Diabetes professionals ‘reeling’
from recent meds-CVD research
DETROIT – The importance of health-care providers communicating cardiovascular issues to diabetes patients can’t be over-estimated---especially with recent treatment developments.
“We need to communicate to patients that we now have medications with the potential to provide cardiovascular benefits,” says Davida F. Kruger, a certified nurse practitioner (NP) in diabetes at Henry Ford Health System’s Division of Endocrinology, Diabetes, Bone and Mineral Disease, Detroit.
Kruger, a faculty member of Metabolic & Endocrine Disease Summit (MEDS) and American Diabetes Association (ADA) 2017 educator of the year, notes that while patients hear about new medications from television commercials, from articles in print and online, it is important that their health-care providers be knowledgeable and explain these medications and their benefits to their patients, both in terms of lowering A1C and in their potential cardiovascular benefits.
“We need to talk,” says Kruger, “with patients about the fact that the risks of diabetes complications include cardiovascular disease, and that some of these (newer) medications lower blood glucose and A1C, and also have some protection in terms of cardiovascular outcomes, and the importance of selecting drugs for patients at risk for cardiovascular complications. That there are drugs that might also provide cardiovascular benefits.”
An article published in October in The Nurse Practitioner, co-authored by Kruger, addresses sodium-glucose cotransporter-2 (SGLT2) inhibitors and their potential benefits for type 2 diabetes mellitus (T2DM) patients at high cardiovascular disease (CVD) risk who already take multiple medications.
The article lists two such medications approved in the United States---canagliflozin and empagliflozin---and makes the following points in setting patient expectations:
- it is important that patients understand what percentage increase in A1C can be expected from these medications
- SGLT2 clinical trials report A1C decreases from -0.5% to 1.5% when used as monotherapy
- if patients are treatment-naïve or have higher-baseline A1C values, reductions may be larger than observed in clinical trials
- patients should be warned to expect urine-volume increases as they initiate therapy and maintain adequate hydration levels
The road to diabetes medications addressing CVD issues was repaved in 2008, when the U.S. Food & Drug Administration (FDA) issued guidance requiring robust assessment of cardiovascular safety for all anti-diabetic drugs to be licensed in the future. The agency recommended that when drugs are developed for glycemic management of type 2 diabetes, it be shown that these medications do not increase the risk of cardiovascular events over placebo levels.
“New drugs,” Kruger explains, “must be shown to be equal to placebos, to cause no more harm than placebos, to show no increase in myocardial infarctions, sudden death or stroke.” These three issues comprise three-point primary major adverse cardiac events (MACE)---cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke.
Empagliflozin treatment, as noted in The Nurse Practitioner article, was found in secondary analysis to result in a 38% relative risk reduction (RRR) in cardiovascular death and improved overall survival with a 32% RRR in all-cause mortality. Data from the EMPAG-REG OUTCOME study lists it as the first of the recently-approved glucose-lowering agents to significantly reduce cardiovascular-mortality risk among T2DM patients with pre-existing CVD.
Canagliflozin treatment, as noted in a study published in August in the New England Journal of Medicine (NEJM), reporting on two recent CANVAS, or CANagliflozin CardioVascular Assessment Study, trials, resulted in lower risks of cardiovascular events than for patients receiving placebos---with greater amputation risk.
The increased amputation risk, as reported in the NEJM article, was 6.3 versus 3.4 participants per 1,000 patient-years, with hazard ratio, 1.97; 95% confidence interval (CI), 1.41 to 2.75; amputations were primarily at the level of the toe or metatarsal.
The Nurse Practitioner article adds that trials for dapagliflozin indicate that rates of genital mycotic infections (GMIs) are higher with this drug than placebos.
Another recent article in the same publication, addressing dipeptidyl peptidase-4 (DPP4) inhibitors, lists four drugs approved for U.S. use for T2DM patients: saxagliptin and alogliptin (with warnings that patients taking these should be monitored for heart failure), linagliptin, and sitagliptin (for which the ADA this year notes has neutral effects on cardiovascular risk and raises no significant safety concerns among older patients with well-controlled type 2 diabetes and CVD).
Lastly, a study published in August in NEJM addresses treatment for type 2 diabetes patients at high cardiovascular risk with liraglutide and indicates lower diabetic-kidney disease rates than placebo; the study also notes that liraglutide resulted in lower risks of the primary end point (non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes) and death.
“We are reeling,” Kruger concludes, from the succession of drugs being developed and researched for those battling diabetes coupled with CVD.
CITATION: Novak, Lucia M. MSN, ANP-BC, BC-ADM, CDTC; Kruger, Davida F. MSN, APN-BC, BC-ADM. Bolstering your armamentarium with SGLT2 inhibitors. The Nurse Practitioner. 18 October, 2017. Volume 42, Issue 10, P. 28-34. http://journals.lww.com/tnpj/Fulltext/2017/10000/Bolstering_your_armamentarium_with_SGLT2.6.aspx Bernard Zinman, M.D., Christoph Wanner, M.D., et. al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. The New England Journal of Medicine. November 26, 2015. http://www.nejm.org/doi/full/10.1056/NEJMoa1504720#t=article
Bittle, Polly A. MSN, ARNP, FNP-C. The use of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes & chronic kidney disease. The Nurse Practitioner. 16 June 2017. Volume 42, Issue 6. P. 31-37. http://journals.lww.com/tnpj/Fulltext/2017/06000/The_use_of_dipeptidyl_peptidase_4_inhibitors_in.8.aspx
Bruce Neal, M.B., Ch.B., Ph.D., Vlado Perkovic, M.B., B.S., Ph.D., et. al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. The New England Journal of Medicine. August 17, 2017. http://www.nejm.org/doi/full/10.1056/NEJMoa1611925
Johannes F.E. Mann, M.D., David D. Ørsted, M.D., Ph.D. et. al. Liraglutide and Renal Outcomes in Type 2 Diabetes. The New England Journal of Medicine. August 31, 2017. 377:839-848. http://www.nejm.org/doi/full/10.1056/NEJMoa1616011
(Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.) Anthony A. Bavry, M.D., M.P.H., FACC. Canagliflozin Cardiovascular Assessment Study – CANVAS. American College of Cardiology. August 22, 2017. http://www.acc.org/latest-in-cardiology/clinical-trials/2017/06/12/16/25/canvas Oliver Schnell , Lars Rydén, et. al. Current perspectives on cardiovascular outcome trials in diabetes. Cardiovascular Diabetology. 2016. 15:139. 1 October 2016. https://cardiab.biomedcentral.com/articles/10.1186/s12933-016-0456-8
Prevalence of obesity at 39.8%
among adults in United States
ATLANTA – Obesity prevalence was 39.8% among adults and 18.5% among youths in the United States in 2015-to-2016, according to information released by the Centers for Disease Control and Prevention (CDC).
Key points in data released in October by the Atlanta-based CDC and obtained from the National Health and Nutrition Examination Survey (NHANES), include:
- obesity prevalence increased in adults and youths between 1999-to-2000 and 2015-to-2016
- prevalence of obesity was higher among middle-aged adults (42.8%) than among younger adults (35.7%)
- prevalence of obesity was higher among youths aged six-to-11 years (18.4%) and adolescents aged 12-to-19 (20.6%) compared with children aged two-to-five years (13.9%)
- overall prevalence of obesity was higher among non-Hispanic black and Hispanic adults than among non-Hispanic white and non-Hispanic Asian adults, with the same pattern seen among youths
- the observed change in prevalence between 2013-to-2014 and 2015-to-2016 was not significant among both adults and youth
- women had a higher prevalence of obesity than men among non-Hispanic black, non-Hispanic Asian, and Hispanic adults, but not among non-Hispanic white adults
- prevalence of obesity in the United States remains higher than the Healthy People 2020 goals of 14.5% among youths and 30.5% among adults
The study’s lead author, Craig M. Hales, a CDC medical epidemiologist, told CNN that since 1999, there has been a major increase in obesity prevalence, especially among adults, without any “signs of it slowing down.”
Hale adds that while youth obesity rates seemed to have stabilized in recent years, it is “too early to tell” what direction obesity in this demographic will take, as at least four more years of data are needed to gauge the direction.
CITATION: Craig M. Hales, M.D., Margaret D. Carroll, M.S.P.H., et. al. Prevalence of Obesity Among Adults and Youth: United States, 2015–2016. Centers for Disease Control and Prevention. NCHS Data Brief No. 288, October 2017. https://www.cdc.gov/nchs/products/databriefs/db288.htm
Cardiovascular, mortality benefits said
to outweigh CKD risks of SBP-lowering
SALT LAKE CITY – Intensive systolic blood pressure (SBP)-lowering increases the risk of incident chronic kidney disease (CKD) events, according to a study published recently by the Annals of Internal Medicine also indicating that this is outweighed by cardiovascular and all-cause mortality benefits.
Authors of the study published in September and primarily funded by the National Institutes of Health (NIH) include Srinivasan Beddhu, University of Utah School of Medicine, Salt Lake City, and Michael V. Rocco, who practices medicine in Winston-Salem, N.C.
The researchers set out to examine the effects of intensive SBP lowering on kidney-and-cardiovascular outcomes and contrast its apparent beneficial-and-adverse effects.
They assessed 6,662 adults with high blood pressure and elevated cardiovascular risk, randomly assigned to an intensive or standard SBP goal (120 or 140 mm Hg, respectively).
- differences in mean estimated glomerular filtration rate (eGFR) during follow-up (estimated with a linear mixed-effects model)
- pre-specified incident CKD (defined as a decrease of more than 30% in eGFR to a value of less than 60 mL/min/1.73 m2)
- a composite of all-cause death or cardiovascular event, with surveillance every three months
The difference in adjusted mean eGFR between the intensive and standard groups was − 3.32 mL/min/1.73 m2 (95% CI, −3.90 to −2.74 mL/min/1.73 m2) at six months; − 4.50 mL/min/1.73 m2 (CI, −5.16 to −3.85 mL/min/1.73 m2) at 18 months; and remained relatively stable thereafter.
An incident CKD event occurred in 3.7% of participants in the intensive group and 1.0% in the standard group at three-year follow-up, with a hazard ratio of 3.54 (CI, 2.50 to 5.02).
The corresponding percentages for the composite of death or cardiovascular event were 4.9% and 7.1% at three-year follow-up, with a hazard ratio of 0.71 (CI, 0.59 to 0.86).
The researchers noted the limitation of a lack of long-term data.
CITATION: Srinivasan Beddhu, MD, Michael V. Rocco, MD, MSCE, et. al.
Effects of Intensive Systolic Blood Pressure Control on Kidney and Cardiovascular Outcomes in Persons Without Kidney Disease: A Secondary Analysis of a Randomized Trial. Annals of Internal Medicine. ORIGINAL RESEARCH |19 SEPTEMBER 2017. http://annals.org/aim/article/2652565/effects-intensive-systolic-blood-pressure-control-kidney-cardiovascular-outcomes-persons
Pre-term infants’ improvements
linked to 800-IU vitamin-D doses
OMAHA, NEB. – A recent study indicates that improvements in 25(OH)D3 levels at four weeks, bone density, and trends towards improvement in linear growth support consideration of daily vitamin-D doses of 800 international units (IUs) for infants younger than 32 weeks in neonatal intensive care units (NICUs).
The study published in October in PLoS ONE was designed to evaluate serum 25(OH)D3 concentration changes after four weeks in response to two different doses of vitamin D3 supplementation in a population of premature infants, and quantify the impact on NICU outcomes.
Its authors---including Ann Anderson-Berry, University of Nebraska Medical Center, Omaha, Neb.---prospectively randomized 32 infants born at 24-to-32 weeks gestation to receive 400 or 800 IU/day vitamin D3 supplementation.
Serum 25(OH)D3 levels were measured every four weeks. The Wilcoxon signed rank test was used to compare serum levels of 25(OH)D3 at four weeks and each subsequent time point; a p-value of less than 0.05 was considered statistically- significant.
Serum 25(OH)D3 levels at birth were 41.9 and 42.9 nmol/l for infants in the 400 IU group and 800 IU group, respectively. Cord 25(OH)D3 concentrations significantly correlated with gestational age.
After four weeks of D3 supplementation, median 25(OH)D3 levels increased in both groups. Infants in the 400 IU group were significantly more likely to have dual energy X-ray absorptiometry (DEXA) bone-density measurements less than 10 percentile.
Vitamin D supplementation for pre-term and term neonates is recommended by such groups as the American Academy of Pediatrics (AAP); the Institute of Medicine (IOM), now the National Academy of Medicine (NAM); the Endocrine Society; and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).
Also: A study of vitamin D and hypertension published in September in Electrolytes and Blood Pressure---whose authors include Hye Yun Jeong, CHA University, South Korea---indicates that the results of randomized controlled trials (RCTs) and meta-analysis do not support the use of vitamin D or its analogues as an individual-patient treatment for hypertension or as a population-level intervention to lower blood pressure. The study can be accessed at https://synapse.koreamed.org/DOIx.php?id=10.5049/EBP.2017.15.1.1
CITATION: Ann Anderson-Berry, Melissa Thoene, et al. Randomized trial of two doses of vitamin D3 in preterm infants <32 weeks: Dose impact on achieving desired serum 25(OH)D3 in a NICU population. PLoS ONE. 12(10): e0185950. Received: April 5, 2017. Accepted: September 23, 2017. Published: October 10, 2017. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185950
Romosozumab boosted by study
involving post-menopausal women
BIRMINGHAM, ALA. – A study involving more than 4,000 subjects indicates that among post-menopausal women with osteoporosis at high-fracture risk, romosozumab treatment for 12 months followed by alendronate results in a significantly-lower fracture risk than alendronate alone.
Authors of the study published in October in the New England Journal of Medicine---including Kenneth G. Saag, UAB School of Medicine, Birmingham, Ala.---note that romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption.
The researchers enrolled 4,093 post-menopausal women with osteoporosis and a fragility fracture and randomly assigned them in a one-to-one ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by open-label alendronate in both groups.
The primary-end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (non-vertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in at least 330 patients).
Secondary end points included the incidences of non-vertebral and hip fracture at the time of the primary analysis.
Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group.
Clinical fractures occurred in 198 of 2,046 patients in the romosozumab-to-alendronate group versus 266 of 2,047 in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab.
The risk of non-vertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group, and the risk of hip fracture was lower by 38%.
Overall adverse events and serious adverse events were balanced between the two groups. During year one, positively-adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 patients versus 38 of 2,014).
CITATION: Kenneth G. Saag, M.D., Jeffrey Petersen, M.D., et. al. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. New England Journal of Medicine. 2017; 377:1417-1427. October 12, 2017. ARCH Clinical Trials.gov number, NCT01631214. http://www.nejm.org/doi/full/10.1056/NEJMoa1708322
Positive troponin tests in CKD
explained in Clinician Reviews
An October Q & A in Clinician Reviews addresses the issue of patients with chronic kidney disease (CKD) sent to emergency departments (EDs) for chest pain or shortness of breath whose troponin levels are high. Marlene Shaw-Gallagher, MS, PA-C, University of Detroit Mercy, Detroit, explains that cardiac troponins are the gold standard for detecting myocardial injuries in patients presenting to EDs with suggestive symptoms, and that the reason for more positive troponin results in the CKD population is increased accuracy in newer tests and the fact that CKD often causes a false-positive result. The article can be accessed at http://www.mdedge.com/clinicianreviews/article/147685/nephrology/how-interpret-positive-troponin-tests-ckd