SGLT-2 Inhibitors in Heart Failure: Guide for Prescribing and Future Perspectives.

PURPOSE OF REVIEW: Heart failure is responsible for a significant part of diabetes-associated cardiovascular mortality and morbidity. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are novel agents approved for the treatment of diabetes mellitus; in recent clinical trials, these agents have shown a significant reduction in cardiovascular death and hospitalization secondary to heart failure. RECENT FINDINGS: Clinical trials with specific heart failure outcomes have shown the benefit of SGLT-2 inhibitors in reducing the mortality and morbidity associated with heart failure. The guidelines for the management of diabetes mellitus recommend the preferential use of SGLT-2 inhibitors in patients with a history of cardiovascular disease. SGLT-2 inhibitors are potential game changers in the treatment of heart failure. Guidelines for prescription of these agents help assess risk-benefit analysis and personalize treatment for maximal benefit.

The role of sodium glucose co-transporter inhibitors in heart failure prevention.

The worldwide prevalences of diabetes mellitus (DM) and of heart failure (HF) have collectively been on the rise. HF accounts for a large portion of the cardiovascular mortality and morbidity associated with DM. DM increases the risk of developing heart failure by promoting atherosclerosis and exerting direct deleterious effects on the myocardium. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are agents approved for the treatment of DM; they exert their anti-hyperglycemic effects by blocking renal reabsorption of glucose and inducing glycosuria. SGLT-2 inhibitors have consistently decreased the hospitalization rate of HF and cardiovascular mortality in several clinical trials. SGLT-2 inhibitors also possess anti-inflammatory, anti-fibrotic, and antihypertensive in addition to beneficial effects on the myocardial metabolism, which may account for their heart failure benefits. However, further research still needs to be done to evaluate the use of SGLT-2 inhibitors in non-diabetic patients and their efficacy in preventing or treating different heart failure phenotypes.

Antihyperglycemic Therapies With Expansions of US Food and Drug Administration Indications to Reduce Cardiovascular Events: Prescribing Patterns Within an Academic Medical Center.

Sodium-glucose cotransport protein-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to reduce cardiovascular events in high-risk patients with type 2 diabetes mellitus (T2DM). We examined real-world use of these agents at a US academic medical center in the state of Mississippi. Prescriptions, provider specialty, and insurance status of users of SGLT2is and GLP-1RAs in patients with T2DM, and T2DM and cardiovascular disease (CVD) seen from 1st January 2013 to 30th June 2019 were obtained by electronic health records review. We identified 21,173 patients with T2DM and CVD. Overall, 306 (1.4%) and 349 (1.6%) patients received a SGLT2i and GLP-1RA, respectively. After the US Food and Drug Administration (FDA) expanded empagliflozin and liraglutide indications, a mean difference of 19.2 and 12.7 greater quarterly new prescriptions was noted, respectively, whereas no such rise in canagliflozin was observed. Primary care physicians accounted for 53.4% SGLT2i prescriptions, endocrinology for 30.3%, and cardiology for 6.0%. Primary care physicians accounted for 45.1% GLP-1RA prescriptions, endocrinology for 45.0%, and cardiology for 1.4%. Prescription patterns did not largely differ by patient insurance status. In conclusion, prescription of evidence-based therapies to improve CVD outcomes in high-risk patients with T2DM remains very low after several years of evidence generation. Low uptake was evident across insurance types. Modest increases in use were observed after regulatory expansions in labeling; however, cardiologists rarely engaged in prescription, underscoring the need for widespread implementation strategies across health care systems.

Clinical aspects of heart failure in individuals with diabetes.

Heart failure (HF) is an important comorbidity in individuals with diabetes. Most commonly, the condition is secondary to ischaemia and hypertension. Diabetic cardiomyopathy is becoming increasingly recognised as a cause of HF and blood glucose control plays a pivotal role in the prevention and treatment of HF. Since the US Food and Drug Administration regulatory guidance in 2008, new glucose-lowering agents are evaluated routinely by cardiovascular outcome trials. These trials offer a wealth of knowledge and allow better understanding of the risks and benefits of contemporary diabetes medications. In this review, we will focus on the risks of HF with emerging glucose-lowering therapies and the safety of these medications in patients with established HF. We will summarise the guidance that is available for the treatment algorithm of diabetes in those with HF and highlight future areas of research.

Assessment of Heart Failure in Diabetes Cardiovascular Outcomes Trials: Is What We Are Currently Capturing Adequate?

PURPOSE OF REVIEW: Since the 2008 FDA guidance restructuring the design of trials for the approval of novel glucose-lowering agents, 13 medications have now been evaluated by dedicated cardiovascular outcome trials. All of the completed trials have included data (though with varying definitions) on rates of hospitalization for heart failure. This review is aimed at summarizing current heart failure outcome data available from cardiovascular safety trials for novel glucose-lowering agents in patients with type 2 diabetes mellitus. RECENT FINDINGS: There appears to be growing evidence for the benefit of sodium-glucose cotransporter-2 inhibitors, and there are still not enough data to fully support the safety of glucagon-like peptide 1 receptor agonists in heart failure. Increased rates of hospitalization for heart failure were seen with both saxagliptin and alogliptin, and this has led to a class warning for all dipeptidyl peptidase-4 inhibitors. Future studies should have a standardized definition of "hospitalization for heart failure," should consider including hospitalization for heart failure as a component of the primary composite endpoint, and should provide a more detailed description of the baseline characteristics of enrolled study participants with heart failure.

Management of diabetes mellitus in chronic kidney disease.

Diabetes mellitus (DM) and chronic kidney disease (CKD) are two chronic diseases whose prevalence and coprevalence are on the rise. CKD is also the most debilitating and expensive complication of DM while management of DM in CKD is most challenging. CKD is developing in much younger patients with DM, and its presentation is also changing. Various methods of glycemic assessment are affected by CKD and dosage of DM medications needs to be adjusted according to the kidney function. One of the significant barriers to glycemic control in DM patients with CKD is hypoglycemia; close monitoring of glucose levels is essential. Dialysis affects the glucose homeostasis and insulin pharmacokinetics; therefore diabetic medication regimen needs to be adjusted accordingly. Kidney transplants are being increasingly performed as an alternative to dialysis. With the increased survival of transplants secondary to improved immunosuppressive regimen, the prevalence of post-transplant diabetes mellitus is on the increase. Good glycemic control is necessary for the survival of the transplant.

Treatment of Diabetes in Patients with Heart Failure.

PURPOSE OF REVIEW: This review aims to summarize and discuss heart failure outcomes for current glucose-lowering agents in patients with type 2 diabetes mellitus. RECENT FINDINGS: Current regulations require cardiovascular outcomes trials for new glucose-lowering therapies to establish that there is no unacceptable increase in cardiovascular risk prior to approval. These cardiovascular outcomes trials include glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose cotransporter-2 inhibitors. Overall, 87,162 patients have been studied in 10 published cardiovascular outcomes trials. There was no significant increase in major adverse cardiovascular events including cardiovascular mortality, myocardial infarction, and stroke in any of these trials. Heart failure was a component of the secondary endpoint of all of these trials, but only two of these studies show a significant improvement in rates of hospitalization for heart failure. Expanded regulatory labeling for reduction in cardiovascular mortality (empagliflozin) and reduction in major adverse cardiovascular events (liraglutide) has recently been established. Saxagliptin and to a lesser part alogliptin have been associated with an increased rate of hospitalization for heart failure. Canagliflozin and empagliflozin are the only two medications that have shown a clear benefit in rates of heart failure hospitalization in treatment of patients with type 2 diabetes mellitus.

Current therapeutic approaches in the management of hyperglycemia in chronic renal disease.

Diabetes mellitus (DM) and chronic kidney disease (CKD) are intricately intertwined. DM is the most common cause of CKD. Adequate control of DM is necessary for prevention of progression of CKD, while careful management of the metabolic abnormalities in CKD will assist in achieving better control of DM. Two of the key organs involved in glucose production are the kidney and the liver. Furthermore, the kidney also plays a role in glucose filtration and reabsorption. In CKD, monitoring of glycemic control using traditional methods such as Hemoglobin A1c (Hba1c) must be done with caution secondary to associated hematological abnormalities in CKD. With regard to medication management in the care of patients with DM, CKD has significant effects. For example, the dosages of oral and non-insulin anti-hyperglycemic agents often need to be modified according to renal function. Insulin metabolism is altered in CKD, and a reduction in insulin dose is almost always needed. Dialysis also affects various aspects of glucose homeostasis, necessitating appropriate changes in therapy. Due to the aforementioned factors glycemic management in patients with DM and CKD can be quiet challenging.

Transitioning safely from intravenous to subcutaneous insulin.

The transition from intravenous (IV) to subcutaneous (SQ) insulin in the hospitalized patient with diabetes or hyperglycemia is a key step in patient care. This review article suggests a stepwise approach to the transition in order to promote safety and euglycemia. Important components of the transition include evaluating the patient and clinical situation for appropriateness, recognizing factors that influence a safe transition, calculation of proper SQ insulin doses, and deciding the appropriate type of SQ insulin. This article addresses other clinical situations including the management of patients previously on insulin pumps and recommendations for patients requiring glucocorticoids and enteral tube feedings. The use of institutional and computerized protocols is discussed. Further research is needed regarding the transition management of subgroups of patients such as those with type 1 diabetes and end-stage renal disease.

The implementation and evaluation of an evidence-based protocol to treat diabetic ketoacidosis: a quality improvement study.

This retrospective observational quality improvement study was conducted to determine whether an evidence-based protocol for the treatment of diabetic ketoacidosis improved patient outcomes in our academic medical center. This study evaluated fidelity of providers to the protocol, as well as time to resolution of diabetic ketoacidosis as measured by closure of the anion gap (AG). Other secondary outcomes included time to intravenous fluids, time to potassium replacement, and rates of hypoglycemia and hypokalemia.Two cohorts including historical (N = 41) and current (N = 37) were compared to evaluate the effectiveness of the protocol. There were no differences between group demographics at baseline. After implementation of the protocol, 43.2% of patients were treated using full protocol fidelity, 21.6% were treated with partial fidelity, and 35.1% were not treated using the protocol. Although none of the outcomes reached statistical significance, patients in the current group who were treated with full protocol fidelity had an average time to AG closure that was 3 hr less than those who were not treated according to the protocol, and an average time to potassium replacement that was 2 hr less. When comparing the historical cohort with the patients treated with full protocol fidelity, there was improvement in protocol-treated patients in time to AG closure (2 hr), time to dextrose replacement (1.7 hr), and time to potassium replacement (2 hr). The rates of hypokalemia were improved with protocol treatment; 37.5% of protocol-treated patients had hypokalemia as opposed to 63.4% of those not treated according to protocol.Overall, despite the low fidelity in our institution, the protocol promoted evidence-based practice and patients treated according to the protocol had decreased time to treatment outcomes including quicker AG closure, improved intravenous fluids resuscitation, and more accurate and timely electrolyte correction.

Psychosocial predictors of weight regain in the weight loss maintenance trial.

This study's purpose was to identify psychosocial predictors of weight loss maintenance in a multi-site clinical trial, following a group-based weight loss program. Participants (N = 1025) were predominately women (63%) and 38% were Black (mean age = 55.6 years; SD = 8.7). At 12 months, higher SF-36 mental health composite scores were associated with less weight regain (p < .01). For Black participants, an interaction existed between race and friends' encouragement for exercise, where higher exercise encouragement was related to more weight regain (p < .05). At 30 months, friends' encouragement for healthy eating was associated with more weight regain (p < .05), whereas higher SF-36 mental health composite scores were related to less weight regain (p < .0001). Perceived stress and select health-related quality of life indices were associated with weight regain; this relationship varied across gender, race, and treatment conditions. Temporal changes in these variables should be investigated for their impact on weight maintenance.

Pathways to quality inpatient management of hyperglycemia and diabetes: a call to action.

Currently patients with diabetes comprise up to 25-30% of the census of adult wards and critical care units in our hospitals. Although evidence suggests that avoidance of hyperglycemia (>180 mg/dL) and hypoglycemia (<70 mg/dL) is beneficial for positive outcomes in the hospitalized patient, much of this evidence remains controversial and at times somewhat contradictory. We have recently formed a consortium for Planning Research in Inpatient Diabetes (PRIDE) with the goal of promoting clinical research in the area of management of hyperglycemia and diabetes in the hospital. In this article, we outline eight aspects of inpatient glucose management in which randomized clinical trials are needed. We refer to four as system-based issues and four as patient-based issues. We urge further progress in the science of inpatient diabetes management. We hope this call to action is supported by the American Diabetes Association, The Endocrine Society, the American Association of Clinical Endocrinologists, the American Heart Association, the European Association for the Study of Diabetes, the International Diabetes Federation, and the Society of Hospital Medicine. Appropriate federal research funding in this area will help ensure high-quality investigations, the results of which will advance the field. Future clinical trials will allow practitioners to develop optimal approaches for the management of hyperglycemia in the hospitalized patient and lessen the economic and human burden of poor glycemic control and its associated complications and comorbidities in the inpatient setting.

Sex hormone changes during weight loss and maintenance in overweight and obese postmenopausal African-American and non-African-American women.

INTRODUCTION: Changes in sex hormones with weight loss might have implications for breast cancer prevention but have not been examined extensively, particularly in African-American (AA) women. METHODS: We conducted a prospective study of 278 overweight/obese postmenopausal women (38% AA) not taking hormone therapy within the Weight Loss Maintenance Trial. All participants lost at least 4 kg after a 6-month weight-loss phase and attempted to maintain weight loss during the subsequent 12 months. We evaluated the percentage changes in estrone, estradiol, free estradiol, testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate and sex hormone-binding globulin (SHBG) using generalized estimating equations. RESULTS: In all study phases, AA women had higher levels of estrogen and testosterone concentrations, independent of adiposity. On average, participants lost 7.7 kg during the weight-loss phase, and concentrations of estrone (-5.7%, P = 0.006), estradiol (-9.9%, P <0.001), free estradiol (-13.4%, P <0.0001), and free testosterone (-9.9%, P <0.0001) decreased, while the SHBG concentration (16.2%, P <0.001) increased. Weight change did not significantly affect total testosterone or other androgen concentrations. Compared with non-AA women, AA women experienced less change in estrogens per kilogram of weight change (that is, per 1 kg weight loss: estrone, -0.6% vs. -1.2%, P-interaction = 0.10; estradiol, -1.1% vs. -1.9%, P-interaction = 0.04; SHBG, 0.9% vs. 1.6%, P-interaction = 0.006; free estradiol, -1.4% vs. -2.1%, P-interaction = 0.01). CONCLUSION: To the best of our knowledge this is the first study to examine and compare the effects of intentional weight loss and maintenance on a panel of sex hormones in AA women and non-AA women. Although speculative, these data suggest hormonal differences may contribute to different racial patterns of breast cancer incidence and mortality and encourage further investigations to understand the long-term effects of weight loss on sex hormones in obese postmenopausal women. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00054925.

Blood Pressure-Lowering Mechanisms of the DASH Dietary Pattern.

Potential blood pressure- (BP-) lowering mechanisms of the DASH dietary pattern were measured in 20 unmedicated hypertensive adults in a controlled feeding study. At screening, participants averaged 44.3 ± 7.8 years, BMI 33.9 ± 6.6 Kg/m(2), and BP 144.2 ± 9.38/88.5 ± 6.03 mmHg. All consumed a control diet for one week, then were randomized to control or DASH for another two weeks (week one and two). With DASH, but not controls, SBP fell by 10.65 ± 12.89 (P = 0.023) and 9.60 ± 11.23 (P = 0.039) mmHg and DBP by 5.95 ± 8.01 (P = 0.069) and 8.60 ± 9.13 mmHg (P = 0.011) at the end of week one and two, respectively. Univariate regressions showed that changes in urinary sodium/potassium ratio (ß = 1.99) and plasma renin activity (ß = -15.78) and percent change in plasma nitrite after hyperemia were associated with SBP changes at week one (all P < 0.05). Plasma nitrite following hyperemia showed a treatment effect (P = 0.014) and increased at week two (P = 0.001). Pulse wave velocity decreased over time with DASH (trend P = 0.019), and reached significance at week two (P = 0.026). This response may be mediated by an improvement in upregulation of nitric oxide bioavailability. Early natriuresis and reductions in oxidative stress cannot be ruled out. Future studies are needed to verify these findings, assess the possibility of earlier effects, and examine other potential mediators.

Influence of change in aerobic fitness and weight on prevalence of metabolic syndrome.

INTRODUCTION: The metabolic syndrome is the clustering of several cardiometabolic risk factors that can lead to the development of coronary heart disease and type 2 diabetes. We evaluated whether a change in aerobic fitness resulting from a lifestyle intervention could significantly change the odds of metabolic syndrome prevalence. METHODS: Participants (n = 810) were recruited into PREMIER, a multicenter, randomized, controlled clinical trial with outcome assessments at 6 and 18 months. The primary eligibility criterion was a diagnosis of prehypertension or stage 1 hypertension. PREMIER randomized participants to 2 lifestyle interventions, both of which included increased physical activity, or an advice-only control group. Participants completed a submaximal treadmill exercise test; we used reduction in heart rate as the measure of improved aerobic fitness. We used logistic regression to determine intervention effects on metabolic syndrome prevalence. Our models controlled for dietary pattern change. RESULTS: The lifestyle interventions had no significant effect on metabolic syndrome prevalence at 6 months or 18 months. When combining intervention and control groups, at 6 and 18 months, a 1-beat-per-minute reduction in heart rate was associated with a 4% reduction in prevalence of metabolic syndrome (P < .001). When we tested for weight change as a mediator, the association was no longer significant. CONCLUSION: Increased aerobic fitness may reduce prevalence of metabolic syndrome. This association appears to be mediated through concomitant weight change.

Predictors of long-term weight loss in adults with modest initial weight loss, by sex and race.

Effective weight management interventions could reduce race-sex disparities in cardiovascular disease (CVD), yet little is known about factors associated with successful weight loss maintenance in race-sex subgroups. In the Weight Loss Maintenance trial (WLM), overweight/obese (BMI 25-45 kg/m(2)) adults who lost ≥4 kg in a 6-month behavioral weight loss intervention (phase I) were randomized into one of three 30-month maintenance interventions (phase II). To investigate predictors in subgroups, randomized groups were combined for this analysis. Of 1,685 phase I participants, 1,032 (61%) entered phase II, including 12% black men (BM), 26% black women (BW), 25% white men (WM), and 37% white women (WW). Weight change over the 36-month study ranged from -2.3% (95% confidence interval = -3.1 to -1.5%) in BW to -4.5% (95% confidence interval = -5.7 to -4.0%) in WM, the result of differential weight loss during phase I. Within race, men lost significantly more weight than women, but within sex group, weight loss did not differ significantly between races. Although participants regained weight during phase II, regain did not differ by race-sex group, and mean weight at the end of the study was significantly lower than phase I entry weight for each subgroup. In regression models, phase I weight loss predicted overall 36-month weight loss in all race-sex groups. Healthy dietary pattern at entry, improvement in dietary pattern, or both were predictive in three of four race-sex groups. Few other variables other than initial weight loss and dietary pattern were predictive. Future research should identify additional modifiable influences on long-term maintenance after a modest weight loss.

Dietary intakes associated with successful weight loss and maintenance during the Weight Loss Maintenance trial.

BACKGROUND: Dietary components effective in weight maintenance efforts have not been adequately identified. OBJECTIVE: To determine the effects of changes in dietary consumption on weight loss and maintenance during the Weight Loss Maintenance clinical trial. DESIGN: Weight Loss Maintenance was a randomized controlled trial. Successful weight loss participants who completed Phase I of the trial and lost 4 kg were randomized to one of three maintenance intervention arms in Phase II and followed for an additional 30 months. PARTICIPANTS/SETTING: The multicenter trial was conducted from 2003 through 2007. This substudy included 828 successful weight loss participants. METHODS: The Block Food Frequency Questionnaire (FFQ) was used to assess nutrient intake levels and food group servings. Carbohydrates, proteins, fats, dietary fiber, fruit/vegetable, and dairy servings were utilized as predictor variables. The FFQ was collected on all participants at study entry (beginning of Phase I). Those randomized to Phase II completed the FFQ at three additional time points: randomization (beginning of Phase II), 12 months, and 30 months. INTERVENTION: The main intervention focused on long-term maintenance of weight loss using the Dietary Approaches to Hypertension diet. This substudy examined if changes to specific dietary variables were associated with weight loss and maintenance. STATISTICAL ANALYSES PERFORMED: Linear regression models that adjusted for change in total energy examined the relationship between changes in dietary intake and weight for each time period. Site, age, race, sex, and a race-sex interaction were included as covariates. RESULTS: Participants who substituted protein for fat lost, on average, 0.33 kg per 6 months during Phase I (P<0.0001) and 0.07 kg per 6 months during Phase II (P<0.0001) per 1% increase in protein. Increased intake of fruits and vegetables was associated with weight loss in Phases I and II: 0.29 kg per 6 months (P<0.0001) and 0.04 kg per 6 months (P=0.0062), respectively, per 1-serving increase. Substitution of carbohydrates for fat and protein for carbohydrates were associated with weight loss during both phases. Increasing dairy intake was associated with significant weight loss during Phase II (-0.17 kg per 6 months per 1-serving increase, P=0.0002), but not during Phase I. Dietary fiber revealed no significant findings. CONCLUSIONS: Increasing fruits, vegetables, and low-fat dairy may help achieve weight loss and maintenance.

Gene by sex interaction for measures of obesity in the framingham heart study.

Obesity is an increasingly prevalent and severe health concern with a substantial heritable component and marked sex differences. We sought to determine if the effect of genetic variants also differed by sex by performing a genome-wide association study modeling the effect of genotype-by-sex interaction on obesity phenotypes. Genotype data from individuals in the Framingham Heart Study Offspring cohort were analyzed across five exams. Although no variants showed genome-wide significant gene-by-sex interaction in any individual exam, four polymorphisms displayed a consistent BMI association (P-values .00186 to .00010) across all five exams. These variants were clustered downstream of LYPLAL1, which encodes a lipase/esterase expressed in adipose tissue, a locus previously identified as having sex-specific effects on central obesity. Primary effects in males were in the opposite direction from females and were replicated in Framingham Generation 3. Our data support a sex-influenced association between genetic variation at the LYPLAL1 locus and obesity-related traits.

Measurement of weight in clinical trials: is one day enough?

Background. Weight is typically measured on a single day in research studies. This practice assumes negligible day-to-day weight variability, although little evidence exists to support this assumption. We compared the precision of measuring weight on one versus two days among control participants in the Weight Loss Maintenance trial. Methods. Trained staff measured weight on two separate days at baseline, 12 months, and 30 months (2004-2007). We calculated the standard deviation (SD) of mean weight change from baseline to the 12- and 30-month visits using (a) the first and (b) both daily weights from each visit and conducted a variance components analysis (2009). Results. Of the 316 participants with follow-up measurements, mean (SD) age was 55.8 (8.5) years, BMI was 30.8 (4.5) kg/m(2), 64% were women, 36% were black, and 50% were obese. At 12 months, the SD of mean weight change was 5.1 versus 5.0 kg using one versus two days of weight measurements (P = .76), while at 30 months the corresponding SDs were 6.3 and 6.3 kg (P = .98). We observed similar findings within subgroups of BMI, sex, and race. Day-to-day variability within individuals accounted for <1% of variability in weight. Conclusions. Measurement of weight on two separate days has no advantage over measurement on a single day in studies with well-standardized weight measurement protocols.