A provider toolkit with clinically relevant resources related to diagnosis and management of central precocious puberty.

CPP Provider Toolkit

A pair of experts in the management of diabetes review the role of insulin therapy and review the approval process for biosimilars, including the FDA's approval of the first interchangeable insulin biosimilar.

Interchangeable Insulin Biosimilars: A Game Changer in Diabetes Management

Podcast hosted by Diana Isaacs, PharmD, and Natalie Bellini, DNP aimed at providing real-world perspective on the latest advances in diabetes management.

This article was originally published on 

Data from an analysis of DECLARE-TIMI 58 suggests the efficacy and safety of dapagliflozin (Farxiga) was not altered by use of different background cardiovascular medications in patients with 

A prespecified secondary analysis assessing the cardiorenal efficacy and safety of the SGLT2 inhibitor, the results of the study provide an overview of the observed cardiorenal protective benefits with dapagliflozin across subgroups defined by use of background cardiovascular medications.

“Dapagliflozin consistently reduced the risk of cardiovascular death/hospitalization for heart failure and progression of kidney disease irrespective of the baseline concurrent use of various cardiovascular medications commonly used for heart failure and kidney disease in patients with type 2 diabetes, with significant reductions in the risk of both even in patients receiving ACEi/ARBs, β-blockers, and diuretics,” wrote investigators.

In recent years, a multitude of clinical trials have outlined the safety and efficacy of SGLT2 inhibitors in patient populations with and without type 2 diabetes for 

. A prespecified secondary analysis of DECLARE-TIMI 58, the current study was designed with the intent of furthering the knowledge base surrounding the efficacy and safety profile of dapagliflozin, based on concurrent use of other cardiovascular medications, in patients with type 2 diabetes.

A randomized, double-blind, multinational trial, DECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes and either established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD and with a creatinine clearance of 60 mL/min or greater to either placebo therapy or dapagliflozin. With primary endpoints of major adverse cardiovascular events (MACE) and a composite of cardiovascular death or hospitalization for heart failure, results of the study demonstrated use of dapagliflozin did not result in a lower rate of MACE (HR, 0.93 [95% CI, 0.84-1.03]; 

=.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (HR, 0.83 [95% CI, 0.73-0.95]; 

For the current study, investigators sought to compare the effects of dapagliflozin against placebo therapy in patient subgroups stratified by baseline use of ACEI/ARBs, β-blockers, diuretics, and mineralocorticoid receptor antagonists (MRAs). The outcomes of interest for the current analyses were the composite of CV death or hospitalization for heart failure, hospitalization for heart failure alone, and a kidney-specific composite outcome, which consisted of a 40% decline in eGFR, end-stage kidney disease, or kidney-related death.

Of the 17,160 patients included in DECLARE-TIMI 58, 81% reported use of ACEi/ARBs, 53% used β-blockers, 36% used diuretics, and 4% used MRAs at baseline. Investigators pointed out no patients were taking sacubitril/valsartan at the time as the agent had not yet received regulatory approval. Initial analyses demonstrated there were no differences in the effects of dapagliflozin on blood pressure and eGFR from baseline to 48 months relative to placebo therapy based on background medications (placebo-corrected change, −1.6 mmHg [95% CI, −4.2 to 1.0] to −2.6 mmHg [95% CI, −3.3 to −2.9]; 

Further analysis suggested dapagliflozin use consistently reduced the risk of cardiovascular death and heart failure hospitalization regardless of the background use of CV medications, including ACEiARBs, β-blockers, diuretics, and MRAs (

 >.05 for each interaction). Additionally, the association did not differ between those with concurrent use of all 3 other cardiovascular medications and those using 2 or fewer of these medications 

 >.05 for interaction). When assessing the renal endpoint, investigators found also consistently reduced the risk of the kidney-specific composite outcome regardless of the concomitant use of cardiovascular medications except for diuretics (

When assessing safety outcomes, results indicated the safety profile for serious adverse events, symptoms of volume depletion, acute kidney injury, and incident hyperkalemia did not differ with dapagliflozin when compared to placebo and no effect modification was observed based on the use of cardiovascular medications at baseline (

 > .05 for each interaction). However, investigators did note results suggested dapagliflozin could reduce the risk of hyperkalemia in patients with MRA use at baseline compared to those without.

“Dapagliflozin consistently reduced the risk of cardiovascular death/hospitalization for heart failure, hospitalization for heart failure alone, and a kidney-specific composite outcome regardless of background use of cardiovascular medications, including ACEI/ARBs, β-blockers, diuretics, and MRAs. Even in patients receiving ACEI/ARBs plus β-blockers plus diuretics, dapagliflozin reduced the risk of cardiovascular death/hospitalization for heart failure and of the kidney-specific outcome by 24% and 38%, respectively,” investigators added.

Efficacy and Safety of Dapagliflozin According to Background Use of Cardiovascular Medications in Patients With Type 2 Diabetes,

Articles

Data from a major trial detail the cardiorenal benefits of dapagliflozin use among patients with type 2 diabetes based on use of background cardiovascular medications. 

Background Medications Do Not Alter Benefits of Dapagliflozin in Type 2 Diabetes

A man in his 30s with a history of type 1 diabetes mellitus on insulin presents to the emergency department for left index finger pain and swelling. He states about a week ago he had a puncture wound to the tip of that finger from a frayed bike cable. He removed a foreign body but the pain never went away. In the past 24-36 hours it has become rapidly more painful and swollen and he can’t straighten his finger. He denies any drainage, fever, or other complaints.

Vital signs are normal. Physical exam is normal except for the images below:


: WBC: 14. Glucose: 220; Bicarb: 21; Other labs normal

: Hand x-ray showed no foreign body, gas, or bony involvement

Our latest case report from Brady Pregerson, MD, features a man in his 30s with a history of type 1 diabetes mellitus on insulin presenting to the emergency department for left index finger pain and swelling. Can you determine the correct diagnosis?

Endocrine Case Report:  Finger Swelling in T1D

An analysis of real-world data suggests rosuvastatin use could be placing patients at risk of 

The National Institute of Diabetes and Digestive and Kidney Disease-funded study demonstrate use of rosuvastatin was associated with an 8% greater risk of hematuria, a 17% greater risk of proteinuria, and a 15% higher risk of developing kidney failure requiring replacement therapy such as dialysis or transplantation over a median follow-up of 3.1 years compared to use of atorvastatin.

“We observed a higher risk of hematuria, proteinuria, as well as kidney failure with rosuvastatin use and similar cardiovascular benefits between the rosuvastatin and atorvastatin groups,” said Jung-Im Shin, MD, PhD, assistant professor at the Johns Hopkins Bloomberg School of Public Health, 

. “Because rosuvastatin may cause proteinuria and hematuria, especially with high dose, high dose rosuvastatin may not merit the risk—even if small—particularly for patients with advanced kidney disease.”

Although reports of hematuria and proteinuria observed with rosuvastatin around the time of approval prompted concern around nephrotoxicity, FDA labeling only mentions dose reductions for those with severe chronic kidney disease and few studies have examined the risk of nephrotoxicity seen with rosuvastatin since its approval in 2003. With this in mind, Shin and a team of colleagues designed their study as an analysis of data from the Optum Labs Data Warehouse, which provided investigators with deidentified EHR data from 152,101 new users of rosuvastatin and 795,799 new users of atorvastatin from 2011-2019 for inclusion in their study.

Using inverse-probability of treatment weight models, the primary outcome of interest for the analyses was the association of hematuria, proteinuria, and kidney failure with replacement therapy with rosuvastatin and with atorvastatin. Investigators also noted plans to assess associations between initial rosuvastatin dose across eGFR categories and for a dose-effect on hematuria and proteinuria.

The overall study cohort had a mean age of 60 (SD, 12) years and 47.58% were female. Investigators pointed out that, prior to IPTW, most patient characteristics were similar between the study groups, including eGFR, BMI, blood pressure, cholesterol, comorbidities, and medication use. After IPTW, coverage balance was achieved for each covariate included in the analyses.

Upon analysis, investigators identified hematuria and proteinuria in 2.9% and 1.0% of the overall study cohort, respectively, during a follow-up period lasting a median of 3.1 years. Compared to atorvastatin, results indicated rosuvastatin was associated with an increased risk of hematuria (HR, 1.08 [95% CI, 1.04-1.11]), proteinuria (HR, 1.17 [95% CI, 1.10-1.25]), and kidney failure requiring replacement therapy (HR, 1.15 [95% CI, 1.02- 1.30]). In subgroup analyses, investigators found more than a third of patients with an eGFR below 30 ml/min/1.73m

 were prescribed high-dose rosuvastatin, with 29.9% prescribed a 20 mg dose and 14.0% prescribed a 40 mg dose. Investigators pointed out further subgroup analyses suggested risk of nephrotoxicity was greater with increased doses of rosuvastatin.

“While the overall absolute as well as relative risk of hematuria and proteinuria with rosuvastatin use was low, patients with eGFR <30 ml/min/1.73 m2 were at the highest risk, with approximately 2-fold risk of hematuria and 9-fold risk of proteinuria than those with eGFR ≥60 ml/min/1.73 m2,” investigators wrote. “We observed a higher risk of kidney failure requiring replacement therapy with rosuvastatin use and similar cardiovascular benefits between rosuvastatin and atorvastatin group; and evidence that rosuvastatin may cause proteinuria and hematuria, especially with high dose.”

Association of Rosuvastatin Use with Risk of Hematuria and Proteinuria

Journal of the American Society of Nephrology.

An analysis of real-world EHR data from more than 900,000 statin users suggests use of rosuvastatin was associated with an 8% greater risk of hematuria, a 17% greater risk of proteinuria, and a 15% higher risk of developing kidney failure requiring replacement therapy such as dialysis or transplantation compared to atorvastatin use.

Real-World Data Links Rosuvastatin to Nephrotoxicity

 had a 34% greater risk of stroke compared to their counterparts without endometriosis, according to real-world data from more than 110,000 women.

An analysis of the Nurses Health Study II, which contained data from registered nurses between 25-42 years of age followed from 1989 through 2017, results of the study demonstrate women with the chronic inflammatory condition had a 34% greater 

 in adjusted models, with the largest proportion of this association driven by was hysterectomy/oophorectomy and hormone therapy.

“These findings suggest that women with a history of endometriosis may be at higher risk of stroke,” said senior investigator Stacey A. Missmer, ScD, professor of obstetrics, gynecology, and reproductive biology at Michigan State University College of Human Medicine in Grand Rapids, 

. “Clinicians should look at the health of the whole woman, including elevated blood pressure, high cholesterol and other new stroke risk factors, not only symptoms specifically associated with endometriosis, such as pelvic pain or infertility.”

A chronic inflammatory gynecologic condition, previous research has linked endometriosis to greater risk of hypertension and dyslipidemia. Additional research has pointed to a link between alterations in endogenous inflammatory, immunologic, and hormonal milieu to a subsequent increase stroke risk among these patients. With an interest in learning more about the association between endometriosis and stroke risk, as well as the impact of treatment choices for the condition, Missmer and a team of colleagues sought to estimate these associations using data from the Nurses’ Health Study II, which contained data related to 116,429 female registered nurses aged 25-42 years of age during enrollment in 1989 and followed through 2017.

As part of the Nurses Health Study II, these participants completed biennial questionnaires beginning in 1993 that assessed if they had been diagnosed with endometriosis and whether it or not it had been confirmed by laparoscopy. Diagnoses of stroke, both ischemic and hemorrhagic, were also ascertained through biennial questionnaires that began at enrollment in 1989. Limiting their study to those without a history of stroke, myocardial infarction, cancer, or coronary artery bypass grafting prior to enrollment, or had endometriosis that was not confirmed by laparoscopy. Using these criteria, investigators identified a cohort of 112,056 women with 2,770,152 person-years of follow-up for inclusion in their analyses.

Compared to their counterparts without endometriosis, those with laparoscopically confirmed endometriosis were more likely than women without a history of endometriosis to report a BMI greater than 25 kg/m2 at age 18, an earlier age at menarche, irregular menstrual cycles, a history of infertility, nulliparity, and to have been past or current oral contraceptive users at baseline. Investigators pointed out no differences were observedbetween women with and without a history of endometriosis for physical activity patterns, alcohol intake, or Alternative Health Eating Index dietary intake score, but women with endometriosis were more likely to report a family history of myocardial infarction and stroke.

In adjusted models, women with a history of laparoscopically confirmed endometriosis were at a 34% greater risk of stroke compared to those without a history of endometriosis (HR, 1.34 [95% CI, 1.10-1.62]). Further analysis suggested this association between laparoscopically confirmed endometriosis and stroke was partially mediated occurrence of hysterectomy or oophorectomy (percent mediated: 39%), postmenopausal hormone therapy (percent mediated: 15.5%), age at menopause less than 45 years (percent mediated: 12.3%), history of hypertension (percent mediated: 8.4%), or history of high cholesterol (percent mediated: 4.9%).

Investigators pointed out there were no differences in the association based on by age, BMI, history of infertility, menopausal status, smoking history, history of hysterectomy or oophorectomy, history of hypertension, history of hypercholesterolemia, history of hormone therapy use, and history of age at menopause. Additionally, sensitivity analyses using all reports of endometriosis, regardless of whether or not it was confirmed via laparoscopy, did not significantly alter results.

“These results do not indicate that women who have endometriosis will have a stroke. Instead, these findings signify only an association of moderate relative risk. The absolute risk of stroke in women is low,” Missmer said. “Women with endometriosis should pay attention to their whole body and discuss added risks and preventive options with their health care team.”

Laparoscopically Confirmed Endometriosis and Risk of Incident Stroke: A Prospective Cohort Study

Women with endometriosis had a 34% greater risk of stroke than women without the chronic inflammatory gynecological condition, according to an analysis of the Nurses Health Study II. 

Endometriosis Linked to 34% Increase in Stroke Risk 

 for menopausal symptoms does not increase the risk of breast cancer recurrence in women treated for breast cancer, according to a new study of more than 8000 women.

An analysis of longitudinal data from a national cohort of 

 diagnosed with early-stage invasive estrogen receptor (ER)–positive nonmetastatic breast cancer who received no treatment or 5 years of adjuvant endocrine therapy, results of the analysis suggests there was no statistically significant increase in the risk of recurrence or mortality for those who received either vaginal estrogen therapy or menopausal hormone therapy.

“In postmenopausal women treated for early-stage ER-positive breast cancer, use of vaginal estrogen therapy or menopausal hormone therapy was not associated with increased risk of recurrence or mortality. In patients treated with vaginal estrogen therapy and adjuvant aromatase inhibitors, we observed an increased risk of recurrence but not mortality. This association was not observed among women who received tamoxifen or in those who did not receive adjuvant endocrine therapy,” wrote investigators.

Despite more recent trials alleging no increased risk of recurrence with use, a pair of trials in the 1990s cast doubt over the safety of menopausal hormone therapy in women with history of breast cancer. Citing limitations within study demonstrating no increased risk of recurrence, a team representing Odense University Hospital, the Danish Breast Cancer Group (DBCG) at Copenhagen University Hospital, and Aarhus University Hospital conducted the current study to assess risk of recurrence of breast cancer and mortality following treatment with vaginal estrogen therapy or menopausal hormone therapy in postmenopausal women.

To do so, investigators designed their study as an analysis of longitudinal data from the DBCG clinical database, the Danish National Prescription Database, the Danish National Patient Registry, and the Danish Civil Registration System. With patients of interest defined as postmenopausal women aged 35-95 years, diagnosed with invasive early-stage nonmetastatic, ER-positive breast cancer from 1997-2004 registered in the DBCG clinical database, and who did not receive chemotherapy. From the databases, investigators identified 8461 women with a median follow-up of 9.8 years for recurrence and 15.2 years for mortality for inclusion in their analyses. Of these, 1957 used vaginal estrogen therapy and 133 used menopausal hormone therapy.

For the purpose of analysis, each woman included in the study was categorized as vaginal estrogen therapy, menopausal hormone therapy, or never-user according to hormone therapy prescription data obtained from the Danish National Prescription Database. Investigators noted women who received both vaginal estrogen therapy and menopausal hormone therapy were categorized as menopausal hormone therapy users and menopausal hormone therapy were categorized as menopausal hormone therapy alone or menopausal hormone therapy and vaginal estrogen therapy.

The primary outcome of interest for investigators analyses were mortality and risk of recurrence associated with use of vaginal estrogen therapy and menopausal hormone therapy vs nonuse using multivariable models adjusted for age at surgery, tumor size, nodal status, histological type and grade, ER, progesterone receptor, lymphovascular invasion, locoregional therapy, CCI, and, as time-dependent variables, use of tamoxifen, use of adjuvant aromatase inhibitors, and noncompliance for endocrine therapy.

Upon analysis, results indicated the adjusted relative risk of recurrence was 1.08 (95% CI, 0.89-1.32) for vaginal estrogen therapy, 1.39 (95% CI, 1.04-1.85) for a subgroup receiving vaginal estrogen therapy and adjuvant aromatase inhibitors, and 1.05 (95% CI, 0.62-1.78) for menopausal hormone therapy. Assessments of mortality risk yielded adjusted hazard ratios of e 0.78 (95% CI, 0.71-0.87) and 0.94 (95% CI, 0.70-1.26) for vaginal estrogen therapy and menopausal hormone therapy, respectively.

, Elizabeth Cathcart-Rake, MD, and Kathryn Ruddy, MD, MPH, both of the Mayo Clinic, suggest the results of the current study provide reassurance of the safety of menopausal hormone therapy in this patient population, but warn against overinterpretation of results and underline the importance of patient monitoring.

“This large cohort study helps to inform the nuanced discussions between clinicians and breast cancer survivors about the safety of vaginal estrogen therapy,” wrote the pair. “These results suggest that breast cancer survivors on tamoxifen with severe genitourinary symptoms can take vaginal estrogen therapy without experiencing an increase in their risk for breast cancer recurrence. However, caution is still advised when considering vaginal estrogen for breast cancer survivors on aromatase inhibitors, or when considering menopausal hormonal therapy.”

Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Study,

Journal of the National Cancer Institute.

An analysis of data from more than 8400 postmenopausal women with a history of early-stage nonmetastatic, ER-positive breast cancer suggests there was no increase in risk of breast cancer recurrence or mortality observed with use of vaginal estrogen therapy or menopausal hormone therapy.

Hormone Replacement Therapy Does Not Increase Breast Cancer Recurrence, Mortality in Survivors

“The cure for diabetes is just X years away”

It’s something countless patients have heard and clinicians have been told since they entered medicine. More than 100 years after Sir Frederick Banting discovered insulin and altered the course of 

 forever, generations of patients with type 1 diabetes have been given hope for a cure and have endured the burdens of diabetes waiting for this cure to arrive one day. As a result of the constant innovations and wide array of approaches surrounding pursuit of a potential cure, progress has been hard to gauge, leading to questions of how much closer to a cure is the community than it was 5, 10, or even 50 years ago.

Diabetes Dialogue: Therapeutics, Technology, and Real-World Perspectives

, hosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, sit down to provide perspective on the latest advances in the fight to cure type 1 diabetes and offer insight into their experiences at the Practical Ways to Achieve Targets in Diabetes Care Conference held in Keystone, CO in mid-July.

 is available in an audio-only format on 

For the July 2022 episode of Diabetes Dialogue: Therapeutics, Technology, and Real-World Perspectives, hosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, sit down to provide perspective on the latest advances in the fight to cure type 1 diabetes and offer insight into their experiences at the Practical Ways to Achieve Targets in Diabetes Care Conference held in Keystone, CO in mid-July.

Diabetes Dialogue: The Race to Cure T1D

A weight loss trial assessing the use of a fully automated, online obesity treatment program in primary care settings has returned promising results.

 trial, which assessed the effect of the no-cost, online education program called the Rx Weight Loss (RxWL) program in more than 450 patients, found those who participated in the program achieved a mean reduction in body weight of 5.1% by the end of the trial period, with greater levels of participation associated with increased efficacy.

“Our study shows that primary care clinicians can help their patients seeking to lose weight by providing them with an automated online program based in behavioral science that is very low-cost and does not overburden busy providers,” said study investigator J. Graham Thomas, PhD, professor in the Department of Psychiatry and Human Behavior at the Warren Alpert Medical School of Brown University and associate director of the Weight Control & Diabetes Research Center of The Miriam Hospital, 

As the obesity pandemic worsens, identification and implementation of low-cost, but effective weight loss interventions in primary care settings, particularly those that focus on patient education, has become a main focal point for many in healthcare. With funding from the National Institute of Diabetes and Digestive and Kidney Diseases, the program and study were designed and conducted by investigators within the Rhode Island Primary Care Physicians Corporation, which is a primary care practice organization that includes approximately 60 practices and 100 clinicians.

Designed based on the interventions from the Diabetes Prevention Program and in the Look AHEAD study, the RxWL program included 3 core components aimed at improving healthy eating, physical activity, and behavioral skills for promoting weight change. These components consisted of weekly online lessons, self-reporting of data, including body weight, energy intake, and activity, and providing personalized, automated feedback. As part of the trial, participants were asked to weigh themselves at least once weekly, with daily measurements preferred, and to submit these weights into the online portal each week. To encourage healthy lifestyle behaviors, the programs assigned goals for weight loss and energy intake as well as options to lower energy intake and support Mediterranean-style eating plans.

Initially, 1765 patients were referred for participation in the program. Of these, 721 were assessed for eligibility, 654 began treatment, and 464 had at least 1 reported body weight within the program. The final analytical cohort of 464 patients had a mean age of 52.6 (SD, 13.2) years, a mean BMI of 36.2 (SD, 6.9) kg/m2, 70% were female, and 94% were White. At weeks 4, 8, and 12 of the program, data was submitted by 331, 268, and 210 participants, respectively.

Upon conclusion of the 12-week program, the estimated mean weight change was -5.1% (SE, 0.2), which corresponded with a change of -5.1 kg (SE, 0.02). No significant effects were observed for age, BMI, sex, or racial/ethnic background on weight loss observed in the study (

.18). Results indicated the mean number of weeks with an entry during participation in the program was 7.8 (SD, 0.3), with 37% of participants reporting weight on all 12 weeks. Results also indicated the mean number of lessons viewed among participants was 6.5 (SD, 4.1), with 20% of participants accessing all 12 lessons.

Further analysis demonstrated those who reported their weight in all 12 weeks achieved a greater degree of weight loss than their counterparts who reported their weight in fewer than 12 weeks, with estimated mean weight loss of 7.2% (SE, 0.3%) and 3.4% (SE, 0.3%), respectively (

 <.0001). A similar trend was observed when assessing access to sessions, with those accessing all 12 sessions achieving a greater degree of weight loss (8.0%; SE, 0.4%) than their counterparts who accessed fewer lessons (4.2%; SE, 0.2%)(

“Pragmatic implementation of an established, fully automated, online behavioral obesity treatment in a large primary care practice network produced a mean weight loss of 5% of initial body weight at the end of the initial 12-week treatment period. This is consistent with national guidelines for minimum clinically significant weight loss for first-line treatment,” wrote investigators.

Pragmatic implementation of a fully automated online obesity treatment in primary care,

A trial assessing a 12-week fully automated, no-cost online education program suggests participation in the program was linked to a mean weight loss of 5.1% of starting body weight, with greater levels of participation linked to greater weight loss among participants. 

No-Cost, Fully Automated Weight Loss Programs Show Promise in Primary Care Setting

New research from an analysis of patient data from the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) study suggests patients with 

 with the highest doses of daily insulin were at an increased risk of developing cancer over 28 years follow-up.

Nearly 40 and 30 years after the launch of the DCCT and EDIC studies, results of the analysis provide evidence from 2 different multivariable-adjusted models suggesting those in the highest category of daily insulin dose was associated with a more than 4-fold increase in the incidence of cancer among patients with type 1 diabetes.

“This study showed that daily insulin dose was associated with cancer risk in type 1 diabetes. The HRs were significantly higher in the high-dose vs low-dose group,” wrote investigators.

Citing previous reports detailing an association between type 1 diabetes and increased incidence of cancer relative to the general population, Wenjun Zhong, PhD, a principal scientist in epidemiology at Merck, and Yuanjie Mao, MD, PhD, an assistant clinical professor of endocrinology at the Ohio University, sought to assess risk factors associated with cancer incidence among patients with type 1 diabetes. With this in mind, investigators designed the current study as an analysis of data from the DCCT and EDIC studies. Launched in 1983, the DCCT study enrolled more than 1400 patients from 29 centers in North America and followed them to assess the impact of glycemic control on event risk in diabetes. 

At the conclusion, 1375 of the 1441 patients initially enrolled in the trial volunteered to continue in the EDIC follow-up study. Of these patients, 1303 participants who were free from cancer at enrollment in DCCT and had completed the annual cancer history update were identified for inclusion in the current study.

Of the 1303 patients included in the study, 7% had cancer diagnoses during a total of 33,813 person-years of follow-up, which corresponded to an incidence rate of 2.8 (95% CI, 2.2-3.3) per 1000 person-years. The mean age at first diagnosis was 50 years and the mean duration of diabetes at the time was 25 years. 

The most commonly reported forms of cancer were skin, breast, reproductive, and digestive cancers. Among the 93 patients with cancer diagnoses, 61% were female, 9% developed cancer within 10 years, 33% developed cancer between 11-20 years, and 58% developed cancer between 21-28 years. For the purpose of analysis, investigators calculate cancer incidence using Cox proportional hazards regression models adjusted for age and sex. Investigators noted their first model included time-dependent variables and a second model was created with daily insulin dose used as a fixed variable. Based on reported insulin use, participants were classified into the low-, medium- or high-dose groups.

Upon analysis, results indicated both age (HR, 1.08 [95% CI, 1.05-1.12]) and female sex (HR, 1.74 [95% CI, 1.15-2.64]) were associated with an increased incidence of cancer. Inverse associations with risk of cancer were observed for exercising habits and high-density lipoprotein cholesterol. However, an association was observed between daily insulin dose and increased incidence of cancer, even after adjustment for age and sex. In the model assessing daily insulin dose as a time-dependent variable, results indicated use of a high daily dose of insulin was associated with a nearly 6-fold increase in cancer incidence (HR, 5.93 [95% CI, 1.21-29.06]; 

 =.03). In models assessing daily insulin dose as a fixed variable, results indicated use of a high daily dose of insulin was associated with a 4-fold increase in cancer incidence (HR, 4.13 [95% CI, 1.13-15.17]; 

When assessing cancer incidence per 1000 person-years based on what category of insulin dose level patients are categorized into demonstrated an incidence rate of 2.11, 2.87, and 2.91 per 1000 person-years in the low-, medium-, and high-dose grouper respectively. Before concluding their study, the authors cautioned clinicians to consider limitations within their study before overinterpretation of results.

“A limitation of this study is the relatively small sample size, which precluded analyses with specific cancer types and resulted in a wide confidence interval for daily insulin dose. Moreover, the association found may be subject to residual confounding and was not necessarily causal. Furthermore, larger studies in type 1 diabetes are needed to validate this association,” wrote investigators.

Daily Insulin Dose and Cancer Risk Among Patients With Type 1 Diabetes

An analysis of the DCCT and EDIC studies provides clinicians with insights into the risk factors associated with incident cancer diagnoses among patients with type 1 diabetes, suggesting those using higher daily doses of insulin had a more than 4-fold increase in risk of a cancer diagnosis. 

In Type 1 Diabetes, Higher Insulin Doses Could Increase Cancer Risk 

New data from an ancillary study of the Vitamin D and Omega-3 Trial (VITAL) may close the book on vitamin D3 supplementation for reducing 

An analysis of data from the randomized, controlled trial, results of the ancillary study demonstrate vitamin D3 supplementation among older adults in the US did not contribute to a reduction in risk of fractures compared to placebo therapy among adults without vitamin D deficiency, low bone mass, or osteoporosis.

“Overall, the results from this large clinical trial do not support the use of vitamin D supplements to reduce fractures in generally healthy US men and women,” said lead investigator Meryl LeBoff, MD, chief of the Calcium and Bone Section in the Endocrine Division at Brigham and Women’s Hospital, 

. “These findings do not apply to adults with vitamin D deficiency or low bone mass or osteoporosis. Most participants in the trial were not deficient and may have already reached the vitamin D level needed for bone health. Our ongoing studies are focusing on whether free vitamin D levels or genetic variation in vitamin D absorption, metabolism, or receptor function will provide information about individuals who may benefit from supplemental vitamin D on musculoskeletal health.”

Despite being among the most commonly used supplements for purported benefits in bone health and other areas, data surrounding the benefits versus harms of vitamin D supplementation have failed to return a conclusive stance for or against their use. With this in mind, the VITAL trial, which is sponsored by multiple organizations including the National Heart, Lung, and Blood Institute, was launched in 2010, enrolled 25,871 US adults, and included a 5-year intervention phase assessing whether supplemental vitamin D3 at 2000 IU per day, omega-3 fatty acids at 1 gram per day, or both would prevent cancer and cardiovascular disease in men 50 years of age or older and women 55 years of age or older.

Results of the VITAL trial concluded none of the approaches examined within the trial provided a meaningful reduction in risk of primary cardiovascular disease or cancer vents during the follow-up period. Since results were initially presented in 2018, the trial’s dataset has been used to examine the impact of vitamin D3 supplementation on other outcomes. In the current study, LeBoff and a team of colleagues sought to evaluate whether supplementation impacted total, non-vertebral, or hip fracture risk in older adults, which were used as the primary outcomes of interest for the investigators’ analyses. These end points were assessed using proportional-hazards models that estimated the treatment effect in intention-to-treat analyses.

In the VITAL trial, Investigators identified 1991 occurrences of incident fracture among 1551 participants during a follow-up period lasting a median of 5.3 years. Upon analysis, results indicated vitamin D3 supplementation was no associated with a significant decrease in risk of total fracture, with 769 fractures occurring among 12,927 participants in the vitamin D group and 782 of 12,944 participants in the placebo group (HR 0.98 [95% CI< 0.89-1.08]; 

=.70). Further analysis pointed to a similar trend for risk of nonvertebral fractures (HR, 0.97 [95% CI, 0.87-1.07]; 

=.50) and hip fractures (HR, 1.01 [95% CI, 0.70-1.47]; 

Investigators pointed out there was no treatment modification observed based on characteristics, including age, sex, race or ethnic group, body-mass index, or serum 25-hydroxyvitamin D levels. Additionally, no substantial between-group differences were noted for occurrence of adverse events in the trial.

“Although VITAL was originally designed to look at cardiovascular and cancer outcomes, this is a wonderful example of how it has shed light on health outcomes far beyond its original goals,” added JoAnn Manson, MD, study investigator and chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, in the aforementioned statement.

Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults,”

An ancillary study of the landmark VITAL trial provides clinicians with evidence related to the lack of reduction in fracture risk observed with vitamin D3 supplementation in older adults.

Vitamin D Supplements Do Not Reduce Fracture Risk in Older Adults

As debate around the efficacy of various 

 continues, new research into the impact of a time-restricted eating protocol details the potential metabolic benefits of such an approach in adult patients with 

A randomized crossover trial assessing a 3-week time-restricted eating regimen, which restricted intake to a 10-hour period, compared to a control regimen, results of the study suggest adherence to time-restricted eating was associated with a reduction in 24-hour glucose levels and a nearly 3-hour increase in mean time spent in normal glucose range.

“Time-restricted eating is a novel strategy to improve metabolic health and has been proposed to counteract the detrimental effects of eating throughout the day by limiting food intake to daytime hours. To date, only a few studies have examined the metabolic effects of time-restricted eating in adults with type 2 diabetes,” wrote investigators.

As major organizations, accrediting bodies, and educational institutions begin to emphasize the role of nutrition in disease management, research interest in dietary regimens has grown in tandem. The current study, which was led by investigators from the NUTRIM School of Nutrition and Translational Research in Metabolism at Maastricht University Medical Center, was designed to test the investigators’ hypothesis that impairments in metabolic rhythmicity in adults with type 2 diabetes were due to a disturbed-eating fasting cycle and adherence to a time-restricted eating regimen might improve metabolic health beyond purported benefits in weight loss.

As such, the study was designed as a randomized crossover study to co [pare the effect of limiting food intake to a f10-hour daily time frame for 3 weeks in free-living conditions on hepatic glycogen utilization and insulin sensitivity in adults with type 2 diabetes. Conducted between April 2019 and February 2021, the study enrolled 14 adults with type 2 diabetes. The patients had a mean age of 67.5±5.2 years, 50% were female, and the mean HbA1c was 6.4±0.7% at baseline.

As part of the study protocol, during the 3-week time-restricted eating intervention, participants were instructed to consume their typical diet within a 10-hour window during the daytime, with the last meal completed no later than 18:00 hours. In the control arm, volunteers were instructed to consume their typical diet over at least a 14-hour period each day. Investigators noted all patients received a continuous glucose monitoring device at the start of each intervention period. In addition to hepatic glycogen levels and insulin sensitivity, the study also included multiple other outcomes of interest, including glucose homeostasis, 24-hour energy expenditure, substrate oxidation, hepatic lipid content, and skeletal muscle mitochondrial capacity.

Upon completion of the trial, results indicated hepatic glycogen contentment was similar between the time-restricted eating and control regimens (0.15±0.01 vs 0.15±0.01 arbitrary units; 

=.88) and there was no significant impact on 

value with time-restricted eating compared to the control regimen (19.6±1.8 vs 17.7±1.8 μmol kg−1 min−1; 

=.10). Additionally, results suggested there was no significant impact on both hepatic and peripheral insulin sensitivity with time-restricted eating (

However, investigators pointed an increase was observed for insulin-induced non-oxidative glucose disposal with time-restricted eating compared to the control regimen (4.3±1.1 vs 1.5±1.7 μmol kg−1 min−1; 

=.04). Further analysis also revealed time-restricted eating was associated with increased time spent in the normoglycemic range (15.1±0.8 vs 12.2±1.1 hours per day; 

=.01) as well as decreases in fasting glucose (7.6±0.4 vs 8.6±0.4 mmol/l; 

=.03) and 24-hour glucose levels (6.8±0.2 vs 7.6±0.3 mmol/l; 

<.01). Investigators noted that while energy expenditure during a 24-hour period was not impacted, a decrease in 24-hour glucose oxidation was observed with time-restricted eating (260.2±7.6 vs 277.8±10.7 grams per day; 

“Despite the lack of changes in hepatic glycogen and insulin sensitivity, we did find that our 10-hour time-restricted eating protocol decreased 24-hour glucose levels in individuals with type 2 diabetes, primarily driven by decreased nocturnal glucose levels,” wrote investigators. “Notably, time-restricted eating also lowered overnight fasting glucose, increased the time spent in the normal glucose range and decreased time spent in the high glucose range, all of which are clinically relevant variables in type 2 diabetes.”

Three weeks of time-restricted eating improves glucose homeostasis in adults with type 2 diabetes but does not improve insulin sensitivity: a randomised crossover trial,