SUMMARY

The prevalence of type 2 diabetes mellitus (T2DM) in the elderly grew sharply over the last decade. Reduced insulin sensitivity and secretory capacity, weight gain, sarcopenia, and elevated adiposity are all common metabolic and body changes in the aging population that favor an increased risk of hypoglycemia, frailty syndrome, falls, and cognitive dysfunction. First line antidiabetic therapy is frequently not safe in older individuals because of its high risk of hypoglycemia and prevalent co-morbid diseases, such as chronic kidney disease, osteoporosis, cardiovascular disease, and obesity. Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a new class of antidiabetic therapy that inhibits glucose and sodium reabsorption on renal proximal convoluted tubule. Its effect is well demonstrated in various clinical scenarios in the younger population. This review and metanalysis describe particularities of the SGLT2i on the elderly, with mechanistic insights of the potential benefit and remaining challenges about the use of these drugs in this important age group. Further, we will present a meta-analysis of the main effects of SGLT2i reported in post-hoc studies in which the median age of the subgroups analyzed was over 60 years. Despite the absence of specific clinical trials for this population, our findings suggest that SGLT2i therapy on older individuals is effective to lower glucose and maintain its effect on systolic blood pressure and body weight.

Sodium-glucose transporter/antagonists & inhibitors; Diabetes mellitus; Aging; Effectiveness

RESUMO

A prevalência da diabetes mellitus tipo 2 em idosos cresceu muito na última década. A redução na sensibilidade à insulina e na capacidade secretora, ganho de peso, sarcopenia e adiposidade elevada são todas alterações metabólicas e corporais comuns entre a população idosa. Essas mudanças críticas favorecem o aumento no risco de hipoglicemia, síndrome de fragilidade, quedas e disfunções cognitivas. A primeira linha de tratamento contra a diabete muitas vezes não é segura para indivíduos mais velhos devido ao alto risco de hipoglicemia e a prevalência de comorbidades patogênicas, como doença renal crônica, osteoporose, doença cardiovascular e obesidade. Os inibidores do cotransportador sódio-glicose 2 (SGLT2) são uma nova classe de tratamento contra a diabete que inibe reabsorção de glicose e sódio na parte convoluta do túbulo proximal. Seu efeito é claramente demonstrado em diversos cenários clínicos em populações mais jovens. Esta revisão e meta-análise descreve as particularidades dos SGLT2 na população idosa, abordando os mecanismos dos potenciais benefícios e desafios ainda presentes do uso destes medicamentos nesse grupo etário tão importante. Além disso, apresentaremos uma meta-análise dos principais efeitos dos SGLT2 encontrados em estudos post-hoc nos quais a idade média dos subgrupos analisados foi acima de 60 anos. Apesar da ausência de ensaios clínicos que incluem essa população, os dados encontrados sugerem que o tratamento com SGLT2 em idosos é eficaz para diminuir os níveis de glicose e tem efeitos na pressão arterial sistólica e no peso corporal.

Transportador 2 de glucose-sódio/antagonistas e inibidores; Diabetes mellitus; Idoso; Eficácia

INTRODUCTION

The rapid increase in longevity and the prevalence of type 2 diabetes mellitus (T2DM) are among the most striking epidemiological challenges of recent decades. As a consequence, nearly 50% of individuals with T2DM are 65 years old or older¹1. Viljoen A, Sinclair AJ. Diabetes and insulin resistance in older people. Med Clin North Am. 2011;95(3):615-29., and 27% of those aged 65 years or older have T2DM²2. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;13(6):805-13.. These figures represent an increase of 62% over the last decade³3. Sloan FA, Bethel MA, Ruiz D Jr., Shea AM, Feinglos MN. The growing burden of diabetes mellitus in the US elderly population. Arch Intern Med. 2008;168(2):192-9..

Over the last 25 years, population aging was the main factor for the 41% global increase in deaths due to cardiovascular disease⁴4. Roth GA, Forouzanfar MH, Moran AE, Barber R, Nguyen G, Feigin VL, et al. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med. 2015;372(14):1333-41.. For these older individuals, the presence of T2DM has doubled the risk of death⁵5. Sinclair A, Dunning T, Rodriguez-Manas L. Diabetes in older people: new insights and remaining challenges. Lancet Diabetes Endocrinol. 2015;3(4):275-85.. Since these evolving changes are of particular importance, special attention must be paid to clinical and mechanistic features related to aging as well as to the interaction of these biological changes with hypoglycemic therapies.

Aging predisposes a person to T2DM in a number of mechanisms, which include apoptosis of beta cells, reduced insulin sensitivity from sarcopenia, decreased mitochondrial activity, and increased lipid content in cell membranes – particularly in hepatocyte and myocyte⁶6. Johannsen DL, Conley KE, Bajpeyi S, Punyanitya M, Gallagher D, Zhang Z, et al. Ectopic lipid accumulation and reduced glucose tolerance in elderly adults are accompanied by altered skeletal muscle mitochondrial activity. J Clin Endocrinol Metab. 2012;97(1):242-50.,⁷7. Cnop M, Igoillo-Esteve M, Hughes SJ, Walker JN, Cnop I, Clark A. Longevity of human islet alpha- and beta-cells. Diabetes Obes Metab. 2011;13(Suppl 1):39-46.. Beta cells of aged individuals have reduced secretory capacity. This is probably due to different mechanisms such as reduced glucose sense transporters, reduced insulin secretion related to mitochondrial activity, and impaired function of K-ATP voltage channels⁸8. Gong Z, Muzumdar RH. Pancreatic function, type 2 diabetes, and metabolism in aging. Int J Endocrinol. 2012;2012:320482.. In clinical studies, this phenomenon has been related to reductions in the amplitude of insulin pulse secretion and glucose-stimulated insulin secretion ⁸8. Gong Z, Muzumdar RH. Pancreatic function, type 2 diabetes, and metabolism in aging. Int J Endocrinol. 2012;2012:320482.,⁹9. Meneilly GS, Ryan AS, Veldhuis JD, Elahi D. Increased disorderliness of basal insulin release, attenuated insulin secretory burst mass, and reduced ultradian rhythmicity of insulin secretion in older individuals. J Clin Endocrinol Metab. 1997;82(12):4088-93.. Aging also leads to a progressive decline in insulin sensitivity, which is the result of processes that include increased adiposity, sarcopenia, and mitochondrial dysfunction ⁶6. Johannsen DL, Conley KE, Bajpeyi S, Punyanitya M, Gallagher D, Zhang Z, et al. Ectopic lipid accumulation and reduced glucose tolerance in elderly adults are accompanied by altered skeletal muscle mitochondrial activity. J Clin Endocrinol Metab. 2012;97(1):242-50.,⁷7. Cnop M, Igoillo-Esteve M, Hughes SJ, Walker JN, Cnop I, Clark A. Longevity of human islet alpha- and beta-cells. Diabetes Obes Metab. 2011;13(Suppl 1):39-46.,¹⁰10. Amati F, Dube JJ, Coen PM, Stefanovic-Racic M, Toledo FG, Goodpaster BH. Physical inactivity and obesity underlie the insulin resistance of aging. Diabetes Care. 2009;32(8):1547-9.,¹¹11. Bryhni B, Jenssen TG, Olafsen K, Eikrem JH. Age or waist as determinant of insulin action? Metabolism. 2003;52(7):850-7.. A successful glucose-lowering strategy for the elderly must account for the limitations in increasing insulin secretion and the reduced effect of insulin on muscular and adipose tissues. In line with these assumptions, lowering the threshold for glycosuria has emerged as a promising therapeutic target for T2DM elderlies.

About 90% of glucose filtered by the kidney is reabsorbed by the sodium glucose co-transporter 2 (SGLT2), which is the most active co-transporter expressed at the proximal convoluted tubule ¹²12. DeFronzo RA, Hompesch M, Kasichayanula S, Liu X, Hong Y, Pfister M, et al. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care. 2013;36(10):3169-76.. In healthy individuals, virtually all filtered glucose above 180 mg/dL is excreted; however, in diabetic individuals, glucose threshold excretion is at least 20% higher, probably due to up-regulation of SGLT2 and glucose transport channels in the nephron ¹³13. DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab. 2012;14(1):5-14..

From an evolutionary perspective, it seems reasonable that an efficient mechanism to preserve energy loss through urine has been selected ¹³13. DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab. 2012;14(1):5-14.. On the other hand, higher glycemic levels may contribute to metabolic disturbances, such as insulin resistance and reduced insulin secretion. Therefore, an adequate balance between retaining and losing glucose through the kidney is of particular interest and certainly plays a role in helping the maintenance of a favorable metabolic profile. Accordingly, SGLT2 inhibitors (SGLT2i) reduce glycemia in an insulin-independent manner and contribute to the improvement of beta cells function ¹⁴14. Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124(2):509-14.,¹⁵15. Cefalu WT, Leiter LA, Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ. Dapagliflozin’s effects on glycemia and cardiovascular risk factors in high-risk patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. Diabetes Care. 2015;38(7):1218-27. and insulin sensitivity ¹⁴14. Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124(2):509-14.

15. Cefalu WT, Leiter LA, Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ. Dapagliflozin’s effects on glycemia and cardiovascular risk factors in high-risk patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. Diabetes Care. 2015;38(7):1218-27.

16. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499-508.-¹⁷17. Bode B, Stenlof K, Harris S, Sullivan D, Fung A, Usiskin K, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes Obes Metab. 2015;17(3):294-303..

Only recently, clinical trials with SGLT2i started enrolling older individuals, and many questions remain open to debate. To tackle this issue, this review presents a meta-analysis of the main effects of SGLT2i reported in post-hoc studies focused on elderly individuals (Table 1 and Table 2) and describes particularities of the SGLT2i effect on the elderly, with mechanistic insights of the potential benefits and remaining challenges about the use of these drugs in this important age group.

Methods for Systematic Review and Meta-analysis of SGLT2i Trials in Elderly

We used the methods recommended by the Cochrane guidelines to conduct the meta-analysis and reported our findings according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) statement²⁹29. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.. All procedures performed for this analysis are presented in detail in the supplement.

Role of the funding source

There was no funding source for this study. The corresponding authors had full access to all the data in the study and were fully responsible for the decision to submit it for publication.

EFFICACY IN CLINICAL TRIALS

Anti-hyperglycemic effects

Recent guidelines have defined glycemic therapeutic goals that are less stringent in older individuals when compared to younger ones, based on the increased risk of hypoglycemia. Customized therapeutic targets consider functional status, comorbidities, and life expectancy³⁰30. Du YF, Ou HY, Beverly EA, Chiu CJ. Achieving glycemic control in elderly patients with type 2 diabetes: a critical comparison of current options. Clin Interv Aging. 2014;9:1963-80.. More leniency with higher glucose levels, however, does not necessarily prevent hypoglycemia³¹31. Munshi MN, Segal AR, Suhl E, Staum E, Desrochers L, Sternthal A, et al. Frequent hypoglycemia among elderly patients with poor glycemic control. Arch Intern Med. 2011;171(4):362-4., but it could instead favor dehydration, cognitive decline, falls, and other complications³⁰30. Du YF, Ou HY, Beverly EA, Chiu CJ. Achieving glycemic control in elderly patients with type 2 diabetes: a critical comparison of current options. Clin Interv Aging. 2014;9:1963-80.. Therefore, a more desirable option would be a potent antidiabetic treatment that bears a low risk for hypoglycemia. SGLT2i qualifies for this premise being associated with a risk of hypoglycemia of less than 1% in the elderly when used alone, a number three times lower than that obtained with DPP-IV inhibitors and 15 to 20 times lower than the one observed with sulphonylurea³²32. Farahani P. Non-severe hypoglycemia risk difference between sulfonylurea and sodium-glucose cotransporter-2 inhibitors (SGLT2-I) as an add-on to metformin in randomized controlled trials. J Popul Ther Clin Pharmacol. 2017;24(2):e32-e40..

Aging may influence the efficacy of SGLT2i by either indirect or direct mechanisms. Indirectly, the age-dependent decline in glomerular filtration rate (GFR) may reduce the glucose-lowering effect of these drugs via down-regulation of the tubular expression of SGLT2. Directly, early and still poorly explored findings have suggested that aging may reduce the expression of SGLT2³³33. Treves C, Favilli F, Stio M, Iantomasi T, Vincenzini MT. Changes in metabolite transport by small intestine and kidney of young and old rats. Mech Ageing Dev. 1990;52(2-3):263-76.. In order to verify these arguments, we assessed the effect of SGLT2i in elderly individuals and as shown in Figure 1, we found an overall decrease of 0.402% in HbA1c (95% CI: -0.432, -0.370; p<0.001; I²2. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;13(6):805-13.=0%), which is overall comparable to findings in younger age groups¹⁵15. Cefalu WT, Leiter LA, Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ. Dapagliflozin’s effects on glycemia and cardiovascular risk factors in high-risk patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. Diabetes Care. 2015;38(7):1218-27.,¹⁷17. Bode B, Stenlof K, Harris S, Sullivan D, Fung A, Usiskin K, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes Obes Metab. 2015;17(3):294-303.,²⁴24. Leiter LA, Cefalu WT, Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ. Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc. 2014;62(7):1252-62.,²⁷27. Sinclair A, Bode B, Harris S, Vijapurkar U, Mayer C, Fung A, et al. Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. BMC Endocr Disord. 2014;14:37..

Blood Pressure Reduction

Although the coexistence of hypertension and T2DM could be related to their increased prevalence later in life, it may also stem from many common contributors such as aging, diabetic nephropathy, volume expansion, hyperinsulinemia, increased arterial stiffness, hyperglycemia³⁴34. Laffin LJ, Bakris GL. Update on blood pressure goals in diabetes mellitus. Curr Cardiol Rep. 2015;17(6):37.,³⁵35. Maliha G, Townsend RR. SGLT2 inhibitors: their potential reduction in blood pressure. J Am Soc Hypertens. 2015;9(1):48-53.. More than 50% of hypertensive individuals are older than 60 years; and among individuals older than 60 years, up to 67% have hypertension³⁶36. Wright JT Jr., Fine LJ, Lackland DT, Ogedegbe G, Dennison Himmelfarb CR. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med. 2014;160(7):499-503.. Typically, isolated systolic hypertension (ISH) is the most frequent type of age-related hypertension and is responsible for up to 90% of cases in individuals older than 70³⁷37. Aronow WS, Fleg JL, Pepine CJ, Artinian NT, Bakris G, Brown AS, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus documents developed in collaboration with the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension. J Am Coll Cardiol. 2011;57(20):2037-114..

Arterial stiffness seems to be the main link between aging and ISH, and its mechanistic basis is strongly related to elastin fracture and increased collagen deposition in blood vessel walls³⁸38. Palombo C, Kozakova M. Arterial stiffness, atherosclerosis and cardiovascular risk: pathophysiologic mechanisms and emerging clinical indications. Vascul Pharmacol. 2016;77:1-7.. Among diabetic individuals, the process of arterial stiffening is accelerated by the deposition of advanced glycation products like glyoxal and methylglyoxal, which are responsible for a number of collagen cross-links³⁹39. Xue M, Rabbani N, Thornalley PJ. Glyoxalase in ageing. Semin Cell Dev Biol. 2011;22(3):293-301.. The binding of these glycation products with endothelial cells also induces cell signaling that results in oxidative stress, increased expression of cytokines and adhesion molecules, and activation of nuclear factor-kappa B (NF-kB)⁴⁰40. Choi KM, Yoo HJ, Kim HY, Lee KW, Seo JA, Kim SG, et al. Association between endogenous secretory RAGE, inflammatory markers and arterial stiffness. Int J Cardiol. 2009;132(1):96-101.. Similarly, modifiable causes such as endothelial dysfunction or those related to the metabolism of uric acid, calcium or potassium may influence the stiffness of conductance arteries leaving room for therapeutic interventions⁴¹41. Elewa U, Fernandez-Fernandez B, Alegre R, Sanchez-Niño MD, Mahillo-Fernández I Perez-Gomez MV, et al. Modifiable risk factors for increased arterial stiffness in outpatient nephrology. PLoS One. 2015;10(4):e0123903.. In fact, treatment with empagliflozin, which attenuates oxidative stress and improves endothelial function, has led to a reduction in both arterial stiffness and vascular resistency⁴²42. Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17(12):1180-93.

43. Cherney DZ, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014;13:28.-⁴⁴44. Oelze M, Kroller-Schon S, Welschof P, Jansen T, Hausding M, Mikhed Y, et al. The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PloS One. 2014;9(11):e112394..

In several studies, including some with older individuals, SGLT2i has reduced systolic BP¹⁷17. Bode B, Stenlof K, Harris S, Sullivan D, Fung A, Usiskin K, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes Obes Metab. 2015;17(3):294-303.,²⁷27. Sinclair A, Bode B, Harris S, Vijapurkar U, Mayer C, Fung A, et al. Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. BMC Endocr Disord. 2014;14:37.,²⁸28. Bode B, Stenlof K, Sullivan D, Fung A, Usiskin K. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract. 2013;41(2):72-84.,⁴²42. Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17(12):1180-93.. For example, canagliflozin 300 mg has led to a 7.5 mmHg (95% CI −9.8, −5.2) reduction in systolic BP compared to the placebo over a 104 weeks treatment¹⁷17. Bode B, Stenlof K, Harris S, Sullivan D, Fung A, Usiskin K, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes Obes Metab. 2015;17(3):294-303.,²⁷27. Sinclair A, Bode B, Harris S, Vijapurkar U, Mayer C, Fung A, et al. Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. BMC Endocr Disord. 2014;14:37.,²⁸28. Bode B, Stenlof K, Sullivan D, Fung A, Usiskin K. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract. 2013;41(2):72-84., which was consistent with further studies in individuals over 75 years-old treated with empagliflozin⁴²42. Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17(12):1180-93.. It is noteworthy that such an effect was independent of background therapies, such as metformin, sulphonylurea, GLP-1 agonists, and insulin²²22. Matthaei S, Bowering K, Rohwedder K, Sugg J, Parikh S, Johnsson E; et al. Durability and tolerability of dapagliflozin over 52 weeks as add-on to metformin and sulphonylurea in type 2 diabetes. Diabetes Obes Metab. 2015;17(11):1075-84.,²⁵25. Neal B, Perkovic V, Zeeuw D, Mahaffey KW, Fulcher G, Ways K, et al. Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care. 2015;38(3):403-11.,⁴⁵45. Fulcher G, Matthews DR, Perkovic V, Zeeuw D, Mahaffey KW, Mathieu C, et al. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18(1):82-91.. Importantly, the magnitude of the effect achieved with SGLT2i is approximately half of that obtained with hydrochlorothiazide 25 mg⁴⁶46. Lambers Heerspink HJ, Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15(9):853-62., reaching a mean reduction in systolic BP of 3.45 mmHg (95% CI: (-4.10, -2.81); p <0.001; I²2. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;13(6):805-13.=43.2%). Although this effect may not reach clinical benefit alone, it could solve the problem of the increasing number of drugs or dose in the antihypertensive therapy⁴⁷47. Basile J. Hypertension in the elderly: a review of the importance of systolic blood pressure elevation. J Clin Hypertens (Greenwich). 2002;4(2):108-12..

The effect of SGLT2i therapy on BP was tested on two specific trials, though none of these were exclusively performed on elders. The EMPA-REG BP trial assessed the efficacy of empagliflozin on BP reduction on hypertensive patients monitored by ambulatory BP monitoring (ABPM) using up to two hypotensive medications. The mean 24h systolic BP on empagliflozin 25 mg reduced by 4.16 mmHg (95% CI: -5.5, -2.83; p<0.001) and diastolic BP by -1.72 mmHg (95% CI: -2.51, -0.93; p<0.0001) compared to the placebo¹⁹19. Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38(3):420-8.. In a similar trial performed on hypertensive diabetic patients using on angiotensin-converting-enzyme inhibitor (ACEi) or angiotensin II receptor blockers (ARB) plus other anti-hypertensive medication, dapagliflozin 10 mg was associated to a mean 24-h systolic BP reduction of 4.28 mmHg (95% CI: –6.54, –2.02)⁴⁸48. Weber MA, Mansfield TA, Cain VA, Iqbal N, Parikh S, Ptaszynska A. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016;4(3):211-20.. This effect was similar across others antihypertensive medications such as thiazide diuretic, a calcium-channel blocker, and beta-blocker, though less intensive when dapagliflozin was added to thiazide diuretic⁴⁸48. Weber MA, Mansfield TA, Cain VA, Iqbal N, Parikh S, Ptaszynska A. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016;4(3):211-20..

Different factors may contribute to BP reduction on SGLT2i therapy³⁵35. Maliha G, Townsend RR. SGLT2 inhibitors: their potential reduction in blood pressure. J Am Soc Hypertens. 2015;9(1):48-53.. In the early stage, increased natriuresis and osmotic diuresis favor systolic BP reduction³⁵35. Maliha G, Townsend RR. SGLT2 inhibitors: their potential reduction in blood pressure. J Am Soc Hypertens. 2015;9(1):48-53.. This is likely the reason why a reduction of BP was observed as soon as 1 week after treatment with dapagliflozin²³23. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85(4):962-71.. Plasma volume contraction of -7.3% on dapagliflozin and -5.4% on canagliflozin was observed early on during the treatment⁴⁶46. Lambers Heerspink HJ, Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15(9):853-62.,⁴⁹49. Sha S, Polidori D, Heise T, Natarajan J, Farrell K, Wang SS, et al. Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2014;16(11):1087-95.. Paradoxically, this effect on BP is maintained while sodium excretion and diuresis tend to return to previous levels over the first 12 weeks¹⁹19. Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38(3):420-8.,⁴⁹49. Sha S, Polidori D, Heise T, Natarajan J, Farrell K, Wang SS, et al. Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2014;16(11):1087-95..

In addition to these effects, weight loss and glycemic control may also take part in the observed effect SGLT2i on BP³⁵35. Maliha G, Townsend RR. SGLT2 inhibitors: their potential reduction in blood pressure. J Am Soc Hypertens. 2015;9(1):48-53.. Hyperglycemia is associated with up-regulation of SGLT2 and activation of both renin-angiotensin-aldosterone axis and sympathetic system³⁵35. Maliha G, Townsend RR. SGLT2 inhibitors: their potential reduction in blood pressure. J Am Soc Hypertens. 2015;9(1):48-53.. Even weight loss obtained exclusively by dietary treatment can reduce BP⁵⁰50. Siebenhofer A, Jeitler K, Berghold A, Waltering A, Hemkens LG, Semlitsch T, et al. Long-term effects of weight-reducing diets in hypertensive patients. Cochrane Database Syst Rev. 2011:(9):CD008274., contributing in up to 28% of systolic BP reduction⁵¹51. Sjostrom CD, Hashemi M, Sugg J, Ptaszynska A, Johnsson E. Dapagliflozin-induced weight loss affects 24-week glycated haemoglobin and blood pressure levels. Diabetes Obes Metab. 2015;17(8):809-12..

Therefore, it seems possible that SGLT2i therapy could contribute to the control of the hypertension burden in older individuals. It is unlikely that this effect in BP will be the determinant factor for choosing these medications in the future, but they could pose as ancillary therapy.

2.3 Weight loss

Weight loss in older individuals is a debating theme. In the general population, obesity has been extensively associated with multiple comorbidities and an increased incidence of cardiovascular events. In the elderly, observational studies have reported that weight loss is associated with falls, disability⁵²52. Iqbal J, Denvir M, Gunn J. Frailty assessment in elderly people. Lancet. 2013;381(9882):1985-6., increased morbidity⁵³53. Fabbri E, Tanaka T, An Y, Zoli M, Bandinelli S, Guralnik JM, et al. Loss of weight in obese older adults: a biomarker of impending expansion of multimorbidity? J Am Geriatr Soc. 2015;63(9):1791-7. and mortality⁵²52. Iqbal J, Denvir M, Gunn J. Frailty assessment in elderly people. Lancet. 2013;381(9882):1985-6.,⁵⁴54. Newman AB, Yanez D, Harris T, Duxbury A, Enright PL, Fried LP, et al. Weight change in old age and its association with mortality. J Am Geriatr Soc. 2001;49(10):1309-18.. Multiple adjustments have been made in these studies in order to mitigate the interference of confounders. Still, the inability to exclude the potential interaction by unapparent or unknown disease-mechanisms underlying such spontaneous weight loss has carried on this controversy.

Intentional weight loss was not associated with increased mortality during a 12-years follow-up in obese individuals older than 65 years⁵⁵55. Shea MK, Nicklas BJ, Houston DK, Miller ME, Davis CC, Kitzman DW, et al. The effect of intentional weight loss on all-cause mortality in older adults: results of a randomized controlled weight-loss trial. Am J Clin Nutr. 2011;94(3):839-46.. In a cohort of older adults, weight loss due to psychosocial stress was not associated with increased mortality, though an adverse outcome was still associated with spontaneous weight loss⁵⁶56. Wijnhoven HA, van Zon SK, Twisk J, Visser M. Attribution of causes of weight loss and weight gain to 3-year mortality in older adults: results from the Longitudinal Aging Study Amsterdam. J Gerontol A Biol Sci Med Sci. 2014;69(10):1236-43.. Hence, it is conceivable that spontaneous and induced weight loss could not be the same; the latter may even be considered as a therapeutic target.

Studies with induced weight loss on elders have found improvement in both lipid profile⁵⁷57. Katzel LI, Bleecker ER, Colman EG, Rogus EM, Sorkin JD, Goldberg AP. Effects of weight loss vs aerobic exercise training on risk factors for coronary disease in healthy, obese, middle-aged and older men. A randomized controlled trial. JAMA. 1995;274(24):1915-21.,⁵⁸58. Purnell JQ, Kahn SE, Albers JJ, Nevin DN, Brunzell JD, Schwartz RS. Effect of weight loss with reduction of intra-abdominal fat on lipid metabolism in older men. J Clin Endocrinol Metab. 2000;85(3):977-82. and glucose metabolism⁵⁷57. Katzel LI, Bleecker ER, Colman EG, Rogus EM, Sorkin JD, Goldberg AP. Effects of weight loss vs aerobic exercise training on risk factors for coronary disease in healthy, obese, middle-aged and older men. A randomized controlled trial. JAMA. 1995;274(24):1915-21.,⁵⁹59. Dengel DR, Pratley RE, Hagberg JM, Rogus EM, Goldberg AP. Distinct effects of aerobic exercise training and weight loss on glucose homeostasis in obese sedentary men. J Appl Physiol. 1996;81(1):318-25.. In such studies, two-thirds of the weight loss is from fat and a third from lean tissue. While one might assume that this loss of lean body mass can trigger or intensify a loss of physical function, the results available indicate otherwise. In fact, the improvement of physical function is related to the amount of fat mass lost regardless of the amount of lean mass lost⁶⁰60. Beavers KM, Miller ME, Rejeski WJ, Nicklas BJ, Kritchevsky SB. Fat mass loss predicts gain in physical function with intentional weight loss in older adults. J Gerontol A Biol Sci Med Sci. 2013;68(1):80-6.. The muscle’s fat content is inversely related to its strength and directly related to its decline over time⁶¹61. Sipila S, Koskinen SO, Taaffe DR, Takala TE, Cheng S, Rantanen T, et al. Determinants of lower-body muscle power in early postmenopausal women. J Am Geriatr Soc. 2004;52(6):939-44.

62. Sipila S, Suominen H. Knee extension strength and walking speed in relation to quadriceps muscle composition and training in elderly women. Clin Physiol. 1994;14(4):433-42.

63. Goodpaster BH, Carlson CL, Visser M, Kelley DE, Scherzinger A, Harris TB, et al. Attenuation of skeletal muscle and strength in the elderly: the Health ABC Study. J Appl Physiol. 2001;90(6):2157-65.-⁶⁴64. Visser M, Kritchevsky SB, Goodpaster BH, Newman AB, Nevitt M, Stamm E, et al. Leg muscle mass and composition in relation to lower extremity performance in men and women aged 70 to 79: the health, aging and body composition study. J Am Geriatr Soc. 2002;50(5):897-904.. Thus, reduced muscle strength is a reliable marker of mortality and loss of mobility independently of lean body mass⁶⁵65. Newman AB, Kupelian V, Visser M, Simonsick EM, Goodpaster BH, Kritchevsky SB, et al. Strength, but not muscle mass, is associated with mortality in the health, aging and body composition study cohort. J Gerontol A Biol Sci Med Sci. 2006;61(1):72-7.,⁶⁶66. Visser M, Goodpaster BH, Kritchevsky SB, Newman AB, Nevitt M, Rubin SM, et al. Muscle mass, muscle strength, and muscle fat infiltration as predictors of incident mobility limitations in well-functioning older persons. J Gerontol A Biol Sci Med Sci. 2005;60(3):324-33.. Also, the proportional increase in lean mass is associated with a gain in bone mineral density, an improvement regarding frailty syndrome⁶⁷67. Aguirre L, Napoli N, Waters D, Qualls C, Villareal DT, Armamento-Villareal R. Increasing adiposity is associated with higher adipokine levels and lower bone mineral density in obese older adults. J Clin Endocrinol Metab. 2014;99(9):3290-7. and a reduction in mortality⁶⁸68. Jahangir E, De Schutter A, Lavie CJ. Low weight and overweightness in older adults: risk and clinical management. Prog Cardiovasc Dis. 2014;57(2):127-33..

Although weight loss goals have not yet been established, this effect of SGLT2i in the elderly has been tested in different backgrounds. As seen in Figure 1, the pooled effect of SGLT2i therapy across trials with the elderly was of - 1.72 kg (95% CI: -2.48, -0.97; p<0.0001; I²2. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;13(6):805-13.=38.3%). For instance, canagliflozin 300 mg was associated with 3.0% (-2.7 kg) weight loss at 26 weeks²⁸28. Bode B, Stenlof K, Sullivan D, Fung A, Usiskin K. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract. 2013;41(2):72-84., which was maintained over 104 weeks¹⁷17. Bode B, Stenlof K, Harris S, Sullivan D, Fung A, Usiskin K, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes Obes Metab. 2015;17(3):294-303.. Clinically relevant weight reduction (considered as 5% of weight reduction) increased by 23% with this treatment¹⁷17. Bode B, Stenlof K, Harris S, Sullivan D, Fung A, Usiskin K, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes Obes Metab. 2015;17(3):294-303.,²⁷27. Sinclair A, Bode B, Harris S, Vijapurkar U, Mayer C, Fung A, et al. Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. BMC Endocr Disord. 2014;14:37.. On individuals ≥65 years, dapagliflozin induced a progressive weight reduction that reached -3.4 kg at 52 weeks²⁴24. Leiter LA, Cefalu WT, Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ. Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc. 2014;62(7):1252-62..

This is also observed in individuals using medications associated with weight gain such as sulphonylurea or insulin, the addition of SGLT2i reduced body weight significantly²²22. Matthaei S, Bowering K, Rohwedder K, Sugg J, Parikh S, Johnsson E; et al. Durability and tolerability of dapagliflozin over 52 weeks as add-on to metformin and sulphonylurea in type 2 diabetes. Diabetes Obes Metab. 2015;17(11):1075-84.,²⁵25. Neal B, Perkovic V, Zeeuw D, Mahaffey KW, Fulcher G, Ways K, et al. Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care. 2015;38(3):403-11.,⁶⁹69. Matthaei S, Bowering K, Rohwedder K, Grohl A, Parikh S, Study 05 Group. Dapagliflozin improves glycemic control and reduces body weight as add-on therapy to metformin plus sulfonylurea: a 24-week randomized, double-blind clinical trial. Diabetes Care. 2015;38(3):365-72.,⁷⁰70. Fulcher G, Matthews DR, Perkovic V, Zeeuw D, Mahaffey KW, Weiss R, et al. Efficacy and safety of canagliflozin used in conjunction with sulfonylurea in patients with type 2 diabetes mellitus: a randomized, controlled trial. Diabetes Ther. 2015;6(3):289-302.. Moreover, this effect is additive for other therapies associated with weight loss such as GLP-1 agonists⁴⁵45. Fulcher G, Matthews DR, Perkovic V, Zeeuw D, Mahaffey KW, Mathieu C, et al. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18(1):82-91..

The amount of glucose lost through urine provides a deficit of 200–400 kcal/day. With such caloric loss during a long-term follow-up, one could expect that the weight loss would be more significant than what was actually verified. The increase in caloric intake71 partially explains this reduced expected effect¹1. Viljoen A, Sinclair AJ. Diabetes and insulin resistance in older people. Med Clin North Am. 2011;95(3):615-29.. Such a compensatory increase in the caloric intake is proportional to the glucose excretion⁷¹71. Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy balance after sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38(9):1730-5.. Potentially, the association between SGLT2i and appetite suppression would provide a higher and longer weight loss than the use of these drugs as monotherapy.

Besides hyperphagia, SGLT2i treatment in mice was associated with a decrease in oxygen consumption and brown adipose tissue thermogenesis via down-regulation of an inter-organ neural network consisting of the common hepatic vagal branch and sympathetic nerves⁷²72. Chiba Y, Yamada T, Tsukita S, Takahashi K, Munakata Y, Shirai Y, et al. Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, acutely reduces energy expenditure in BAT via neural signals in mice. PloS One. 2016;11(3):e0150756.. Together, the reduction of energy consumption and increased caloric intake promote a balance to caloric loss through urine that keeps the initial weight loss achieved with SGLT2i in the first few weeks till up to 208 weeks⁷³73. Del Prato S, Nauck M, Duran-Garcia S, Maffei L, Rohwedder K, Theuerkauf A, et al. Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4-year data. Diabetes Obes Metab. 2015;17:581-90..

Regarding the effect of SGLT2i in body composition, over 102 weeks of dapagliflozin treatment, fat mass changed by -1.34 kg (-2.44, -0.23) and lean mass changed by -0.4 kg (-1.0, 0.2)²³23. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85(4):962-71.. This led to a proportional change in body composition, with a decrease of −1.5% (−2.1, −0.8) of fat mass and an increase of 1.3% (0.5, 2.1) of lean mass²¹21. Bolinder J, Ljunggren O, Johansson L, Wilding J, Langkilde AM, Sjöström CD, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2014;16(2):159-69.. In the mechanistic point of view, one possible explanation could be the effect of SGLT2i in increasing insulin sensitivity, thus favoring the anabolism of the muscle tissue¹⁴14. Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124(2):509-14.,⁷⁴74. Lee CG, Boyko EJ, Barrett-Connor E, Miljkovic I, Hoffman AR, Everson-Rose SA, et al. Insulin sensitizers may attenuate lean mass loss in older men with diabetes. Diabetes Care. 2011;34(11):2381-6..

Another issue yet to be clarified is the preferred effect of fat mass loss after SGLT2i in visceral or subcutaneous tissue. In a study using magnetic resonance imaging, the decrease in visceral adipose tissue (-258.4 cm³3. Sloan FA, Bethel MA, Ruiz D Jr., Shea AM, Feinglos MN. The growing burden of diabetes mellitus in the US elderly population. Arch Intern Med. 2008;168(2):192-9. (-448.1, -68.6)) tended to be higher than that on subcutaneous adipose tissue (-184.9 cm³3. Sloan FA, Bethel MA, Ruiz D Jr., Shea AM, Feinglos MN. The growing burden of diabetes mellitus in the US elderly population. Arch Intern Med. 2008;168(2):192-9. (-359.7, -10.1)), though this difference did not reach statistical significance in up to 102 weeks of treatment²¹21. Bolinder J, Ljunggren O, Johansson L, Wilding J, Langkilde AM, Sjöström CD, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2014;16(2):159-69.,⁷⁴74. Lee CG, Boyko EJ, Barrett-Connor E, Miljkovic I, Hoffman AR, Everson-Rose SA, et al. Insulin sensitizers may attenuate lean mass loss in older men with diabetes. Diabetes Care. 2011;34(11):2381-6..

EFFECT ON KIDNEY AND RENAL DISEASE PROGRESSION

As a result of the natural decline in glomerular filtration rate (GFR), the elderly often present clinically relevant renal dysfunction, particularly with diabetes. Indeed, chronic kidney disease (CKD) affects more than 50% of individuals over 70 years⁷⁵75. Levey AS, Inker LA, Coresh J. Chronic kidney disease in older people. JAMA. 2015;314(6):557-8.. Although less than 2% of stage 3 CKD patients require renal replacement in mid-term follow-up (8 years)⁷⁶76. Hallan SI, Dahl K, Oien CM, Grootendorst DC, Aasberg A, Holmen J, et al. Screening strategies for chronic kidney disease in the general population: follow-up of cross sectional health survey. BMJ. 2006;333(7577):1047., almost half end-stage kidney disease is attributed to DM2⁷⁷77. Tuttle KR, Bakris GL, Bilous RW, Chiang JL, Boer IH, Goldstein-Fuchs J, et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Am J Kidney Dis. 2014;64(4):510-33.. The relative risk of death and progression of end-stage renal disease is increased in elders with low GFR and high albuminuria, though its corresponding effect on mortality wanes at an older age⁷⁸78. Hallan SI, Matsushita K, Sang Y, Mahmoodi BK, Black C, Ishani A, et al. Age and association of kidney measures with mortality and end-stage renal disease. JAMA. 2012;308(22):2349-60..

Aging induces changes in the kidney as compared to a disease that occurs in some but not all individuals. The microanatomical structural changes of the kidney with older age include a decreased number of functional glomeruli from an increased prevalence of glomerulosclerosis, arteriosclerosis and tubular atrophy with interstitial fibrosis and compensatory hypertrophy of remaining nephrons. Among carefully screened healthy kidney donors, glomerular filtration rate (GFR) declines at a rate of 6.3 mL/min/1.73 m²2. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;13(6):805-13. per decade. The elderly have less kidney functional reserve when they do actually develop CKD, and they are at higher risk for diabetic kidney disease and its progression⁷⁹79. Denic A, Glassock RJ, Rule AD. Structural and functional changes with the aging kidney. Adv Chronic Kidney Dis. 2016;23(1):19-28.. Diabetes accelerates these age-related changes leading to a higher functional decline and precocity⁸⁰80. Blazer S, Khankin E, Segev Y, Ofir R, Yalon-Hacohen M, Kra-Oz Z, et al. High glucose-induced replicative senescence: point of no return and effect of telomerase. Biochem Biophys Res Commun. 2002;296(1):93-101.,⁸¹81. Yokoi T, Fukuo K, Yasuda O, Hotta M, Miyazaki J, Takemura Y, et al. Apoptosis signal-regulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells. Diabetes. 2006;55(6):1660-5.. In fact, senescent tubular phenotype cells could be induced by high glucose concentrations⁸²82. Verzola D, Gandolfo MT, Gaetani G, Ferraris A, Mangerini R, Ferrario F, et al. Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy. Am J Physiol Renal Physiol. 2008;295(5):F1563-73., and these alterations on tubular proximal cultured cells are associated with increased expression of SGLT2⁸³83. Kitada K, Nakano D, Ohsaki H, Hitomi H, Minamino T, Yatabe J, et al. Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy. J Diabetes Complications. 2014;28(5):604-11..

Increased glomerular filtration is one of the earlier markers of diabetic nephropathy. The renin-angiotensin system (RAS) plays a significant role in glomerular hyperfiltration on diabetic nephropathy. Glucose can induce angiotensin II (AngII) generation by local activation of RAS⁸⁴84. De Nicola L, Gabbai FB, Liberti ME, Sagliocca A, Conte G, Minutolo R. Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes. Am J Kidney Dis. 2014;64:16-24., constriction of efferent arteriole thus influencing sodium reabsorption and increasing glomerular permeability⁸⁵85. Gallagher H, Suckling RJ. Diabetic nephropathy: where are we on the journey from pathophysiology to treatment? Diabetes Obes Metab. 2016;18(7):641-7..

Similarly, the increased sodium reabsorption through SGLT2 may also contribute to renal hyperfiltration. SGLT2 expression is increased at the proximal tubule of diabetic experimental models⁸⁶86. Freitas HS, Anhe GF, Melo KF, Okamoto MM, Oliveira-Souza M, Bordin S, et al. Na(+) -glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1alpha expression and activity. Endocrinology. 2008;149(2):717-24. and in diabetic patients⁸⁷87. Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes. 2005;54(12):3427-34.. This promotes a reduction of sodium on macula densa, thus increasing vasodilation on afferent arteriole⁸⁸88. Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129(5):587-97.. The therapeutic use of SGLT2i increases the sodium delivery to the macula densa, thus decreasing GFR⁸⁹89. Skrtic M, Cherney DZ. Sodium-glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathy. Curr Opin Nephrol Hypertens. 2015;24(1):96-103.. In parallel, other mediators participate in the regulation of renal hemodynamics, such as adenosine, nitric oxide, and calcium influx, contributing to the glomerular filtration rate. Thus, the hyperfiltration of diabetic kidney disease and its control will depend on the outcome of the balance of this set of players.

On aging CKD patients, an increased rate of nephron loss units is observed. In parallel, there is an adaptive decrease in SGTL2 transcription rate⁹⁰90. Nakamura N, Masuda S, Takahashi K, Saito H, Okuda M, Inui K. Decreased expression of glucose and peptide transporters in rat remnant kidney. Drug Metab Pharmacokinet. 2004;19(1):41-7. and, consequently, a decrease in SGLT2i effectiveness on CKD patients, as SGLT2i acts on the extracellular surface of the tubule lumen cell⁹¹91. Ghezzi C, Hirayama BA, Gorraitz E, Loo DD, Liang Y, Wright EM. SGLT2 inhibitors act from the extracellular surface of the cell membrane. Physiol Rep. 2014;2(6).. Therefore, clinical trials on SGLT2i observed reduced effectiveness on glycemic control. A progressive decline on HbA1c effectiveness was reported on empagliflozin 25mg in individuals with CKD stage 2 (-0.68%), to stage 3 (-0.42%) and to stage 4 (+0.04%)²⁰20. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2(5):369-84.. An investigation of dapagliflozin effect on CKD individuals indicated that the cut-off point for the decline of SGLT2i glucose-lowering effect is GFR ≤45mL/min²³23. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85(4):962-71.. In the general population, the concomitant inhibition of SGLT1 and SGLT2 increases the glycosuria as compared with the isolated inhibition of SGLT2⁹²92. Sha S, Polidori D, Farrell K, Ghosh A, Natarajan J, Vaccaro N, et al. Pharmacodynamic differences between canagliflozin and dapagliflozin: results of a randomized, double-blind, crossover study. Diabetes Obes Metab. 2015;17(2):188-97.. In CKD patients, however, a head-to-head comparison of their effect is unavailable.

Hypertension is the most common comorbidity among CKD patients and its prevalence increases as renal function worsens⁹³93. Townsend RR, Taler SJ. Management of hypertension in chronic kidney disease. Nat Rev Nephrol. 2015;11(9):555-63.. Particularly in this population, BP controlling could attenuate the progression of kidney disease⁹⁴94. Palmer SC, Mavridis D, Navarese E, Craig JC, Tonelli M, Salanti G, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet. 2015;385(9982):2047-56.. On stage 3 and 4 CKD, SGLT2i therapy reduced SBP by - 5.46 mmHg (95% CI: -7.83, -3.07; p=0.001; I²2. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;13(6):805-13.=0%). SGLT2i therapy was associated with a reduction on SBP and DBP by 52²⁰20. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2(5):369-84.,²³23. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85(4):962-71.,²⁶26. Yale JF, Bakris G, Cariou B, Nieto J, David-Neto E, Yue D, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab. 2014;16(10):1016-27. and 104 weeks²³23. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85(4):962-71. among CKD patients. As with glycemia, empagliflozin effects on BP wane as renal insufficiency worsens²⁰20. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2(5):369-84..

On CKD patients, not only the above-cited mechanisms could be beneficial; body weight management is associated with hindering proteinuria and the prevention of GFR decline⁹⁵95. Navaneethan SD, Yehnert H, Moustarah F, Schreiber MJ, Schauer PR, Beddhu S. Weight loss interventions in chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2009;4(10):1565-74.. Indeed, SGLT2i therapy is associated with body weight reduction in CKD patients, which is inversely proportional to the severity of renal dysfunction⁹²92. Sha S, Polidori D, Farrell K, Ghosh A, Natarajan J, Vaccaro N, et al. Pharmacodynamic differences between canagliflozin and dapagliflozin: results of a randomized, double-blind, crossover study. Diabetes Obes Metab. 2015;17(2):188-97.. This coupling is consistent with the reduced tubular expression of SGLT2 and the glycosuria induced by SGLT2i, which is proportional to the decline in GFR.

Probably as a consequence of constriction of the proximal arteriole, eGFR decreases by approximately 4 mL/min/1.73 m²2. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;13(6):805-13. on the general population and older patients⁹⁶96. Perkovic V, Jardine M, Vijapurkar U, Meininger G. Renal effects of canagliflozin in type 2 diabetes mellitus. Curr Med Res Opin. 2015;31(12):2219-31.. The magnitude of the reduction on GFR during SGLT2i therapy is similar to that observed after distal arteriole dilation by ACEi⁸⁸88. Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129(5):587-97.,⁹⁷97. Cherney DZ, Perkins BA, Soleymanlou N, Xiao F, Zimpelmann J, Woerle HJ, et al. Sodium glucose cotransport-2 inhibition and intrarenal RAS activity in people with type 1 diabetes. Kidney Int. 2014;86(5):1057-8.. This effect is observed as soon as after 1 week⁹⁸98. Kohan DE, Fioretto P, Johnsson K, Parikh S, Ptaszynska A, Ying L. The effect of dapagliflozin on renal function in patients with type 2 diabetes. J Nephrol. 2016;29(3):391-400. and tended to return to baseline values during follow-up¹⁷17. Bode B, Stenlof K, Harris S, Sullivan D, Fung A, Usiskin K, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes Obes Metab. 2015;17(3):294-303.,⁹⁶96. Perkovic V, Jardine M, Vijapurkar U, Meininger G. Renal effects of canagliflozin in type 2 diabetes mellitus. Curr Med Res Opin. 2015;31(12):2219-31.,⁹⁸98. Kohan DE, Fioretto P, Johnsson K, Parikh S, Ptaszynska A, Ying L. The effect of dapagliflozin on renal function in patients with type 2 diabetes. J Nephrol. 2016;29(3):391-400., though persistent reductions can be observed²⁵25. Neal B, Perkovic V, Zeeuw D, Mahaffey KW, Fulcher G, Ways K, et al. Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care. 2015;38(3):403-11.. During SGLT2i therapy, older patients had similar or slightly higher reductions of eGFR compared to their younger counterpart²⁷27. Sinclair A, Bode B, Harris S, Vijapurkar U, Mayer C, Fung A, et al. Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. BMC Endocr Disord. 2014;14:37.,⁹⁶96. Perkovic V, Jardine M, Vijapurkar U, Meininger G. Renal effects of canagliflozin in type 2 diabetes mellitus. Curr Med Res Opin. 2015;31(12):2219-31.,⁹⁸98. Kohan DE, Fioretto P, Johnsson K, Parikh S, Ptaszynska A, Ying L. The effect of dapagliflozin on renal function in patients with type 2 diabetes. J Nephrol. 2016;29(3):391-400.. However, even though aging does not significantly influence the variation in absolute GFR values, the percent loss of renal function may be higher due to preexisting renal dysfunction often found in the elderly⁹⁶96. Perkovic V, Jardine M, Vijapurkar U, Meininger G. Renal effects of canagliflozin in type 2 diabetes mellitus. Curr Med Res Opin. 2015;31(12):2219-31.,⁹⁹99. Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15(5):463-73.. Even though, a clinically significant decrease of GFR (at least 50%) is infrequent even in Stage 3 CKD (12.2%)⁹⁶96. Perkovic V, Jardine M, Vijapurkar U, Meininger G. Renal effects of canagliflozin in type 2 diabetes mellitus. Curr Med Res Opin. 2015;31(12):2219-31..

Since the approval of the first SGL2i in March 2013 until October 2015, the FDA received reports of 101 confirmed cases of acute kidney injury (canagliflozin=73, dapagliflozin=28). Hospitalization and need of dialysis were required for a selected number of patients. Most improved with the discontinuation of the drug. There were no signs of direct drug toxicity, and most cases were observed in patients with predisposing factors to pre-renal AKI: decreased blood volume, chronic kidney insufficiency, congestive heart failure, concomitant medications such as diuretics, ACEi, ARBs, NSAID. The warning reinforces that the patient’s kidney function should be assessed prior to starting treatment and be monitored periodically after that before being started on SGLT2 therapy. Also, one should consider temporarily discontinuing treatment in any setting of severe acute illness, prolonged fasting, or severe fluid losses. If acute kidney injury occurs, the drug should be discontinued promptly.

SAFETY CONCERNS

Volume-depletion-related events

Adverse events (AE) related to volume depletion are of particular concern of this drug class. As it would be expectable, SGLT2i therapy induces plasma volume contraction through its effect on the proximal tubular cells. An increase in 24-h urine output of approximately 370 mL and up to 10% contraction of plasma volume have been reported on this treatment⁴⁶46. Lambers Heerspink HJ, Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15(9):853-62.,⁴⁹49. Sha S, Polidori D, Heise T, Natarajan J, Farrell K, Wang SS, et al. Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2014;16(11):1087-95.,¹⁰⁰100. Wilding JP, Norwood P, T’Joen C, Bastien A, List JF, Fiedorek FT. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care. 2009;32(9):1656-62.,¹⁰¹101. List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009;32(4):650-7.. Whether or not and in what degree the plasma volume returns to baseline levels during therapy is still a debated theme⁴⁶46. Lambers Heerspink HJ, Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15(9):853-62.,⁴⁹49. Sha S, Polidori D, Heise T, Natarajan J, Farrell K, Wang SS, et al. Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2014;16(11):1087-95.. However, safety concern on volume depletion has been assessed in recent clinical trials.

In safety clinical trials, volume depletion has been characterized by postural dizziness, orthostatic hypotension, increased in heart rate, dehydration, hypotension, orthostatic hypotension, pre-syncope, and syncope. In 104 weeks, the incidence is reported to be 5.9% on canagliflozin¹⁷17. Bode B, Stenlof K, Harris S, Sullivan D, Fung A, Usiskin K, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes Obes Metab. 2015;17(3):294-303..

Probably as a consequence of plasma volume contraction, RAS activity and aldosterone levels are increased during SGLT2i therapy⁴⁶46. Lambers Heerspink HJ, Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15(9):853-62.. Actually, an elegant study demonstrated that during SGLT2i therapy there is an increase in both systemic and intrarenal RAS activity⁹⁷97. Cherney DZ, Perkins BA, Soleymanlou N, Xiao F, Zimpelmann J, Woerle HJ, et al. Sodium glucose cotransport-2 inhibition and intrarenal RAS activity in people with type 1 diabetes. Kidney Int. 2014;86(5):1057-8.. It is established the proatherosclerotic role of the RAS axis activation via a spectrum of mechanisms including inflammatory pathways, insulin resistance, hypertension, and oxidative stress¹⁰²102. Hayashi T, Takai S, Yamashita C. Impact of the renin-angiotensin-aldosterone-system on cardiovascular and renal complications in diabetes mellitus. Curr Vasc Pharmacol. 2010;8(2):189-97.. The long-term effects of these pathways’ activation with SGLT2i remain to be assessed. In the only published study in which the cardiovascular effect of SGLT2i was tested, about 80% of patients were on concomitant use of RAS inhibitors¹⁸18. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28.. By presumption, it would be gainful to associate RAS inhibitor therapy with SGLT2i⁴⁸48. Weber MA, Mansfield TA, Cain VA, Iqbal N, Parikh S, Ptaszynska A. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016;4(3):211-20.,⁴⁹49. Sha S, Polidori D, Heise T, Natarajan J, Farrell K, Wang SS, et al. Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2014;16(11):1087-95..

The incidence of volume-depletion-related AE is low, but it may increase as renal function worsens. For example, the incidence after empagliflozin is 1.0% on stage 2, 3.7% on stage 3 CKD and 5.4% on stage 4²⁰20. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2(5):369-84.. Likewise, the incidence of volume depletion AE is dose-dependent¹⁰³103. Yamout H, Perkovic V, Davies M, Woo V, Zeeuw D, Mayer C, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes and stage 3 nephropathy. Am J Nephrol. 2014;40(1):64-74. and increased overtime²⁶26. Yale JF, Bakris G, Cariou B, Nieto J, David-Neto E, Yue D, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab. 2014;16(10):1016-27.,⁹⁹99. Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15(5):463-73.. There is no apparent influence of the concomitant use of anti-hypertensive medications¹⁹19. Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38(3):420-8. or even thiazide therapy on the incidence of these AE⁴⁸48. Weber MA, Mansfield TA, Cain VA, Iqbal N, Parikh S, Ptaszynska A. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016;4(3):211-20.,¹⁰⁴104. Devineni D, Vaccaro N, Polidori D, Rusch S, Wajs E. Effects of hydrochlorothiazide on the pharmacokinetics, pharmacodynamics, and tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants. Clin Ther. 2014;36(5):698-710.. Among the elderly, special attention must be paid to orthostatic hypotension, whose incidence is increased in up to 9% after SGLT2i¹⁹19. Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38(3):420-8..

Osmotic diuresis-related AE

Since long-term therapy with osmotic diuresis became available for clinical practice for the first time after SGLT2i development, the pros and cons of this therapy remain theoretical. Potential AE includes pollakiuria, polyuria, dry mouth, dry throat, micturition urgency, nocturia, polydipsia, and increased thirst, among others. So, particular attention must be paid on elderly individuals to be treated by SGLT2i whose baseline pre-treatment condition is already associated with some of these symptoms. Osmotic diuresis symptoms are dose-related²⁸28. Bode B, Stenlof K, Sullivan D, Fung A, Usiskin K. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract. 2013;41(2):72-84., GFR-influenced²³23. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85(4):962-71.,²⁶26. Yale JF, Bakris G, Cariou B, Nieto J, David-Neto E, Yue D, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab. 2014;16(10):1016-27.,⁹⁶96. Perkovic V, Jardine M, Vijapurkar U, Meininger G. Renal effects of canagliflozin in type 2 diabetes mellitus. Curr Med Res Opin. 2015;31(12):2219-31.,⁹⁹99. Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15(5):463-73.,¹⁰³103. Yamout H, Perkovic V, Davies M, Woo V, Zeeuw D, Mayer C, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes and stage 3 nephropathy. Am J Nephrol. 2014;40(1):64-74. and time-dependent, raising up to 12.3% over 104 weeks¹⁷17. Bode B, Stenlof K, Harris S, Sullivan D, Fung A, Usiskin K, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes Obes Metab. 2015;17(3):294-303.. Also in patients in use of therapies associated with sodium retention such as insulin and sulfonylurea, similar rates of osmotic diuresis AE have been reported²⁵25. Neal B, Perkovic V, Zeeuw D, Mahaffey KW, Fulcher G, Ways K, et al. Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care. 2015;38(3):403-11.,⁴⁵45. Fulcher G, Matthews DR, Perkovic V, Zeeuw D, Mahaffey KW, Mathieu C, et al. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18(1):82-91.. However, a SGLT2i-induced 3-fold rise (from 0.1 to 0.3%) in the incidence of volume-related AE were previously reported⁹⁸98. Kohan DE, Fioretto P, Johnsson K, Parikh S, Ptaszynska A, Ying L. The effect of dapagliflozin on renal function in patients with type 2 diabetes. J Nephrol. 2016;29(3):391-400..

Diabetes Ketoacidosis

A particular type of diabetic ketoacidosis (DKA) has been reported during SGLT2i therapy which differs from the usual form by the attenuated expression of hyperglycemia and ketonuria; the called euglycemic DKA (eDKA). On a pooled analysis, eDKA frequency was overall low but slightly higher on SGLT2i (2-3 times) than with other anti-diabetic therapies¹⁸18. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28.,¹⁰⁵105. Erondu N, Desai M, Ways K, Meininger G. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care. 2015;38(9):1680-6..

SGLT2i therapy increases ketonemia in a dose-dependent manner via a spectrum of mechanisms¹⁰⁶106. Kaku K, Watada H, Iwamoto Y, Utsunomiya K, Terauchi Y, Tobe K, et al. Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter-2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: a combined Phase 2 and 3 randomized, placebo-controlled, double-blind, parallel-group comparative study. Cardiovasc Diabetol. 2014;13:65.. In animal and cell models, SGLT2i therapy induces ketone production by directly inducing glucagon secretion by alpha pancreatic cells¹⁰⁷107. Bonner C, Kerr-Conte J, Gmyr V, Queniat G, Moerman E, Thévenet J, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pareatic alpha cells triggers glucagon secretion. Nat Med. 2015;21(5):512-7.. Consistently, in clinical studies, hepatic glucose production is up-regulated after SGLT2i treatment¹⁴14. Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124(2):509-14.,¹⁶16. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499-508., at least in part due to the increase in glucagon levels stimulating hepatic ketogenesis and gluconeogenesis¹⁰⁸108. Taylor SI, Blau JE, Rother KI. Perspective: SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab. 2015;100(8):2849-52.. Likewise, SGLT2i increases the risk of eDKA by augmenting ketone absorption and reducing ketonuria¹⁰⁸108. Taylor SI, Blau JE, Rother KI. Perspective: SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab. 2015;100(8):2849-52..

Among the reported eDKA cases, a high proportion of individuals had concurrent conditions which may increase their susceptibility, such as of autoimmune diabetes, reduction of insulin background therapy and acute illness¹⁰⁵105. Erondu N, Desai M, Ways K, Meininger G. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care. 2015;38(9):1680-6.. Moreover, the eDKA cases were one decade older than their counterparts, and at least 50% had late autoimmune diabetes on adults (LADA)¹⁰⁹109. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 2015;38(9):1638-42., while the prevalence of LADA is up to 10% on diabetic population¹¹⁰110. Tuomi T, Santoro N, Caprio S, Cai M, Weng J, Groop L. The many faces of diabetes: a disease with increasing heterogeneity. Lancet. 2014;383(9922):1084-94.,¹¹¹111. Itariu BK, Stulnig TM. Autoimmune aspects of type 2 diabetes mellitus: a mini-review. Gerontology. 2014;60(3):189-96.. Thus, although the incidence of eDKA during SGLT2i is low (1.3/1000 patients-year), the possibility of this diagnosis must be borne in mind particularly among the elderly and those insulin-requiring¹⁰⁹109. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 2015;38(9):1638-42..

Hypoglycemia

In elderly diabetics, the casual detection of hypoglycemia indicates a fourfold increase in the risk of death, which is a risk predictor even greater than pre-existing ischemic heart disease¹¹²112. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129-39.. Beyond that, in this age group hypoglycemia is associated with an increased risk of fall¹¹³113. Signorovitch JE, Macaulay D, Diener M, Yan Y, Wu EQ, Gruenberger JB, et al. Hypoglycaemia and accident risk in people with type 2 diabetes mellitus treated with non-insulin antidiabetes drugs. Diabetes Obes Metab. 2013;15(4):335-41., fracture¹¹⁴114. Johnston SS, Conner C, Aagren M, Ruiz K, Bouchard J. Association between hypoglycaemic events and fall-related fractures in Medicare-covered patients with type 2 diabetes. Diabetes Obes Metab. 2012;14(7):634-43., and cognitive decline¹¹⁵115. Feinkohl I, Aung PP, Keller M, Robertson CM, Morling JR, McLachlan S, et al. Severe hypoglycemia and cognitive decline in older people with type 2 diabetes: the Edinburgh type 2 diabetes study. Diabetes Care. 2014;37(2):507-15.,¹¹⁶116. Mattishent K, Loke YK. Bi-directional interaction between hypoglycaemia and cognitive impairment in elderly patients treated with glucose lowering agents: systematic review and meta-analysis. Diabetes Obes Metab. 2016;18(2):135-41..

From a pathophysiological point of view, direct and indirect effects of hypoglycemia ensues a set of metabolic, thrombotic, inflammatory and vasomotor effects, favoring the remodeling of atherosclerotic plaques to an unstable phenotype and its thrombotic occlusion. In the short term, hypoglycemia can reduce the energy source for myocardial cells, particularly in individuals with diabetes or ischemic heart disease, prolonging QT interval, a substrate for life-threatening ventricular arrhythmias. In the elderly, impaired counter-regulatory mechanisms may result in higher susceptibility to hypoglycemia’s duration and its deleterious effects¹¹⁷117. Lipska KJ, Montori VM. Glucose control in older adults with diabetes mellitus: more harm than good? JAMA Intern Med. 2013;173(14):1306-7.. Consistent with the short-term effect, while the blood glucose decreased by about 16% the risk of nonfatal myocardial infarction, the incidence of cardiovascular death is not reduced.

SGLT2i therapy in the elderly did not increase the risk of hypoglycemia. The relative risk of hypoglycemia was 1.11 (95% CI: 0.84, 1.45; p=0.554; I²2. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;13(6):805-13.=0%) across SGLT2i and comparators on patients on a background therapy not prone to hypoglycemia, as seen in figure 2A. Hypoglycemia was not described slightly more often when SGLT2i was added to a background prone to hypoglycemia (insulin or sulphonylurea), posing a RR of 1.05 (95% CI: 0.99, 1.11; p = 0.198; I²2. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;13(6):805-13.=39.1%) (Figure 2B), although considerable heterogeneity was observed. Although hypoglycemic adverse events were higher on SGLT2 inhibitors when compared to the placebo, these AE were much higher on insulin or sulphonylurea therapy backgrounds. It is also described as an increase of hypoglycemic AE when renal function worsens. However, specifically on the elderly, there are no head-a-head trials of other hypoglycemic therapies vs. SGLT2i. Therefore, although it is possible that SGLT2i could reduce hypoglycemia rates in comparison to other drugs on older individuals, more studies are needed to assess this issue.

In stage 3 or 4 CKD individuals, hypoglycemia rate was similar among SGLT2i and placebo on individuals not on hypoglycemia prone therapy, with RR of 1.01 (95% CI 0.75, 1.37; p=0.688; I²2. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;13(6):805-13.=0%), though on insulin or sulphonylurea background therapy RR was 1.05 (95% CI: 0.85, 1,30; p=0.311; I²2. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;13(6):805-13.=57%) with substantial heterogeneity among trials in this last comparison. Comparing the effect of empagliflozin on different stages of CKD, progressively renal impairment was associated with higher rates of hypoglycemia²⁰20. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2(5):369-84.. In fact, stage 4 CKD on empagliflozin had an incidence of 37.8% of hypoglycemic AE vs. 32.4% on placebo, but lower incidence of AE were noted on stage 3 CKD (27.8% vs. 28.3% on empagliflozin and placebo, respectively) or stage 2 CKD (22.7% vs. 26.5% vs. 24.2% on empagliflozin 25 and 10 mg and placebo, respectively)²⁰20. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2(5):369-84..

Genital urinary-tract infections

Urinary tract infections (UTI) incidence is higher on older TSDM females, specifically those with poorly controlled diabetes¹¹⁸118. Hirji I, Guo Z, Andersson SW, Hammar N, Gomez-Caminero A. Incidence of urinary tract infection among patients with type 2 diabetes in the UK General Practice Research Database (GPRD). J Diabetes Complications. 2012;26(6):513-6.. Actually, in T2DM, moderate to severe glycosuria is associated with asymptomatic bacteriuria and also to pyelonephritis¹¹⁹119. Geerlings S, Fonseca V, Castro-Diaz D, List J, Parikh S. Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract. 2014;103(3):373-81.. As a concern of diabetic and older individuals and because of increased glycosuria on SGLT2i therapy, most of the clinical trials and reviews involving SGLT2 inhibitors reported UTI and GTI incidences¹¹⁷117. Lipska KJ, Montori VM. Glucose control in older adults with diabetes mellitus: more harm than good? JAMA Intern Med. 2013;173(14):1306-7.

118. Hirji I, Guo Z, Andersson SW, Hammar N, Gomez-Caminero A. Incidence of urinary tract infection among patients with type 2 diabetes in the UK General Practice Research Database (GPRD). J Diabetes Complications. 2012;26(6):513-6.

119. Geerlings S, Fonseca V, Castro-Diaz D, List J, Parikh S. Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract. 2014;103(3):373-81.

120. Johnsson KM, Ptaszynska A, Schmitz B, Sugg J, Parikh SJ, List JF. Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J Diabetes Complications. 2013;27(5):479-84.

121. Liakos A, Karagiannis T, Athanasiadou E, Sarigianni M, Mainou M, Papatheodorou K, et al. Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2014;16(10):984-93.-¹²²122. Nyirjesy P, Sobel JD, Fung A, Mayer C, Capuano G, Ways K, et al. Genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. Curr Med Res Opin. 2014;30(6):1109-19..

As observed in Figure 3, SGLT2i therapy did not increase the incidence of UTI events in trials with elderly individuals. The RR of uncomplicated and complicated UTI on SGLT2i therapy was respectively 1.04 (0.95, 1.14; p=0.186; I²2. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;13(6):805-13.=24.9%) and 0.93 (0.66, 1.31; p=0.745; I²2. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;13(6):805-13.=0%). However, as expected on SGLT2i therapy, females had a higher risk of GTI, with a RR of 4.13 (2.96, 5.76; p<0.001; I²2. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;13(6):805-13.=32.6%), while males had a RR of 4.02 (2.91, 5.57; p<0.001; I²2. Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;13(6):805-13.=0%). However, few participants discontinued medication due to this AE, and the majority of GTI and UTI are benign conditions that were resolved with appropriate medication.

The overall incidence of UTI was higher on EMPAREG trial than others (on females, 40.6% on placebo and 36.4% on empagliflozin; on male individuals, 9.4% on placebo and 10.4% on empagliflozin). Paradoxically, the placebo branch had higher rates of complicated urinary tract infections than the empagliflozin (1.8% vs. 1.7%), though urosepsis developed on 17 individuals on empagliflozin and 3 on placebo¹⁸18. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28.. The RR of UTI on CKD patients was 1.09 (0.83, 1.44; p=0.517). Similar to that of subjects without renal disease, RR of GTI was 2.31 (95% CI: 1.13, 4.75; p=0.22) on males and 4.00 (95% CI: 1.62, 9.86; p=0.003) on females on SGLT2i therapy.

Bone Metabolism

From the fifth decade of life, there is a progressive loss of bone mass, which may reach the osteoporosis degree according to the peak of bone mass achieved, the rate of bone loss and longevity. Genetic factors, hormonal status, physical inactivity, low calcium intake, low sun exposure, smoking and comorbidities such as CKD and DM2 may all contribute to an accelerated deterioration of bone mass; thus, they may favor the risk for osteoporotic fragility fracture. In parallel, regardless of the bone mineral density (BMD), individuals with T2DM may have an osteopathic disease with significant changes in bone quality and architecture¹²³123. Jackuliak P, Payer J. Osteoporosis, fractures, and diabetes. Int J Endocrinol. 2014;2014:820615.. Finally, T2DM is also associated with increased risk of fractures among the older population due to peripheral neuropathy and increased risk of falls¹²⁴124. Strotmeyer ES, Cauley JA, Schwartz AV, Nevitt MC, Resnick HE, Bauer DC, et al. Nontraumatic fracture risk with diabetes mellitus and impaired fasting glucose in older white and black adults: the health, aging, and body composition study. Arch Intern Med. 2005;165(14):1612-7..

In regards to pharmacodynamics of SGLT2i, this therapy may favor mineral and electrolytes disturbances, which can further contribute to the rate of bone loss by increasing phosphate, calciuria and production of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23)¹²⁵125. Thrailkill KM, Clay Bunn R, Nyman JS, Rettiganti MR, Cockrell GE, Wahl EC, et al. SGLT2 inhibitor therapy improves blood glucose but does not prevent diabetic bone disease in diabetic DBA/2J male mice. Bone 2016;82:101-7.. In up to 50 weeks, SGLT2i treatment on subjects ≥60 years presented no significant differences between SGLT2i therapy and the placebo on markers of bone reabsorption, such as procollagen type 1 N-terminal propeptide and C-terminal cross-linking telopeptides of type I collagen¹²⁶126. Ljunggren O, Bolinder J, Johansson L, Wilding J, Langkilde AM, Sjöström CD, et al. Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin. Diabetes Obes Metab. 2012;14(11):990-9.. However, on a longer follow-up of 104 weeks, different bone turnover markers such as β-carboxy-telopeptide and osteocalcin were increased with SGLT2i therapy¹²⁷127. Bilezikian JP, Watts NB, Usiskin K, Polidori D, Fung A, Sullivan D, et al. Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with canagliflozin. J Clin Endocrinol Metab. 2016;101(1):44-51.. However, the increased bone turnover does not seem to impact on BMD of the femoral neck, lumbar spine, and total hip after 50 weeks¹²⁶126. Ljunggren O, Bolinder J, Johansson L, Wilding J, Langkilde AM, Sjöström CD, et al. Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin. Diabetes Obes Metab. 2012;14(11):990-9. or 104 weeks²¹21. Bolinder J, Ljunggren O, Johansson L, Wilding J, Langkilde AM, Sjöström CD, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2014;16(2):159-69. of SGLT2i.

In a recent trial performed on individuals between 55-80 years, canagliflozin was associated with a 1.2% decrease in total hip BMD over 104 weeks, though not on other sites measured¹²⁷127. Bilezikian JP, Watts NB, Usiskin K, Polidori D, Fung A, Sullivan D, et al. Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with canagliflozin. J Clin Endocrinol Metab. 2016;101(1):44-51.. Despite the hypothesis-generating nature of the study, the possibility of a more significant impact on the decline in bone mass after SGLT2i was raised by these findings. It is not plausible that it could be a direct action of the drug since SLGT2 is not expressed on bone cell types¹²⁸128. Alba M, Xie J, Fung A, Desai M. The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on mineral metabolism and bone in patients with type 2 diabetes mellitus. Curr Med Res Opin. 2016;32(8):1375-85.. It is possible that the decrease in BMD is attributable to weight loss. On a post hoc analysis, 40% of BMD decline could be attributed to weight loss¹²⁷127. Bilezikian JP, Watts NB, Usiskin K, Polidori D, Fung A, Sullivan D, et al. Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with canagliflozin. J Clin Endocrinol Metab. 2016;101(1):44-51.. Similar results were observed in other weight loss situations¹²⁹129. Palermo A, D’Onofrio L, Eastell R, Schwartz AV, Pozzilli P, Napoli N. Oral anti-diabetic drugs and fracture risk, cut to the bone: safe or dangerous? A narrative review. Osteoporos Int. 2015;26(8):2073-89..

In the animal model, prolonged treatment with canagliflozin was associated with trabecular bone deterioration¹²⁵125. Thrailkill KM, Clay Bunn R, Nyman JS, Rettiganti MR, Cockrell GE, Wahl EC, et al. SGLT2 inhibitor therapy improves blood glucose but does not prevent diabetic bone disease in diabetic DBA/2J male mice. Bone 2016;82:101-7.. However, in subjects with T2DM treated for a long time, improved glycemic control and insulin resistance attenuation can compensate an initial loss in bone calcification. In fact, oral hypoglycemic drugs are generally safe on clinical trials¹²⁹129. Palermo A, D’Onofrio L, Eastell R, Schwartz AV, Pozzilli P, Napoli N. Oral anti-diabetic drugs and fracture risk, cut to the bone: safe or dangerous? A narrative review. Osteoporos Int. 2015;26(8):2073-89.. Few clinical trials have assessed bone health and the majority has reported fracture as an adverse event, posing a limitation to accurate analysis. Thus, a clearer picture of the mechanisms and clinical implications of the interaction between the inhibition of SGLT2 receptors and bone metabolism is still pending.

Another aspect to be considered in this scenario is diabetic osteopathy leading to weakness from BMD-independent structural changes in the bone¹³⁰130. Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes: a meta-analysis. Osteoporos Int. 2007;18(4):427-44.. Thus, the hard endpoint to be considered during clinical trials or in real life situations must be the incidence of fractures. In patients ≥65 years, the incidence of fractures was higher on the placebo branch than on dapagliflozin (2.7% vs. 0.4%, respectively)²⁴24. Leiter LA, Cefalu WT, Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ. Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc. 2014;62(7):1252-62.. In a pooled analysis of canagliflozin trials, the incidence of fractures was similar in both canagliflozin and the placebo, 2.7% vs. 1.9 (HR 1.32 [1.00–1.74]), respectively. However, in a subpopulation of high cardiovascular risk patients, canagliflozin was associated with a higher incidence of fracture (4% vs. 2.6%), possibly due to increased incidence of falls, as volume-related AE were more frequent on canagliflozin than on placebo (HR 1.76 (1.27–2.44))¹³¹131. Watts NB, Bilezikian JP, Usiskin K, Edwards R, Desai M, Law G, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2016;101(1):157-66.. Possibly endorsing fall-related fractures, this incidence was higher early on the beginning of treatment, and the fracture sites were the fists and feet. A sensitivity analysis including only osteoporotic fractures showed a similar risk increase of with canagliflozin¹³¹131. Watts NB, Bilezikian JP, Usiskin K, Edwards R, Desai M, Law G, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2016;101(1):157-66.. It was also observed on the SGLT2i group a tendency (RR 1.30 (1.00-1.68)) to increase the risk of stroke, and this could be related to the risk of falls, especially for the elderly¹³²132. Wu JH, Foote C, Blomster J, Toyama T, Perkovic V, Sundström J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2016;4(5):411-9.. Therefore, it is possible that fractures related to SGLT2i therapy are associated with volume depletion.

In individuals with increased susceptibility to fractures due to osteoporotic fragility such as CKD patients, there is no clear evidence of an adverse effect of SGLT2i therapy. The incidence of fractures on CKD patients was indeed lower on canagliflozin 300 mg (1.1%) than on the placebo (2.2%) over 104 weeks²⁶26. Yale JF, Bakris G, Cariou B, Nieto J, David-Neto E, Yue D, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab. 2014;16(10):1016-27.. Patients on empagliflozin had a reduced number of fractures compared to those on the placebo with progressive renal failure from stage 2 to 3 CKD²⁰20. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2(5):369-84.. Although one study observed higher rates of fractures with dapagliflozin (7.7%), all reported events were related to trauma, and only 2 were considered severe adverse events²³23. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85(4):962-71..

In conclusion, although the available data are insufficient to confirm or exclude a specific deleterious effect of these drugs on bone metabolism, falls due to hypovolemia were reported and the risk of falling should be considered in therapy indication with SGLT2 or SGLT2 / SGLT1 in elderly individuals.

Effect on mortality

Recently, the EMPA-REG Outcome trial showed a decrease in all-cause and cardiovascular mortality after the short-term use of SGLT2i in high-risk diabetic individuals¹⁸18. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28.. Although SGLT2i could have a positive influence on cardiovascular risk factors (i.e., HbA1c, systolic BP, weight excess), the role of SGLT2i on survival improvement via atherosclerotic risk is unlikely. In this trial, for each non-fatal myocardial infarction prevented with empagliflozin three cardiovascular deaths were spared. This number speaks for itself against the attenuation of atherosclerosis as the primary mechanism of benefit. In fact, in statin trials, for each nonfatal myocardial infarction prevented 0.5 cardiovascular deaths are spared¹³³133. Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371(9607):117-25.. Moreover, the early opening of the survival curves in about one month is unlikely a consequence of complex, long-lasting phenotypic changes such as stabilization of atherosclerotic plaques.

Potentially, a change in the heart-kidney crosstalk would favor the SGLT2i effect on cardiovascular mortality. Several mediators for this crosstalk have been reported, many with apparent impact on survival. Fibroblast growth factor 23 (FGF23)¹³⁴134. Brandenburg VM, Kleber ME, Vervloet MG, Tomaschitz A, Pilz S, Stojakovic T, et al. Fibroblast growth factor 23 (FGF23) and mortality: the Ludwigshafen Risk and Cardiovascular Health Study. Atherosclerosis. 2014;237(1):53-9., renalase¹³⁵135. Yin J, Lu Z, Wang F, Jiang Z, Lu L, Miao N, et al. Renalase attenuates hypertension, renal injury and cardiac remodelling in rats with subtotal nephrectomy. J Cell Mol Med. 2016;20(6):1106-17., asymmetric dimethylarginine (ADMA), erythropoietin, trimethylamine-N-Oxide (TMAO) and PTH are among the most studied players. As noted above, with aging there is a progressive decline in GFR generating an imbalance in the heart-kidney crosstalk in favor of increased cardiovascular risk. In fact, in the EMPA-REG trial¹⁸18. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28., there was a significant interaction between age and cardiovascular benefit provided by SGLT2 inhibition, which was higher among those with 65 years or older.

Looking from a different perspective, as a co-transporter of sodium and glucose, its inhibition can hypothetically reduce the sodium influx into cardiomyocytes reducing the propensity for life-threatening ventricular arrhythmias¹³⁶136. Anzawa R, Bernard M, Tamareille S, Baetz D, Confort-Gouny S, Gascard JP, et al. Intracellular sodium increase and susceptibility to ischaemia in hearts from type 2 diabetic db/db mice. Diabetologia. 2006;49(3):598-606.. Consistent with this finding, the risk of sudden death was about 30% lower in those treated with SGLT2i¹⁸18. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28.. Both aging¹³⁷137. Tung P, Albert CM. Causes and prevention of sudden cardiac death in the elderly. Nat Rev Cardiol. 2013;10(3):135-42. and T2DM¹³⁸138. El-Menyar AA. Dysrhythmia and electrocardiographic changes in diabetes mellitus: pathophysiology and impact on the incidence of sudden cardiac death. J Cardiovasc Med. 2006;7(8):580-5. increase the incidence of sudden cardiac death⁸8. Gong Z, Muzumdar RH. Pancreatic function, type 2 diabetes, and metabolism in aging. Int J Endocrinol. 2012;2012:320482.; the severity of coronary artery disease and hypoglycemia are mediators of the risk in both cases. In disagreement with this assumption, although the evidence is still scarce, studies in humans have indicated that SGLT1 is the predominant receptor in the myocardium and small intestine, while SGLT2 is predominant in the kidney¹³⁹139. Banerjee SK, McGaffin KR, Pastor-Soler NM, Ahmad F. SGLT1 is a novel cardiac glucose transporter that is perturbed in disease states. Cardiovasc Res 2009;84(1):111-8.. We still do not know if the proportion of SGLT1 and SGLT2 in the myocardium changes during the life course or under different stimuli. So far, aside from canagliflozin, other SGLT inhibitors have had minimal effect on the SGLT1¹⁴⁰140. Scheen AJ. Pharmacokinetic and pharmacodynamic profile of empagliflozin, a sodium glucose co-transporter 2 inhibitor. Clin Pharmacokinet. 2014;53(3):213-25..

In subjects with T2D¹⁴¹141. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care. 2016;39(7):1115-22. or heart failures (HF)¹⁴²142. Kupari M, Lommi J, Ventila M, Karjalainen U. Breath acetone in congestive heart failure. Am J Cardiol. 1995;76(14):1076-8., the liver converts abundant plasma FFA into ketone bodies (KB) such as acetoacetate and 3-hydroxybutyrate. This KB excess in plasma is highly absorbed in the myocardium and in a dose-dependent manner is converted to acetyl-CoA¹⁴³143. Ashrafian H, Frenneaux MP, Opie LH. Metabolic mechanisms in heart failure. Circulation. 2007;116(4):434-48.. In rodents, KB is used as the primary source of energy by cardiac cells¹⁴⁴144. Jeffrey FM, Diczku V, Sherry AD, Malloy CR. Substrate selection in the isolated working rat heart: effects of reperfusion, afterload, and concentration. Basic Res Cardiol. 1995;90(5):388-96., and such use might hypothetically occur in individuals with T2D and heart failure, favoring the improvement in energy reserves¹⁴¹141. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care. 2016;39(7):1115-22.. Nevertheless, it is also possible that overfeeding myocardium with KB may induce insulin resistance and block the citrate cycle, thus reducing the power supply¹⁴³143. Ashrafian H, Frenneaux MP, Opie LH. Metabolic mechanisms in heart failure. Circulation. 2007;116(4):434-48.. This controversy has been highlighted recently with the confrontation of two SGLT2i effects: increasing plasma KB and decreasing cardiovascular mortality in individuals with T2D and HF. In healthy elderly individuals, the KB output is similar to that in younger adults¹⁴⁵145. Freemantle E, Vandal M, Tremblay Mercier J, Plourde M, Poirier J, Cunnane SC. Metabolic response to a ketogenic breakfast in the healthy elderly. J Nutr Health Aging. 2009;13(4):293-8.. However, as commented above, among diabetic elderlies, the KB production tends to be increased due to insulin deficiency and malnutrition¹⁰⁹109. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 2015;38(9):1638-42.. Hence, if this mechanism is in fact involved in the SGLT2i effects, elderly diabetic patients will be among the most improved populations.

Effect on stroke

A neutral or even beneficial effect has been reported with hypoglycemic therapies in stroke risk¹⁴⁶146. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374(14):1321-31.. The possibility of benefits concerning stroke risk becomes even more likely if we consider the reduction of systolic blood pressure during treatment with SGLT2i¹⁴⁷147. Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA 2015;313(6):603-15.. However, despite the clear cardiovascular benefit SGLT2i, some concern was raised with a tendency to increase the incidence of stroke. In the EMPA-REG Outcome trial, the incidence of stroke tended to increase by 24% (95% CI 0.92, 1.67; p = 0.16)¹⁸18. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28.. Considering the EMPA-REG trials outcome together with phase 2 or 3 studies, the risk of stroke increased by 30% (95% CI: 1.00, 1.68; p=0.049)¹³²132. Wu JH, Foote C, Blomster J, Toyama T, Perkovic V, Sundström J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2016;4(5):411-9.. An overall set of mechanisms that may be behind this potential adverse effect is unclear. However, orthostatic hypotension¹⁴⁸148. Ricci F, Fedorowski A, Radico F, Romanello M, Tatasciore A, Di Nicola M, et al. Cardiovascular morbidity and mortality related to orthostatic hypotension: a meta-analysis of prospective observational studies. Eur Heart J. 2015;36(25):1609-17., hemoconcentration¹⁴⁹149. Laragh JH, Sealey JE. Abnormal sodium metabolism and plasma renin activity (renal renin secretion) and the vasoconstriction volume hypothesis: implications for pathogenesis and treatment of hypertension and its vascular consequences (heart attack, stroke). Clin Chem. 1991;37(10 pt 2):1820-7.and increased activity of renin-angiotensin-aldosterone system (RAAS)¹⁵⁰150. Mollsten A, Stegmayr B, Wiklund PG. Genetic polymorphisms in the renin-angiotensin system confer increased risk of stroke independently of blood pressure: a nested case-control study. J Hypertens. 2008;26(7):1367-72.are among consequences of SGLT2i therapy that would favor stroke incidence.

In the elderly, this potential adverse effect may have greater significance for the natural propensity to hemoconcentration and orthostatic hypotension. To date, however, the relationship between the SGLT2i and the risk of stroke remains hypothetical as the number of events is small and only one prospective outcome-driven trial analysis is published. Two other studies are underway with dapagliflozin and canagliflozin, and its completion will help to discern more clearly this finding.

CONCLUSION

Few studies performed pre-specified analysis on the elderly. Therefore, to accurately assess its effects in older individuals, prospective studies are necessary. SGLT2i therapy is associated with glycemic effects on older individuals that are similar to younger ones. Similar effects on BP and BW have also been observed. In fact, as intentional body weight is not associated with higher AE, it is plausible that drug-induced decrease on BW would have no increase in mortality. One limitation of these new agents is the higher prevalence of CKD on older individuals that could, in turn, reduce effectiveness. Other safety concerns are being outlined recently. DKA could influence SGLT2i prescription on insulin users but is rare on other individuals. Few cases of urosepsis were described on the largest SGLT2i trial to this date, and it is possible that this low number will be maintained in the long-term. The forthcoming studies regarding the cardiovascular safety of these new agents may establish this class as a top second- or first-line option in diabetes therapy.

REFERENCES

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