Insulin resistance and type 2 diabetes mellitus (DM) are highly prevalent conditions among participants in cardiac rehabilitation (CR).1 Diabetes is associated with a cluster of cardiovascular disease (CVD) risk factors including abdominal obesity, hypertension, and dyslipidemia. More than 34 million individuals have DM and, yet, one in four, including some patients with CVD, are undiagnosed.2,3
Cardiac rehabilitation provides a unique opportunity to ensure that individuals are optimally managed from both a medical and lifestyle perspective.4 The core components of CR including weight management, prescribed physical activity, and dietary counseling are all integral to the long-term care of individuals with DM.5 Moreover, optimizing medical therapy is an important aspect in the care of participants in CR. Some classes of antihyperglycemic agents not only help achieve glycemic control but have also been found to reduce incident hospitalizations for congestive heart failure (HF), decrease macrovascular disease risk, and provide significant weight loss.6 Thus, DM medication management based on CVD risk factors and mitigation of hypoglycemia risk are critical aspects of managing patients who attend CR.
The purpose of this article was to review medications that are generally described as novel antihyperglycemic agents, as well as discuss traditional DM medications. A particular focus of the review was on the relevance and pertinent consideration of these antihyperglycemic medications for individuals participating in CR.
REDUCING CARDIOVASCULAR RISK IN NEW ANTIDIABETIC THERAPIES
Due to the increased CVD risk among individuals with DM, the US Food and Drug Administration (FDA) and European Medicines Agency mandate that all new DM drugs demonstrate CVD safety. This mandate was established in response to the evidence linked to the use of rosiglitazone, a thiazolidinedione antidiabetic drug that was found to be associated with a significant increase in myocardial infarction (MI) and death from cardiovascular causes.7 Thus, in 2008, the FDA specifically recommended that any new DM medication should demonstrate CVD safety.8,9 Further, it was recommended that trials should focus on high-risk populations, for example, those with advanced age, renal impairment, or peripheral vascular disease and include data on long-term follow-up. As these medications were studied for CVD safety, some antihyperglycemic agents have been found to provide cardiovascular benefit in both primary and secondary prevention. In particular, these newer agents have demonstrated efficacy in individuals with a diagnosis of HF.6 Additionally, these agents are associated with significant weight loss, which is particularly relevant in the CR setting as >80% of participants are overweight.10
NOVEL DIABETES MEDICATIONS
INCRETIN MEDICATIONS: DIPEPTIDYL PEPTIDASE-4 INHIBITORS AND GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS
Care for individuals with DM has been transformed beyond medications affecting insulin release and sensitivity. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and gastric inhibitory peptide (GIP) are gastrointestinal peptides within the incretin category of medications that increase glucose-dependent insulin release, increase glucose uptake and glycogen synthesis, delay gastric emptying, and increase satiety.11 Dipeptidyl peptidase-4 (DPP-4) is an enzyme that was found to inactivate GLP-1 and GIP; therefore, dipeptidyl peptidase-4 inhibitors (DPP-4i) reduce the breakdown of these peptides.12 Given that these categories of medications act in a glucose-dependent manner, they are not typically associated with hypoglycemia unless combined with another hypoglycemic agent.13
The GLP-1 RA medications have superior efficacy to DPP-4i both in terms of hemoglobin A1c (HbA1c) reduction and weight loss, although they are more commonly associated with side effects.13 All GLP-1 RA are injectable except for semaglutide, which is available in both subcutaneous and oral forms. Among the injectable medications, extended-release exenatide, dulaglutide, and semaglutide are once-weekly injections, whereas liraglutide and lixisenatide are daily injections.13–16 The once-weekly injections are often preferred because of less frequent injections, superior HbA1c lowering, and greater weight loss compared with other available GLP-1 RAs (semaglutide and dulaglutide).13 The most common side effect of GLP-1 RAs is nausea, reported in up to 50% of patients.17 However, symptoms typically improve with time and the large majority of patients are able to continue therapy. Other side effects include dyspepsia and local injection site reactions.17 Additionally, a black box warning (an alert of a rare but potentially dangerous side effect) remains for the risk of thyroid C-cell tumors that were discovered in rodents. Although there is no evidence of this in humans, GLP-1 RA should be avoided in patients with a personal or family history of medullary thyroid cancer or the hereditary syndrome multiple endocrine neoplasia type 2.17 Semaglutide, dulaglutide, and liraglutide require no adjustment for renal function.18 As will be discussed, only some of the GLP-1 RAs have been shown to reduce adverse CVD outcomes and this should be considered when picking which GLP-1 RA to use in patients with established CVD.
The Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes (LEADER) trial was the first cardiovascular outcome trial (CVOT) among GLP-1 RA to show superiority of liraglutide compared with placebo in primary composite outcome of death from cardiovascular causes, nonfatal MI or nonfatal stroke.19 This study followed 9340 high-risk individuals with DM (81% also had established CVD) for a median of 3.8 yr. Results from the LEADER trial demonstrated significantly lower composite outcomes in the liraglutide group compared with placebo (13 vs 14.9%, respectively), as well as significantly lower nephropathy events compared with placebo (1.5 vs 1.9 events/100 patient yr, respectively).19
The Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) enrolled 3297 individuals with DM (72% also had established CVD) and followed participants for a median of 2.1 yr.20 The primary outcome was the same composite outcome as the LEADER trial. The results demonstrated a significantly lower composite outcome in the once-weekly semaglutide group compared with the placebo (6.6 vs 8.9%, respectively).20
The Researching Cardiovascular Events with a Weekly Icretin in Diabetes (REWIND) trial examined the use of dulaglutide.21 In contrast to the LEADER trial, REWIND was designed to test the hypothesis that the use of dulaglutide was superior (rather than noninferior) as compared with placebo in CVD outcomes. The REWIND trial enrolled 9901 subjects, including approximately 32% with established CVD. The median follow-up was 5.4 yr, and the primary outcome was the same composite outcome of death from cardiovascular causes, nonfatal MI and nonfatal stroke. The dulaglutide group had significantly fewer CVD events compared with the placebo (12 vs 13.4%, respectively), as well as fewer adverse renal-related outcomes (development of microalbuminuria or worsening of renal function based on glomerular filtration rate) compared with placebo (17.1 vs 19.6%, respectively).21 Since this study only had a minority of patients with established CVD, dulaglutide is the only GLP-1 RA with an FDA-approved indication for both primary and secondary prevention of CVD, whereas semaglutide and liraglutide are approved for secondary prevention only.
Another class of incretin medications, DPP-4i, reduce the breakdown of GLP-1 and GIP resulting in a modest reduction in HbA1c, between 0.6 and 0.8%.12 As a medication that is taken orally, DPP-4is are generally well tolerated, with the most common side effect being arthralgia.18 Thus, for patients experiencing significant joint pain, careful review of medications should be completed and oftentimes a trial off of DPP-4i can be made to determine whether this is a precipitating factor. Hypersensitivity reactions are rare but have been reported.22 All DPP-4is need to be dosed based on renal function with the exception of linagliptin, which can be used at any level of renal impairment.18
Results from the CVOTs using DPP-4i have largely been neutral. Hallmark trials specifically examining the use of saxagliptin (SAVOR-TIMI53), alogliptin (EXAMINE), sitagliptin (TECOS), and linagliptin (CARMELINA) demonstrated noninferiority, but not superiority, when compared with placebo regarding CVD outcomes (cardiovascular death, nonfatal MI, and nonfatal stroke, and the linagliptin and sitagliptin study included hospitalization for unstable angina).23–25 Unfortunately, some of these medications can lead to worsening HF in individuals with established CVD.26 In 2016, the FDA issued a warning that saxagliptin increased the risk of HF-related hospitalizations (3.5 vs 2.8% in the placebo group) as did alogliptin (3.9 vs 3.3% in the placebo group). Similarly, a pooled analysis suggested use of linagliptin increased HF events.27 Another trial examined use of vildagliptin in patients with DM and HF with reduced ejection fraction (HFrEF) and noted an increased risk in mortality, which may be attributed to the adverse effect of the medication on cardiac remodeling.28 Although DDP-4i medications are a popular choice for management of DM, these agents should be used with caution and, perhaps, avoided in individuals with HF.29
SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS: ERTUGLIFLOZIN, DAPAGLIFLOZIN, CANAGLIFLOZIN, AND EMPAGLIFLOZIN
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are designed to reduce blood glucose (BG) concentration by increasing urinary glucose excretion. Located in the proximal tubule of the kidney, SGLT2i is the main site of glucose reabsorption. Lowering the threshold for filtered glucose increases urinary excretion of glucose and reduces plasma glucose levels. This effect has also been shown to modestly reduce blood pressure and body weight.30 Like GLP-1 RA, their anti-hyperglycemic effect is glucose dependent and, generally, does not cause hypoglycemia. The HbA1c-lowering efficacy of SGLT2i is considered intermediate with an average HbA1c reduction of 0.5-0.8%.31
Since 2015, there have been multiple CVOTs looking at SGLT2i. The initial SGLTi study, Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG), evaluated empagliflozin versus placebo on CVD outcomes in individuals with DM and existing CVD.32 Empagliflozin reduced the composite outcome of MI, stroke, and cardiovascular death by 14% compared with placebo. In 2017, the canagliflozin trial, Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes (CANVAS), which included subjects with DM and either preexisting CVD or >2 CVD risk factors, was also found to reduce the same composite cardiovascular outcome (HR = 0.88: 95% CI, 0.75-0.97) as the EMPA-REG trial.33 Empagliflozin and canagliflozin are FDA approved for CVD benefit. Dapagliflozin in the Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes trial (DECLARE-TIMI 58) showed noninferiority compared with placebo but did not show a reduced rate of major adverse cardiovascular events, defined as the same composite cardiovascular outcomes as previous trials.34 The Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes (VERTIS CV) trial demonstrated noninferiority, but not superiority, compared with placebo for the primary outcome of major adverse cardiac events.35
The most common side effects of SGLT2i are genitourinary infections, volume depletion, and hypotension.36 A meta-analysis of randomized control trials showed no significant difference in urinary tract infections but a three times greater risk of genital infections with SGLT2i compared with control.36 Another meta-analysis of randomized control trials found a similar increased relative risk of genital infections along with a significant increased risk of volume depletion events.37
The use of SGLT2i increases the risk of euglycemic diabetic ketoacidosis—a medical condition where there is a risk of anion gap metabolic acidosis from diabetic ketoacidosis without significantly elevated glucose levels created by the loss of glucose in the urine and, thus, insulin deficiency.38 In a multicenter cohort study of 200 000 patients, the incidence of euglycemic diabetic ketoacidosis in the patient group taking SGLT2i was 2.03/1000 person-yr, compared with 0.75/1000 person-yr in a similar patient group taking DPP4i.38 This is especially concerning in a fasting patient; if a patient experiences nausea, vomiting, or malaise while taking SGLT2i, a medical provider should be notified as additional laboratory testing may be warranted.
It should additionally be noted that while the glucose-lowering effect is lower for SGLT2i at lower renal function, these agents have proven safe in patients with chronic kidney disease, and are FDA approved to slow progression of diabetic kidney disease.
ROLE OF ANTIHYPERGLYCEMIC AGENTS BEYOND DIABETES
The GLP-1 RAs are associated with significant weight loss and, more recently, several medications in this category have been FDA approved for weight loss regardless of the presence of DM. Liraglutide was the first to be FDA approved as a weight loss medication. A randomized controlled trial evaluated a higher dose of liraglutide than used as a treatment for DM compared with placebo and found 63.2% of patients taking liraglutide lost >5% of their body weight compared with 27.1% in the placebo control group.39 Semaglutide has more recently been FDA approved for weight loss at a higher dose than is prescribed for the treatment of DM. A randomized control trial of 68 wk of treatment found 86.4% of patients in the semaglutide group achieved weight loss of >5% of their body weight compared with 31.5% in the placebo group, with a mean weight loss of 15.3 kg in the semaglutide group.40
More recently, there is also the first combined GLP-1 and GIP receptor agonist, tirzepatide, which has been studied in both DM, as well as weight loss, irrespective of DM status. Tirzepatide very recently achieved FDA approval for type 2 DM after a randomized control trial compared it to semaglutide. This study was a 40-wk open-label trial with 1879 subjects and found that the group randomized to tirzepatide achieved significantly lower HbA1c levels compared with semaglutide (−2.3 vs −1.86 points, respectively), as well as significantly greater weight loss (−11.2 vs −5.7 kg, respectively).41 Additionally, a randomized controlled trial compared tirzepatide to placebo among patients with obesity, irrespective of DM status, and found significantly more weight loss with tirzepatide compared with placebo, 20.9 versus 3.1% body weight loss, respectively, which is the largest weight loss seen among obesity medications.42
For patients with HF, regardless of DM status, SGLTis have proven to be beneficial. Both dapagliflozin and empagliflozin were shown to reduce risk of hospitalization for HF.32,34 The DAPA-HF study evaluated subjects with HFrEF, nearly half of whom had a history of DM. Compared with placebo, dapagliflozin reduced the primary outcome of a composite of HF events (defined as hospitalization for HF, or urgent HF visit) or CVD death (HR = 0.74: 95% CI, 0.65-0.85).34 Empagliflozin was compared to placebo on a primary outcome of composite CVD-related death and hospitalization for worsening HF in a cohort of individuals with HFrEF, half of whom had DM. The empagliflozin group had a 25% reduction in CVD-related death and hospitalization.32 Consequently, empagliflozin and dapagliflozin have FDA approval for HFrEF and, more recently, empagliflozin has also been FDA approved for patients with HF and preserved ejection fraction.43,44
GENERAL CONSIDERATIONS FOR ANTIHYPERGLYCEMIC AGENTS IN INDIVIDUALS ENTERING CR
The majority of individuals entering CR have or are at high risk for developing DM and >80% of participants in CR are overweight.10 In addition, individuals with HFrEF are eligible for CR. Taken together, a relatively large number of participants in CR could benefit from these novel DM medications. In many ways, CR provides an ideal setting to identify individuals who might benefit from one of these therapeutic agents (Figure). Participants entering CR undergo a comprehensive assessment of CVD risk factors. As standard practice, medications are reviewed with a goal optimizing medical therapy to minimize future CVD risk. It is becoming increasingly clear that, when indicated, there is strong evidence supporting the practice of prescribing novel medications for participants enrolling in CR.
Given the cardiac benefits of GLP-1 RA and SGLT2i, these agents should be considered among those with established CVD and DM even when the HbA1c of an individual is at, or close to, goal. For those overweight individuals with or without DM, GLP-1 RAs can be considered for weight loss alone, although denial of insurance coverage can often be a barrier. Similarly, all HF patients, regardless of ejection fraction or DM status, should be on an SGLT2i given the reduction in hospitalizations.
ROLE OF EXERCISE IN DIABETES MANAGEMENT
Exercise is a foundational component of CR. Prior to commencing with an exercise program, it is important for the CR team to obtain a detailed medical history; oftentimes, those with DM may have long-term complications such as peripheral neuropathy, blindness, or vascular disease involving amputation or claudication and this may make it challenging for them to engage in CR. The comprehensive assessment that occurs at CR entry is an opportune time to consider the wide variety of therapeutics, including novel DM agents that are available for CVD risk reduction.
Obtaining detailed information about DM medications, adherence to heart healthy diet, body habitus (weight, waist circumference, and body mass index), BG values, CVD risk factors, physical activity level, and exercise capacity can help the CR team determine the individual needs for BG monitoring, medication adjustments, and patient self-awareness.45,46 Within the CR setting, there are no explicit guidelines regarding the frequency of glucose measurements. Therefore, the recommendation should be tailored based on the patient medical history including history of hyper/hypoglycemia, time of medications as relates to exercise, and food intake.
Medication Management and Exercise
While all DM medications have the potential to induce hypoglycemia either during or following exercise, the vast majority, including the newer agents, carry minimal risk (Table).47 However, there are other side effects, which can impede exercise and are discussed below.
Novel and Traditional Antihyperglycemic Medications
||Mechanism of Action
||Medications (Trade Name)
||Risk of Hypoglycemia
||Effect on CVD Events
||Effect on Weight
|Sodium-glucose cotransporter-2 inhibitors (SGLT2i)
||Promote renal excretion of glucose
||CVD and HF benefit
|Glucagon-like peptide-1 receptor agonists (GLP-1 RA)
||Stimulate insulin secretion and suppress glucagon
|Dipeptidyl peptidase-4 inhibitors (DPP-4i)
||Inhibit breakdown of incretin hormones
||Neutral CVD benefit and potential risk of HF (saxagliptin)
||Increase insulin sensitivity
||Increased risk of HF
|Suppress glucose production in liver
Stimulate insulin secretion after eating
Glyburide (Diabeta, Glynase)
|Potential CVD benefit
||Replace deficiency of insulin
Regular insulin (Novolin, Humulin)
||Delayed absorption of glucose
Abbreviations: CVD, cardiovascular disease; HF, heart failure.
Depending on the formulation, insulin, in particular, contributes to the vast majority of hypoglycemic episodes. Patients who use rapid acting-insulin 1-2 hr before exercise are more susceptible as the peak effect of the short-acting insulin coincides with time of exercise. Similarly, sulfonylurea stimulates insulin secretion from pancreas and can significantly increase risk of hypoglycemia as well.47 Individuals may need to monitor BG levels before, during, and after exercise and, if needed, can compensate with dietary or medication changes. Additionally, staff should be cautious whether there is concomitant use of β-blockers (specifically metoprolol, atenolol, and bisoprolol), as this class can increase risk of asymptomatic hypoglycemia.48 Long-acting insulin, such as basal insulin, lasts roughly 24 hr and hypoglycemic risks are much lower. Over time, as individuals on insulin increase the volume of exercise and, perhaps, lose weight, adjustments may be needed to minimize the risk of hypoglycemia.
The majority of individuals with DM are on biguanides, which act by reducing hepatic glucose output. While common side effects include gastrointestinal upset or diarrhea, the risk of hypoglycemia is low. Staff, however, should be attentive to individuals with liver disease/dysfunction, as they may be more susceptible to having hypoglycemia while on biguanides.48
The SGLT2i medications lower BG levels by promoting renal excretion of glucose. These medications are glucose dependent and, thus, the overall risk of hypoglycemia is low.18
The DDP-4i medications and GLP-1 analogs stimulate insulin production depending on the level of BG and carry a low risk of hypoglycemia. Thiazolidinediones improve insulin sensitivity but do not affect insulin production; therefore, they are unlikely to contribute to hypoglycemia during or after exercise. α-Glucosidase inhibitors affect absorption of carbohydrates and, when used alone, are not associated with hypoglycemia.
It is important to note that although, in and of themselves, many antihyperglycemic agents do not typically cause hypoglycemia, the use of concomitant insulin or sulfonylureas may increase the risk of low BG levels.18
Management of Blood Glucose Levels in Cardiac Rehabilitation
Compared with participants without DM, individuals with DM starting CR present particular challenges. While regular exercise helps maintain appropriate BG levels and is a class I indication in the management of DM, many individuals starting CR have not been historically physically active. Additionally, some individuals starting CR have only recently been diagnosed with DM. Therefore, some individuals with DM entering CR are unfamiliar with how exercise and medications can affect their BG levels. Consequently, for individuals with DM starting CR, particular attention to BG levels prior to, during, and after exercise is warranted. Also, if changes to DM-related treatment regimen are made during CR then heightened surveillance of BG levels may be indicated. It is important to note that the greatest potential for an acute adverse event is associated with the more traditional, rather than the newer antihyperglycemic agents (Table).
The CR setting represents an excellent opportunity to monitor and manage DM because of the frequent repeated contact with participants. Closely monitoring individuals, particularly when first starting an exercise program or when adjustments are made to medical therapy, provides critical information to increase safety and efficacy. Detailed recommendations of how to monitor and manage patients with DM in CR have been described elsewhere.45,46 Programs need to develop the policies and procedures of how to properly respond to adverse events during CR.49 It is incumbent on professionals in CR to have the knowledge necessary to provide education and guidance to patients so as to identify the risks associated with hypo- and hyperglycemia. Also, it is important for CR professionals to assist individuals with DM to develop appropriate long-term strategies to avoid or, when necessary, treat adverse events.
Physical Activity Recommendations
As with all participants in CR, lifestyle modification is a critical component of secondary prevention for individuals with DM. There is an agreement between the recommendations from the American Diabetes Association (ADA) for individuals with DM and the general CR population.45,48–50 The ADA recommends ≥150 min/wk of moderate-to-vigorous physical activity done over the course of ≥3 d/wk.8 Additionally, resistance exercise should be included. Moreover, increasing daily physical activity and reducing time spent in sedentary pursuits should be encouraged.
While these general recommendations are helpful, it is important to consider alternatives to the traditional CR programming. A comprehensive approach to weight loss that includes a behavioral weight loss intervention should be developed.51 Additionally, the exercise prescription should be individualized with a goal of maximizing CVD risk reduction. A greater volume of exercise (ie, higher caloric exercise training), for example, has been used as an effective intervention to aid individuals in losing weight in CR. Specifically, two studies in CR have used higher caloric exercise training, as a sole intervention (ie, no dietary restriction), to promote weight loss.52,53 The exercise prescription for both these studies included gradually increasing walking distance up to >60 min/session as tolerated, 5-7 d/wk. Individuals in both studies achieved a mean weight loss of 4.5 kg, more than twice the weight loss that is typically seen in CR.51 The combination of exercise and weight loss was associated with favorable effects on the lipid profile, lower insulin levels, and cardiorespiratory fitness increased by 21%.52,53
The use of high caloric exercise training, in tandem with a behavioral weight loss intervention, results in significant weight loss and remission of DM in newly diagnosed individuals who had not yet initiated treatment with a hypoglycemic agent.54 Moreover, for participants in CR, the intervention of high caloric exercise training and behavioral weight loss results in significantly greater weight loss and improvements in multiple metabolic measures as compared with standard CR exercise.51 Both of these studies highlight the significant benefit of the combination of high caloric exercise training and a behavioral weight loss intervention in assisting individuals achieve meaningful weight loss.54,55
Beyond aerobic exercise targeting caloric expenditure, it is important to recognize that individuals with DM have significantly reduced muscle strength as compared with people without DM.56 Evidence suggests that the greater the length of time with a diagnosis of DM and poorer glycemic control were associated with a further reduction of muscle strength. Moreover, the progressive reduction of muscle strength normally associated with the physiologic aging process occurs at an accelerated rate in patients with DM.56 Evidence suggests, however, that greater levels of muscular strength are inversely associated with several CVD risk factors and CVD-related mortality and all-cause mortality.57 Therefore, to mitigate the deleterious effects of reduced muscle strength, resistance training should be considered an integral component of CR programming.57,58 Very briefly, a resistance training exercise prescription should consist of a minimum of one set of 8-15 repetitions of 8-10 exercises that target the major muscle groups of the body. Resistance training should be performed 2-3 times/wk at a moderate to intense level of exertion. Specific details for prescribing resistance training in CR have been described elsewhere.59,60
To our knowledge, there has been no study on the impact of any of the novel medications in the CR setting. Future investigation is needed to assess outcomes and to evaluate the value of these medications for participants in CR. Anecdotally, however, there is evidence that the addition of novel agents may be beneficial. A case study of an individual with a diagnosis of HFrEF and who was treated with a novel DM agent while participating in CR is provided in Supplemental Digital Content 1 (available at: https://links.lww.com/JCRP/A433).
Given the prevalence of obesity, DM and associated risk factors, and HF, CR provides an opportune time to ensure that patients are optimally treated medically and are being encouraged to adopt the appropriate lifestyle behaviors. Newer antihyperglycemic agents not only provide DM management but have also been found to assist with weight loss and reduce the incidence of HF events. Thus, it is important for the CR team to be aware of the utility of these agents, given the benefits beyond glycemic control and to ensure that, when appropriate, patients are treated accordingly.
This research was supported by the National Institutes of Health Center of Biomedical Research Excellence award from the National Institute of General Medical Sciences: P20GM103644 and by the National Heart, Lung and Blood Institute: R33HL143305.
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