Preventive Cardiology

Comprehensive Glycemic Goals and Hypoglycemia Management in Diabetes: 2025 ADA Standards

13 Jan, 2025 | 12:39h | UTC

Introduction: This summary provides key points from the American Diabetes Association’s (ADA) 2025 guidance on glycemic targets, monitoring, and hypoglycemia management in type 1 and type 2 diabetes. It emphasizes individualized A1C goals, the clinical use of continuous glucose monitoring (CGM)—a system that measures interstitial glucose levels throughout the day—and the prevention and treatment of hypoglycemia. The main objective is to help clinicians optimize glucose control, reduce acute and chronic complications, and improve patient outcomes.

Key Recommendations:

1. Individualized Glycemic Targets
   • An A1C goal of <7% (<53 mmol/mol) is generally appropriate for many nonpregnant adults without frequent or severe hypoglycemia.
   • Lower or higher A1C goals may be appropriate in specific situations. For example:
     • Comorbidities: Individuals with significant cardiovascular disease, kidney dysfunction, or other conditions may benefit from a more conservative A1C target (e.g., <8%), balancing the risks of intensive treatment (such as hypoglycemia) against the benefits of tighter control.
     • Hypoglycemia Risk: Those with a history of severe or frequent hypoglycemia might need to relax A1C targets to avoid life-threatening low glucose episodes. In contrast, highly motivated patients with robust hypoglycemia awareness and access to advanced monitoring tools could safely aim for A1C closer to 6%.
     • Life Expectancy: Younger, healthier individuals with fewer complications can pursue tighter A1C targets because they have time to benefit from reduced microvascular and macrovascular risks. Older adults or those with serious illnesses and limited life expectancy may adopt higher A1C goals to reduce treatment burden and prevent hypoglycemic events.
2. Monitoring Glycemic Status
   • A1C Testing: Measure at least twice a year when glucose levels are stable and quarterly (or more often) when adjusting therapy or when targets are not met. If A1C is unreliable (e.g., hemoglobin variants), fructosamine or glycated albumin may be used.
   • Continuous Glucose Monitoring (CGM): CGM devices automatically measure glucose day and night, providing valuable data for clinical decision-making. Key CGM metrics include:
     • Time in Range (TIR): The percentage of readings between 70 and 180 mg/dL, with >70% as a common target in most nonpregnant adults.
     • Time Below Range: Ideal is <4% of readings under 70 mg/dL and <1% for older adults.
     • Time Above Range: Common goals are <25% for mild hyperglycemia and <5% for severe hyperglycemia, though this may vary with age and comorbidities.
   • When refining diabetes therapies, review CGM reports (e.g., ambulatory glucose profiles) to identify patterns of high or low glucose. This helps personalize adjustments to medications, diet, and exercise. For instance, consistent nocturnal hypoglycemia might prompt a reduction or timing change of basal insulin, while excessive morning hyperglycemia may require earlier medication dosing or lifestyle interventions.
3. Hypoglycemia Prevention and Management
   • Classification: Level 1 (<70 mg/dL), Level 2 (<54 mg/dL), and Level 3 (severe, requiring assistance).
   • Assessment: At each visit, review hypoglycemia history, symptom awareness, and potential triggers (e.g., exercise, medication errors, missed meals).
   • Treatment: In conscious patients, use 15 g of fast-acting carbohydrates (glucose tablets or similar). Recheck glucose in 15 minutes and repeat if still low.
   • Glucagon Prescription: Recommended for anyone on insulin or otherwise high-risk. Ready-to-inject or nasal glucagon formulations are preferred for ease of use.
   • Therapeutic Adjustment: Deintensify or modify medications (insulin, sulfonylureas) if patients experience recurrent moderate or any severe hypoglycemia.
4. Hyperglycemic Crises
   • DKA and HHS: Promptly recognize and treat diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS), especially in patients presenting with nausea, vomiting, dehydration, or altered mental status.
   • Prevention: Provide “sick day” advice on ketone checks, hydration, and insulin adjustments during illness. Recurrent crises often reflect limited access to medications or inadequate education; address these barriers to reduce re-hospitalizations.
5. Long-Term Impact on Complications
   • Early intensive glycemic control significantly lowers the risk of microvascular complications (retinopathy, nephropathy, neuropathy) in both type 1 and type 2 diabetes.
   • Long-term studies in type 1 diabetes show that sustained glucose management can reduce cardiovascular events. In type 2 diabetes, the addition of newer agents (e.g., GLP-1 receptor agonists or SGLT2 inhibitors) can further decrease cardiovascular and kidney risks, independent of current A1C levels.

Conclusion: The 2025 ADA Standards reinforce the need for customized glycemic targets, informed by comorbidities, hypoglycemia risk, life expectancy, and patient preferences. Using a combination of A1C and CGM data provides a more complete picture of glucose patterns and helps clinicians fine-tune therapies. Preventing hypoglycemia through medication adjustments, structured self-management education, and tailored CGM strategies is paramount. Overall, consistent and individualized glucose control offers better long-term outcomes, fewer complications, and improved quality of life for individuals with diabetes.

Reference: American Diabetes Association Professional Practice Committee. 6. Glycemic Goals and Hypoglycemia: Standards of Care in Diabetes—2025. Diabetes Care 2025;48(Supplement_1):S128–S145.
https://doi.org/10.2337/dc25-S006

 

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RCT: Chlorthalidone Shows No Renal Advantage Over Hydrochlorothiazide Under Equivalent Dosing in Older Adults With Hypertension

3 Jan, 2025 | 09:00h | UTC

Background: Hypertension is a critical factor in chronic kidney disease (CKD) progression and cardiovascular risk. Thiazide-type diuretics, such as chlorthalidone and hydrochlorothiazide, are first-line antihypertensive treatments. However, whether one agent confers stronger renal protection remains contested, especially at doses considered pharmacologically comparable. Prior observational studies suggested potential discrepancies in kidney outcomes and hypokalemia incidence. This secondary analysis of the Diuretic Comparison Project (DCP) further clarifies the comparative effectiveness of chlorthalidone versus hydrochlorothiazide on renal endpoints.

Objective: To evaluate whether chlorthalidone (12.5–25 mg/day) prevents CKD progression more effectively than hydrochlorothiazide (25–50 mg/day) in adults ≥65 years with hypertension and no pre-specified exclusion by renal function.

Methods: The DCP is a pragmatic, open-label randomized clinical trial embedded in Veterans Affairs (VA) facilities across the United States. Between June 1, 2016, and December 31, 2023, patients already receiving hydrochlorothiazide (25 or 50 mg/day) for hypertension were randomized either to continue that medication or switch to chlorthalidone (12.5–25 mg/day), reflecting equivalent potency.
The prespecified primary kidney outcome was a composite of doubling of serum creatinine, a terminal estimated glomerular filtration rate (eGFR) <15 mL/min, or dialysis initiation. Secondary measures included ≥40% eGFR decline, incident CKD (new eGFR <60 mL/min), eGFR slope, and relevant adverse events. Laboratory data were obtained through usual clinical care rather than protocol-driven testing.

Results: Among 13,523 randomized participants, 12,265 had analyzable renal data (mean [SD] age, 71 [4] years; 96.8% male). The mean (SD) follow-up was 3.9 (1.3) years. Chlorthalidone did not demonstrate superiority over hydrochlorothiazide for the composite kidney endpoint (6.0% vs 6.4%; hazard ratio, 0.94; 95% CI, 0.81–1.08; P=.37). Additional analyses showed no differences in CKD incidence, ≥40% eGFR decline, or eGFR slope. Hypokalemia occurred more frequently in chlorthalidone users (overall ~2% higher rate of low potassium measurements), and hospitalizations for hypokalemia also trended higher.

Conclusions: Under dosing regimens designed to achieve equivalent antihypertensive potency, chlorthalidone provided no measurable renal benefit over hydrochlorothiazide but posed a modestly elevated risk of hypokalemia. These findings reinforce the clinical interchangeability of both agents for long-term blood pressure management in older adults, provided serum potassium is monitored.

Implications for Practice: Clinicians can confidently employ either chlorthalidone or hydrochlorothiazide in older patients with hypertension, including those with mild or moderate CKD, since renal deterioration rates did not differ significantly. Importantly, the trial used half the milligram amount of chlorthalidone (12.5–25 mg/day) to match the usual doses of hydrochlorothiazide (25–50 mg/day). Recognizing this equivalence helps guide therapy transitions and dosing decisions. Vigilant monitoring of electrolytes remains essential, particularly when prescribing chlorthalidone, given the slightly higher incidence of hypokalemia.

Study Strengths and Limitations: Strengths include the randomized design, broad participant inclusion, and pragmatic structure that mirrors real-world prescribing. Limitations involve potential underestimation or overestimation of renal events due to reliance on routine (rather than scheduled) lab tests. Also, nearly all participants had prior hydrochlorothiazide exposure, which may have influenced tolerance and adherence patterns.

Future Research: Further clinical trials focusing on more advanced CKD stages, distinct comorbidities, or combination regimens (e.g., with potassium-sparing agents) would expand our understanding of how thiazide-type diuretics influence long-term kidney outcomes. Extended follow-up or additional subgroup analyses could also shed light on the interplay of dose-response effects in highly vulnerable populations.

Reference: Ishani A, Hau C, Raju S, et al. “Chlorthalidone vs Hydrochlorothiazide and Kidney Outcomes in Patients With Hypertension: A Secondary Analysis of a Randomized Clinical Trial.” JAMA Netw Open. 2024;7(12):e2449576. DOI: http://doi.org/10.1001/jamanetworkopen.2024.49576

 

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Dose-Response Meta-Analysis: At Least 150 Weekly Minutes of Aerobic Exercise Needed for Significant Waist and Fat Reduction

2 Jan, 2025 | 09:30h | UTC

Background: Elevated body weight and adiposity remain major public health concerns worldwide, with overweight and obesity affecting nearly half of the adult population. Although various guidelines advocate for aerobic exercise as a core strategy in weight management, robust meta-analyses exploring dose-response relationships are scarce.

Objective: To clarify how different doses and intensities of supervised aerobic exercise affect body weight, waist circumference, and body fat in adults with overweight or obesity.

Methods: This systematic review and meta-analysis encompassed 116 randomized clinical trials (RCTs) including a total of 6880 participants (mean [SD] age, 46 [13] years). All studies involved supervised continuous aerobic interventions (e.g., walking or running) for at least 8 weeks. Comparisons were made against sedentary or usual-activity controls. Frequency, duration (minutes per week), and intensity (moderate, vigorous, or combined) of aerobic sessions were extracted.

Results: Across all trials, each additional 30 minutes per week of aerobic exercise was linked to a mean reduction of 0.52 kg in body weight (95% CI, −0.61 to −0.44), 0.56 cm in waist circumference, and 0.37 percentage points in body fat. Body weight and waist circumference showed largely linear decreases with increasing weekly exercise, whereas body fat percentage displayed a pattern suggesting that at least 150 minutes per week may be required to achieve clinically meaningful reductions (>2% reduction in body fat). Aerobic training was generally well tolerated, although a modest increase in mild musculoskeletal complaints was noted (risk difference, 2 more events per 100 participants).

Conclusions: Engaging in up to 300 minutes per week of aerobic exercise was associated with progressively greater benefits for weight control, waist circumference, and body fat. While even small doses yielded modest improvements, these findings suggest that an intensity of at least moderate level and a duration of at least 150 minutes per week may be necessary to achieve clinically important reductions in central obesity and fat percentage.

Implications for Practice: Clinicians managing patients with overweight or obesity can recommend a minimum of 150 minutes per week of moderate-to-vigorous aerobic training to achieve significant anthropometric changes. Gradual progression is essential to balance effectiveness and safety, especially in individuals with musculoskeletal constraints.

Study Strengths and Limitations: Strengths include the large number of RCTs, robust dose-response analyses, and consistent directions of effects. However, high heterogeneity, publication bias for certain fat measures, and limited data on medication use and health-related quality of life in longer trials were noted.

Future Research: Further trials should explore additional subgroup analyses (e.g., older adults, individuals with chronic comorbidities), longer durations of follow-up, and the integration of resistance training to optimize cardiometabolic outcomes.

Reference: Jayedi A, Soltani S, Emadi A, et al. Aerobic Exercise and Weight Loss in Adults: A Systematic Review and Dose-Response Meta-Analysis. JAMA Network Open. 2024;7(12):e2452185. DOI: http://doi.org/10.1001/jamanetworkopen.2024.52185

 

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Prospective Cohort: Combined CRP, LDL Cholesterol, and Lipoprotein(a) Levels Predict 30-Year Cardiovascular Risk in Women

8 Dec, 2024 | 20:58h | UTC

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Phase 2 RCT: Zerlasiran Lowers Lipoprotein(a) Levels by Over 80% in Patients With ASCVD

24 Nov, 2024 | 20:18h | UTC

Background: Elevated lipoprotein(a) [Lp(a)] is a genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. Traditional lipid-lowering therapies, including statins and lifestyle modifications, do not effectively reduce Lp(a) levels. Small-interfering RNA (siRNA) therapies targeting hepatic production of apolipoprotein(a) offer a potential approach to lowering Lp(a) concentrations.

Objective: To evaluate the efficacy and safety of zerlasiran, an siRNA targeting apolipoprotein(a) synthesis, in reducing serum Lp(a) concentrations in patients with ASCVD.

Methods: In this randomized, double-blind, placebo-controlled phase 2 trial, 178 adults with stable ASCVD and elevated Lp(a) levels (≥125 nmol/L) were enrolled across 26 sites in Europe and South Africa. Participants were randomized to receive subcutaneous zerlasiran at doses of 450 mg every 24 weeks (n=45), 300 mg every 16 weeks (n=42), or 300 mg every 24 weeks (n=44), or matching placebo every 16 weeks (n=23) or every 24 weeks (n=24). The primary outcome was the time-averaged percent change in Lp(a) concentration from baseline to week 36.

Results: Zerlasiran significantly reduced Lp(a) levels compared to placebo. The placebo-adjusted time-averaged percent reductions were −85.6% (95% CI, −90.9% to −80.3%) for 450 mg every 24 weeks, −82.8% (95% CI, −88.2% to −77.4%) for 300 mg every 16 weeks, and −81.3% (95% CI, −86.7% to −76.0%) for 300 mg every 24 weeks. Median percent reductions at week 36 exceeded 90% in all zerlasiran groups. The most common adverse events were mild injection site reactions, occurring in up to 7.1% of participants. No serious adverse events were attributed to the study drug.

Conclusions: Zerlasiran was well-tolerated and produced substantial reductions in Lp(a) levels over 36 weeks in patients with ASCVD.

Implications for Practice: If validated in larger, long-term studies that assess cardiovascular outcomes, zerlasiran may offer a novel treatment for patients with elevated Lp(a), addressing a significant unmet need in cardiovascular risk management. Clinicians should, however, exercise caution until the impact on hard endpoints such as myocardial infarction and stroke, as well as long-term safety, are confirmed.

Study Strengths and Limitations: Strengths include the randomized, double-blind design and significant Lp(a) reductions observed. Limitations involve the predominantly White, male study population, limiting generalizability. The study did not assess clinical endpoints like cardiovascular events, so the impact on actual cardiovascular risk remains unknown. Additionally, the moderate sample size and duration may not detect rare adverse events or long-term effects, necessitating further investigation.

Future Research: Larger, long-term phase 3 trials are needed to confirm these findings, assess the impact on cardiovascular events, and evaluate efficacy and safety in more diverse populations.

Reference: Nissen SE, Wang Q, Nicholls SJ, et al. Zerlasiran—A Small-Interfering RNA Targeting Lipoprotein(a): A Phase 2 Randomized Clinical Trial. Journal of the American Medical Association. Published online November 18, 2024. DOI: http://doi.org/10.1001/jama.2024.21957

 

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Meta-analysis: Low/Moderate-Intensity Statins with Ezetimibe May Offer Better LDL-C Reduction and Safety over High-Intensity Statins

24 Nov, 2024 | 20:01h | UTC

Background: Despite widespread use of high-intensity statin therapy, achieving target LDL-C levels and reducing cardiovascular events remain challenging in patients with or at high risk of atherosclerotic cardiovascular disease (ASCVD). High-intensity statins can have dose-dependent adverse effects, limiting their tolerability. Combining low/moderate-intensity statins with ezetimibe, a cholesterol absorption inhibitor, may enhance lipid-lowering efficacy with fewer side effects.

Objective: To compare the clinical effectiveness and safety of low/moderate-intensity statins combined with ezetimibe versus high-intensity statin monotherapy in reducing major adverse cardiovascular events (MACEs) and lowering LDL-C levels.

Methods: A systematic review and meta-analysis were conducted according to PRISMA guidelines. Fifteen studies (6 randomized controlled trials [RCTs] and 9 observational studies) encompassing 251,450 participants were included. The primary outcome was a composite of cardiovascular death or major cardiovascular events. Secondary outcomes included lipid-lowering efficacy and safety measures such as muscle-related adverse events and liver enzyme elevations.

Results: Observational studies indicated that combination therapy was associated with lower rates of the primary composite outcome (HR = 0.76; 95% CI [0.73, 0.80]), cardiovascular death (HR = 0.80; 95% CI [0.74, 0.88]), all-cause death (HR = 0.84; 95% CI [0.78, 0.91]), and non-fatal stroke (HR = 0.81; 95% CI [0.75, 0.87]). RCTs showed that combination therapy resulted in a greater number of patients achieving LDL-C levels < 70 mg/dL (RR = 1.27; 95% CI [1.21, 1.34]) and significant reductions in LDL-C (MD = –7.95 mg/dL; 95% CI [–10.02, –5.89]) and total cholesterol (MD = –26.77 mg/dL; 95% CI [–27.64, –25.89]). Combination therapy also reduced muscle-related adverse events (RR = 0.52; 95% CI [0.32, 0.85]) and liver enzyme elevations (RR = 0.51; 95% CI [0.29, 0.89]) in RCTs.

Conclusions: Combining low/moderate-intensity statins with ezetimibe may offer superior lipid-lowering effects and better safety profiles compared to high-intensity statin monotherapy. While observational studies suggest improved clinical outcomes, these findings need confirmation from large-scale, long-term RCTs.

Implications for Practice: The combination therapy could be a viable option for patients intolerant to high-intensity statins or those requiring additional LDL-C lowering to reach target levels. However, clinicians should interpret these potential benefits cautiously due to reliance on observational data for clinical outcomes and the lack of robust RCT evidence.

Study Strengths and Limitations: Strengths include a comprehensive search strategy and a large patient population. Limitations involve heavy reliance on observational studies for clinical outcomes.

Future Research: Large, well-designed RCTs with longer follow-up periods are needed to confirm the clinical benefits and safety of the combination therapy over high-intensity statin monotherapy across diverse populations.

Reference: Sydhom P, et al. The clinical effectiveness and safety of low/moderate-intensity statins & ezetimibe combination therapy vs. high-intensity statin monotherapy: a systematic review and meta-analysis. BMC Cardiovascular Disorders. 2024; DOI: https://doi.org/10.1186/s12872-024-04144-y

 

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Phase 2 RCT: Oral Muvalaplin Significantly Reduces Lipoprotein(a) Levels in High-Risk Patients

20 Nov, 2024 | 14:22h | UTC

Background: Elevated lipoprotein(a) [Lp(a)] levels are an independent risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Current therapeutic options to lower Lp(a) are limited, and no approved pharmacotherapies specifically target Lp(a) reduction.

Objective: To evaluate the efficacy and safety of muvalaplin, an oral small-molecule inhibitor of Lp(a) formation, in reducing Lp(a) levels in patients at high risk of cardiovascular events.

Methods: In this phase 2, randomized, double-blind, placebo-controlled trial, 233 adults aged 40 years or older with Lp(a) concentrations of 175 nmol/L or greater and high cardiovascular risk (due to atherosclerotic cardiovascular disease, diabetes, or familial hypercholesterolemia) were enrolled across 43 sites worldwide. Participants were randomized to receive muvalaplin at doses of 10 mg/d (n = 34), 60 mg/d (n = 64), or 240 mg/d (n = 68), or placebo (n = 67) for 12 weeks. The primary endpoint was the placebo-adjusted percentage change from baseline in Lp(a) levels at week 12, measured using both an intact Lp(a) assay and a traditional apolipoprotein(a)-based assay.

Results

At week 12, muvalaplin achieved significant, dose-dependent reductions in Lp(a) levels compared with placebo. Using the intact Lp(a) assay, placebo-adjusted reductions were:

• 47.6% (95% CI, 35.1%-57.7%) for 10 mg/d
• 81.7% (95% CI, 78.1%-84.6%) for 60 mg/d
• 85.8% (95% CI, 83.1%-88.0%) for 240 mg/d

Using the apolipoprotein(a)-based assay, reductions were:

• 40.4% (95% CI, 28.3%-50.5%) for 10 mg/d
• 70.0% (95% CI, 65.0%-74.2%) for 60 mg/d
• 68.9% (95% CI, 63.8%-73.3%) for 240 mg/d

Dose-dependent decreases in apolipoprotein B levels were also observed, with placebo-adjusted reductions ranging from 8.9% to 16.1%. Muvalaplin was well tolerated across all doses, with no significant safety or tolerability concerns reported.

Conclusions: Muvalaplin significantly reduced Lp(a) levels in high-risk patients over a 12-week period and was well tolerated. These findings suggest that muvalaplin could be an effective oral therapy for lowering Lp(a) levels.

Implications for Practice: Muvalaplin may offer a convenient oral option to reduce elevated Lp(a) levels, potentially lowering cardiovascular risk in high-risk patient populations.

Study Strengths and Limitations: Strengths of the study include its randomized, double-blind, placebo-controlled design and the use of both traditional and novel assays to accurately measure Lp(a) levels. Limitations involve the short duration of the trial, the relatively small sample size for each dosage group, and the lack of assessment of long-term cardiovascular outcomes and safety.

Future Research: Long-term studies are necessary to determine whether the reduction in Lp(a) levels with muvalaplin translates into decreased cardiovascular events. Future research should also explore optimal dosing strategies and assess the long-term safety profile of muvalaplin.

Reference: Nicholls SJ, Ni W, Rhodes GM, et al. Oral Muvalaplin for Lowering of Lipoprotein(a): A Randomized Clinical Trial. JAMA. Published online November 18, 2024. DOI: http://doi.org/10.1001/jama.2024.24017

 

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Phase 3 RCT: Resmetirom Significantly Improves NASH Resolution and Liver Fibrosis

16 Nov, 2024 | 13:56h | UTC

Background: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatments. It significantly increases the risk of liver-related complications, especially in patients with type 2 diabetes. Resmetirom, a thyroid hormone receptor beta-selective agonist, is being investigated for its potential to treat NASH and liver fibrosis.

Objective: To evaluate the efficacy and safety of resmetirom in resolving NASH and improving fibrosis in adults with biopsy-confirmed NASH and fibrosis stages F1B to F3.

Methods: This double-blind, placebo-controlled phase 3 trial randomized 966 adults with NASH to receive once-daily resmetirom (80 mg or 100 mg) or placebo for 52 weeks. Primary endpoints included (1) NASH resolution with no fibrosis worsening and (2) fibrosis improvement by at least one stage without NAFLD activity score worsening. Secondary outcomes included changes in lipid profiles and liver biomarkers.

Results: At 52 weeks, NASH resolution occurred in 25.9% of patients receiving 80 mg and 29.9% receiving 100 mg of resmetirom, compared with 9.7% in the placebo group (P<0.001 for both doses vs. placebo). Fibrosis improved by at least one stage in 24.2% (80 mg) and 25.9% (100 mg) of resmetirom-treated patients versus 14.2% for placebo (P<0.001). LDL cholesterol reductions were −13.6% (80 mg) and −16.3% (100 mg) at 24 weeks versus 0.1% for placebo (P<0.001). Improvements were also noted in triglycerides, liver enzymes, and imaging biomarkers. Adverse events, primarily mild gastrointestinal symptoms, were more frequent with resmetirom. Serious adverse events were similar across groups (10.9%–12.7%).

Conclusions: Resmetirom significantly improved NASH resolution and fibrosis compared to placebo, demonstrating its potential as a treatment for NASH with liver fibrosis.

Implications for Practice: Resmetirom offers a promising treatment option for NASH, potentially altering the disease course and improving outcomes. Clinicians should monitor for regulatory approval and long-term safety data.

Study Strengths and Limitations: Strengths include robust biopsy-confirmed endpoints and a large sample size. Limitations include short follow-up and lack of clinical-outcome data.

Future Research: Long-term studies are needed to assess durability, safety, and effects on clinical outcomes like cirrhosis and liver-related mortality.

Reference: Harrison SA, Bedossa P, Guy CD, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. New England Journal of Medicine. 2024;390(6):497-509. DOI: http://doi.org/10.1056/NEJMoa2309000

 

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RCT: Lipoprotein(a) and LDL-C as Independent Cardiovascular Risk Factors in Statin Trials

5 Nov, 2024 | 17:50h | UTC

Background: Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] are both known risk factors for atherosclerotic cardiovascular disease (ASCVD). However, the interaction between Lp(a) and LDL-C levels in relation to ASCVD risk, especially in the context of LDL-C-lowering treatments like statins, remains unclear. This study aimed to clarify if LDL-C reduction impacts Lp(a)-associated ASCVD risk.

Objective: This meta-analysis examined whether LDL-C reduction with statins affects ASCVD risk mediated by elevated Lp(a) levels.

Methods: Data from 27,658 participants across six statin trials were analyzed, including both placebo and statin groups. ASCVD risk was assessed using multivariable Cox proportional hazards models with adjustments for various cardiovascular risk factors. The study evaluated continuous associations between Lp(a) levels, LDL-C levels, and ASCVD risk.

Results: Elevated Lp(a) levels were associated with higher ASCVD risk across all LDL-C levels, even among patients with the lowest LDL-C achieved through statin therapy. Statin-treated patients with Lp(a) >50 mg/dL exhibited a significantly higher ASCVD risk, even in the lowest quartile of achieved LDL-C (HR 1.38, 95% CI 1.06–1.79). The highest risk was observed in individuals with both elevated Lp(a) and LDL-C levels (HR 1.90, 95% CI 1.46–2.48).

Conclusions: Lp(a) and LDL-C are independent risk factors for ASCVD, with LDL-C lowering alone insufficient to mitigate the risk associated with elevated Lp(a).

Implications for Practice: These findings underscore the need for distinct strategies to manage patients with elevated Lp(a), particularly as LDL-C reduction alone does not fully address the associated ASCVD risk.

Study Strengths and Limitations: This study’s strength lies in its large participant pool and robust statistical analysis; however, variability in Lp(a) measurement methods across trials may limit precision.

Future Research: Investigations into therapies specifically targeting Lp(a) may offer additional ASCVD risk reduction beyond LDL-C lowering alone.

Reference: Bhatia HS, et al. Independence of Lipoprotein(a) and Low-Density Lipoprotein Cholesterol–Mediated Cardiovascular Risk: A Participant-Level Meta-Analysis. Circulation. 2024;150:00–00. DOI: http://doi.org/10.1161/CIRCULATIONAHA.124.069556

 

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Retrospective Study: Automated Multiorgan CT Markers Predict Diabetes and Cardiometabolic Comorbidities – Radiology

10 Aug, 2024 | 21:36h | UTC

Study Design and Population: This retrospective study analyzed data from 32,166 Korean adults (mean age, 45 years) who underwent health screenings, including fluorodeoxyglucose PET/CT scans, between 2012 and 2015. The study aimed to evaluate the predictive ability of automated CT-derived markers, such as visceral and subcutaneous fat, muscle area, bone density, liver fat, and aortic calcification, for diabetes and associated cardiometabolic conditions.

Main Findings: Visceral fat index showed the highest predictive performance for both prevalent and incident diabetes, with an AUC of 0.70 for men and 0.82 for women in cross-sectional analyses. Combining visceral fat, muscle area, liver fat, and aortic calcification improved prediction, yielding a C-index of 0.69 for men and 0.83 for women. Additionally, the study found that these CT markers were effective in identifying metabolic syndrome, fatty liver, coronary artery calcium scores >100, sarcopenia, and osteoporosis, with AUCs ranging from 0.80 to 0.95.

Implications for Practice: Automated CT-derived markers can effectively predict diabetes and multiple cardiometabolic comorbidities, surpassing traditional anthropometric measures. These findings suggest that integrating such automated assessments into routine clinical practice could enhance risk stratification and preventive care, particularly through opportunistic screening during routine CT scans.

Reference: Chang Y, Yoon SH, Kwon R, et al. (2024). Automated Comprehensive CT Assessment of the Risk of Diabetes and Associated Cardiometabolic Conditions. Radiology, 312(2), e233410. DOI: https://doi.org/10.1148/radiol.233410.

 

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M-A: Effects of long-term salt substitution on cardiovascular mortality and events – Ann Intern Med

5 May, 2024 | 15:10h | UTC

This systematic review and meta-analysis assessed the impact of long-term salt substitution on cardiovascular outcomes by analyzing data from 16 randomized controlled trials (RCTs). The primary investigation focused on mortality, major cardiovascular events (MACE), and adverse events with a study period of six months or longer. Key findings include a potential reduction in all-cause mortality (rate ratio [RR] of 0.88) and cardiovascular mortality (RR of 0.83), based on low-certainty evidence from studies predominantly conducted in China or Taiwan among older adults or those at higher cardiovascular risk. Results also indicated a slight reduction in MACE (RR of 0.85) with very low certainty. Evidence suggests no significant increase in serious adverse events. Limitations include the dominance of a single large RCT and limited generalizability of results to Western populations. The study concludes that while salt substitution could reduce mortality, the effects on cardiovascular events remain uncertain, with more robust evidence needed for broader demographic applicability.

 

Reference (link to abstract – $ for full-text):

Hannah Greenwood et al. (2024). Long-Term Effect of Salt Substitution for Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. Annals of Internal Medicine, Volume 178, Pages 23-31. DOI: 10.7326/M23-2626.

 

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RCT: Acute impact of provoked anger on endothelial health in healthy adults – J Am Heart Assoc

4 May, 2024 | 13:00h | UTC

This study explored the immediate effects of negative emotions on vascular endothelial health in a sample of 280 healthy adults. Participants were assigned to recall tasks that induced feelings of anger, anxiety, sadness, or a neutral emotional state, followed by assessments of endothelial health. The primary measure, endothelium-dependent vasodilation (reactive hyperemia index), significantly deteriorated in the anger group compared to the neutral condition (mean change: 0.20±0.67 vs. 0.50±0.60; P=0.007). Anxiety and sadness did not significantly affect this measure. Additionally, there were no significant changes in endothelial cell-derived microparticles or endothelial progenitor cells across all conditions. The findings indicate that short-term anger provocation can impair endothelial function, suggesting a specific pathway by which anger could increase cardiovascular disease risk.

 

Reference (link to free full-text):

Daichi Shimbo et al. (2024). Translational Research of the Acute Effects of Negative Emotions on Vascular Endothelial Health: Findings From a Randomized Controlled Study. Journal of the American Heart Association, 0:e032698. DOI: https://doi.org/10.1161/JAHA.123.032698

 

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ACP Guidelines for the pharmacologic management of type 2 diabetes in adults – Ann Intern Med

3 May, 2024 | 14:05h | UTC

The American College of Physicians (ACP) has issued an updated guideline focusing on the pharmacological management of type 2 diabetes. This guideline reviews the efficacy and safety of new medications, including GLP-1 agonists, SGLT-2 inhibitors, and others, emphasizing a systematic evaluation using the GRADE methodology. Key recommendations advise the integration of SGLT-2 inhibitors or GLP-1 agonists with metformin and lifestyle changes for better glycemic control and reduction in mortality and major cardiovascular events. Conversely, the use of DPP-4 inhibitors in similar therapeutic contexts is not recommended due to insufficient evidence of benefit. This guideline targets healthcare providers managing nonpregnant adults with type 2 diabetes.

 

Reference (link to free full-text):

Qaseem et al. (2024). Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Clinical Guideline From the American College of Physicians. Annals of Internal Medicine. DOI:10.7326/M23-2788.

 

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ACP cost-effectiveness analysis: Newer antidiabetic medications in type 2 diabetes – Ann Intern Med

3 May, 2024 | 13:57h | UTC

This systematic review evaluates the cost-effectiveness of newer antidiabetic medications for type 2 diabetes from U.S. clinical and economic perspectives. Analyzing non-industry funded cost-effectiveness analyses (CEAs) using GRADE and Drummond criteria, the study identifies varying cost per quality-adjusted life-year (QALY) values for medications such as GLP1a and SGLT2i. It concludes that while GLP1a and SGLT2i offer low value as primary therapies due to high costs, they may present intermediate value as adjunct treatments to metformin. The study highlights the methodological variability in CEAs and the influence of drug cost and effectiveness assumptions on outcomes. The results suggest cautious interpretation in clinical decision-making due to varied evidence quality and cost-effectiveness profiles among the reviewed medications.

 

Reference (link to free full-text):

Schousboe, J. T et al. Cost-Effectiveness of Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Systematic Review of Cost-Effectiveness Studies for the American College of Physicians. Annals of Internal Medicine. DOI: [10.7326/M23-1492].

 

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ACP Meta-Analysis: Comparative efficacy of newer antidiabetic agents in type 2 diabetes management – Ann Intern Med

3 May, 2024 | 13:49h | UTC

This systematic review and network meta-analysis evaluates the effectiveness and safety of modern antidiabetic drugs in managing type 2 diabetes mellitus. The study analyzed 130 publications from 84 randomized controlled trials, using GRADE criteria for evidence assessment. Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP1) agonists demonstrated significant reductions in all-cause mortality and major adverse cardiovascular events when compared to usual care, with SGLT2 inhibitors also showing benefits in reducing chronic kidney disease progression and hospitalizations due to heart failure. In contrast, dipeptidyl peptidase-4 (DPP4) inhibitors, insulin, and tirzepatide showed no significant mortality benefits. The study identified limitations including sparse direct drug comparisons and inadequate data for certain patient subgroups. Overall, SGLT2 inhibitors and GLP1 agonists were associated with fewer serious adverse events and severe hypoglycemia compared to insulin and sulfonylureas.

 

Reference (link to free full-text):

Drake, T. et al. (2023). Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Systematic Review and Network Meta-analysis for the American College of Physicians. Annals of Internal Medicine. DOI: 10.7326/M23-1490.

 

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Review: Key findings from the Women’s Health Initiative studies on postmenopausal interventions – JAMA

3 May, 2024 | 13:34h | UTC

The Women’s Health Initiative (WHI) studied the impact of various interventions on postmenopausal women aged 50-79, using data from 161,808 participants between 1993 and 2018. The findings suggest that hormone therapy, specifically with conjugated equine estrogens and medroxyprogesterone acetate, does not reduce the risk of cardiovascular diseases, dementia, or other chronic conditions in postmenopausal women. It is, however, effective for managing severe menopausal symptoms when initiated before age 60 in women without contraindications. The trials also concluded that universal supplementation of calcium and vitamin D does not effectively prevent fractures and should be limited to those not meeting dietary intake recommendations. Furthermore, a low-fat diet rich in fruits, vegetables, and grains did not reduce the incidence of breast or colorectal cancer, though it may decrease breast cancer mortality rates, indicating the need for further investigation.

 

Reference (link to free full-text for a limited period):

Manson JE et al. (2024). The Women’s Health Initiative Randomized Trials and Clinical Practice: A Review. JAMA, Published online May 1, 2024. DOI: 10.1001/jama.2024.6542.

 

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M-A Proportional increase in new-onset diabetes with different intensities of statin therapy

27 Apr, 2024 | 15:41h | UTC

Study Design and Population:

This research is a meta-analysis of individual participant data from large, long-term, randomized, double-blind controlled trials involving statins. The study encompasses 19 trials comparing statin use to placebo and four trials comparing varying intensities of statin therapy, involving a total of 154,664 participants over periods ranging from 4.3 to 4.9 years. Participants were adults enrolled in statin trials with a scheduled duration of at least two years and a participant count of at least 1000.

 

Main Findings:

The study revealed a dose-dependent increase in the incidence of new-onset diabetes when using statins. Participants receiving low to moderate-intensity statin therapy showed a 10% increase in new-onset diabetes annually compared to placebo, while those on high-intensity statin therapy exhibited a 36% increase. The absolute increases in new-onset diabetes were significantly influenced by the extent of HbA1c measurement. Notably, a large portion of new-onset diabetes cases occurred among participants with baseline glycaemic levels nearing the diabetes diagnostic threshold. Furthermore, the study found a moderate rise in mean glucose levels and HbA1c among those without baseline diabetes, and a significant worsening of glycemia among those with existing diabetes.

 

Implications for Practice:

The findings highlight a moderate, dose-dependent risk of new-onset diabetes associated with statin therapy, especially in individuals close to the diagnostic threshold for diabetes. These results should be considered in the clinical management of statin therapy, balancing the small increases in glycemia against the substantial benefits of statins in reducing cardiovascular risk. Healthcare providers should monitor glycaemic control in patients on statin therapy, particularly those prescribed high-intensity doses.

 

Reference (free full-text):

Cholesterol Treatment Trialists’ (CTT) Collaboration. (2024). Effects of statin therapy on diagnoses of new-onset diabetes and worsening glycaemia in large-scale randomised blinded statin trials: an individual participant data meta-analysis. Lancet Diabetes & Endocrinology, (Online First), 1-12. DOI: https://doi.org/10.1016/S2213-8587(24)00040-8

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Cohort Study: Increased fracture risk linked with initiation of antihypertensive medication in older veterans

26 Apr, 2024 | 12:29h | UTC

Study Design and Population:
This retrospective cohort study evaluated the association between antihypertensive medication initiation and fracture risk among older long-term care nursing home residents within the Veterans Health Administration. Conducted from 2006 to 2019 with data analysis spanning 2021 to 2023, the study utilized target trial emulation techniques and included 29,648 residents. A 1:4 propensity score-matched method was employed to compare medication initiators with non-initiators.

 

Main Findings:
Out of the matched cohort of 64,710 residents, those who initiated antihypertensive medication showed a higher incidence of fractures (5.4 per 100 person-years) compared to controls (2.2 per 100 person-years). The adjusted hazard ratio for fractures was 2.42. Notably, higher risks were observed in subgroups with dementia or elevated blood pressure thresholds (systolic ≥140 mm Hg or diastolic ≥80 mm Hg). Risks for severe falls and syncope were also elevated in the medication-initiating group.

 

Implications for Practice:
The study indicates a significant association between the initiation of antihypertensive medications and increased fracture risks among older, frail nursing home residents. Given these findings, clinicians should exercise caution and consider enhanced monitoring and preventive strategies when prescribing these medications to this vulnerable population.

 

Reference (link to abstract – $ for full-text):
Dave, C. V. et al. (2024). Antihypertensive Medication and Fracture Risk in Older Veterans Health Administration Nursing Home Residents. JAMA Intern Med, Published online April 22, 2024. DOI:10.1001/jamainternmed.2024.0507.

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Pragmatic Cluster-Randomised Trial: Efficacy of a Fixed-Dose Polypill in Reducing Cardiovascular Disease Risk in Rural Iran

21 Apr, 2024 | 21:05h | UTC

Study Design and Population: The PolyPars Study was structured as a two-arm pragmatic cluster-randomised trial within the larger PARS cohort study. It targeted residents aged over 50 in a district in southern Iran, dividing 91 villages into two groups: one receiving a once-daily polypill (containing two antihypertensives, a statin, and aspirin) alongside non-pharmacological interventions, and the other receiving only the non-pharmacological interventions. The trial included 4,415 participants aged 50-75 years, with the primary endpoint being the first occurrence of major cardiovascular events.

Main Findings: Over a median follow-up of 4.6 years, adherence to the polypill was high at 86%. The intervention arm showed a significant reduction in the incidence of the primary outcome, with only 4.0% (88 participants) experiencing major cardiovascular events compared to 8.0% (176 participants) in the control arm. This translates to a hazard ratio of 0.50, indicating a 50% reduction in risk, and an absolute risk reduction of 4.0%.

Implications for Practice: The study demonstrates the significant potential of fixed-dose combination therapy with the polypill to halve the risk of major cardiovascular diseases in a population-level intervention. This finding supports the polypill as a safe and effective strategy for both primary and secondary prevention of cardiovascular diseases, particularly in settings where access to individual medications and consistent medical supervision might be limited.

Reference: Fatemeh Malekzadeh et al. (2024). Effectiveness of polypill for primary and secondary prevention of cardiovascular disease: a pragmatic cluster-randomised controlled trial (PolyPars). Heart, heartjnl-2023-323614. DOI: 10.1136/heartjnl-2023-323614.

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Genetic analysis reveals Lipoprotein(a) is significantly more atherogenic than LDL on a per-particle basis

20 Mar, 2024 | 19:24h | UTC

Study Design and Population: This study utilized genome-wide association studies (GWAS) within the UK Biobank population to examine the atherogenicity of lipoprotein(a) (Lp(a)) compared to low-density lipoprotein (LDL), focusing on their apolipoprotein B (apoB) content. The researchers identified two clusters of single nucleotide polymorphisms (SNPs) associated with mass concentrations of Lp(a) and LDL, comprising 107 and 143 variants, respectively. The sample included subjects from the UK Biobank, allowing for a broad and genetically diverse analysis.

Main Findings: The study’s Mendelian randomization approach found that a 50 nmol/L increase in Lp(a)-apoB was associated with a 1.28 times higher odds ratio (OR) for coronary heart disease (CHD) compared to a 1.04 times increase for the same increment in LDL-apoB. Furthermore, a comparison using polygenic scores demonstrated that the hazard ratio (HR) for CHD per 50 nmol/L increase in apoB was significantly higher for the Lp(a) cluster (1.47) than for the LDL cluster (1.04), suggesting that Lp(a) is approximately 6.6 times more atherogenic than LDL on a per-particle basis.

Implications for Practice: These findings highlight the substantial atherogenic potential of Lp(a) compared to LDL, indicating that Lp(a) should be a key focus for drug intervention strategies in populations at risk for CHD. The marked difference in atherogenicity underscores the importance of targeted treatments and monitoring for individuals with elevated Lp(a) levels.

Reference: Björnson, E., Adiels, M., Taskinen, M.-R., Burgess, S., Chapman, M. J., Packard, C. J., & Borén, J. (2024). Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis. Journal of the American College of Cardiology, 83(3), 385-395. DOI: https://doi.org/10.1016/j.jacc.2023.10.039. Access the study here: Link

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Meta-Analysis: Efficacy of exercise modalities in major depressive disorder treatment

20 Mar, 2024 | 17:54h | UTC

Study Design and Population: This article presents a systematic review and network meta-analysis of randomized controlled trials to assess the optimal dose and modality of exercise for treating major depressive disorder, comparing its effects to psychotherapy, antidepressants, and control conditions such as usual care or placebo. The review included 218 unique studies encompassing 495 arms with a total of 14,170 participants who met the clinical cutoffs for major depression.

Main Findings: The findings revealed moderate reductions in depression symptoms for several exercise modalities when compared to active controls. Notably, walking or jogging, yoga, and strength training demonstrated the most significant effects. The effectiveness of exercise was found to be proportional to the intensity of the activity prescribed. Among these, yoga and strength training were identified as the most acceptable modalities for participants. However, the overall confidence in these results is low due to the high risk of bias in the included studies, with only one study meeting the criteria for a low risk of bias.

Implications for Practice: The study concludes that exercise, particularly walking or jogging, yoga, and strength training at sufficient intensities, can be an effective treatment for major depressive disorder. These modalities could be recommended alongside traditional treatments such as psychotherapy and antidepressants. Future research should focus on blinding participants and staff to mitigate expectancy effects and improve the reliability of findings. The inclusivity of exercise as a core treatment for depression could significantly impact treatment strategies and patient outcomes.

Reference: Noetel, M., et al. (2024). Effect of exercise for depression: systematic review and network meta-analysis of randomised controlled trials. BMJ, 384, e075847. DOI: https://doi.org/10.1136/bmj-2023-075847. Access the study here: [Link]

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Pragmatic Cluster-Randomised Trial: Efficacy of a Fixed-Dose Polypill in Reducing Cardiovascular Disease Risk in Rural Iran

25 Mar, 2024 | 11:40h | UTC

Study Design and Population: The PolyPars Study was structured as a two-arm pragmatic cluster-randomised trial within the larger PARS cohort study. It targeted residents aged over 50 in a district in southern Iran, dividing 91 villages into two groups: one receiving a once-daily polypill (containing two antihypertensives, a statin, and aspirin) alongside non-pharmacological interventions, and the other receiving only the non-pharmacological interventions. The trial included 4,415 participants aged 50-75 years, with the primary endpoint being the first occurrence of major cardiovascular events.

Main Findings: Over a median follow-up of 4.6 years, adherence to the polypill was high at 86%. The intervention arm showed a significant reduction in the incidence of the primary outcome, with only 4.0% (88 participants) experiencing major cardiovascular events compared to 8.0% (176 participants) in the control arm. This translates to a hazard ratio of 0.50, indicating a 50% reduction in risk, and an absolute risk reduction of 4.0%.

Implications for Practice: The study demonstrates the significant potential of fixed-dose combination therapy with the polypill to halve the risk of major cardiovascular diseases in a population-level intervention. This finding supports the polypill as a safe and effective strategy for both primary and secondary prevention of cardiovascular diseases, particularly in settings where access to individual medications and consistent medical supervision might be limited.

Reference: Fatemeh Malekzadeh et al. (2024). Effectiveness of polypill for primary and secondary prevention of cardiovascular disease: a pragmatic cluster-randomised controlled trial (PolyPars). Heart, heartjnl-2023-323614. DOI: 10.1136/heartjnl-2023-323614.

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AHA Scientific Statement | Contaminant metals as cardiovascular risk factors

13 Jun, 2023 | 14:04h | UTC

Contaminant metals as cardiovascular risk factors: a scientific statement from the American Heart Association – Journal of the American Heart Association

News Release: Chronic exposure to lead, cadmium and arsenic increases risk of cardiovascular disease – American Heart Association

Top Things to Know: Contaminant Metals as CV Risk Factors – American Heart Association

Commentary: Toxic Metals: The Poisons that are “Killing Us Softly” – American Heart Association

 

Commentary on Twitter

⚠️ Chronic exposure to lead, cadmium & arsenic ⬆️ risk of CVD

Monitoring exposure in 💨, 💧& 🌱is important for reducing inequity in CVD risk, according to a new AHA scientific statement published in @JAHA_AHA

✍️ @GLamasMD @anavasachttps://t.co/v5TOvvettD pic.twitter.com/36iCmfDmDP

— AHA Science (@AHAScience) June 12, 2023

 

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M-A | Plant-based diets reduce key atherogenic lipoproteins

30 May, 2023 | 11:48h | UTC

Vegetarian or vegan diets and blood lipids: a meta-analysis of randomized trials – European Heart Journal

Editorial: Plant-based dietary patterns and atherogenic lipoproteins – European Heart Journal

 

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M-A | Mediterranean & low-fat diets may reduce mortality and non-fatal MI in patients with high cardiovascular risk

3 Apr, 2023 | 13:59h | UTC

Summary: This systematic review and network meta-analysis aimed to determine the relative efficacy of different diets for preventing mortality and major cardiovascular events in patients at increased risk of cardiovascular disease. The study identified 40 randomized trials with 35,548 participants across seven dietary programs.

Moderate certainty evidence showed that Mediterranean and low-fat diets, with or without physical activity or other interventions, reduced all-cause mortality and non-fatal myocardial infarction in patients with increased cardiovascular risk. Mediterranean diet programs were also likely to reduce stroke risk.

Other dietary programs generally were not superior to minimal intervention. When compared with one another, no convincing evidence was found that the Mediterranean diet was superior to the low-fat diets in preventing mortality or non-fatal myocardial infarction.

Article: Comparison of seven popular structured dietary programmes and risk of mortality and major cardiovascular events in patients at increased cardiovascular risk: systematic review and network meta-analysis – The BMJ

News Release: Benefits of Mediterranean and low fat diet programmes in patients at risk of cardiovascular disease – BMJ Newsroom

Commentary: Mediterranean, Low-Fat Diets Both Good for Health: Network Meta-analysis – TCTMD

 

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