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.

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.

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.

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.

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.

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.

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.

Associations of internet website use with weight change in a long-term weight loss maintenance program.

BACKGROUND: The Weight Loss Maintenance Trial (WLM) compared two long-term weight-maintenance interventions, a personal contact arm and an Internet arm, with a no-treatment control after an initial six-month Phase I weight loss program. The Internet arm focused on use of an interactive website for support of long-term weight maintenance. There is limited information about patterns of website use and specific components of an interactive website that might help promote maintenance of weight loss. OBJECTIVE: This paper presents a secondary analysis of the subset of participants in the Internet arm and focuses on website use patterns and features associated with long-term weight maintenance. METHODS: Adults at risk for cardiovascular disease (CVD) who lost at least 4 kilograms in an initial 20-week group-based, behavioral weight-loss program were trained to use an interactive website for weight loss maintenance. Of the 348 participants, 37% were male and 38% were African American. Mean weight loss was 8.6 kilograms. Participants were encouraged to log in at least weekly and enter a current weight for the 30-month study period. The website contained features that encouraged setting short-term goals, creating action plans, and reinforcing self-management habits. The website also included motivational modules, daily tips, and tailored messages. Based on log-in and weight-entry frequency, we divided participants into three website use categories: consistent, some, and minimal. RESULTS: Participants in the consistent user group (n = 212) were more likely to be older (P = .002), other than African American (P = .02), and more educated (P = .01). While there was no significant difference between website use categories in the amount of Phase I change in body weight (P = .45) or income (P = .78), minimal website users (n = 75) were significantly more likely to have attended fewer Phase I sessions (P = .001) and had a higher initial body mass index (BMI) (P < .001). After adjusting for baseline characteristics including initial BMI, variables most associated with less weight regain included: number of log-ins (P = .001), minutes on the website (P < .001), number of weight entries (P = .002), number of exercise entries (P < .001), and sessions with additional use of website features after weight entry (P = .002). CONCLUSION: Participants defined as consistent website users of an interactive behavioral website designed to promote maintenance of weight loss were more successful at maintaining long-term weight loss. TRIAL REGISTRATION: NCT00054925; http://clinicaltrials.gov/ct2/show/NCT00054925 (Archived by WebCite at http://www.webcitation.org/5rC7523ue).

Development and implementation cost analysis of telephone- and Internet-based interventions for the maintenance of weight loss.

OBJECTIVES: The Weight Loss Maintenance Trial (WLM) was a multicenter, randomized trial comparing two weight loss maintenance interventions, a personal contact (PC) program with primarily telephone-based monthly contacts, and an Internet-based program (interactive technology, IT), to a self-directed control group, among overweight or obese individuals at high cardiovascular risk. This study describes implementation costs of both interventions as well as IT development costs. METHODS: Resources were micro-costed in 2006 dollars from the primary perspective of a sponsoring healthcare system considering adopting an extant intervention, rather than developing its own. Costs were discounted at 3 percent annually. Length of trial participation was 30 months (randomization during February-November 2004). IT development costs were assessed over 36 months. Univariate and multivariate, including probabilistic, sensitivity analyses were performed. RESULTS: Total discounted IT development costs over 36 months were $839,949 ($2,414 per IT participant). Discounted 30-month implementation costs for 342 PC participants were $537,242 ($1,571 per participant), and for 348 IT participants, were $214,879 ($617 per participant). Under all plausible scenarios, PC implementation costs exceeded IT implementation costs. CONCLUSIONS: Costs of implementing and operating an Internet-based intervention for weight loss maintenance were substantially less than analogous costs of an intervention using standard phone and in-person contacts and are of a magnitude that would be attractive to many health systems, subject to demonstration of cost-effectiveness.

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.

Metabolic syndrome.

Hirsutism is a finding that can lead to subsequent metabolic diagnoses such as the metabolic syndrome. Metabolic syndrome describes a cluster of cardiometabolic risk factors associated with overweight and obesity. Although it has been the subject of some controversy, perhaps due to the many definitions proposed by different health organizations, metabolic syndrome is clinically relevant in that it is a predictor of vascular risk, even independent of any associated type 2 diabetes. While various definitions may differ in precise cut-off points, they uniformly emphasize key pathophysiologic processes: visceral obesity, dyslipidemia, insulin resistance, and hypertension. Management of metabolic syndrome focuses on methods of reducing the component risk factors, and therapies thus target the above processes as well as controlling inflammation and the prothrombotic state. Treatments can include not only pharmacologic approaches but behavior modification as well.

Comparison of strategies for sustaining weight loss: the weight loss maintenance randomized controlled trial.

CONTEXT: Behavioral weight loss interventions achieve short-term success, but re-gain is common. OBJECTIVE: To compare 2 weight loss maintenance interventions with a self-directed control group. DESIGN, SETTING, AND PARTICIPANTS: Two-phase trial in which 1032 overweight or obese adults (38% African American, 63% women) with hypertension, dyslipidemia, or both who had lost at least 4 kg during a 6-month weight loss program (phase 1) were randomized to a weight-loss maintenance intervention (phase 2). Enrollment at 4 academic centers occurred August 2003-July 2004 and randomization, February-December 2004. Data collection was completed in June 2007. INTERVENTIONS: After the phase 1 weight-loss program, participants were randomized to one of the following groups for 30 months: monthly personal contact, unlimited access to an interactive technology-based intervention, or self-directed control. Main Outcome Changes in weight from randomization. RESULTS: Mean entry weight was 96.7 kg. During the initial 6-month program, mean weight loss was 8.5 kg. After randomization, weight regain occurred. Participants in the personal-contact group regained less weight (4.0 kg) than those in the self-directed group (5.5 kg; mean difference at 30 months, -1.5 kg; 95% confidence interval [CI], -2.4 to -0.6 kg; P = .001). At 30 months, weight regain did not differ between the interactive technology-based (5.2 kg) and self-directed groups (5.5 kg; mean difference -0.3 kg; 95% CI, -1.2 to 0.6 kg; P = .51); however, weight regain was lower in the interactive technology-based than in the self-directed group at 18 months (mean difference, -1.1 kg; 95% CI, -1.9 to -0.4 kg; P = .003) and at 24 months (mean difference, -0.9 kg; 95% CI, -1.7 to -0.02 kg; P = .04). At 30 months, the difference between the personal-contact and interactive technology-based group was -1.2 kg (95% CI -2.1 to -0.3; P = .008). Effects did not differ significantly by sex, race, age, and body mass index subgroups. Overall, 71% of study participants remained below entry weight. CONCLUSIONS: The majority of individuals who successfully completed an initial behavioral weight loss program maintained a weight below their initial level. Monthly brief personal contact provided modest benefit in sustaining weight loss, whereas an interactive technology-based intervention provided early but transient benefit. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00054925.

Protease inhibitor-induced diabetic complications : incidence, management and prevention.

Protease inhibitors (PIs) have become a crucial element in the treatment of patients infected with HIV. However, the widespread use of PI therapy has also been associated with a number of metabolic adverse effects, including fat redistribution and hyperglycaemia. The objective of this review is a discussion of the incidence, pathophysiology, management and prevention of PI-associated hyperglycaemia. Initial case reports have been followed by large cross-sectional and cohort studies, which demonstrate that the incidence of PI-induced impaired glucose tolerance, as well as frank diabetes mellitus, is significant and demands attention. Investigations into the pathophysiology behind PI-associated hyperglycaemia have identified an underlying problem of insulin resistance that is presumably caused by both direct PI-induced mechanisms and lipotoxicity. Given this, clinical trials have explored the use of various classes of oral hypoglycaemic agents in the management of PI-induced diabetic complications, and the use of insulin therapy must be considered as well. Newer PI agents are also under development, with the hope of reducing metabolic adverse effects. In the meantime, prevention, in the form of dietary modification, regular physical activity and periodic screening for impaired glucose tolerance, must receive heightened attention in the care plan of patients receiving long-term PI therapy.

The Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) weight loss project: Rationale and design.

This paper outlines the rationale and design of the Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) weight loss project, in which detailed biologic profiling of three hundred and fifty obese individuals (body mass index (BMI): 30-50 kg/m(2)) will be conducted as they lose weight via seven distinct interventions. These profiles will be compared to those of fifty normal, healthy, control participants (BMI: 18.5-24.9 kg/m(2)). The interventions include the following: Roux-en-Y gastric bypass surgery, dietary interventions of differing macronutrient composition and diverse pharmacologic interventions. Outcome variables include eight conventional metabolites and CRP measured by standard clinical chemistry techniques, twenty hormones of energy balance and fuel homeostasis measured by radioimmunoassay (RIA) or by enzyme-linked Immunosorbent assay (ELISA), ten pro- and anti-inflammatory cytokines measured using Luminex xMAP technology, one hundred and one intermediary metabolites measured by targeted mass-spectrometry-based methods, and physiologic variables such as body composition measured by dual energy X-ray absorptiometry (DEXA), air displacement plethysmography, and abdominal computerized tomography (CT), insulin sensitivity measured by intravenous glucose tolerance test (IV-GTT) and metabolic rate measured by indirect calorimetry. Results from this study will expand our knowledge of the biology of obesity and weight regulation and may lead to targeted strategies for its treatment and control.

Optimizing hospital use of intravenous insulin therapy: improved management of hyperglycemia and error reduction with a new nomogram.

OBJECTIVE: To assess the efficacy and safety of intravenous (IV) insulin administration with use of our institution's old protocol (pre-nomogram phase) as compared with our new insulin nomogram (post-nomogram phase), which titrates insulin dose based on the rate of change of plasma glucose values and uses multipliers to determine the new insulin infusion rate. METHODS: Hospitalized adults receiving an IV insulin infusion in our tertiary care medical center were enrolled in this study after informed consent was obtained. The study was an observational analysis conducted before and after implementation of the new insulin infusion nomogram. Measurements included episodes of hypoglycemia and incidence of the following errors in the insulin infusion process: (1) episodes of documented failure to increase insulin infusion rate despite persistent hyperglycemia and (2) number of times the IV infusion was stopped without subcutaneous administration of insulin. RESULTS: Overall, 66 patients were analyzed (38 in the pre-nomogram phase and 28 in the post-nomogram phase). The new nomogram reduced by nearly 3-fold (from 0.89 +/- 0.68 to 0.36 +/- 0.49 occurrence per patient per 24 hours; P<0.001) the mean incidence of failure to give insulin subcutaneously before discontinuation of IV insulin infusion. Moreover, the nomogram nearly eliminated the error of caregiver nonresponsiveness to persistent hyperglycemia: mean incidence 0.39 +/- 0.65 occurrence per patient per 24 hours before implementation of the new nomogram versus 0.02 +/- 0.09 afterward (P<0.002). There was no statistically significant difference in episodes of hypoglycemia between the 2 study groups. CONCLUSION: Safe IV administration of insulin through error prevention is essential. Implementation of a new IV insulin infusion nomogram, which adjusts insulin infusion using multipliers, reduces errors and improves glycemic control without increasing hypoglycemic episodes.