- Email: [email protected]
Renoprotection in LEADER and EMPA-REG OUTCOME
Correspondence
Type 1 diabetes: the need for cultureappropriate nutritional information for carbohydrate counting Published Online July 25, 2016 http://dx.doi.org/10.1016/ S2213-8587(16)30101-2
This online publication has been corrected. The corrected version first appeared at thelancet.com/ diabetes-endocrinology on September 28, 2016
812
Diabetes education for patients with new-onset type 1 diabetes places a heavy emphasis on training patients to count carbohydrates, since it is a cornerstone of disease management.1 The concept of carbohydrate counting relies on patients being able to identify the amount of carbohydrates expected to be eaten in a meal to calculate an appropriate insulin dose. Nutrition labels on food packaging and information available from national and international diabetes associations can allow patients to calculate the carbohydrate content of foods commonly prepared at home.2 In this context, we were faced with a problem when we encountered a child of Arab descent with newonset type 1 diabetes in our clinic in Cleveland, OH, USA. After the initial counselling by diabetes educators on carbohydrate counting, we were unable to help when the child’s mother asked us how to do this for the traditional foods she cooks at home. We searched our institute’s files for relevant pamphlets, but found only Arabiclanguage translations of our usual pamphlets, which did not contain any information about traditional Middle Eastern foodstuffs. An internet search led us to several research articles that provided examples of cuisine-specific nutritional information (eg, tabbouleh, hareeseh, and chicken shawarma), 3 which we were eventually able to give to the family. Although resources such as books and websites for carbohydrate counting for patients with type 1 diabetes are numerous, most of these tend to focus on foods commonly eaten in European and North
American countries. It can be difficult to find information for culturally and linguistically diverse communities. Translations from Western resources tend to be non-specific and thus do not address carbohydrate counts for traditional foods. Conversely, resources from other countries with information about specific foods are often only available in native languages, posing another challenge, since a physician cannot give these texts to patients without being fully aware of their content. Some extensive ethnic food resources are available, but they are generally insufficient because they focus more on the nutritive values of specific ingredients rather than on full meals (although variation in recipes for many dishes could make it challenging to establish accurate meal-based resources).4 Also, these databases tend to be in the format of research articles, which can be inaccessible for patients. In times when the world has become a global village and the cultural diversity clinicians typically encounter in their practice is increasing, it is imperative that diabetes associations look into formulating culturally appropriate food lists in multiple languages, for patients and physicians. Creating standardised recipes for patients could also be helpful for patients.5 A good starting point would be for international diabetes associations to consolidate the scattered information available through national associations and research publications into a centralised database to ensure easy accessibility for physicians. Such a development would allow clinicians and patients to improve the management of diabetes, reduce the burden of carbohydrate counting on families, and ensure that they do not have to abandon traditional homecooked meals. We declare no competing interests.
*Hamza Nasir, Sumana Narasimhan [email protected]
Dow Medical College, Dow University of Health Sciences, Karachi 74200, Pakistan (HN); and Center for Pediatric Endocrinology, Cleveland Clinic, Cleveland, OH, USA (SN) 1
2
3
4
5
American Diabetes Association. Carbohydrate counting. http://www.diabetes.org/food-andfitness/food/what-can-i-eat/understandingcarbohydrates/carbohydrate-counting.html (accessed Feb 27, 2016). Warshaw HS, Kulkarni K. The complete guide to carb counting, 3rd edn. American Diabetes Association, 2011. Bawadi HA, Al-Shwaiyat NM, Tayyem RF, Mekary R, Tuuri G. Developing a food exchange list for Middle Eastern appetizers and desserts commonly consumed in Jordan. Nutr Diet 2009; 66: 20–26. International Network of Food Data Systems. INFOODS: Tables and databases. http://www. fao.org/infoods/infoods/tables-anddatabases/en/ (accessed April 30, 2016). Joslin Diabetes Center. Pan-Asian recipes. https://aadi.joslin.org/en/educationalmaterials/pan-asian-recipes (accessed April 30, 2016).
Renoprotection in LEADER and EMPA-REG OUTCOME In their research digest, Sattar and Preiss1 highlight the beneficial renal outcomes in LEADER2 and EMPA-REG OUTCOME,3 two landmark, placebocontrolled trials that assessed the cardiovascular safety of glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide (LEADER) and sodiumglucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA-REG OUTCOME) in patients with type 2 diabetes. In both trials, baseline blood pressure was well controlled (about 136/77 mm Hg), and about 80% of patients used renin–angiotensin system (RAS) inhibitors and lipidlowering drugs; thus the renoprotective effects seem to complement prevailing treatment strategies.4 Once-daily liraglutide (1·8 mg) for 3·8 years reduced incident or worsening nephropathy by 22% 2 and once-daily empagliflozin (10 or 25 mg) for 3·1 years reduced the same composite outcome by 39%. 3 However, the four separate exploratory components of this renal composite outcome were
www.thelancet.com/diabetes-endocrinology Vol 4 October 2016
Correspondence
Liraglutide (LEADER; n=9340)
Empagliflozin (EMPA-REG OUTCOME; n=7020)
Incident or worsening nephropathy
0·78 (0·67–0·92); p=0·003
0·61 (0·53–0·70); p<0·001
New-onset macroalbuminuria
0·74 (0·60–0·91); NR
0·62 (0·54–0·72); p<0·001
Doubling of serum creatinine concentration and eGFR ≤45 mL/min/1·73m²
0·88 (0·66–1·18); NR 0·56 (0·39–0·79); p<0·001
Need for renal replacement therapy
0·87 (0·61–1·24); NR
0·45 (0·21–0·97); p=0·04
Death due to renal disease
1·59 (0·52–4·87); NR
3 (empagliflozin) vs 0 (placebo);* NR
Data are hazard ratio (95% CI); p value. Doubling of serum creatinine concentration did not require a second confirmatory measurement in both trials. Need for continuous renal replacement therapy in EMPA-REG OUTCOME included five cases of acute kidney injury requiring temporary dialysis (appendix). eGFR=estimated glomerular filtration rate. NR=not reported. *No hazard ratio is reported for death due to renal disease in EMPA-REG OUTCOME.
Table: Effects of liraglutide and empagliflozin on renal outcomes
differently affected (table). In LEADER,2 results were predominantly driven by reductions in the potential surrogate renal endpoint of incident macroalbuminuria. 4 In EMPA-REG OUTCOME, 3 additional profound changes in established surrogate and hard renal endpoints 4 were reported, although the US Food and Drug Administration remarked that these endpoints differed from those typically used in renoprotection trials in diabetic nephropathy (appendix). Remarkably, empagliflozin did not affect albuminuria occurrence in patients who were normoalbuminuric, suggesting that the drug’s renoprotective potential principally affects individuals with established kidney damage or single-nephron hyperfiltration. Several mechanisms might underlie the renoprotection seen in both trials. First, as intensified glycaemic control in type 2 diabetes reduces microalbuminuria risk by 14% and macroalbuminuria risk by 26%,4 the considerable between-group HbA1c differences (appendix) might—at least partly—explain the albuminuria benefit, particularly in LEADER. Notably, in the ELIXA trial, 5 the favourable effect of the GLP-1 receptor agonist lixisenatide versus placebo on change in urinary albumin-tocreatinine ratio at week 108 (24% vs 34%) was attenuated (p=0·07) after correction for an initial HbA1c
difference of about 0·3%. Therefore, the role of glycaemic control in current and ongoing trials should be explored to establish drug-specific benefits. Second, well documented glucose-independent actions of both drug classes on renal risk factors might also have contributed.4 Modest improvements in bodyweight (about 2 kg), systolic blood pressure (about 1–3 mm Hg) and lipids were seen, while empagliflozin additionally reduced plasma uric acid concentrations (appendix). Finally, empagliflozin and liraglutide might have directly affected renal physiology. Both drugs decrease proximal tubular sodium reabsorption, leading to (initial) natriuresis. 4 This effect theoretically increases afferent arteriolar resistance and alleviates glomerular hydraulic pressure (PGLO) through tubuloglomerular feedback activation. 8 week empagliflozin treatment has been reported to reduce inulin-measured glomerular filtration rate by 19% and estimated PGLO by 10%, albeit only in patients with type 1 diabetes and baseline hyperfiltration. 6 Hence, in EMPAREG OUTCOME, the initial roughly 5% fall in estimated glomerular filtration rate (eGFR) probably reflects acute reductions in single-nephron hyperfiltration, which is associated with subsequent long-term renal function preservation. 4 Such an
www.thelancet.com/diabetes-endocrinology Vol 4 October 2016
eGFR trajectory, also reported in phase 3 trials of SGLT2 inhibitors dapagliflozin and canagliflozin in type 2 diabetes (appendix), is highly reminiscent of the trajectory that occurs after RAS inhibition (which decreases PGLO by relieving efferent arteriolar resistance). 4 The alleged beneficial renal haemodynamic nature of this response is further substantiated by the eGFR upsurge that was seen 34 days after discontinuation of empagliflozin.3 For liraglutide, although suggested by an uncontrolled small study in type 2 diabetes (appendix),4 similar eGFR trajectories have not been reported in the large-scale phase 3 LEAD programme or the LIRA-RENAL trial (appendix). Furthermore, no renal haemodynamic alterations assessed by gold-standard clearance techniques were reported after 12 week liraglutide treatment in patients with type 2 diabetes who were overweight.7 Empagliflozin seems to address an important unmet need in diabetic nephropathy, probably improving relevant outcomes via multiple unique mechanisms. Glucose-independent renoprotective properties of liraglutide are more uncertain, and perhaps longer follow-up duration than was used in LEADER would have been necessary to see differences in hard endpoints.
See Online for appendix
DHvR has received a research grant from AstraZeneca for his institution. All other authors declare no competing interests.
*Marcel H A Muskiet, Lennart Tonneijck, Erik J M van Bommel, Mark M Smits, Daniël H van Raalte [email protected] Diabetes Centre, Department of Internal Medicine, VU University Medical Centre, 1081 HV Amsterdam, Netherlands 1 2
3
Sattar N, Preiss D. Research digest. Lancet Diabetes Endocrinol 2016; 4: 651. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311–22. Wanner C, Inzucchi SE, Lachin JM, et al, for the EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323–34.
813
Correspondence
4
5
6
7
Muskiet MH, Tonneijck L, Smits MM, Kramer MH, Heerspink HJ, van Raalte DH. Pleiotropic effects of type 2 diabetes management strategies on renal risk factors. Lancet Diabetes Endocrinol 2015; 3: 367–81. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015; 373: 2247–57. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014; 129: 587–97. Tonneijck L, Smits MM, Muskiet MH, et al. Renal effects of DPP-4 inhibitor sitagliptin or GLP-1 receptor agonist liraglutide in overweight patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 2016; published online Sep 1. DOI:10.2337/dc16-1371.
SGLT2 inhibitors: β blockers for the kidney? In their research digest, Sattar and Preiss 1 describe current thinking that attributes the beneficial effects on kidney disease progression in the EMPA-REG OUTCOME trial 2 to haemodynamic changes. Such changes, whereby increased sodium delivery to the macula densa in the setting of sodium-glucose cotransporter 2 (SGLT2) inhibition augments glomerular afferent arteriolar tone, nicely explain the initial decrease in estimated glomerular filtration rate, which is reversed by withdrawal of the study drug. How such a reduction in single-nephron hyperfiltration might lead to kidney protection is a far more vexing issue than these aforementioned changes, particularly considering that tubulointerstitial pathology is often the major feature of kidney disease in type 2 diabetes and that SGLT2 inhibition does not ameliorate the glomerular filtration rate decline in the remnant kidney model, where disease progression is driven by increased single-nephron glomerular filtration rate.3 But perhaps most telling of all are the effects of empagliflozin on acute kidney injury and acute renal failure in EMPA-REG OUTCOME,2 the 814
caveats of this post-hoc analysis of adverse events notwithstanding. By reducing postglomerular perfusion, the haemodynamic theory would posit an increase in both acute kidney injury and acute renal failure with empagliflozin, but the reverse occurred. Such findings suggest that non-haemodynamic, non-glomerular mechanisms might contribute to the salutary renal effects of SGLT2 inhibition. Charged with an enormous role in electrolyte, organic solute, and water reabsorption, the high energy requirements of the proximal tubule render it particularly susceptible to hypoxia and oxidative stress. As a result of increased luminal glucose concentration, sodiumglucose cotransporter (SGLT) activity increases in diabetes, mandating a commensurate increase in proximal tubular sodium ion reabsorption. Although SGLT-mediated transport is frequently viewed as not requiring energy, translocation of glucose and sodium ions across the apical membrane is a result of the electrochemical gradient generated by basolateral extrusion of sodium ions. This extrusion is, notably, energy dependent, mediated by sodium-potassium ATPase. Indeed, reclamation of filtered sodium ions by the proximal tubule accounts for most of the kidney’s oxygen consumption.4 As might therefore be expected, the enhanced proximal tubule glucose and sodium ion reabsorption of diabetes brings with it an increase in oxygen demand, which can be abolished by administration of the sodium-glucose cotransporter 1 and 2 inhibitor phlorizin.5 Such effects, analogous to those of a β blocker in reducing the excessive energy demands of the failing heart, would seemingly provide a cogent basis for the renoprotective effect of SGLT2 inhibition. To understand how proximal tubular hypoxia might lead to the structural and functional manifestations of diabetic kidney disease, the work of Fine and Norman,6 which establishes hypoxia
as a major driver of kidney disease progression, seems particularly relevant. The elegant studies of Bonventre,7 the findings from which show how selective proximal tubular injury leads to interstitial fibrosis, microvascular loss, and glomerulosclerosis, are also worth reflecting on. By reducing the excessive energy demands of the proximal tubule in diabetes, SGLT inhibition might ameliorate the functional and structural manifestations of diabetic kidney disease, in addition to or independently of any haemodynamic effects. This non-haemodynamic paradigm has implications for the role of SGLT inhibition, not only in the setting of diabetic kidney disease, but also in other forms of kidney injury that are similarly characterised by proximal tubular injury, including those that result from drug toxicity. I have received grants, personal fees, and continuing medical education honoraria from AstraZeneca and Boehringer-Ingelheim, personal fees and continuing medical education honoraria from Merck and Jannsen, and personal fees from Servier.
Richard E Gilbert [email protected] Division of Endocrinology, University of Toronto, St Michael’s Hospital, ON, Canada 1 2
3
4
5
6
7
Sattar N, Preiss D. Research digest. Lancet Diabetes Endocrinol 2016; 4: 651. Wanner C, Inzucchi SE, Lachin JM, et al, for the EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323–34. Zhang Y, Thai K, Kepecs DM, Gilbert RE. Sodium-glucose linked cotransporter-2 inhibition does not attenuate disease progression in the rat remnant kidney model of chronic kidney disease. PLoS One 2016; 11: e0144640. Hansell P, Welch WJ, Blantz RC, Palm F. Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension. Clin Exp Pharmacol Physiol 2013; 40: 123–37. Korner A, Eklof AC, Celsi G, Aperia A. Increased renal metabolism in diabetes: mechanism and functional implications. Diabetes 1994; 43: 629–33. Fine LG, Norman JT. Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics. Kidney Int 2008; 74: 867–72. Bonventre JV. Can we target tubular damage to prevent renal function decline in diabetes? Semin Nephrol 2012; 32: 452–62.
www.thelancet.com/diabetes-endocrinology Vol 4 October 2016
Type 1 diabetes: the need for cultureappropriate nutritional information for carbohydrate counting Published Online July 25, 2016 http://dx.doi.org/10.1016/ S2213-8587(16)30101-2
This online publication has been corrected. The corrected version first appeared at thelancet.com/ diabetes-endocrinology on September 28, 2016
812
Diabetes education for patients with new-onset type 1 diabetes places a heavy emphasis on training patients to count carbohydrates, since it is a cornerstone of disease management.1 The concept of carbohydrate counting relies on patients being able to identify the amount of carbohydrates expected to be eaten in a meal to calculate an appropriate insulin dose. Nutrition labels on food packaging and information available from national and international diabetes associations can allow patients to calculate the carbohydrate content of foods commonly prepared at home.2 In this context, we were faced with a problem when we encountered a child of Arab descent with newonset type 1 diabetes in our clinic in Cleveland, OH, USA. After the initial counselling by diabetes educators on carbohydrate counting, we were unable to help when the child’s mother asked us how to do this for the traditional foods she cooks at home. We searched our institute’s files for relevant pamphlets, but found only Arabiclanguage translations of our usual pamphlets, which did not contain any information about traditional Middle Eastern foodstuffs. An internet search led us to several research articles that provided examples of cuisine-specific nutritional information (eg, tabbouleh, hareeseh, and chicken shawarma), 3 which we were eventually able to give to the family. Although resources such as books and websites for carbohydrate counting for patients with type 1 diabetes are numerous, most of these tend to focus on foods commonly eaten in European and North
American countries. It can be difficult to find information for culturally and linguistically diverse communities. Translations from Western resources tend to be non-specific and thus do not address carbohydrate counts for traditional foods. Conversely, resources from other countries with information about specific foods are often only available in native languages, posing another challenge, since a physician cannot give these texts to patients without being fully aware of their content. Some extensive ethnic food resources are available, but they are generally insufficient because they focus more on the nutritive values of specific ingredients rather than on full meals (although variation in recipes for many dishes could make it challenging to establish accurate meal-based resources).4 Also, these databases tend to be in the format of research articles, which can be inaccessible for patients. In times when the world has become a global village and the cultural diversity clinicians typically encounter in their practice is increasing, it is imperative that diabetes associations look into formulating culturally appropriate food lists in multiple languages, for patients and physicians. Creating standardised recipes for patients could also be helpful for patients.5 A good starting point would be for international diabetes associations to consolidate the scattered information available through national associations and research publications into a centralised database to ensure easy accessibility for physicians. Such a development would allow clinicians and patients to improve the management of diabetes, reduce the burden of carbohydrate counting on families, and ensure that they do not have to abandon traditional homecooked meals. We declare no competing interests.
*Hamza Nasir, Sumana Narasimhan [email protected]
Dow Medical College, Dow University of Health Sciences, Karachi 74200, Pakistan (HN); and Center for Pediatric Endocrinology, Cleveland Clinic, Cleveland, OH, USA (SN) 1
2
3
4
5
American Diabetes Association. Carbohydrate counting. http://www.diabetes.org/food-andfitness/food/what-can-i-eat/understandingcarbohydrates/carbohydrate-counting.html (accessed Feb 27, 2016). Warshaw HS, Kulkarni K. The complete guide to carb counting, 3rd edn. American Diabetes Association, 2011. Bawadi HA, Al-Shwaiyat NM, Tayyem RF, Mekary R, Tuuri G. Developing a food exchange list for Middle Eastern appetizers and desserts commonly consumed in Jordan. Nutr Diet 2009; 66: 20–26. International Network of Food Data Systems. INFOODS: Tables and databases. http://www. fao.org/infoods/infoods/tables-anddatabases/en/ (accessed April 30, 2016). Joslin Diabetes Center. Pan-Asian recipes. https://aadi.joslin.org/en/educationalmaterials/pan-asian-recipes (accessed April 30, 2016).
Renoprotection in LEADER and EMPA-REG OUTCOME In their research digest, Sattar and Preiss1 highlight the beneficial renal outcomes in LEADER2 and EMPA-REG OUTCOME,3 two landmark, placebocontrolled trials that assessed the cardiovascular safety of glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide (LEADER) and sodiumglucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA-REG OUTCOME) in patients with type 2 diabetes. In both trials, baseline blood pressure was well controlled (about 136/77 mm Hg), and about 80% of patients used renin–angiotensin system (RAS) inhibitors and lipidlowering drugs; thus the renoprotective effects seem to complement prevailing treatment strategies.4 Once-daily liraglutide (1·8 mg) for 3·8 years reduced incident or worsening nephropathy by 22% 2 and once-daily empagliflozin (10 or 25 mg) for 3·1 years reduced the same composite outcome by 39%. 3 However, the four separate exploratory components of this renal composite outcome were
www.thelancet.com/diabetes-endocrinology Vol 4 October 2016
Correspondence
Liraglutide (LEADER; n=9340)
Empagliflozin (EMPA-REG OUTCOME; n=7020)
Incident or worsening nephropathy
0·78 (0·67–0·92); p=0·003
0·61 (0·53–0·70); p<0·001
New-onset macroalbuminuria
0·74 (0·60–0·91); NR
0·62 (0·54–0·72); p<0·001
Doubling of serum creatinine concentration and eGFR ≤45 mL/min/1·73m²
0·88 (0·66–1·18); NR 0·56 (0·39–0·79); p<0·001
Need for renal replacement therapy
0·87 (0·61–1·24); NR
0·45 (0·21–0·97); p=0·04
Death due to renal disease
1·59 (0·52–4·87); NR
3 (empagliflozin) vs 0 (placebo);* NR
Data are hazard ratio (95% CI); p value. Doubling of serum creatinine concentration did not require a second confirmatory measurement in both trials. Need for continuous renal replacement therapy in EMPA-REG OUTCOME included five cases of acute kidney injury requiring temporary dialysis (appendix). eGFR=estimated glomerular filtration rate. NR=not reported. *No hazard ratio is reported for death due to renal disease in EMPA-REG OUTCOME.
Table: Effects of liraglutide and empagliflozin on renal outcomes
differently affected (table). In LEADER,2 results were predominantly driven by reductions in the potential surrogate renal endpoint of incident macroalbuminuria. 4 In EMPA-REG OUTCOME, 3 additional profound changes in established surrogate and hard renal endpoints 4 were reported, although the US Food and Drug Administration remarked that these endpoints differed from those typically used in renoprotection trials in diabetic nephropathy (appendix). Remarkably, empagliflozin did not affect albuminuria occurrence in patients who were normoalbuminuric, suggesting that the drug’s renoprotective potential principally affects individuals with established kidney damage or single-nephron hyperfiltration. Several mechanisms might underlie the renoprotection seen in both trials. First, as intensified glycaemic control in type 2 diabetes reduces microalbuminuria risk by 14% and macroalbuminuria risk by 26%,4 the considerable between-group HbA1c differences (appendix) might—at least partly—explain the albuminuria benefit, particularly in LEADER. Notably, in the ELIXA trial, 5 the favourable effect of the GLP-1 receptor agonist lixisenatide versus placebo on change in urinary albumin-tocreatinine ratio at week 108 (24% vs 34%) was attenuated (p=0·07) after correction for an initial HbA1c
difference of about 0·3%. Therefore, the role of glycaemic control in current and ongoing trials should be explored to establish drug-specific benefits. Second, well documented glucose-independent actions of both drug classes on renal risk factors might also have contributed.4 Modest improvements in bodyweight (about 2 kg), systolic blood pressure (about 1–3 mm Hg) and lipids were seen, while empagliflozin additionally reduced plasma uric acid concentrations (appendix). Finally, empagliflozin and liraglutide might have directly affected renal physiology. Both drugs decrease proximal tubular sodium reabsorption, leading to (initial) natriuresis. 4 This effect theoretically increases afferent arteriolar resistance and alleviates glomerular hydraulic pressure (PGLO) through tubuloglomerular feedback activation. 8 week empagliflozin treatment has been reported to reduce inulin-measured glomerular filtration rate by 19% and estimated PGLO by 10%, albeit only in patients with type 1 diabetes and baseline hyperfiltration. 6 Hence, in EMPAREG OUTCOME, the initial roughly 5% fall in estimated glomerular filtration rate (eGFR) probably reflects acute reductions in single-nephron hyperfiltration, which is associated with subsequent long-term renal function preservation. 4 Such an
www.thelancet.com/diabetes-endocrinology Vol 4 October 2016
eGFR trajectory, also reported in phase 3 trials of SGLT2 inhibitors dapagliflozin and canagliflozin in type 2 diabetes (appendix), is highly reminiscent of the trajectory that occurs after RAS inhibition (which decreases PGLO by relieving efferent arteriolar resistance). 4 The alleged beneficial renal haemodynamic nature of this response is further substantiated by the eGFR upsurge that was seen 34 days after discontinuation of empagliflozin.3 For liraglutide, although suggested by an uncontrolled small study in type 2 diabetes (appendix),4 similar eGFR trajectories have not been reported in the large-scale phase 3 LEAD programme or the LIRA-RENAL trial (appendix). Furthermore, no renal haemodynamic alterations assessed by gold-standard clearance techniques were reported after 12 week liraglutide treatment in patients with type 2 diabetes who were overweight.7 Empagliflozin seems to address an important unmet need in diabetic nephropathy, probably improving relevant outcomes via multiple unique mechanisms. Glucose-independent renoprotective properties of liraglutide are more uncertain, and perhaps longer follow-up duration than was used in LEADER would have been necessary to see differences in hard endpoints.
See Online for appendix
DHvR has received a research grant from AstraZeneca for his institution. All other authors declare no competing interests.
*Marcel H A Muskiet, Lennart Tonneijck, Erik J M van Bommel, Mark M Smits, Daniël H van Raalte [email protected] Diabetes Centre, Department of Internal Medicine, VU University Medical Centre, 1081 HV Amsterdam, Netherlands 1 2
3
Sattar N, Preiss D. Research digest. Lancet Diabetes Endocrinol 2016; 4: 651. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311–22. Wanner C, Inzucchi SE, Lachin JM, et al, for the EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323–34.
813
Correspondence
4
5
6
7
Muskiet MH, Tonneijck L, Smits MM, Kramer MH, Heerspink HJ, van Raalte DH. Pleiotropic effects of type 2 diabetes management strategies on renal risk factors. Lancet Diabetes Endocrinol 2015; 3: 367–81. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015; 373: 2247–57. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014; 129: 587–97. Tonneijck L, Smits MM, Muskiet MH, et al. Renal effects of DPP-4 inhibitor sitagliptin or GLP-1 receptor agonist liraglutide in overweight patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 2016; published online Sep 1. DOI:10.2337/dc16-1371.
SGLT2 inhibitors: β blockers for the kidney? In their research digest, Sattar and Preiss 1 describe current thinking that attributes the beneficial effects on kidney disease progression in the EMPA-REG OUTCOME trial 2 to haemodynamic changes. Such changes, whereby increased sodium delivery to the macula densa in the setting of sodium-glucose cotransporter 2 (SGLT2) inhibition augments glomerular afferent arteriolar tone, nicely explain the initial decrease in estimated glomerular filtration rate, which is reversed by withdrawal of the study drug. How such a reduction in single-nephron hyperfiltration might lead to kidney protection is a far more vexing issue than these aforementioned changes, particularly considering that tubulointerstitial pathology is often the major feature of kidney disease in type 2 diabetes and that SGLT2 inhibition does not ameliorate the glomerular filtration rate decline in the remnant kidney model, where disease progression is driven by increased single-nephron glomerular filtration rate.3 But perhaps most telling of all are the effects of empagliflozin on acute kidney injury and acute renal failure in EMPA-REG OUTCOME,2 the 814
caveats of this post-hoc analysis of adverse events notwithstanding. By reducing postglomerular perfusion, the haemodynamic theory would posit an increase in both acute kidney injury and acute renal failure with empagliflozin, but the reverse occurred. Such findings suggest that non-haemodynamic, non-glomerular mechanisms might contribute to the salutary renal effects of SGLT2 inhibition. Charged with an enormous role in electrolyte, organic solute, and water reabsorption, the high energy requirements of the proximal tubule render it particularly susceptible to hypoxia and oxidative stress. As a result of increased luminal glucose concentration, sodiumglucose cotransporter (SGLT) activity increases in diabetes, mandating a commensurate increase in proximal tubular sodium ion reabsorption. Although SGLT-mediated transport is frequently viewed as not requiring energy, translocation of glucose and sodium ions across the apical membrane is a result of the electrochemical gradient generated by basolateral extrusion of sodium ions. This extrusion is, notably, energy dependent, mediated by sodium-potassium ATPase. Indeed, reclamation of filtered sodium ions by the proximal tubule accounts for most of the kidney’s oxygen consumption.4 As might therefore be expected, the enhanced proximal tubule glucose and sodium ion reabsorption of diabetes brings with it an increase in oxygen demand, which can be abolished by administration of the sodium-glucose cotransporter 1 and 2 inhibitor phlorizin.5 Such effects, analogous to those of a β blocker in reducing the excessive energy demands of the failing heart, would seemingly provide a cogent basis for the renoprotective effect of SGLT2 inhibition. To understand how proximal tubular hypoxia might lead to the structural and functional manifestations of diabetic kidney disease, the work of Fine and Norman,6 which establishes hypoxia
as a major driver of kidney disease progression, seems particularly relevant. The elegant studies of Bonventre,7 the findings from which show how selective proximal tubular injury leads to interstitial fibrosis, microvascular loss, and glomerulosclerosis, are also worth reflecting on. By reducing the excessive energy demands of the proximal tubule in diabetes, SGLT inhibition might ameliorate the functional and structural manifestations of diabetic kidney disease, in addition to or independently of any haemodynamic effects. This non-haemodynamic paradigm has implications for the role of SGLT inhibition, not only in the setting of diabetic kidney disease, but also in other forms of kidney injury that are similarly characterised by proximal tubular injury, including those that result from drug toxicity. I have received grants, personal fees, and continuing medical education honoraria from AstraZeneca and Boehringer-Ingelheim, personal fees and continuing medical education honoraria from Merck and Jannsen, and personal fees from Servier.
Richard E Gilbert [email protected] Division of Endocrinology, University of Toronto, St Michael’s Hospital, ON, Canada 1 2
3
4
5
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7
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