Disease Progression

Background: No therapies have been approved to alter bronchiectasis progression. Dipeptidyl peptidase-1 (DPP-1) inhibitors, which target neutrophil serine protease activation, are under investigation as potential disease-modifying agents.

Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing DPP-1 inhibitors versus placebo in patients with non-cystic fibrosis bronchiectasis. PubMed, Cochrane, EMBASE, Web of Science, Scopus, ClinicalTrials.gov, and ICTRP were searched from inception until April 26, 2025. Primary outcomes included time to first exacerbation and proportion of patients remaining exacerbation-free. Secondary outcomes included post-bronchodilator % Forced Expiratory Volume in 1 s (FEV1), Quality of Life-Bronchiectasis (QoL-B) questionnaire scores, and rate of adverse events. Time-to-event outcome was analyzed using Kaplan-Meier (KM)-estimated individual patient data (IPD), whereas random-effects meta-analyses were performed for remaining outcomes.

Results: 2523 patients from four RCTs were included, of whom 1689 (66.9 %) received DPP-1 inhibitors. Compared with placebo, DPP-1 inhibitors prolonged the time to first exacerbation (HR 0.79; 95 % CI: 0.71 to 0.88) and increased the proportion of patients remaining exacerbation-free (RR 1.33; 95 % CI 1.12 to 1.58). A slower decline in post-bronchodilator % FEV1 was observed (MD 1.1 %; 95 % CI 0.05 to 2.15), but no difference in QoL-B scores (MD 1.35; 95 % CI -0.72 to 3.42). The safety profile of DPP-1 inhibitors was acceptable and comparable to placebo. Moderate certainty was found across endpoints.

Conclusions: DPP-1 inhibitors prolong time to first exacerbation and reduce exacerbation rates in patients with bronchiectasis, with an acceptable safety profile. These findings support their potential as a disease-modifying strategy.

Registration: PROSPERO (CRD420251042542).

Keywords: Bronchiectasis; DPP-1 inhibitor; Dipeptidyl-peptidases and tripeptidyl-peptidases; Meta-analysis; Randomized controlled trials; Systematic review.

Author/s:

Giulia Carvalhal, Júlia Moreira Diniz, Larissa Calixto Hespanhol, David Curi Barbosa Izoton Cabral, Jafar Aljazeeri

Canadian guideline for Parkinson disease

Erin Blanchette — Wed, 12 Mar 2025 21:31:08 +0000

Date Added:

March 12, 2025

Journal/Publication:

Canadian Medical Association Journal

Publisher:

Canadian Medical Association

Publication Date:

September 9, 2019

Issue:

Volume:

191

Pages:

E989-E1004

URL:

Canadian guideline for Parkinson disease

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1503/cmaj.181504

Keywords

PMID (1):

31501181

MeSH

Deep Brain Stimulation

Parkinson Disease / diagnosis*

Parkinson Disease / physiopathology

Parkinson Disease / therapy

quality of life

An updated Canadian guideline for the diagnosis and management of Parkinson's Disease. James W. Mold, MD, MPH

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KEY POINTS

This guideline update reflects substantial changes in the literature on diagnosis and treatment of Parkinson disease, and adds information on palliative care.

Impulse control disorders can develop in a person with Parkinson disease who is on any dopaminergic therapy at any stage in the disease course, especially for those taking dopamine agonists.

Advanced therapies like deep brain stimulation and intrajejunal levodopa-carbidopa gel infusion are now routinely used in Parkinson disease to manage motor symptoms and fluctuations.

Evidence exists to support early institution of exercise at the time of diagnosis of Parkinson disease, in addition to the clear benefit now shown in those with well-established disease.

Palliative care requirements of people with Parkinson disease should be considered throughout all phases of the disease, which includes an option of medical assistance in dying.

Parkinson disease is chronic and progressive in nature, decreasing the quality of life for both patients with the disease and their caregivers and placing an onerous economic burden on society.1

The first Canadian guideline on Parkinson disease was published in 2012.2 Since that guideline, there have been substantial advances in the literature on the disease, particularly with respect to diagnostic criteria and treatment options. Parkinson Canada undertook to update the existing guideline to reflect these advances, as well as to add information on palliative care.

With the aim of enhancing care for all Canadians with Parkinson disease, this guideline is based on the best published evidence, involves expert consensus when there is a lack of evidence, offers practical clinical advice, takes patient choice and informed decision-making into account and is relevant to the Canadian health care system. The guideline has been divided into 5 main sections to improve the ease of use: communication, diagnosis and progression, treatment, nonmotor features and palliative care. The full guideline is available in Appendix 1, at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.181504/-/DC1.

Author/s:

David Grimes, Megan Fitzpatrick, Joyce Gordon, Janis Miyasaki, Edward A Fon, Michael Schlossmacher, Oksana Suchowersky, Alexander Rajput, Anne Louise Lafontaine, Tiago Mestre, Silke Appel-Cresswell, Suneil K Kalia, Kerrie Schoffer, Mateusz Zurowski, Ronald B Postuma, Sean Udow, Susan Fox, Pauline Barbeau, Brian Hutton

Firearm-Related Violence in the Pediatric Population

Linda Fowler — Fri, 26 Jan 2024 21:39:50 +0000

Date Added:

January 26, 2024

Journal/Publication:

Pediatric Annals

Publication Date:

January 1, 2024

Issue:

Volume:

Pages:

e28 - e33

URL:

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.3928/19382359-20231114-02

Keywords

PMID (1):

38194661

MeSH

Firearms

Adolescent Health

Mass Shooting Events

Violence / prevention & control

Humans

Disease Progression

Firearm-related events are one of the leading causes of death in children and adolescents. If one of our roles as clinicians is to prevent premature deaths, then we need to be sure that parents are educated regarding safe storage of firearms and other firearm safety measures. James W. Mold, MD, MPH

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Children, particularly adolescents, are dying from firearm-related injuries. Screening for firearms, early recognition of firearm-related concerns, appropriate referrals, and follow-up are crucial to the safety of our patients and their families. Clinicians are strongly encouraged to address firearm-related violence during clinical encounters. Risk reduction, advocacy, and policy implementation are key in mitigating the long-term negative sequelae of firearm violence in youth. The epidemiology of firearm-related death, mass shootings, school firearm violence, adolescent health, prevention, injury patterns, postinjury care, policy, and resources are all discussed in this article. [Pediatr Ann. 2024;53(1):e28–e33.]

Author/s:

Katherine M Marsh, Felicia Scott-Wellington

Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes The GRADE Randomized Clinical Trial

Aubrey Delammermore — Sat, 27 May 2023 05:00:00 +0000

Date Added:

May 27, 2023

Journal/Publication:

JAMA

Publisher:

American Medical Association

Publication Date:

May 22, 2023

Pages:

E1-E10

URL:

Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes The GRADE Randomized Clinical Trial

Type:

Clinical Research Results

Format:

Article

DOI (1):

10.1001/jamainternmed.2023.1487

Keywords

Intention to Treat Analysis

PMID (1):

37213109

MeSH

Disease Progression

Kidney Diseases

renal dialysis

diabetes mellitus, type 2

glucose

In patients with T2DM, if your objective is to protect the kidneys, there is no need to switch to newer, more expensive meds. James W. Mold, MD, MPH.

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Importance: Type 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function.

Objective: To evaluate kidney outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) trial comparing 4 classes of glucose-lowering medications added to metformin for glycemic management in individuals with T2D.

Design, setting, and participants: A randomized clinical trial was conducted at 36 sites across the US. Participants included adults with T2D for less than 10 years, a hemoglobin A1c level between 6.8% and 8.5%, and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m2 who were receiving metformin treatment. A total of 5047 participants were enrolled between July 8, 2013, and August 11, 2017, and followed up for a mean of 5.0 years (range, 0-7.6 years). Data were analyzed from February 21, 2022, to March 27, 2023.

Interventions: Addition of insulin glargine, glimepiride, liraglutide, or sitagliptin to metformin, with the medication combination continued until the HbA1c was greater than 7.5%; thereafter, insulin was added to maintain glycemic control.

Main outcomes and measures: Chronic eGFR slope (change in eGFR between year 1 and trial end) and a composite kidney disease progression outcome (albuminuria, dialysis, transplant, or death due to kidney disease). Secondary outcomes included incident eGFR less than 60 mL/min/1.73 m2, 40% decrease in eGFR to less than 60 mL/min/1.73 m2, doubling of urine albumin-to-creatinine ratio (UACR) to 30 mg/g or greater, and progression of Kidney Disease Improving Global Outcomes stage. Analyses were intention-to-treat.

Results: Of the 5047 participants, 3210 (63.6%) were men. Baseline characteristics were mean (SD) age 57.2 (10.0) years; HbA1c 7.5% (0.5%); diabetes duration, 4.2 (2.7) years; body mass index, 34.3 (6.8); blood pressure 128.3/77.3 (14.7/9.9) mm Hg; eGFR 94.9 (16.8) mL/min/1.73 m2; and median UACR, 6.4 (IQR 3.1-16.9) mg/g; 2933 (58.1%) were treated with renin-angiotensin-aldosterone inhibitors. Mean chronic eGFR slope was -2.03 (95% CI, -2.20 to -1.86) mL/min/1.73 m2 per year for patients receiving sitagliptin; glimepiride, -1.92 (95% CI, -2.08 to -1.75) mL/min/1.73 m2 per year; liraglutide, -2.08 (95% CI, -2.26 to -1.90) mL/min/1.73 m2 per year; and insulin glargine, -2.02 (95% CI, -2.19 to -1.84) mL/min/1.73 m2 per year (P = .61). Mean composite kidney disease progression occurred in 135 (10.6%) patients receiving sitagliptin; glimepiride, 155 (12.4%); liraglutide, 152 (12.0%); and insulin glargine, 150 (11.9%) (P = .56). Most of the composite outcome was attributable to albuminuria progression (98.4%). There were no significant differences by treatment assignment in secondary outcomes. There were no adverse kidney events attributable to medication assignment.

Conclusions and relevance: In this randomized clinical trial, among people with T2D and predominantly free of kidney disease at baseline, no significant differences in kidney outcomes were observed during 5 years of follow-up when a dipeptidyl peptidase 4 inhibitor, sulfonylurea, glucagonlike peptide 1 receptor agonist, or basal insulin was added to metformin for glycemic control.

Author/s:

Wexler, D. J., de Boer, I. H., Ghosh, A., Younes, N., Bebu, I., Inzucchi, S. E., McGill, J. B., Mudaliar, S., Schade, D., Steffes, M., Tamborlane, W. V., Tan, M. H., Ismail-Beigi, F., GRADE Research Group

Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer

Rowan Hutchins — Sun, 19 Mar 2023 05:00:00 +0000

Date Added:

March 19, 2023

Journal/Publication:

NEJM

Publisher:

Massachusetts Medical Society

Publication Date:

March 11, 2023

URL:

Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer

Type:

Clinical Research Results

Format:

Article

DOI (1):

10.1056/NEJMoa2214122

Keywords

PMID (1):

36912538

MeSH

Disease Progression

Prostate-Specific Antigen

prostatectomy

Androgen Antagonists

prostatic neoplasms

This is the best evidence we have to date regarding the benefits of, or lack thereof, of treatment of localized prostate cancer. James W. Mold, MD, MPH

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Background

Between 1999 and 2009 in the United Kingdom, 82,429 men between 50 and 69 years of age received a prostate-specific antigen (PSA) test. Localized prostate cancer was diagnosed in 2664 men. Of these men, 1643 were enrolled in a trial to evaluate the effectiveness of treatments, with 545 randomly assigned to receive active monitoring, 553 to undergo prostatectomy, and 545 to undergo radiotherapy.
Methods

At a median follow-up of 15 years (range, 11 to 21), we compared the results in this population with respect to death from prostate cancer (the primary outcome) and death from any cause, metastases, disease progression, and initiation of long-term androgen-deprivation therapy (secondary outcomes).
Results

Follow-up was complete for 1610 patients (98%). A risk-stratification analysis showed that more than one third of the men had intermediate or high-risk disease at diagnosis. Death from prostate cancer occurred in 45 men (2.7%): 17 (3.1%) in the active-monitoring group, 12 (2.2%) in the prostatectomy group, and 16 (2.9%) in the radiotherapy group (P=0.53 for the overall comparison). Death from any cause occurred in 356 men (21.7%), with similar numbers in all three groups. Metastases developed in 51 men (9.4%) in the active-monitoring group, in 26 (4.7%) in the prostatectomy group, and in 27 (5.0%) in the radiotherapy group. Long-term androgen-deprivation therapy was initiated in 69 men (12.7%), 40 (7.2%), and 42 (7.7%), respectively; clinical progression occurred in 141 men (25.9%), 58 (10.5%), and 60 (11.0%), respectively. In the active-monitoring group, 133 men (24.4%) were alive without any prostate cancer treatment at the end of follow-up. No differential effects on cancer-specific mortality were noted in relation to the baseline PSA level, tumor stage or grade, or risk-stratification score. No treatment complications were reported after the 10-year analysis.
Conclusions

After 15 years of follow-up, prostate cancer–specific mortality was low regardless of the treatment assigned. Thus, the choice of therapy involves weighing trade-offs between benefits and harms associated with treatments for localized prostate cancer. (Funded by the National Institute for Health and Care Research; ProtecT Current Controlled Trials number, ISRCTN20141297. opens in new tab; ClinicalTrials.gov number, NCT02044172. opens in new tab.)

Author/s:

Hamdy, Freddie, Donovan, Jenny, Lane, Athene, Metcalfe, Chris, Davis, Michael, Turner, Emma, Martin, Richard, Young, Grace, Walsh, Eleanor, Bryant, Bollina, Prasad, Doble, Andrew

Milestones in Heart Failure: How Far We Have Come and How Far We Have Left to Go

Saige Blanchard — Mon, 03 Jan 2022 06:00:00 +0000

Date Added:

January 3, 2022

Journal/Publication:

Cureus Journal of Medical Science

Publication Date:

December 12, 2021

URL:

Milestones in Heart Failure: How Far We Have Come and How Far We Have Left to Go

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.7759/cureus.20359

Keywords

MeSH

Angiotensin Receptor Antagonists

heart failure

Disease Progression

A nice summary of what we currently know about the pharmacologic treatment of congestive heart failure. James W. Mold, MD, MPH

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Heart failure is a clinically complex syndrome that results due to the failure of the ventricles to function as pump and oxygenate end organs. The repercussions of inadequate perfusion are seen in the form of sympathetic overactivation and third spacing, leading to clinical signs of increased blood pressure, dyspnea, fatigue, palpitations, etc. This article provided a brief overview of the clinical syndrome of heart failure; its epidemiology, risk factors, symptoms, and staging; and the mechanisms involved in disease progression. This article also described several landmark trials in heart failure that tested the efficacy of first-line drugs such as beta-blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and the latest drugs in the field of heart failure: angiotensin receptor neprilysin inhibitors. Most studies described in this article were guideline-setting trials that revolutionized the practice of medicine and cardiology.

Author/s:

H., Kela, I., Kakarlala, C., Hassan, M., Belavadi, R., Gudigopuram, S. V. R., Raguthu, C., Modi, S., Sange, I.

The Potential Emergence of Disease-Modifying Treatments for Alzheimer Disease: The Role of Primary Care in Managing the Patient Journey

Brian Desmarais — Thu, 09 Jan 2020 15:51:26 +0000

Date Added:

January 9, 2020

Journal/Publication:

Journal of the American Board of Family Medicine

Publication Date:

November 1, 2019

Issue:

Volume:

Pages:

931-940

URL:

The Potential Emergence of Disease-Modifying Treatments for Alzheimer Disease: The Role of Primary Care in Managing the Patient Journey

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.3122/jabfm.2019.06.180328

Keywords

MeSH

This opinion piece provides an update on the status of diagnostic tests and possible new treatments for Alzheimer’s Disease. I am posting it so that you can answer patients’ and families’ questions. I do believe that adding a brief cognitive test to the AWV makes sense, since, for clinical purposes, you need to know whether patients have short term memory deficits, and the only way to reliably determine that is with testing. In my practice and in the one I now attend as a patient, we/they use(d) the Short Blessed Test (SBT), which only takes the nurse about 2-3 minutes to administer. James W. Mold, MD, MPH

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Despite recent setbacks, disease-modifying treatments (DMTs) for Alzheimer disease (AD) might become available within a few years. These DMTs are likely to be used in the early stages of AD to avoid the progression to manifest dementia, which implies that a large reservoir of prevalent cases would need to be evaluated when DMTs first become available. Primary care providers (PCPs) would play a vital role in managing the patient flow to specialty care. We review the literature on diagnostic tests that could be used by PCPs and estimate the impact of different testing approaches on demand for specialty care.While many tests have been evaluated, only the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) perform acceptably for detection of early-stage cognitive decline with sensitivities and specificities of 55% to 82% and 72% to 84%, respectively, for the MMSE; and 77% to 96% and 73% to 95%, respectively, for the MoCA. However, neither test is sufficiently specific for the AD pathology and would result in 4 to 5 false positives for each true positive. Blood-based tests for AD biomarkers may soon become available for clinical use. A plasma amyloid-β (Aβ) test has been shown to have a sensitivity of up to 97% and specificity of up to 81%. Adding this test to the MMSE or MoCA could reduce false positives by approximately 80%.These findings suggest a combination of brief cognitive tests and blood-based biomarker tests will allow PCPs to identify patients with potential early stage AD efficiently and triage them for further evaluation.

Author/s:

Lam, J., Hlávka, J., Mattke, S.