Κυριακή, 11 Μαρτίου 2018
The largest-ever prostate cancer screening trial, in which asymptomatic men received a "one-off" blood test for prostate-specific antigen (PSA), has found no mortality benefit.
After 10 years, there was no significant difference in deaths from prostate cancer among men who were screened with this single PSA test and men who were not screened.
The findings come from a British study, the Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP), published today in JAMA.
In an accompanying editorial, Michael Barry, MD, professor of medicine, Harvard Medical School, Boston, Massachusetts, had a plain-spoken summary: "The results of the CAP trial…do not provide compelling support for PSA screening."
"One-time screening isn't effective," he told Medscape Medical News.
The CAP researchers invited more than 400,000 men with a mean age of about 59 years to participate when they made primary care visits throughout United Kingdom between 2001 and 2009. In the end, a total of 67,313 (36%) underwent a one-time PSA test.
After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) in the PSA group died of prostate cancer vs 647 (0.31 per 1000 person-years) in the control group (P = .50).
Lead author, Richard Martin, professor of clinical epidemiology, University of Bristol, United Kingdom, described the single PSA test design as "low-intensity" screening in an email to Medscape Medical News.
That stands in contrast to the repeated or "serial" PSA testing in the two other major PSA trials, the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) trial.
In CAP, at 10 years, there was a higher percentage of prostate cancers in the screened group (8054 [4.3%]) than in the control group (7853 [3.6%]). The difference was mostly related to the increased detection of tumors with a Gleason score of 6 or less. In the screened group, 1.7% (n = 3263) of the men had these low-risk tumors compared with 1.1% (n = 2440) of the control group.
Importantly, both groups had the same percentage of prostate cancer–related deaths (0.29%).
"The problem remains that the PSA test identifies too many low-risk prostate cancers that do not require diagnosis or treatment, while missing some potentially harmful cancers," summarized Dr Martin.
The study participants will be followed for at least another 5 years to see whether a longer-term mortality benefit emerges with more time.
Best Estimates From European Study
In the editorial, Barry comments that for prostate cancer screening with serial PSA tests, the results from the ERSPC trial provide the best "direct estimate" of the benefits (and harms) of that approach. They show a relative rate reduction of prostate cancer–related death of 20% after 9 years and 21% at 13 years.
However, in absolute numbers, prostate cancer mortality benefit in the ERSPC trial "comes at the cost of a considerably higher risk of being diagnosed with prostate cancer," Dr Barry writes. He repeats the ERSPC estimations, noting that "27 additional men were diagnosed with prostate cancer at 13 years for every man who avoided a prostate cancer death through screening."
In comments to Medscape Medical News, Barry said he would include the new CAP results in discussions with his patients in Boston because of its unique one-time design. "I would definitely mention the results of this trial, along with the PLCO and ERSPC trials, in a PSA discussion. I'd make it clear to men that selection of PSA screening [in the United States] commits to doing a series of tests, every 2 to 4 years."
The Issue of 10-Year Data
Approached for comment, William Catalona, MD, professor of urology at the Feinberg School of Medicine, Northwestern University, Chicago, Illinois, and outspoken supporter of PSA screening, opined that the "one-off" study design of CAP is "unrealistic."
"Cancer screening strategies do not rely on a single test performed once to be effective," Catalona said in an email to Medscape Medical News. He explained that "a persistently rising PSA is a better predictor of clinically significant prostate cancer."
Dr Catalona also examined another design element in the trial. As described by the authors, men in the screening group were also, when needed, randomly assigned to the Prostate Testing for Cancer and Treatment (ProtecT) trial. (Results from the ProtecT trial were published last year in the New England Journal of Medicine and reported at the time by Medscape Medical News.) That is, men in the CAP trial diagnosed with prostate cancer were offered randomization to radical prostatectomy, external-beam radiotherapy, or active monitoring in the ProtecT trial.
He criticized the fact that the CAP authors "assert that randomization of their screening arm patients to the ProtecT trial did not affect the prostate cancer mortality results based on the assumption that active treatment was not superior to observation in ProtecT, which has not yet been validated."
Dr Catalona argues that in the ProtecT trial, half the patients randomly assigned to monitoring were treated with surgery or radiation, and the monitoring group had twice the rate of clinical progression and distant metastases, which was statistically significant, and a proportionately higher prostate cancer death rate compared with patients randomly assigned to active treatment.
The CAP authors also likely underestimate the contamination (screening in the control group) that took place, he continued. The investigators estimate that the percentage was only 10% to 15% over 10 years.
"This is low in comparison with other studies in which screening of controls before, during, or after the trial was far higher both in Europe and in the US and was sometimes initially underreported," contended Dr Catalona.
Also, he emphasized that a median follow-up of 10 years is "insufficient" to evaluate prostate cancer–specific mortality.
"Clinical trials conducted over a limited time period do not reveal true information about absolute benefits of screening over a man's lifetime. The early trial data underestimate benefits and exaggerate harms," he argued.
Dr Catalona also asserted that the authors "glossed over the dramatic separation of the PC mortality curves [favoring the intervention] after 12 years of follow-up."
However, the CAP investigators, in their paper's discussion section, addressed that eye-catching graph.
"Although the cumulative incidence of prostate cancer mortality in the intervention and control groups appeared to diverge after 12 years of follow-up, only 71/1196 of the prostate cancer deaths occurred after 12 years and an exploratory analysis found no significant change in the rate ratio over time," they write.
In his editorial, Barry also addressed the 10-year follow-up, but he noted that in the ERSPC trial, while there was an increase in the absolute benefit of periodic screening over time, it was "a modest one."
The lead author of the CAP study left the door open to the possibility of improved performance of the one-time PSA test over more years. "Longer follow-up is needed to see if a difference develops after 15 or 20 years," he told Medscape Medical News.
The CAP trial was funded by grants from Cancer Research UK and the UK Department of Health, and the National Institute of Health Research provided partial funding. The study authors have disclosed no relevant financial relationships. Barry is a member of the US Preventive Services Task Force (USPSTF). Catalona has disclosed no relevant financial relationships.
Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick
There's a great recent paper published by Dr Tsuyoshi Hamada and colleagueslooking at the role of aspirin as an immune checkpoint blockade inhibitor. It's a lovely study. Using part of a retrospective sample collection, they were able to look at the impact of post-primary treatment use of aspirin in patients with resectable colorectal cancer.
They hypothesized that patients who had tumors with low expression of programmed cell death ligand 1 (PD-L1) would be more sensitive to the beneficial effects of aspirin. They looked at just over 600 patients. [The study used] a beautiful statistical analysis that stratified [findings] and accounted for all of the other contributory factors that might be tied up with aspirin's use: PIK3CA mutations, [CDX2 expression], and even tumor-infiltrating lymphocytes. It's what you would expect from a research group of this quality. The analysis was done very carefully indeed.
At the end of the study, they showed that their hypothesis was correct. Patients with tumors with relatively low expression of PD-L1 (also known as CB274) did better than those patients who had tumors that expressed high levels of PD-L1, for which aspirin seemed to have no benefits at all.
This all fits in with the link-up between the prostaglandin E2 pathway and immune suppression. It suggests that aspirin may be yet another potential partner drug that may enhance the activity of the huge excitement around the drugs which block the PD-L1, PD-1, the whole immune checkpoint pathway just now.
It was a really nice, very carefully conducted study. The results were quite compelling in terms of the survival benefits accrued to postsurgical use of aspirin in patients with low levels of PD-L1 expression. It again shows the importance of the microenvironment in determining the outcome of tumor behavior. This gives some potential therapeutic insight into why aspirin might be a very useful companion drug to give in combination with these rather more expensive, more complex immune blockade inhibitors.
Aspirin wins again. There's yet more plausible biological mechanism supporting its use.
I'm grateful for any comments that you may care to post. I'd be very interested in your own thoughts in the matter.
Long-term maintenance therapy with proton-pump inhibitors (PPIs) was shown to be associated with an increased risk for esophageal cancer, even in patients taking PPIs for indications not previously associated with this cancer risk, according to results from a new study from Sweden.
The authors call for "a more restrictive attitude towards maintenance use of PPIs."
However, this "surprising" observation comes from a single cohort study that lacks the evidence to demonstrate a causal relationship, warn experts approached for comment. They say that clinicians shouldn't stop prescribing PPIs as recommended by current guidelines.
The new study was published online February 22 in Cancer Epidemiology by a team led by Nele Brusselaers, MD, PhD, associate professor of clinical epidemiology at the Karolinska Institutet and the Karolinska University Hospital in Stockholm.
In the study, data from four national registers in Sweden were used to identify 796,492 patients without a history of cancer who were exposed to maintenance PPI therapy between 2005 and 2014. Most were female (58.5%), and 34.0% were age 70 years or older.
The indications for PPI use included maintenance therapy with aspirin (34.8%), nonsteroidal anti-inflammatory drugs (NSAIDs) (30.4%), gastroesophageal reflux disease (GERD) (25.3%), gastroduodenitis (13.2%), and peptic ulcer disease (10.0%). Less than 10% of participants were taking PPIs for other indications.
The team compared this cohort of nearly 800,000 patients taking PPIs to adults in the general population matched for sex and age over the same period.
They found that the overall standardized incidence ratio (SIR) for esophageal adenocarcinoma (EAC) in PPI users was 3.93, and the overall SIR for esophageal squamous cell carcinoma (SCC) was 2.77.
The study also showed that in patients without GERD who were taking PPI maintenance therapy with NSAIDs or aspirin, the SIR for EAC was 2.74 and 2.06, respectively.
To evaluate confounding by indication, stratified analyses were performed for each indication not associated with an increased risk for EAC. This separate analysis was one of the study's chief strengths because it minimized the risk for confounding by indication that has limited previous research, Brusselaers and colleagues say. However, they were unable to identify the indication for PPI therapy in 25% of the cohort.
Increase in Cancer Not Seen With H2-Antagonists
A comparative analysis in 20,177 patients taking only histamine-2 receptor (H2) antagonists (such as ranitidine) found no increased risk for EAC (SIR, 0.39) or SCC (SIR, 0.50).
This finding "lends support to the hypothesis that this association may be due to PPI medication per se, and not related to other factors that predispose to using anti-acidic medications," the study authors say.
"To assess generalizability and validity of these results, further investigations in other settings with other distributions of risk factors for oesophageal cancer is necessary," they write. "Yet, we believe that a more restrictive attitude towards maintenance use of PPIs may be indicated…. Long term use of PPIs should be addressed with caution."
Assuming that 10.7% of Swedish adults are taking PPI maintenance therapy, 5.4% of all esophageal cancer cases seen in that country's population during the study period could be conservatively estimated to be attributable to PPI use, they suggest. The population of Sweden was 9.03 million in 2005 and had increased to 9.519 million by 2012.
This is not the first time that long-term PPI therapy has been implicated in increased cancer risk. Most recently, Medscape Medical News reported a Hong Kong study showing that long-term PPI therapy doubled gastric cancer risk after Helicobacter pylori eradication.
Dramatic Increase in Esophageal Cancer
When approached for comment, David A Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, said this study "potentially does more harm than good." A discussion with patients about whether PPI therapy is necessary "is always appropriate," but clinicians shouldn't stop prescribing PPIs as recommended, he emphasized.
"These findings are surprising because of the lack of evidence that goes with this observation. The allegation of harm should always start with a hypothesis as to why a reported association may be causal. None is suggested in this report," Johnson told Medscape Medical News.
Since the introduction of PPIs, the incidence of SCC of the esophagus has increased dramatically, Johnson acknowledged. The incidence of EAC in industrialized countries has also increased.
However, investigations into whether PPIs may be causally related have not provided any evidence to support this, he pointed out.
In fact, observational studies have shown an inverse relationship between the two, with lower rates of EAC seen in patients receiving PPIs. This evidence prompted prospective controlled studies evaluating the EAC risk reduction for patients with Barrett's esophagus as well as several cohort observational studies, Johnson noted.
Ultimately, evidence from these investigations led the American Gastroenterological Association to recommend that PPIs be given to all patients with Barrett's esophagus regardless of heartburn symptoms, stating that PPIs also had a chemoprevention role.
Johnson noted that "well-recognized significant risks for both SCC and EAC, including smoking, alcohol, and obesity, are strikingly absent from this analysis." In addition, "the lack of logistic regression analysis to account for stratification bias is unfortunate and undermines the conclusions."
The fact that the study didn't demonstrate an increased risk for cancer over time suggests a lead time bias in which PPI therapy was initiated in response to symptoms of esophageal cancer, Johnson said. "Well-done analyses of this type of potential risk would exclude these early cases for at least 6 months to avoid protopathic bias."
Jeffrey Meyerhardt, MD, a medical oncologist at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School in Boston, Massachusetts, agreed. Even though the study authors "made efforts to try and tease this up, the strongest associations were still observed in patients taking PPIs for acid reflux, which could be an early sign of esophageal cancer."
The greatest cancer risk was seen with short-term PPI use, he pointed out. In patients who had been receiving PPIs for 5 years or longer, the association was not significant, Meyerhardt noted. "This seems to be the reverse of what you would observe if PPIs cause esophageal cancer," he told Medscape Medical News.
Meyerhardt said that patients who require long-term PPI therapy should be screened with upper endoscopy at least once. "That is standard in guidelines but often not done."
Study Should Not Change Practice
Scott Gabbard, MD, a gastroenterologist at the Cleveland Clinic, Ohio, also warned that findings from this cohort study must be interpreted with caution. Like Johnson, he advised against clinicians making any practice changes, pointing out that maintenance PPI therapy is generally recommended in patients with Barrett's esophagus. In one meta-analysis, PPI therapy decreased the risk for adenocarcinoma and high-grade dysplasia by 71% in patients with Barrett's esophagus, he noted.
"I would not let one cohort study change my practice," Gabbard told Medscape Medical News. "This study demonstrates an association, not a cause and effect. I would be very careful not to state that PPIs cause esophageal cancer based on these data."
Gabbard said he encourages once-daily PPI therapy in his own patients with Barrett's esophagus. In patients with GERD who don't have Barrett's esophagus, he prescribes the lowest effective dose of PPI.
"I would be most interested in [the outcomes for] patients with Barrett's esophagus who did and did not take maintenance PPI," Gabbard said. This wasn't reported in the current study, he pointed out. "That said, we need more well-done studies to answer these questions fully."
Both Johnson and Gabbard said they would encourage practitioners to follow published guidelines for prescribing PPIs.
In its guideline for the diagnosis and management of Barrett's esophagus, the American College of Gastroenterology recommends maintenance PPI therapy for patients with GERD who continue to have symptoms after PPI therapy is discontinued.
The guidelines also recommend long-term PPI therapy for patients with complications, such as erosive esophagitis and Barrett's esophagus. It is advised that PPI maintenance therapy be administered in the lowest effective dose, including on-demand or intermittent therapy.
This study was supported by the Karolinska Institutet, the Swedish Research Council, and the Swedish Cancer Society. Brusselaers and study coauthors and Gabbard have disclosed no relevant financial relationships. Johnson has or has had financial ties to Pfizer Inc, which makes a PPI; Epigenomics; WebMD; CRH Medical; and Medtronic. Meyerhardt reports relationships with Chugai Pharma, Ignyta, and Roche/Genentech.
Cancer Epidemiol. Published online February 22, 2018. Abstract
In new guidance, the American College of Physicians (ACP) recommends a target HbA1c of 7% to 8% for most nonpregnant adults with type 2 diabetes.
"ACP's analysis of the evidence behind existing guidelines found that treatment with drugs to targets of 7% or less, compared with targets of about 8%, did not reduce deaths or macrovascular complications, such as heart attack or stroke, but did result in substantial harms,” said Jack Ende, MD, ACP president, in a statement.
"For most people with type 2 diabetes, achieving an HbA1c between 7% and 8% will best balance long-term benefits with harms such as low blood sugar, medication burden, and costs,” he added.
But experts from the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) contacted by Medscape Medical News take issue with these higher glycemic control targets, which they argue don't consider, for example, the cardiovascular disease (CVD) benefits of newer therapies which often lower HbA1c levels.
The new ACP guidance could therefore cause confusion for internists and primary care physicians, who may not know whether to follow the new guidance or stick with the advice from the ADA and AACE.
But Timothy J Wilt, MD, MPH, who coauthored the ACP statement, noted, "Importantly, HbA1c target recommendations from other guideline groups also did not include information about these newer drugs which have been mainly studied in higher risk [those with, or at high risk of, CVD] individuals."
"ACP's guidance statement reviewed evidence and guideline recommendations related to HbA1c treatment targets and did not specifically address newer diabetes drugs that may have benefits and harms beyond the specific HbA1c target or lowering effect," he added.
The new ACP guidance was published online March 5 in the Annals of Internal Medicine.
One issue all the societies agree on is that type 2 diabetes treatment should be individualized, but William T Cefalu, MD, chief scientific, medical and mission officer, ADA, said all clinicians caring for people with diabetes should rely on the same patient factors, "and so HbA1c targets should not vary between types of clinicians or clinical settings."
Yehuda Handelsman, MD, Metabolic Institute of America, Tarzana, California, chair of the diabetes scientific committee and 2012 & 2015 comprehensive diabetes guidelines, AACE, was more vocal in his criticism of the ACP's stance, noting that their “new guidance will surely add confusion."
ADA and AACE guidelines are "quite similar as both endorse personalized treatment, focusing on lower HbA1c goals and recommending newer medications with lower risk of hypoglycemia," he said.
"Hopefully most primary care clinicians will continue to follow the current leading guidelines" — those from the ADA and AACE.
But Wilt responded: "ACP's guidance statement is based on evidence of benefits and harms. We encourage other guideline groups to review our statement, the evidence included, and adopt our statements to enhance consistency and improve the care we provide our patients with type 2 diabetes."
"ACP believes that, given the evidence, most primary care physicians will implement ACP's recommendations and that many patients with type 2 diabetes will be pleased to learn that less intensive care leads to better health outcomes," he stressed.
Guidance Development Process
ACP aimed to develop a guidance statement for HbA1c targets for adults with type 2 diabetes based on a review of existing guidelines in May 2017.
The authors identified six guidelines from AACE/American College of Endocrinology (ACE); ADA; Scottish Intercollegiate Guidelines Network (SIGN); US Department of Veterans Affairs and Department of Defense (VA/DoD); UK National Institute for Health and Care Excellence (NICE); and Institute for Clinical Systems Improvement (ICSI).
These guidelines analyzed evidence from five large, long-term randomized trials of a "treat-to-target" strategy in type 2 diabetes: Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), United Kingdom Prospective Diabetes Study (UKPDS) trials 33 and 34, and Veterans Affairs Diabetes Trial (VADT).
Recent cardiovascular outcomes studies evaluating newer diabetes drugs such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists were not designed to evaluate treat-to-target strategies, the authors note, so they were not included in the evaluation.
Four Guidance Statements
The ACP guidance includes four statements.
Statement 1: "Clinicians should personalize goals for glycemic control in patients with type 2 diabetes on the basis of a discussion of benefits and harms of pharmacotherapy, patients' preferences, patients' general health and life expectancy, treatment burden, and costs of care."
"This guidance is consistent with ADA's 2018 Standards of Medical Care," Cefalu told Medscape Medical News. "We have long recommended that treatment goals be individualized based on factors ... such as age, life expectancy, duration of disease, resources and support systems, and comorbid conditions."
"This is important, and we are in agreement," Handelsman concurred.
Statement 2: "Clinicians should aim to achieve an HbA1c level between 7% and 8% in most patients with type 2 diabetes."
This differs from ADA and AACE recommendations. It is most closely aligned with the ICSI guideline, which "highlights that efforts to achieve HbA1c levels below 7% may increase risk for death, weight gain, hypoglycemia, and other adverse effects in many patients," the ACP authors write. "We share these concerns." Moreover, none of the three trials achieving an HbA1c level below 7% showed a reduction in all-cause or cardiovascular mortality, they add.
"The ADA recommends that a reasonable HbA1c goal for 'many' nonpregnant adults is less than 7% based on evidence available to date," Cefalu said.
It is unlikely that "most patients" with type 2 diabetes have severe hypoglycemia, limited life expectancy, advanced micro- and/or macrovascular complications, extensive comorbid conditions, or long-standing diabetes, so "a reasonable goal remains less than 7%," based on the UKPDS.
Patients in ACCORD, ADVANCE, and VADT (cited in the ACP guidance) were older and sicker than in the UKPDS. The UKPDS, which included patients with newly diagnosed type 2 diabetes with an average age of 54 years, showed the benefits of an HbA1c less than 7% and a continual reduction in risk for microvascular complications.
"The ADA believes all people diagnosed with type 2 diabetes ... should have the opportunity to reduce their risk of serious diabetes complications through appropriate blood glucose targets," Cefalu stressed.
"Individualization of targets is the key factor, and by lumping 'most' people with type 2 diabetes into a 7–8% target range, ACP's new guidance may cause potential harm to those who may safely benefit from lower evidence-based targets."
"This is absolutely wrong and regressive," Handelsman asserted. "We were quite (terribly) surprised by such gross neglect of data and the evidence."
"It is sad that ... the ACP, has stepped back in time, ignoring all the scientific and pharmaceutical development of the past 10–15 years, displaying a lack of understanding of the available data and resort to this plausible statement, calling their position 'evidence-based guidance' to support their conclusions."
"There is no evidence to support higher goals in the management of the majority of patients with diabetes, while there is overabundance of evidence to show that lower HbA1c is better."
"The top diabetes experts, nationally and internationally, through the leading medical societies in diabetes — ADA, AACE, EASD, International Diabetes Federation [IDF], and others — all agree that the HbA1c goal for most patients should be ≤ 6.5% (AACE, IDF) or < 7% (ADA, EASD). Clearly the evidence supports these goals, while the ACP's position is not supported."
ACP Defends Its Position
But Wilt argues: "There is no high quality evidence that achieving an HbA1c of < 7% improves clinical outcomes, and it leads to harms, medication burden, and costs."
Any benefits, for example, reductions in microvascular complications in the UKPDS and other studies "were small in absolute numbers, required many years to accrue, were not consistently found, and typically were limited to 'laboratory or physiologic' measures, such as protein in the urine, rather than clinical outcomes, such as painful neuropathy, impaired vision, or kidney failure," he added.
"Evidence does not support an HbA1c of < 6.5%, but rather demonstrates that this leads to no benefit and substantial harms and costs," Wilt said.
"ACP's guidance statement ... demonstrates that a target range of 7–8% for most patients provides an optimal balance of clinical benefits and harms," he reiterated.
Statement 3: "Clinicians should consider de-intensifying pharmacologic therapy in patients with type 2 diabetes who achieve HbA1c levels less than 6.5%."
"Results from studies included in all the guidelines demonstrate that health outcomes are not improved by treating to HbA1c levels below 6.5%,” Ende said.
"This guidance is different from the ADA's 2018 Standards of Care," noted Cefalu.
"However, we do recommend de-intensification or simplification of complex regimens to reduce the risk of hypoglycemia in older adults, if this can be achieved within the individualized HbA1c target. Any de-intensification should be based on these factors, such as the presence of hypoglycemia, and not on a number."
"In 2018, the ADA recommended that patients with existing cardiovascular disease not meeting HbA1c targets on metformin alone receive a medication proven to reduce risk of CVD death and/or events," he noted.
"It's possible that this add-on therapy may reduce HbA1c levels to below 6.5% — the ACP guidance would suggest that the add-on therapy be removed, thus increasing the risk of morbidity and mortality."
Higher targets for people with existing CVD may mean that treatment intensification with these potentially life-saving medications isn't considered, Cefalu observed.
"How not smart ... to reduce pharma therapy in patients who are at goal. Once the medication stops, that patient will lose [glycemic] control," Handelsman opined.
"Contemporary management of diabetes is simple, effective, and safe," he said. A common option is to prescribe a once-weekly GLP-1 receptor agonist with a fixed-dose combination of slow-release metformin and an SGLT-2 inhibitor. Such a combination has the potential to reduce HbA1c by at least 2.5–3% without hypoglycemia and promotes weight loss and blood pressure reduction.
"This type of combination treatment, together with lifestyle, can offer good control (HbA1c < 7%, even < 6.5%) safely to patients even with high baseline HbA1c of up to 10%, which represents nearly 80% of all patients with type 2 diabetes."
Other new therapies, like longer-acting and hence more stable insulin, reduce hypoglycemia (compared with older insulins), and drugs from the SGLT-2 inhibitor and GLP-1 receptor agonist families reduce morbidity and mortality in patients with diabetes who have established CVD.
Wilt stressed that the ACP's guidance "did not specifically address newer diabetes drugs that may have benefits and harms beyond the specific HbA 1c target or lowering effect."
Statement 4: "Clinicians should treat patients with type 2 diabetes to minimize symptoms related to hyperglycemia and avoid targeting an HbA1c level in patients with a life expectancy less than 10 years due to advanced age (80 years or older), residence in a nursing home, or chronic conditions (such as dementia, cancer, end-stage kidney disease, or severe chronic obstructive pulmonary disease or congestive heart failure) because the harms outweigh the benefits in this population."
"This guidance is consistent with ADA's end-of-life recommendations; however, the ADA disagrees that this applies broadly to anyone over age 80, anyone living in a nursing home, or anyone with chronic conditions, and who has a limited life expectancy," said Cefalu.
Each specific case should be individually evaluated, as a person in a nursing home or with a chronic condition may have years to live and would likely prefer to live without diabetes complications, he stressed.
"It's important to note that the average life expectancy for an 80-year-old man is more than 8 years, and it's nearly 10 years for a woman the same age. And that's an average — for some individuals, it's even longer."
"For the very sick, those with cancers, short lifespan, etc, rather than using HbA1c, focusing on just glucose makes more sense," agreed Handelsman.
Keeping glucose between, for example, 100–250 mg/dL (or possibly 80–300 mg/dL) would assure no hypoglycemia nor symptoms of hyperglycemia such as polydipsia or polyuria.
Handelsman has received research grants, consultant fees, and speaker honoraria from Aegerion, Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gan & Lee, Gilead, Grifols, Hamni Pharmaceutical, Intarcia, Janssen, Lexicon, Lilly, Merck, Mylan, Merck-Pfizer, Novo Nordisk, Regeneron, and Sanofi. Ce falu had no financial disclosures as an ADA employee.
Ann Intern Med. Published online March 5, 2018. Article
Being younger when diagnosed with type 2 diabetes is associated with an increased risk of all-cause and cardiovascular disease (CVD) mortality compared with being diagnosed at a later stage in life, a large Australian cohort study has shown.
"Evidence is accumulating to suggest that earlier onset of type 2 diabetes is associated with an increased risk of complications and comorbidities compared with later onset, and that the development and progression of complications might be more aggressive in those with earlier onset," say the authors, led by Lili Huo, MD, of the Baker Heart and Diabetes Institute in Melbourne, Australia.
"Early and aggressive risk factor management is warranted for individuals with young-onset type 2 diabetes," they conclude.
The research was published online February 22 in Diabetologia by Huo and colleagues.
Greater Risk of Noncancer Death With Younger Age at Diagnosis
Type 2 diabetes was considered a disease largely confined to older people, but the global epidemic of obesity and overweight in almost all countries has seen diagnoses rocket in young adults, adolescents, and even younger children.
Diabetes rates are increasing substantially in younger adults aged 20 to 45 years, which means there is a steadily growing pool of patients with type 2 diabetes exposed to the disease for a longer period in their lives.
The researchers analyzed data on 743 709 Australians diagnosed with type 2 diabetes between 1997 and 2011 from the National Diabetes Services Scheme.
The sample represented approximately 90% of all Australians diagnosed with type 2 diabetes over the study interval. Mortality was determined using data from the National Death Index.
The median age at diagnosis was 59 years and 115 363 deaths occurred over the 15-year study interval. The median follow-up was 7.2 years.
"At any given age, all-cause mortality rates were higher for a lower age of diagnosis (therefore longer duration) in both men and women," Huo and colleagues report.
For example, for two, 50-year-old men, one of whom was diagnosed with diabetes at the age of 45 years and the other at the age of 50 years, mortality from CVD was about 1.4 times higher in the one diagnosed 5 years earlier.
And the gap between mortality risk and death from any cause, as well as from CVD, was even greater when the difference in diabetes diagnosis was even longer.
So the risk of death from any cause was about 30% greater for a 50-year-old man whose type 2 diabetes was diagnosed 10 years earlier while the risk of death from CVD was about 60% greater, compared with a 50-year-old man whose disease was diagnosed at age 50 years.
"Similar patterns were seen in women, though the excess risks of earlier-onset diabetes were slightly higher among women than among men," the researchers observe.
But Lower Cancer Mortality Associated With Younger Age at Diagnosis
In contrast, at any given age, "the earlier age at diagnosis was associated with lower cancer mortality and was most pronounced among women," the researchers observe.
They note that mortality rates from cancer were high just after being diagnosed with diabetes but then declined during the first 3 years following the diagnosis.
This may reflect the fact that patients with newly diagnosed diabetes are more likely to be in contact with healthcare professionals, making it more likely that undiagnosed cancer would be detected, the authors speculate.
They also hypothesize that the excess mortality risk in patients with younger-onset diabetes likely reflects increased exposure to hyperglycemia with longer disease duration.
"Our findings suggest that younger-onset type 2 diabetes increases mortality risk, and that this is mainly through earlier CVD mortality," investigators conclude.
"Efforts to delay the onset of type 2 diabetes might, therefore, reduce mortality," they conclude.
The study was funded by the National Health and Medical Research Council and the Victoria government's Operational Infrastructure Support program.
Diabetologia. Published online February 22, 2018. Abstract