inhibitor and acid levels could play at least a partial role in the the GLP-1 receptor agonist could be decreased deceleration of renal decline. by lowered hepatic ketone production, which is Therefore, it can be concluded that the dependent on glucagon activity that will be decreases in cardiac and total mortality seen acutely suppressed by GLP-1 receptor agonists. with SGLT inhibitors is a class effect and However, chronic treatment, at least with probably only due to a decreased incidence and liraglutide, is associated with a decrease or even frequency of heart failure. The potential causes a loss of glucagon suppression, which may for this decrease in heart failure are protean, but negate this effect [32]. a decrease in weight and blood pressure causing Despite beneficial effects on cardiovascular a decrease in the preload and afterload of the mortality noted in the EMPA-REG OUTCOME myocardium are likely hemodynamic candi- [16] and CANVAS [17], non-fatal stroke dates. However, the ability of SGLT2 inhibitors increased by 30% with empagliflozin and to shift metabolism away from the utilization of amputations increased by 97% with canagli- carbohydrate and free fatty acids to the utiliza- flozin. Ketoacidosis has been reported with all tion of ketone bodies derived from the break- SGLT2 inhibitors, although its risk may be down of fat is an attractive hypothesis, and in attenuated by combining it with a GLP-1 our opinion a more likely explanation [24, 25]. receptor agonist. Both drug classes have been Ketone bodies are likely to be avidly utilized by associated with acute renal failure, possibly due the myocardium and kidney, resulting in to fluid contraction, and the entire incre- decreases in both cardiac and renal workload. tin–mimetic class has been associated with Thus, the beneficial cardiovascular effect of pancreatitis. The most common side effects, SGLT2 inhibitors are most likely to be through a however, are gastrointestinal and genitourinary, decreased cardiac workload, leading to which tend to improve over time [33]. improvement in existing heart failure, preven- In conclusion, the SGLT2 inhibitor and GLP- tion of ‘‘denovo’’ heart failure and decreased 1 receptor agonist combination has additive cardiac and total mortality. effects on glycemic control without the incon- The effect of GLP-1 receptor agonists in car- venience and dangers of hypoglycemia. There diovascular events is far more complex and are also synergistic effects on weight loss and clearly not due to a decrease in heart failure. In blood pressure, potentially leading to lower a study utilizing GLP-1 receptor agonists in cardiovascular events, heart failure, cardiovas- patients hospitalized for heart failure with cular and total mortality, as well as a decelera- reduced left ventricular ejection fraction, the tion of renal function. However, if increased use of liraglutide did not lead to a greater post- cardiac and renal consumption of ketone bodies hospitalization clinical stability [26]. The car- is indeed the reason for improved outcomes dioprotection provided by GLP-1 receptor with SGLT2 inhibitors, then the combination 924 Diabetes Ther (2018) 9:919–926 may negate the effects of SGLT2 inhibitors on Pharmaceuticals. David S.H. Bell is on the cardiac and renal workload and decrease the Speaker’s bureau of Novo-Nordisk, AstraZeneca cardiorenal benefits. Ultimately, only a cardio- and Janssen Pharmaceuticals. vascular and renal outcomes trial with the Compliance with Ethics Guidelines. This combination would provide an answer to this article is based on previously conducted studies hypothesis. and does not contain any studies with human Despite the beneficial and symbiotic effects participants or animals performed by any of the of a combined therapeutic regimen consisting authors. of a SGLT-2 receptor inhibitor and a GLP-1 agonist, this combination is not being widely Open Access. This article is distributed utilized. Cost and formulary barriers are the under the terms of the Creative Commons probable reason for this, and in the absence of Attribution-NonCommercial 4.0 International more prospective studies, third party payers are License (http://creativecommons.org/licenses/ unlikely ‘‘to foot the bill.’’ So why have these by-nc/4.0/), which permits any non- studies not been performed? The likeliest commercial use, distribution, and reproduction explanation is the reluctance of pharmaceutical in any medium, provided you give appropriate companies to study their drugs in combination credit to the original author(s) and the source, with a non-generic drug for which they do not provide a link to the Creative Commons license, have a patent. One of the prospective random- and indicate if changes were made. ized studies was with dapagliflozin and exe- natide, and notably the patents of both drugs are held by the same company [4]. In addition, there have been no prospective cardiovascular REFERENCES or renal outcomes trials with any GLP-1 recep- tor agonist/SGLT2 inhibitor combination. The 1. Pathak RD, Schroeder EB, Seaquist ER, Zeng C, reluctance to prospectively study this combi- Lafata JE, Thomas A, et al. 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Diabetes TherapySpringer Journals

Published: Apr 5, 2018

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