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Review

The Safety and Efficacy of Sodium-Glucose Cotransporter-2 Inhibitors for Patients with Sarcopenia or Frailty: Double Edged Sword?

by
Ayami Naito
1,
Yuji Nagatomo
1,*,
Akane Kawai
1,
Midori Yukino-Iwashita
1,
Ryota Nakazawa
1,
Akira Taruoka
1,
Asako Takefuji
1,
Risako Yasuda
2,
Takumi Toya
1,
Yukinori Ikegami
1,
Nobuyuki Masaki
2,
Yasuo Ido
1 and
Takeshi Adachi
1
1
Department of Cardiology, National Defense Medical College, Tokorozawa 359-8513, Japan
2
Department of Intensive Care, National Defense Medical College, Tokorozawa 359-8513, Japan
*
Author to whom correspondence should be addressed.
J. Pers. Med. 2024, 14(2), 141; https://doi.org/10.3390/jpm14020141
Submission received: 29 December 2023 / Revised: 19 January 2024 / Accepted: 24 January 2024 / Published: 26 January 2024
(This article belongs to the Special Issue Heart Failure: From Subtype to Personalized Medicine)
Browse Figure
Review Reports Versions Notes

Abstract

:
Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) show cardiovascular protective effects, regardless of the patient’s history of diabetes mellitus (DM). SGLT2is suppressed cardiovascular adverse events in patients with type 2 DM, and furthermore, SGLT-2is reduced the risk of worsening heart failure (HF) events or cardiovascular death in patients with HF. Along with these research findings, SGLT-2is are recommended for patients with HF in the latest guidelines. Despite these benefits, the concern surrounding the increasing risk of body weight loss and other adverse events has not yet been resolved, especially for patients with sarcopenia or frailty. The DAPA-HF and DELIVER trials consistently showed the efficacy and safety of SGLT-2i for HF patients with frailty. However, the Rockwood frailty index that derived from a cumulative deficit model was employed for frailty assessment in these trials, which might not be suitable for the evaluation of physical frailty or sarcopenia alone. There is no fixed consensus on which evaluation tool to use or its cutoff value for the diagnosis and assessment of frailty in HF patients, or which patients can receive SGLT-2i safely. In this review, we summarize the methodology of frailty assessment and discuss the efficacy and safety of SGLT-2i for HF patients with sarcopenia or frailty.

1. Introduction

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are drugs that increase urinary sodium and glucose excretion by inhibiting the effect of SGLT-2 in the proximal renal tubules [1]. Accumulating evidence suggests that SGLT-2is show not only blood-glucose-lowering effects but also cardiovascular protective effects. The various mechanisms mediating its beneficial effect [2] include the diuretic effect by sodium discharge and osmotic diuresis [3,4], glomerular and tubular protection [5], increased erythropoiesis [3,6,7], sympathetic nervous system inhibition [8,9], improvement of myocardial energy metabolism [10,11], suppression of chronic inflammation [12] or oxidative stress [11], and weight reduction [13]. In large-scale randomized control trials such as EMPA-REG OUTCOME, CANVAS program, and DECLARE–TIMI 58, SGLT-2is, including empagliflozin, canagliflozin and dapagliflozin suppressed the composite outcome of cardiovascular death, nonfatal myocardial infarction, and stroke for the patients with type 2 diabetes mellitus (DM) and high risk of cardiovascular events (Table 1) [14,15,16]. As a result, the exploration of SGLT-2is’ beneficial effect was extended to the heart failure (HF) population. In the EMPEROR-Reduced and DAPA-HF trial [17,18], the risk of worsening HF events (hospitalization or urgent visit resulting in intravenous therapy for HF) or cardiovascular death were suppressed in the patients with heart failure and reduced ejection fraction (HFrEF) who received SGLT-2is compared to those who received a placebo. This beneficial effect of SGLT-2is on HFrEF patients has been observed regardless of the history of DM [18,19]. Furthermore, SGLT-2is successfully improved the clinical outcome even in patients with HF and preserved EF (HFpEF), although there had been no agents that demonstrated the prognostic benefit in this population until then [20,21]. In addition, SGLT-2is consistently provide evidence of HF event reduction in these studies, although the mortality benefit has been controversial [17,18,19,20,21]. Further, the treatment effect of SGLT-2is was not significantly influenced by EF [22]. Along with these research findings, SGLT-2is are recommended for patients with HF irrespective of EF in the AHA/ACC/HFSA guidelines [23] and ESC guidelines [24]. Despite these benefits, the concern surrounding the increasing risk of body weight loss, urogenital infection, hypoglycemia, volume depletion, bone fracture, and diabetic ketoacidosis has not yet been resolved [25]. Further, there have been significant concerns surrounding these adverse effects for elderly populations because of the increased susceptibility to side effects, impaired awareness of adverse events, poorer adherence and higher risk of falling. Among these adverse effects, weight loss and bone fracture might be derived from renal glucose excretion and energy loss by inhibiting SGLT-2. Thus, the safety of SGLT-2is in frail patients is still unclear.
The presence of frailty [27,28,29,30,31,32] or sarcopenia [33,34,35,36,37] is known as a prognostic aggravating factor in HF, leading to a higher risk of hospitalization and mortality. According to the remarkably accelerated aging of HF populations [38], the prevalence of frailty or sarcopenia has been dramatically increasing and is further expected to keep rising in the future [39]. Aging is the most significant contributing factor to frailty and these are deeply related to each other but not necessarily parallel. In addition, although there are scales widely used to assess frailty (Table 2), no scale has been established specifically for HF patients.
According to the American Diabetes Association Guideline recommendation [46], management of elderly DM patients requires individualized treatment targets that take account of their comorbidities because of the risk of hypoglycemia or ketosis resulting from the disruption of diet and medication. With the aforementioned risks, some trials indicate that SGLT-2is administration for elderly patients has similar or greater benefits for cardiovascular or renal function than younger patients [46]. Nevertheless, it is necessary to consider the characteristics of each racial group for worldwide consensus, especially Asian populations that have differences in body composition and cardiometabolic risk from Caucasian populations [47].
Hence, in this review, we summarize the methodology of frailty assessment and discuss the efficacy and safety of SGLT-2is for HF patients with frailty.

2. Definition and Etiology of Sarcopenia or Frailty

Sarcopenia and frailty are sometimes associated with a similar clinical picture but these two terms differ substantially in terms of their concept. Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability, poor quality of life and death [48,49]. According to the conceptual definition of sarcopenia by the European Working Group on Sarcopenia in Older People (EWGSOP), diagnosis of sarcopenia is made by the presence of both low muscle mass and low muscle function such as muscle strength or physical performance [50,51]. Further, it is defined as severe sarcopenia when all of these three components (low muscle mass, low strength and low physical performance) are present [50,51]. By the current recommendation, the assessment tool for sarcopenia is composed of muscle mass measured by Appendicular Skeletal Muscle Mass (ASM), muscle strength measured by grip or chair stand, and physical performance measured by gait speed, Short Physical Performance Battery (SPPB) [40], or Timed-Up and Go test (TUG) (Table 2) [41,51]. This recommendation focuses on European populations, while different diagnostic criteria have been proposed for Asian populations by the Asian Working Group for Sarcopenia (AWGS) [52], since body composition substantially differs between these ethnicities [47].
On the other hand, frailty is classically defined as the presence of three or more of the following criteria: unintentional weight loss (more than 4.5 kg in 1 year), slow gait speed, weak grip strength and self-reported physical exhaustion or measured low physical activity [45]. However, the concept of frailty has been broadened and is now defined as the deterioration of multidimensional and multisystem conditions characterized by decreased functional reserves and increased vulnerability to stress and acute adverse events [53]. Thus, it is a broad concept in contrast to sarcopenia, which focuses on muscle mass or weakness. Frailty includes a medical domain, a physical domain, a cognitive/depressive status domain, and a social domain [54]. Although there are various indices and scores proposed to quantify frailty which is the complex multisystem condition, there are two basic concepts of frailty, phenotype model and the cumulative deficit model [55]. The phenotype model is a measure of the presence of symptoms or physical functions such as activity of daily living (ADL), which includes the Barthel index [43], clinical frailty scale [44], and Fried frailty phenotype defined by weight loss, weakness of hand grip, exhaustion, slowness, and low activity (Table 2) [45]. The cumulative deficit model, on the other hand, is a measure of the accumulation of symptoms, function, comorbidities, clinical laboratory abnormalities, and questionnaire of quality of life, which is represented by the Rockwood frailty index using 93 variables (Table 2) [42]. Although various scales have been used in recent HF studies, the following scales are commonly used: Fried frailty phenotype, Rockwood frailty index, Barthel index, and clinical frailty scale [56]. The Rockwood frailty index has recently been adopted as an evaluation scale for frailty in DAPA-HF [57] and DELIVER trials [58], both of which showed the efficacy of SGLT-2is for HF patients with frailty, and these attracted much attention. However, there is no fixed consensus on the cutoff value for these frailty diagnostic scales.
It should not be forgotten that there is regional variability in the prevalence of frailty. A recent meta-analysis reported that the prevalence of frailty in an Asian population aged over 60 years was 20.5% [59], which was roughly equal to those reported in Latin American and Caribbean populations [60], but higher than in European, North American, and Oceanian populations [61,62,63]. However, due to the lack of a uniform evaluation scale, we need to be cautious to interpret these data of regional differences, suggesting the difficulty of making an unbiased regional comparison and development of a global countermeasure against this issue.

3. Heart Failure and Frailty/Sarcopenia

Body weight loss in HF patients was called “cardiac cachexia” especially with a change in body composition [64]. Cachexia is a concept that includes skeletal muscle wasting, anemia, anorexia, and altered immune function, which results in fatigue, impaired quality of life, and an aggregate prognosis [65], and it can occur in patients with a variety of diseases such as HF, chronic obstructive pulmonary disease, renal failure, and cancer. It is different from sarcopenia in terms of its concept, which is not limited to muscle weakness [64]. In HF patients, dyspnea, fatigue, and anorexia can lead to a low nutritional state and reduction in physical activity, which leads to sarcopenia, and further weakening of muscle or physical function. This vicious circle is called the “frailty cycle” [66] (Figure 1).
It is well known that sarcopenia and frailty are strongly associated with a poor prognosis in HF patients. HF patients have a higher prevalence of sarcopenia (by ~20%) compared to healthy subjects of the same age and it is associated with worse clinical outcomes independently [67]. Frailty is prevalent in HF patients, representing 40–80% of overall HF, 30–60% of HF with a reduced ejection fraction (HFrEF), and up to 90% of HF with a preserved ejection fraction (HFpEF) [68,69,70,71,72,73]. In the FRAIL-HF study, HF patients with frailty showed a higher prevalence of depression, worse score of health literacy, few HF medications, and higher risk of mortality and rehospitalization [74]. A recent meta-analysis reported that the presence of frailty in chronic HF is associated with an increased risk of death and hospitalization by approximately 1.5-fold [75]. The reasons why frailty is associated with a worse prognosis are related to HF aggravation by comorbidities such as anemia and renal dysfunction, muscle weakness leading to increased cardiac load [76], difficulty in initiating medications due to organ dysfunction or fall risk by drug-induced hypotension or dehydration, and lower adherence to medication because of cognitive or social frailty.
In addition, in the late 20th century, a subset of older adults was identified as having both obesity and sarcopenia, soon thereafter termed as “sarcopenic obesity”. Sarcopenic obesity is defined by excess adiposity with a loss of muscle mass and/or function [77]. Aging is a systemic process affecting all organ systems and associated with significant alterations in body composition. Typically, fat mass increases with age [78], whereas muscle mass and strength start to decline progressively [79]. While aging is associated with a systemic pro-inflammatory state, oxidative stress, and altered endocrine function leading to the loss of muscles [80], obesity has multiple adverse consequences for skeletal muscle, including inflammation, oxidative stress, and insulin resistance. Along with visceral fat accumulation, loss of skeletal muscle, which is the largest insulin-responsive target tissue, produces insulin resistance. Adding to this, increases in visceral fat may lead to a higher secretion of pro-inflammatory adipokines that further promote insulin resistance as well as potentially direct catabolic effects on muscles [81,82]. The reports on the epidemiology of sarcopenic obesity are limited, but in a 14-year prospective study of the elderly population in the United States, its prevalence was 19–34% in women and 13–27% in men [83]. In the HF population, the prevalence of sarcopenic obesity was reported to be 4.0–18.5% [33,84]. Coexistence of sarcopenic obesity is a predictor of disability and mortality [85,86], and associated with a reduction in cardiorespiratory fitness independent of adiposity [87]. However, the data on its pathophysiology and prognostic impact compared to lean sarcopenia are needed.

4. Safety and Efficacy of SGLT-2is for Sarcopenic or Frail Patients

The hypothetical mechanisms mediating the efficacy of SGLT-2is for HF patients are the following: cardio–renal coupling, ketone production, diuretic effect, hematopoietic effect, direct prevention of myocardial remodeling, and suppression of neurohumoral factor [2], and it is considered that each of them have interrelated effects. Since many studies have recently reported the efficacy of SGLT-2is for HF regardless of the history of DM [18,19], their efficacy seems to be not only related to the blood-glucose-lowering effect. Further, the beneficial effect was observed regardless of left ventricular EF [14,19,20,21,88,89,90,91]. Some randomized controlled studies have carried out sub-analysis that focused on frailty (Table 3). In the DELIVER trial, the presence or severity of frailty was assessed for 6258 study patients by their frailty index (FI) at baseline and they were divided into four classes by their FI [92]. The beneficial effect of dapagliflozin on clinical outcome was observed consistently across the FI values, greater improvement in quality of life with treatment occurred in patients with a higher level of frailty, and there were no differences in the proportions of patients who experienced adverse events or discontinued treatment between dapagliflozin and the placebo [58]. Although this study concluded that SGLT-2is may demonstrate efficacy and safety for HF patients even with frailty, there are several limitations in this study. The FI is derived from a cumulative deficit model composed of symptoms, comorbidities, disabilities, tests of muscle weakness, and laboratory data including indices of malnutrition, kidney failure, anemia, and thyroid hormone. In other words, the FI is a comprehensive vulnerability scale and might not be suitable for the evaluation of physical frailty or sarcopenia alone. Similarly, we can point out this weakness of the FI as an assessment scale of frailty in a sub-analysis of DAPA-HF trial, in which the treatment effect by dapagliflozin on the reduction in primary endpoint reduction was greater in patients with a higher degree of frailty defined by the FI [58]. In the DELIVER trial, despite the absence of exclusion criteria related to a low BMI, the average BMI was as high as 32.1 in the “most frail” group. As mentioned in the previous section, there are substantial differences in body composition or mass between Caucasian and Asian populations [47]. While many Caucasian HF patients are deemed to have sarcopenic obesity, most Asian patients show a low BMI. In this regard, patients with widely varying body compositions can be uniformly categorized as “frailty”. FI is a cumulative deficit model for frailty and does not necessarily evaluate physical function or phenotype. Thus, it needs careful consideration when we determine the efficacy and safety of SGLT-2is for the population with “frailty”. In other study, following the sub-analysis of the EMPEROR-Reduced trial, it can be observed that the efficacy of empagliflozin is consistent regardless of BMI, even at <20 kg/m2 [93]. However, the clinical evidence of SGLT-2is for HF patients with sarcopenia or physical frailty is limited and needs to be explored in the near future.
A recent study showed SGLT-2is are more efficacious for a primary prevention compared to DPP-4 inhibitors in type 2 DM patients with frailty assessed by FI [96]. This study population included type 2 DM patients over 65 years and patients enrolled in Medicare who initiated treatment with SGLT-2is or DPP-4 inhibitors. SGLT-2is were associated with improved cardiovascular outcomes and all-cause mortality, with the largest absolute benefits among patients with frailty. We should take care in interpreting these data because the FI was used to carry out the frailty assessment and the large number of obese patients included was the same as previous HF studies. Further, genital infections were observed among patients who received SGLT-2i and caused greater harm among more frail patients. Infections can worsen HF and ketoacidosis and are sometimes fatal. Therefore, patients should still be carefully selected for the initiation of SGLT-2is treatment.
SGLT2is have been shown to significantly reduce body weight and fat mass and this effect may be beneficial to improve glycemic control and HF [98]. On the other hand, skeletal muscle mass has also been reported to be significantly reduced [98], although a recent report showed that empagliflozin induced a significant reduction in body weight, body fat mass and water volume, but the skeletal muscle mass did not change significantly in type 2 DM patients aged ≥ 65 years [97]. Thus, significant concerns have been raised about SGLT-2is’ effect on aggravating frailty or sarcopenia. This poses the following question: which patients can safely receive SGLT-2is? Even in DM patients, there is still no unified tool for the assessment of frailty and the guideline recommendations do not address frail older patients [99]. Therefore, it is necessary to consider the metabolic phenotypes of heterogeneous frail patients with DM in order to evaluate the influence of SGLT-2is on these patients. Compared to type Ⅰ muscle fibers, type II fiber is associated with an increase in insulin resistance via lipid storage in muscle tissue [100]. Aging is related to an increase in insulin resistance followed by a loss of muscle fiber; however, frailty is associated with accelerated muscle loss compared with age alone with a prominent reduction in type II (rather than type I) fibers, which may result in an overall reduction in insulin resistance. Thus, it is important to assess the metabolism spectrum by considering the loss of muscle fibers and body adipose/muscle tissue ratio and not only the BMI. Classification into two phenotypes has been proposed: the anorexic malnourished (A..22..2223M) frail phenotype with significant muscle loss and the sarcopenic obese (SO) frail phenotype with increased visceral fat [99]. SGLT-2is could be effective for SO phenotype patients, but their use for AM phenotype patients may exacerbate sarcopenia. Luseogliflozin and canagliflozin have shown minimal reductions in skeletal muscle mass in not-severely overweight patients with type 2 DM [101,102,103]. In opposition, dapagliflozin did not show this effect [104] and another study reported that SGLT-2is improve grip strength [105]. Administration of SGLT-2is for AM phenotype patients may lead to an increase in calorie intake and control of weight loss; however, this effect is dependent on the patient’s insulin secretory capacity and it is necessary to identify target patients.

5. Future Direction

As discussed above, the most critical issue is that there are few studies validating the efficacy and safety of SGLT-2is for HF patients with physical frailty (not evaluated by the cumulative deficit model) and/or sarcopenia and there have not yet been unified assessment scales for sarcopenia/frailty for HF. In near future further exploration such as basic research (i.e., experiment using cachexia animal model) is necessary to for further understanding of the pathophysiology of sarcopenia and/or physical frailty and the safety and efficacy of SGLT-2is for patients affected with these conditions. Further, we need to develop assessment tool of sarcopenia and/or physical frailty for HF patients which is useful and readily available in various situations in clinical practice, and reassess the efficacy and safety of SGLT-2is by those indicators in specific populations focused on body size, age, gender, and ethnic differences.

6. Conclusions

The efficacy of SGLT-2is for HF patients has been known widely. Beyond the poor definition of frailty of elderly patients suffering from HF, there seems to be an advantage in taking SGLT-2i. However, its long-term safety has not been sufficiently explored and still remains unclear, especially in those with sarcopenia or physical frailty. According to remarkably accelerated aging and increasing prevalence of frailty or sarcopenia in HF population, it is crucial to construct a unified evaluation scale and conduct large-scale clinical trials focusing on the safety and efficacy of SGLT-2is for HF patients with sarcopenia/physical frailty.

Author Contributions

Conceptualization, Y.N., A.K., M.Y.-I., Y.I. (Yukinori Ikegami), N.M., Y.I. (Yasuo Ido) and T.A.; validation, A.T. (Asako Takefuji) and T.T.; writing—original draft preparation, A.N.; writing—review and editing, Y.N., R.N., A.T. (Akira Taruoka), R.Y., Y.I. (Yukinori Ikegami), N.M., Y.I. (Yasuo Ido) and T.A.; visualization, Y.N., A.K., M.Y.-I., R.N., A.T. (Akira Taruoka), A.T. (Asako Takefuji) R.Y. and T.T.; supervision, Y.I. (Yasuo Ido) and T.A.; project administration, Y.N.; funding acquisition, Y.N. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by a Grant-in-Aid for Scientific Research (C) provided by Japan and supported by the Society for the Promotion of Science (JSPS) (#16K09469, 20K08482 (Y.N.)).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Gallo, L.A.; Wright, E.M.; Vallon, V. Probing SGLT2 as a therapeutic target for diabetes: Basic physiology and consequences. Diabetes Vasc. Dis. Res. 2015, 12, 78–89. [Google Scholar] [CrossRef]
  2. Wojcik, C.; Warden, B.A. Mechanisms and Evidence for Heart Failure Benefits from SGLT2 Inhibitors. Curr. Cardiol. Rep. 2019, 21, 130. [Google Scholar] [CrossRef]
  3. Zelniker, T.A.; Braunwald, E. Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review. J. Am. Coll. Cardiol. 2020, 75, 422–434. [Google Scholar] [CrossRef]
  4. Hallow, K.M.; Helmlinger, G.; Greasley, P.J.; McMurray, J.J.V.; Boulton, D.W. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes. Metab. 2018, 20, 479–487. [Google Scholar] [CrossRef] [PubMed]
  5. Dekkers, C.C.J.; Petrykiv, S.; Laverman, G.D.; Cherney, D.Z.; Gansevoort, R.T.; Heerspink, H.J.L. Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers. Diabetes Obes. Metab. 2018, 20, 1988–1993. [Google Scholar] [CrossRef] [PubMed]
  6. Verma, S.; McMurray, J.J.V. SGLT2 inhibitors and mechanisms of cardiovascular benefit: A state-of-the-art review. Diabetologia 2018, 61, 2108–2117. [Google Scholar] [CrossRef] [PubMed]
  7. Maruyama, T.; Takashima, H.; Oguma, H.; Nakamura, Y.; Ohno, M.; Utsunomiya, K.; Furukawa, T.; Tei, R.; Abe, M. Canagliflozin Improves Erythropoiesis in Diabetes Patients with Anemia of Chronic Kidney Disease. Diabetes Technol. Ther. 2019, 21, 713–720. [Google Scholar] [CrossRef] [PubMed]
  8. Matthews, V.B.; Elliot, R.H.; Rudnicka, C.; Hricova, J.; Herat, L.; Schlaich, M.P. Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J. Hypertens. 2017, 35, 2059–2068. [Google Scholar] [CrossRef] [PubMed]
  9. Herat, L.Y.; Magno, A.L.; Rudnicka, C.; Hricova, J.; Carnagarin, R.; Ward, N.C.; Arcambal, A.; Kiuchi, M.G.; Head, G.A.; Schlaich, M.P.; et al. SGLT2 Inhibitor-Induced Sympathoinhibition: A Novel Mechanism for Cardiorenal Protection. JACC. Basic Transl. Sci. 2020, 5, 169–179. [Google Scholar] [CrossRef]
  10. Santos-Gallego, C.G.; Requena-Ibanez, J.A.; San Antonio, R.; Ishikawa, K.; Watanabe, S.; Picatoste, B.; Flores, E.; Garcia-Ropero, A.; Sanz, J.; Hajjar, R.J.; et al. Empagliflozin Ameliorates Adverse Left Ventricular Remodeling in Nondiabetic Heart Failure by Enhancing Myocardial Energetics. J. Am. Coll. Cardiol. 2019, 73, 1931–1944. [Google Scholar] [CrossRef]
  11. Verma, S.; Rawat, S.; Ho, K.L.; Wagg, C.S.; Zhang, L.; Teoh, H.; Dyck, J.E.; Uddin, G.M.; Oudit, G.Y.; Mayoux, E.; et al. Empagliflozin Increases Cardiac Energy Production in Diabetes: Novel Translational Insights into the Heart Failure Benefits of SGLT2 Inhibitors. JACC Basic Transl. Sci. 2018, 3, 575–587. [Google Scholar] [CrossRef]
  12. Ye, Y.; Bajaj, M.; Yang, H.C.; Perez-Polo, J.R.; Birnbaum, Y. SGLT-2 Inhibition with Dapagliflozin Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Cardiomyopathy in Mice with Type 2 Diabetes. Further Augmentation of the Effects with Saxagliptin, a DPP4 Inhibitor. Cardiovasc. Drugs Ther. 2017, 31, 119–132. [Google Scholar] [CrossRef] [PubMed]
  13. Heerspink, H.J.; Perkins, B.A.; Fitchett, D.H.; Husain, M.; Cherney, D.Z. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. Circulation 2016, 134, 752–772. [Google Scholar] [CrossRef]
  14. Zinman, B.; Wanner, C.; Lachin, J.M.; Fitchett, D.; Bluhmki, E.; Hantel, S.; Mattheus, M.; Devins, T.; Johansen, O.E.; Woerle, H.J.; et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N. Engl. J. Med. 2015, 373, 2117–2128. [Google Scholar] [CrossRef]
  15. Neal, B.; Perkovic, V.; Mahaffey, K.W.; de Zeeuw, D.; Fulcher, G.; Erondu, N.; Shaw, W.; Law, G.; Desai, M.; Matthews, D.R. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N. Engl. J. Med. 2017, 377, 644–657. [Google Scholar] [CrossRef] [PubMed]
  16. Wiviott, S.D.; Raz, I.; Bonaca, M.P.; Mosenzon, O.; Kato, E.T.; Cahn, A.; Silverman, M.G.; Zelniker, T.A.; Kuder, J.F.; Murphy, S.A.; et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 2019, 380, 347–357. [Google Scholar] [CrossRef] [PubMed]
  17. McMurray, J.J.V.; Solomon, S.D.; Inzucchi, S.E.; Køber, L.; Kosiborod, M.N.; Martinez, F.A.; Ponikowski, P.; Sabatine, M.S.; Anand, I.S.; Bělohlávek, J.; et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N. Engl. J. Med. 2019, 381, 1995–2008. [Google Scholar] [CrossRef]
  18. Packer, M.; Anker, S.D.; Butler, J.; Filippatos, G.; Pocock, S.J.; Carson, P.; Januzzi, J.; Verma, S.; Tsutsui, H.; Brueckmann, M.; et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N. Engl. J. Med. 2020, 383, 1413–1424. [Google Scholar] [CrossRef]
  19. Bhatt, D.L.; Szarek, M.; Steg, P.G.; Cannon, C.P.; Leiter, L.A.; McGuire, D.K.; Lewis, J.B.; Riddle, M.C.; Voors, A.A.; Metra, M.; et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N. Engl. J. Med. 2021, 384, 117–128. [Google Scholar] [CrossRef]
  20. Solomon, S.D.; McMurray, J.J.V.; Claggett, B.; de Boer, R.A.; DeMets, D.; Hernandez, A.F.; Inzucchi, S.E.; Kosiborod, M.N.; Lam, C.S.P.; Martinez, F.; et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N. Engl. J. Med. 2022, 387, 1089–1098. [Google Scholar] [CrossRef]
  21. Anker, S.D.; Butler, J.; Filippatos, G.; Ferreira, J.P.; Bocchi, E.; Böhm, M.; Brunner-La Rocca, H.P.; Choi, D.J.; Chopra, V.; Chuquiure-Valenzuela, E.; et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N. Engl. J. Med. 2021, 385, 1451–1461. [Google Scholar] [CrossRef]
  22. Jhund, P.S.; Kondo, T.; Butt, J.H.; Docherty, K.F.; Claggett, B.L.; Desai, A.S.; Vaduganathan, M.; Gasparyan, S.B.; Bengtsson, O.; Lindholm, D.; et al. Dapagliflozin across the range of ejection fraction in patients with heart failure: A patient-level, pooled meta-analysis of DAPA-HF and DELIVER. Nat. Med. 2022, 28, 1956–1964. [Google Scholar] [CrossRef]
  23. Heidenreich, P.A.; Bozkurt, B.; Aguilar, D.; Allen, L.A.; Byun, J.J.; Colvin, M.M.; Deswal, A.; Drazner, M.H.; Dunlay, S.M.; Evers, L.R.; et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 2022, 79, 1757–1780. [Google Scholar] [CrossRef]
  24. McDonagh, T.A.; Metra, M.; Adamo, M.; Gardner, R.S.; Baumbach, A.; Böhm, M.; Burri, H.; Butler, J.; Čelutkienė, J.; Chioncel, O.; et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. Heart J. 2023, 44, 3627–3639. [Google Scholar] [CrossRef]
  25. Evans, M.; Morgan, A.R.; Davies, S.; Beba, H.; Strain, W.D. The role of sodium-glucose co-transporter-2 inhibitors in frail older adults with or without type 2 diabetes mellitus. Age Ageing 2022, 51, afac201. [Google Scholar] [CrossRef] [PubMed]
  26. Voors, A.A.; Angermann, C.E.; Teerlink, J.R.; Collins, S.P.; Kosiborod, M.; Biegus, J.; Ferreira, J.P.; Nassif, M.E.; Psotka, M.A.; Tromp, J.; et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: A multinational randomized trial. Nat. Med. 2022, 28, 568–574. [Google Scholar] [CrossRef] [PubMed]
  27. Lupón, J.; González, B.; Santaeugenia, S.; Altimir, S.; Urrutia, A.; Más, D.; Díez, C.; Pascual, T.; Cano, L.; Valle, V. Prognostic implication of frailty and depressive symptoms in an outpatient population with heart failure. Rev. Esp. De Cardiol. 2008, 61, 835–842. [Google Scholar] [CrossRef]
  28. Forman, D.E.; Fleg, J.L.; Kitzman, D.W.; Brawner, C.A.; Swank, A.M.; McKelvie, R.S.; Clare, R.M.; Ellis, S.J.; Dunlap, M.E.; Bittner, V. 6-min walk test provides prognostic utility comparable to cardiopulmonary exercise testing in ambulatory outpatients with systolic heart failure. J. Am. Coll. Cardiol. 2012, 60, 2653–2661. [Google Scholar] [CrossRef] [PubMed]
  29. Tjam, E.Y.; Heckman, G.A.; Smith, S.; Arai, B.; Hirdes, J.; Poss, J.; McKelvie, R.S. Predicting heart failure mortality in frail seniors: Comparing the NYHA functional classification with the Resident Assessment Instrument (RAI) 2.0. Int. J. Cardiol. 2012, 155, 75–80. [Google Scholar] [CrossRef]
  30. Khan, H.; Kalogeropoulos, A.P.; Georgiopoulou, V.V.; Newman, A.B.; Harris, T.B.; Rodondi, N.; Bauer, D.C.; Kritchevsky, S.B.; Butler, J. Frailty and risk for heart failure in older adults: The health, aging, and body composition study. Am. Heart J. 2013, 166, 887–894. [Google Scholar] [CrossRef]
  31. Gastelurrutia, P.; Lupón, J.; Altimir, S.; de Antonio, M.; González, B.; Cabanes, R.; Rodríguez, M.; Urrutia, A.; Domingo, M.; Zamora, E.; et al. Fragility is a key determinant of survival in heart failure patients. Int. J. Cardiol. 2014, 175, 62–66. [Google Scholar] [CrossRef]
  32. Lo, A.X.; Donnelly, J.P.; McGwin, G., Jr.; Bittner, V.; Ahmed, A.; Brown, C.J. Impact of gait speed and instrumental activities of daily living on all-cause mortality in adults ≥65 years with heart failure. Am. J. Cardiol. 2015, 115, 797–801. [Google Scholar] [CrossRef] [PubMed]
  33. Fülster, S.; Tacke, M.; Sandek, A.; Ebner, N.; Tschöpe, C.; Doehner, W.; Anker, S.D.; von Haehling, S. Muscle wasting in patients with chronic heart failure: Results from the studies investigating co-morbidities aggravating heart failure (SICA-HF). Eur. Heart J. 2013, 34, 512–519. [Google Scholar] [CrossRef] [PubMed]
  34. Narumi, T.; Watanabe, T.; Kadowaki, S.; Takahashi, T.; Yokoyama, M.; Kinoshita, D.; Honda, Y.; Funayama, A.; Nishiyama, S.; Takahashi, H.; et al. Sarcopenia evaluated by fat-free mass index is an important prognostic factor in patients with chronic heart failure. Eur. J. Intern. Med. 2015, 26, 118–122. [Google Scholar] [CrossRef]
  35. Onoue, Y.; Izumiya, Y.; Hanatani, S.; Tanaka, T.; Yamamura, S.; Kimura, Y.; Araki, S.; Sakamoto, K.; Tsujita, K.; Yamamoto, E.; et al. A simple sarcopenia screening test predicts future adverse events in patients with heart failure. Int. J. Cardiol. 2016, 215, 301–306. [Google Scholar] [CrossRef] [PubMed]
  36. Funamizu, T.; Nagatomo, Y.; Saji, M.; Iguchi, N.; Daida, H.; Yoshikawa, T. Low muscle mass assessed by psoas muscle area is associated with clinical adverse events in elderly patients with heart failure. PLoS ONE 2021, 16, e0247140. [Google Scholar] [CrossRef]
  37. Konishi, M.; Kagiyama, N.; Kamiya, K.; Saito, H.; Saito, K.; Ogasahara, Y.; Maekawa, E.; Misumi, T.; Kitai, T.; Iwata, K.; et al. Impact of sarcopenia on prognosis in patients with heart failure with reduced and preserved ejection fraction. Eur. J. Prev. Cardiol. 2021, 28, 1022–1029. [Google Scholar] [CrossRef]
  38. Shimokawa, H.; Miura, M.; Nochioka, K.; Sakata, Y. Heart failure as a general pandemic in Asia. Eur. J. Heart Fail. 2015, 17, 884–892. [Google Scholar] [CrossRef]
  39. Cieza, A.; Causey, K.; Kamenov, K.; Hanson, S.W.; Chatterji, S.; Vos, T. Global estimates of the need for rehabilitation based on the Global Burden of Disease study 2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet 2021, 396, 2006–2017. [Google Scholar] [CrossRef]
  40. Guralnik, J.M.; Ferrucci, L.; Pieper, C.F.; Leveille, S.G.; Markides, K.S.; Ostir, G.V.; Studenski, S.; Berkman, L.F.; Wallace, R.B. Lower extremity function and subsequent disability: Consistency across studies, predictive models, and value of gait speed alone compared with the short physical performance battery. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2000, 55, M221–M231. [Google Scholar] [CrossRef]
  41. Podsiadlo, D.; Richardson, S. The timed “Up & Go”: A test of basic functional mobility for frail elderly persons. J. Am. Geriatr. Soc. 1991, 39, 142–148. [Google Scholar] [CrossRef] [PubMed]
  42. Rockwood, K.; Mitnitski, A. Frailty in relation to the accumulation of deficits. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2007, 62, 722–727. [Google Scholar] [CrossRef] [PubMed]
  43. Mahoney, F.I.; Barthel, D.W. Functional Evaluation: The Barthel Index. Md. State Med. J. 1965, 14, 61–65. [Google Scholar] [PubMed]
  44. Rockwood, K.; Song, X.; MacKnight, C.; Bergman, H.; Hogan, D.B.; McDowell, I.; Mitnitski, A. A global clinical measure of fitness and frailty in elderly people. CMAJ Can. Med. Assoc. J. = J. De L’association Med. Can. 2005, 173, 489–495. [Google Scholar] [CrossRef] [PubMed]
  45. Fried, L.P.; Tangen, C.M.; Walston, J.; Newman, A.B.; Hirsch, C.; Gottdiener, J.; Seeman, T.; Tracy, R.; Kop, W.J.; Burke, G.; et al. Frailty in older adults: Evidence for a phenotype. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2001, 56, M146–M156. [Google Scholar] [CrossRef] [PubMed]
  46. American Diabetes Association Professional Practice Committee. 13. Older Adults: Standards of Care in Diabetes-2024. Diabetes Care 2024, 47, S244–S257. [Google Scholar] [CrossRef]
  47. Finucane, M.M.; Stevens, G.A.; Cowan, M.J.; Danaei, G.; Lin, J.K.; Paciorek, C.J.; Singh, G.M.; Gutierrez, H.R.; Lu, Y.; Bahalim, A.N.; et al. National, regional, and global trends in body-mass index since 1980: Systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9·1 million participants. Lancet 2011, 377, 557–567. [Google Scholar] [CrossRef]
  48. Goodpaster, B.H.; Park, S.W.; Harris, T.B.; Kritchevsky, S.B.; Nevitt, M.; Schwartz, A.V.; Simonsick, E.M.; Tylavsky, F.A.; Visser, M.; Newman, A.B. The loss of skeletal muscle strength, mass, and quality in older adults: The health, aging and body composition study. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2006, 61, 1059–1064. [Google Scholar] [CrossRef]
  49. Delmonico, M.J.; Harris, T.B.; Lee, J.S.; Visser, M.; Nevitt, M.; Kritchevsky, S.B.; Tylavsky, F.A.; Newman, A.B. Alternative definitions of sarcopenia, lower extremity performance, and functional impairment with aging in older men and women. J. Am. Geriatr. Soc. 2007, 55, 769–774. [Google Scholar] [CrossRef]
  50. Cruz-Jentoft, A.J.; Baeyens, J.P.; Bauer, J.M.; Boirie, Y.; Cederholm, T.; Landi, F.; Martin, F.C.; Michel, J.P.; Rolland, Y.; Schneider, S.M.; et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 2010, 39, 412–423. [Google Scholar] [CrossRef]
  51. Cruz-Jentoft, A.J.; Bahat, G.; Bauer, J.; Boirie, Y.; Bruyère, O.; Cederholm, T.; Cooper, C.; Landi, F.; Rolland, Y.; Sayer, A.A.; et al. Sarcopenia: Revised European consensus on definition and diagnosis. Age Ageing 2019, 48, 16–31. [Google Scholar] [CrossRef]
  52. Chen, L.K.; Woo, J.; Assantachai, P.; Auyeung, T.W.; Chou, M.Y.; Iijima, K.; Jang, H.C.; Kang, L.; Kim, M.; Kim, S.; et al. Asian Working Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and Treatment. J. Am. Med. Dir. Assoc. 2020, 21, 300–307.e302. [Google Scholar] [CrossRef]
  53. Richter, D.; Guasti, L.; Walker, D.; Lambrinou, E.; Lionis, C.; Abreu, A.; Savelieva, I.; Fumagalli, S.; Bo, M.; Rocca, B.; et al. Frailty in cardiology: Definition, assessment and clinical implications for general cardiology. A consensus document of the Council for Cardiology Practice (CCP), Association for Acute Cardio Vascular Care (ACVC), Association of Cardiovascular Nursing and Allied Professions (ACNAP), European Association of Preventive Cardiology (EAPC), European Heart Rhythm Association (EHRA), Council on Valvular Heart Diseases (VHD), Council on Hypertension (CHT), Council of Cardio-Oncology (CCO), Working Group (WG) Aorta and Peripheral Vascular Diseases, WG e-Cardiology, WG Thrombosis, of the European Society of Cardiology, European Primary Care Cardiology Society (EPCCS). Eur. J. Prev. Cardiol. 2022, 29, 216–227. [Google Scholar] [CrossRef] [PubMed]
  54. Gorodeski, E.Z.; Goyal, P.; Hummel, S.L.; Krishnaswami, A.; Goodlin, S.J.; Hart, L.L.; Forman, D.E.; Wenger, N.K.; Kirkpatrick, J.N.; Alexander, K.P. Domain Management Approach to Heart Failure in the Geriatric Patient: Present and Future. J. Am. Coll. Cardiol. 2018, 71, 1921–1936. [Google Scholar] [CrossRef] [PubMed]
  55. Dent, E.; Kowal, P.; Hoogendijk, E.O. Frailty measurement in research and clinical practice: A review. Eur. J. Intern. Med. 2016, 31, 3–10. [Google Scholar] [CrossRef]
  56. Chokshi, N.B.K.; Karmakar, B.; Pathan, S.K.; Joshi, V.; Gohel, D.M.; Coulshed, D.S.; Negishi, K.; Pathan, F.K. A Systematic Review of Frailty Scores Used in Heart Failure Patients. Heart Lung Circ. 2023, 32, 441–453. [Google Scholar] [CrossRef] [PubMed]
  57. Butt, J.H.; Dewan, P.; Merkely, B.; Belohlávek, J.; Drożdż, J.; Kitakaze, M.; Inzucchi, S.E.; Kosiborod, M.N.; Martinez, F.A.; Tereshchenko, S.; et al. Efficacy and Safety of Dapagliflozin According to Frailty in Heart Failure with Reduced Ejection Fraction: A Post Hoc Analysis of the DAPA-HF Trial. Ann. Intern. Med. 2022, 175, 820–830. [Google Scholar] [CrossRef]
  58. Butt, J.H.; Jhund, P.S.; Belohlávek, J.; de Boer, R.A.; Chiang, C.E.; Desai, A.S.; Drożdż, J.; Hernandez, A.F.; Inzucchi, S.E.; Katova, T.; et al. Efficacy and Safety of Dapagliflozin According to Frailty in Patients with Heart Failure: A Prespecified Analysis of the DELIVER Trial. Circulation 2022, 146, 1210–1224. [Google Scholar] [CrossRef]
  59. To, T.L.; Doan, T.N.; Ho, W.C.; Liao, W.C. Prevalence of Frailty among Community-Dwelling Older Adults in Asian Countries: A Systematic Review and Meta-Analysis. Healthcare 2022, 10, 895. [Google Scholar] [CrossRef]
  60. Da Mata, F.A.; Pereira, P.P.; Andrade, K.R.; Figueiredo, A.C.; Silva, M.T.; Pereira, M.G. Prevalence of Frailty in Latin America and the Caribbean: A Systematic Review and Meta-Analysis. PLoS ONE 2016, 11, e0160019. [Google Scholar] [CrossRef]
  61. Collard, R.M.; Boter, H.; Schoevers, R.A.; Oude Voshaar, R.C. Prevalence of frailty in community-dwelling older persons: A systematic review. J. Am. Geriatr. Soc. 2012, 60, 1487–1492. [Google Scholar] [CrossRef] [PubMed]
  62. O’Caoimh, R.; Galluzzo, L.; Rodríguez-Laso, Á.; Van der Heyden, J.; Ranhoff, A.H.; Lamprini-Koula, M.; Ciutan, M.; López-Samaniego, L.; Carcaillon-Bentata, L.; Kennelly, S.; et al. Prevalence of frailty at population level in European ADVANTAGE Joint Action Member States: A systematic review and meta-analysis. Ann. Dell’istituto Super. Di Sanita 2018, 54, 226–238. [Google Scholar] [CrossRef]
  63. O’Caoimh, R.; Sezgin, D.; O’Donovan, M.R.; Molloy, D.W.; Clegg, A.; Rockwood, K.; Liew, A. Prevalence of frailty in 62 countries across the world: A systematic review and meta-analysis of population-level studies. Age Ageing 2021, 50, 96–104. [Google Scholar] [CrossRef] [PubMed]
  64. von Haehling, S.; Lainscak, M.; Springer, J.; Anker, S.D. Cardiac cachexia: A systematic overview. Pharmacol. Ther. 2009, 121, 227–252. [Google Scholar] [CrossRef] [PubMed]
  65. Kazemi-Bajestani, S.M.; Becher, H.; Fassbender, K.; Chu, Q.; Baracos, V.E. Concurrent evolution of cancer cachexia and heart failure: Bilateral effects exist. J. Cachexia Sarcopenia Muscle 2014, 5, 95–104. [Google Scholar] [CrossRef]
  66. Xue, Q.L.; Bandeen-Roche, K.; Varadhan, R.; Zhou, J.; Fried, L.P. Initial manifestations of frailty criteria and the development of frailty phenotype in the Women’s Health and Aging Study II. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2008, 63, 984–990. [Google Scholar] [CrossRef] [PubMed]
  67. Talha, K.M.; Pandey, A.; Fudim, M.; Butler, J.; Anker, S.D.; Khan, M.S. Frailty and heart failure: State-of-the-art review. J. Cachexia Sarcopenia Muscle 2023, 14, 1959–1972. [Google Scholar] [CrossRef]
  68. Ijaz, N.; Buta, B.; Xue, Q.L.; Mohess, D.T.; Bushan, A.; Tran, H.; Batchelor, W.; deFilippi, C.R.; Walston, J.D.; Bandeen-Roche, K.; et al. Interventions for Frailty Among Older Adults with Cardiovascular Disease: JACC State-of-the-Art Review. J. Am. Coll. Cardiol. 2022, 79, 482–503. [Google Scholar] [CrossRef]
  69. Vitale, C.; Uchmanowicz, I. Frailty in patients with heart failure. Eur. Heart J. Suppl. J. Eur. Soc. Cardiol. 2019, 21, L12–L16. [Google Scholar] [CrossRef]
  70. Vitale, C.; Spoletini, I.; Rosano, G.M. Frailty in Heart Failure: Implications for Management. Card. Fail. Rev. 2018, 4, 104–106. [Google Scholar] [CrossRef]
  71. Pandey, A.; Kitzman, D.; Reeves, G. Frailty Is Intertwined With Heart Failure: Mechanisms, Prevalence, Prognosis, Assessment, and Management. JACC. Heart Fail. 2019, 7, 1001–1011. [Google Scholar] [CrossRef] [PubMed]
  72. Dewan, P.; Jackson, A.; Jhund, P.S.; Shen, L.; Ferreira, J.P.; Petrie, M.C.; Abraham, W.T.; Desai, A.S.; Dickstein, K.; Køber, L.; et al. The prevalence and importance of frailty in heart failure with reduced ejection fraction—An analysis of PARADIGM-HF and ATMOSPHERE. Eur. J. Heart Fail. 2020, 22, 2123–2133. [Google Scholar] [CrossRef] [PubMed]
  73. Pandey, A.; Segar, M.W.; Singh, S.; Reeves, G.R.; O’Connor, C.; Piña, I.; Whellan, D.; Kraus, W.E.; Mentz, R.J.; Kitzman, D.W. Frailty Status Modifies the Efficacy of Exercise Training Among Patients with Chronic Heart Failure and Reduced Ejection Fraction: An Analysis From the HF-ACTION Trial. Circulation 2022, 146, 80–90. [Google Scholar] [CrossRef] [PubMed]
  74. Vidán, M.T.; Blaya-Novakova, V.; Sánchez, E.; Ortiz, J.; Serra-Rexach, J.A.; Bueno, H. Prevalence and prognostic impact of frailty and its components in non-dependent elderly patients with heart failure. Eur. J. Heart Fail. 2016, 18, 869–875. [Google Scholar] [CrossRef] [PubMed]
  75. Yang, X.; Lupón, J.; Vidán, M.T.; Ferguson, C.; Gastelurrutia, P.; Newton, P.J.; Macdonald, P.S.; Bueno, H.; Bayés-Genís, A.; Woo, J.; et al. Impact of Frailty on Mortality and Hospitalization in Chronic Heart Failure: A Systematic Review and Meta-Analysis. J. Am. Heart Assoc. 2018, 7, e008251. [Google Scholar] [CrossRef] [PubMed]
  76. Duggan, E.; Knight, S.P.; Xue, F.; Romero-Ortuno, R. Haemodynamic Parameters Underlying the Relationship between Sarcopenia and Blood Pressure Recovery on Standing. J. Clin. Med. 2023, 13, 18. [Google Scholar] [CrossRef]
  77. Axelrod, C.L.; Dantas, W.S.; Kirwan, J.P. Sarcopenic obesity: Emerging mechanisms and therapeutic potential. Metab. Clin. Exp. 2023, 146, 155639. [Google Scholar] [CrossRef]
  78. Ding, J.; Kritchevsky, S.B.; Newman, A.B.; Taaffe, D.R.; Nicklas, B.J.; Visser, M.; Lee, J.S.; Nevitt, M.; Tylavsky, F.A.; Rubin, S.M.; et al. Effects of birth cohort and age on body composition in a sample of community-based elderly. Am. J. Clin. Nutr. 2007, 85, 405–410. [Google Scholar] [CrossRef]
  79. Frontera, W.R.; Hughes, V.A.; Fielding, R.A.; Fiatarone, M.A.; Evans, W.J.; Roubenoff, R. Aging of skeletal muscle: A 12-yr longitudinal study. J. Appl. Physiol. 2000, 88, 1321–1326. [Google Scholar] [CrossRef]
  80. Upadhya, B.; Haykowsky, M.J.; Eggebeen, J.; Kitzman, D.W. Sarcopenic obesity and the pathogenesis of exercise intolerance in heart failure with preserved ejection fraction. Curr. Heart Fail. Rep. 2015, 12, 205–214. [Google Scholar] [CrossRef]
  81. Fontana, L.; Eagon, J.C.; Trujillo, M.E.; Scherer, P.E.; Klein, S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes 2007, 56, 1010–1013. [Google Scholar] [CrossRef]
  82. Goodpaster, B.H.; Brown, N.F. Skeletal muscle lipid and its association with insulin resistance: What is the role for exercise? Exerc. Sport Sci. Rev. 2005, 33, 150–154. [Google Scholar] [CrossRef]
  83. Batsis, J.A.; Mackenzie, T.A.; Lopez-Jimenez, F.; Bartels, S.J. Sarcopenia, sarcopenic obesity, and functional impairments in older adults: National Health and Nutrition Examination Surveys 1999–2004. Nutr. Res. 2015, 35, 1031–1039. [Google Scholar] [CrossRef]
  84. Fonseca, G.; Dos Santos, M.R.; de Souza, F.R.; Takayama, L.; Rodrigues Pereira, R.M.; Negrão, C.E.; Alves, M.N.N. Discriminating sarcopenia in overweight/obese male patients with heart failure: The influence of body mass index. ESC Heart Fail. 2020, 7, 84–91. [Google Scholar] [CrossRef] [PubMed]
  85. Roh, E.; Choi, K.M. Health Consequences of Sarcopenic Obesity: A Narrative Review. Front. Endocrinol. 2020, 11, 332. [Google Scholar] [CrossRef] [PubMed]
  86. Saito, H.; Matsue, Y.; Kamiya, K.; Kagiyama, N.; Maeda, D.; Endo, Y.; Ueno, H.; Yoshioka, K.; Mizukami, A.; Saito, K.; et al. Sarcopenic obesity is associated with impaired physical function and mortality in older patients with heart failure: Insight from FRAGILE-HF. BMC Geriatr. 2022, 22, 556. [Google Scholar] [CrossRef] [PubMed]
  87. Billingsley, H.E.; Del Buono, M.G.; Canada, J.M.; Kim, Y.; Damonte, J.I.; Trankle, C.R.; Halasz, G.; Mihalick, V.; Vecchié, A.; Markley, R.R.; et al. Sarcopenic Obesity Is Associated with Reduced Cardiorespiratory Fitness Compared with Nonsarcopenic Obesity in Patients with Heart Failure with Reduced Ejection Fraction. Circulation. Heart Fail. 2022, 15, e009518. [Google Scholar] [CrossRef] [PubMed]
  88. Kato, E.T.; Silverman, M.G.; Mosenzon, O.; Zelniker, T.A.; Cahn, A.; Furtado, R.H.M.; Kuder, J.; Murphy, S.A.; Bhatt, D.L.; Leiter, L.A.; et al. Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus. Circulation 2019, 139, 2528–2536. [Google Scholar] [CrossRef] [PubMed]
  89. Rådholm, K.; Figtree, G.; Perkovic, V.; Solomon, S.D.; Mahaffey, K.W.; de Zeeuw, D.; Fulcher, G.; Barrett, T.D.; Shaw, W.; Desai, M.; et al. Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results from the CANVAS Program. Circulation 2018, 138, 458–468. [Google Scholar] [CrossRef]
  90. Packer, M.; Anker, S.D.; Butler, J.; Filippatos, G.; Ferreira, J.P.; Pocock, S.J.; Carson, P.; Anand, I.; Doehner, W.; Haass, M.; et al. Effect of Empagliflozin on the Clinical Stability of Patients with Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial. Circulation 2021, 143, 326–336. [Google Scholar] [CrossRef] [PubMed]
  91. Docherty, K.F.; Jhund, P.S.; Anand, I.; Bengtsson, O.; Böhm, M.; de Boer, R.A.; DeMets, D.L.; Desai, A.S.; Drozdz, J.; Howlett, J.; et al. Effect of Dapagliflozin on Outpatient Worsening of Patients with Heart Failure and Reduced Ejection Fraction: A Prespecified Analysis of DAPA-HF. Circulation 2020, 142, 1623–1632. [Google Scholar] [CrossRef]
  92. Mitnitski, A.B.; Mogilner, A.J.; Rockwood, K. Accumulation of deficits as a proxy measure of aging. Sci. World J. 2001, 1, 323–336. [Google Scholar] [CrossRef]
  93. Anker, S.D.; Khan, M.S.; Butler, J.; Ofstad, A.P.; Peil, B.; Pfarr, E.; Doehner, W.; Sattar, N.; Coats, A.J.S.; Filippatos, G.; et al. Weight change and clinical outcomes in heart failure with reduced ejection fraction: Insights from EMPEROR-Reduced. Eur. J. Heart Fail. 2023, 25, 117–127. [Google Scholar] [CrossRef]
  94. Adamson, C.; Jhund, P.S.; Docherty, K.F.; Bělohlávek, J.; Chiang, C.E.; Diez, M.; Drożdż, J.; Dukát, A.; Howlett, J.; Ljungman, C.E.A.; et al. Efficacy of dapagliflozin in heart failure with reduced ejection fraction according to body mass index. Eur. J. Heart Fail. 2021, 23, 1662–1672. [Google Scholar] [CrossRef]
  95. Adamson, C.; Kondo, T.; Jhund, P.S.; de Boer, R.A.; Cabrera Honorio, J.W.; Claggett, B.; Desai, A.S.; Alcocer Gamba, M.A.; Al Habeeb, W.; Hernandez, A.F.; et al. Dapagliflozin for heart failure according to body mass index: The DELIVER trial. Eur. Heart J. 2022, 43, 4406–4417. [Google Scholar] [CrossRef]
  96. Kutz, A.; Kim, D.H.; Wexler, D.J.; Liu, J.; Schneeweiss, S.; Glynn, R.J.; Patorno, E. Comparative Cardiovascular Effectiveness and Safety of SGLT-2 Inhibitors, GLP-1 Receptor Agonists, and DPP-4 Inhibitors According to Frailty in Type 2 Diabetes. Diabetes Care 2023, 46, 2004–2014. [Google Scholar] [CrossRef] [PubMed]
  97. Yabe, D.; Shiki, K.; Homma, G.; Meinicke, T.; Ogura, Y.; Seino, Y. Efficacy and safety of the sodium-glucose co-transporter-2 inhibitor empagliflozin in elderly Japanese adults (≥65 years) with type 2 diabetes: A randomized, double-blind, placebo-controlled, 52-week clinical trial (EMPA-ELDERLY). Diabetes Obes. Metab. 2023, 25, 3538–3548. [Google Scholar] [CrossRef] [PubMed]
  98. Zhang, S.; Qi, Z.; Wang, Y.; Song, D.; Zhu, D. Effect of sodium-glucose transporter 2 inhibitors on sarcopenia in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Front. Endocrinol. 2023, 14, 1203666. [Google Scholar] [CrossRef]
  99. Sinclair, A.J.; Pennells, D.; Abdelhafiz, A.H. Hypoglycaemic therapy in frail older people with type 2 diabetes mellitus-a choice determined by metabolic phenotype. Aging Clin. Exp. Res. 2022, 34, 1949–1967. [Google Scholar] [CrossRef] [PubMed]
  100. Pette, D.; Peuker, H.; Staron, R.S. The impact of biochemical methods for single muscle fibre analysis. Acta Physiol. Scand. 1999, 166, 261–277. [Google Scholar] [CrossRef] [PubMed]
  101. Sasaki, T.; Sugawara, M.; Fukuda, M. Sodium-glucose cotransporter 2 inhibitor-induced changes in body composition and simultaneous changes in metabolic profile: 52-week prospective LIGHT (Luseogliflozin: The Components of Weight Loss in Japanese Patients with Type 2 Diabetes Mellitus) Study. J. Diabetes Investig. 2019, 10, 108–117. [Google Scholar] [CrossRef] [PubMed]
  102. Bouchi, R.; Terashima, M.; Sasahara, Y.; Asakawa, M.; Fukuda, T.; Takeuchi, T.; Nakano, Y.; Murakami, M.; Minami, I.; Izumiyama, H.; et al. Luseogliflozin reduces epicardial fat accumulation in patients with type 2 diabetes: A pilot study. Cardiovasc. Diabetol. 2017, 16, 32. [Google Scholar] [CrossRef] [PubMed]
  103. Cefalu, W.T.; Leiter, L.A.; Yoon, K.H.; Arias, P.; Niskanen, L.; Xie, J.; Balis, D.A.; Canovatchel, W.; Meininger, G. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013, 382, 941–950. [Google Scholar] [CrossRef]
  104. Sugiyama, S.; Jinnouchi, H.; Kurinami, N.; Hieshima, K.; Yoshida, A.; Jinnouchi, K.; Nishimura, H.; Suzuki, T.; Miyamoto, F.; Kajiwara, K.; et al. Dapagliflozin Reduces Fat Mass without Affecting Muscle Mass in Type 2 Diabetes. J. Atheroscler. Thromb. 2018, 25, 467–476. [Google Scholar] [CrossRef]
  105. Sano, M.; Meguro, S.; Kawai, T.; Suzuki, Y. Increased grip strength with sodium-glucose cotransporter 2. J. Diabetes 2016, 8, 736–737. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Frailty cycle in HF. Malnutrition can cause body weight loss and muscle loss (sarcopenia), accompanied by deteriorated muscle strength and function, which results in depressed physical activity. As a result, the decrease in oral intake induces further malnutrition. This vicious cycle is often referred to as the frailty cycle. In the setting of HF, the symptoms include dyspnea, fatigue, appetite loss and intestinal malabsorption due to intestinal congestion and malperfusion. These symptoms can accelerate every single step in the frailty cycle. Further, elderly populations are commonly affected by HF and have various problems that further accelerate the frailty cycle. Red arrows indicate the main pathway of the frailty cycle. Orange arrows indicate the aggravation of each component. ↓, decrease. BW, body weight; HF, heart failure.
Figure 1. Frailty cycle in HF. Malnutrition can cause body weight loss and muscle loss (sarcopenia), accompanied by deteriorated muscle strength and function, which results in depressed physical activity. As a result, the decrease in oral intake induces further malnutrition. This vicious cycle is often referred to as the frailty cycle. In the setting of HF, the symptoms include dyspnea, fatigue, appetite loss and intestinal malabsorption due to intestinal congestion and malperfusion. These symptoms can accelerate every single step in the frailty cycle. Further, elderly populations are commonly affected by HF and have various problems that further accelerate the frailty cycle. Red arrows indicate the main pathway of the frailty cycle. Orange arrows indicate the aggravation of each component. ↓, decrease. BW, body weight; HF, heart failure.
Jpm 14 00141 g001
Table 1. The landmark trials that assessed the safety and efficacy of SGLT-2is and their main findings.
Table 1. The landmark trials that assessed the safety and efficacy of SGLT-2is and their main findings.
PopulationSGLT-2isTrialPrimary Endpoint
T2DM and high risk of CVDEmpagliflozinEMPA-REG OUTCOME [14]MACE, HR 0.86 [95%CI, 0.74–0.99]
CanagliflozinCANVAS program [15]MACE, HR 0.86 [95%CI, 0.75–0.97]
DapagliflozinDECLARE-TIIM 58 [16]The composite of CV death and hospitalization for HF, HR 0.83 [95%CI, 0.73–0.95]
HFrEFEmpagliflozinEMPEROR-Reduced [18]The composite of CV death and hospitalization for HF, HR 0.75 [95%CI, 0.65–0.86]
DapagliflozinDAPA-HF [17]The composite of CV death and hospitalization or urgent intravenous therapy for HF, HR 0.74 [95%CI, 0.65–0.85]
T2DM and HFSotagliflozinSOLOIST-WHF [19]The composite of CV death and hospitalization or urgent visit for HF, HR 0.67 [95%CI, 0.52–0.85]
HFpEFDapagliflozinDELIVER [20]The composite of CV death and hospitalization for HF, HR 0.82 [95%CI, 0.73–0.92]
EmpagliflozinEMPEROR-Preserved [21]The composite of CV death and hospitalization for HF, HR 0.79 [95%CI, 0.69–0.90]
Acute HFEmpagliflozinEMPULSE [26]The composite of all-cause death, worsening HF event, and KCCQ-TSS, stratified win ratio 1.36 [95%CI, 1.09–1.68]
HR, hazard ratio; CI, confidence interval; T2DM, type 2 diabetes mellitus; CVD, cardiovascular disease; MACE, major advanced cardiovascular events (defined as the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke); HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; KCCQ-TSS, The Kansas City Cardiomyopathy Questionnaire Total Symptom Score; EMPA-REG, The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose; CANVAS, Canagliflozin Cardiovascular Assessment Study; DECLARE-TIMI, The Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction; EMPEROR-Reduced, The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and Reduced Ejection Fraction; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure; SOLIST-WHF, the Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure; DELIVER, The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure; EMPEROR-Preserved, The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction; EMPULSE, Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized.
Table 2. The main tools for the assessment of frailty or sarcopenia.
Table 2. The main tools for the assessment of frailty or sarcopenia.
Frailty or
Sarcopenia		AssessmentMeasureDescription
SarcopeniaMuscle massSkeletal muscle mass index (SMI) (appendicular skeletal muscle mass/height2)Various cutoffs employed by studies
Muscle strengthHand gripVarious cutoffs employed by studies
Sarcopenia/FrailtyPhysical functionGait speed
Physical functionShort Physical Performance Battery (SPPB) [40]A summation of scores on three tests: balance, gait speed and chair stand
Physical functionTimed-Up and Go test (TUG) [41]
FrailtyMultidimensionalRockwood frailty index [42]Accumulation of symptoms, function, comorbidities, clinical laboratory abnormalities, and impaired quality of life are assessed using 93 variables
Phenotype modelBarthel index [43]Score is calculated based on several daily activities (feeding, bathing, grooming, dressing, bowel and bladder control, toilet use capability, transfer from bed to chair and vice-versa, mobility on level surfaces, and capability to climb stairs)
Medical domainClinical frailty scale [44]A semi-quantitative global judgement
Medical domain and physical functionFried frailty phenotype [45]Weight loss, weakness of hand grip, exhaustion, slowness, and low activity
Table 3. Previous SGLT-2i studies that focused on sarcopenia/frailty, BMI or the elderly.
Table 3. Previous SGLT-2i studies that focused on sarcopenia/frailty, BMI or the elderly.
PopulationStudyTopics of Interest
(Assessment Tool)		Main Findings
HFrEFDAPA-HF sub-analysis [57]Frailty (Frailty index)The efficacy of dapagliflozin for HFrEF patients was consistent across the range of frailty, and the absolute reductions were larger in more frail patients.
DAPA-HF sub-analysis [94]BMIThe efficacy of dapagliflozin for HFrEF patients was consistent across the spectrum of BMI.
EMPEROR-Reduced sub-analysis [93]BMIThe efficacy of dapagliflozin for HFrEF patients was consistent across the spectrum of BMI, and weight loss was associated with higher all-cause mortality regardless of BMI groups.
HFpEFDELIVER sub-analysis [58]Frailty (Frailty index)The benefit of dapagliflozin for HFpEF patients was consistent across the range of frailty and the improvement of QOL with medication was greater in those with a higher level of frailty.
DELIVER sub-analysis [95]BMIThe benefit of dapagliflozin for HFpEF patients was consistent across the spectrum of BMI.
DMKutz et al. (2023) [96]Frailty (Frailty index)Medicare beneficiaries with type 2 DM showed greater cardiovascular effectiveness associated with SGLT-2is and GLP-1 receptor agonists than DPP-4 inhibitors.
EMPA-ELDERLY [97]Elderly (≥65)Empagliflozin for elderly T2DM reduced body weight without compromising muscle mass or strength.
SGLT-2i, sodium–glucose cotransporter 2 inhibitor; BMI, body mass index; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; EMPEROR-Reduced, The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and Reduced Ejection Fraction; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure; EMPA-ELDERLY, Empagliflozin in Elderly T2DM Patients; DM, diabetes mellitus; GLP-1, glucagon-like peptide 1; DPP-4, dipeptidyl-peptidase 4.
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Naito, A.; Nagatomo, Y.; Kawai, A.; Yukino-Iwashita, M.; Nakazawa, R.; Taruoka, A.; Takefuji, A.; Yasuda, R.; Toya, T.; Ikegami, Y.; et al. The Safety and Efficacy of Sodium-Glucose Cotransporter-2 Inhibitors for Patients with Sarcopenia or Frailty: Double Edged Sword? J. Pers. Med. 2024, 14, 141. https://doi.org/10.3390/jpm14020141

AMA Style

Naito A, Nagatomo Y, Kawai A, Yukino-Iwashita M, Nakazawa R, Taruoka A, Takefuji A, Yasuda R, Toya T, Ikegami Y, et al. The Safety and Efficacy of Sodium-Glucose Cotransporter-2 Inhibitors for Patients with Sarcopenia or Frailty: Double Edged Sword? Journal of Personalized Medicine. 2024; 14(2):141. https://doi.org/10.3390/jpm14020141

Chicago/Turabian Style

Naito, Ayami, Yuji Nagatomo, Akane Kawai, Midori Yukino-Iwashita, Ryota Nakazawa, Akira Taruoka, Asako Takefuji, Risako Yasuda, Takumi Toya, Yukinori Ikegami, and et al. 2024. "The Safety and Efficacy of Sodium-Glucose Cotransporter-2 Inhibitors for Patients with Sarcopenia or Frailty: Double Edged Sword?" Journal of Personalized Medicine 14, no. 2: 141. https://doi.org/10.3390/jpm14020141

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