With the publication of two recent Zepbound (tirzepatide) studies, GLP weight-loss drugs continue their streak of positive trials in obesity-related conditions. In the first study, Zepbound was compared to placebo in 731 patients with heart failure with preserved ejection fraction (HFpEF). After two years of follow-up, the absolute risk of a composite of death from cardiovascular causes or worsening heart failure was 5.4% lower in the Zepbound group (9.9% vs 15.3%). [Pubmed abstract] The second trial (N=1032), a substudy of the SURMOUNT-1 weight-loss trial, found that over 3.4 years, Zepbound significantly reduced the incidence of diabetes compared to placebo in individuals with prediabetes (1.3% vs 13.3%). [Pubmed abstract] These studies add to a growing list of trials, summarized below, where Zepbound and Wegovy (semaglutide) have been found to improve outcomes in obesity-related conditions.

• Obstructive sleep apnea (OSA): In a 52-week trial enrolling overweight adults with OSA (N=469), Zepbound significantly reduced the apnea-hypopnea index, body weight, hypoxic burden, and systolic blood pressure compared to placebo. [Pubmed abstract] In December 2024, Zepbound received FDA approval for moderate to severe OSA in adults with obesity.
• Nonalcoholic steatohepatitis (NASH): In a 52-week study (N=190) enrolling adults with NASH, more patients treated with Zepbound had NASH resolution compared to placebo (62% [15 mg dose] vs 10%) [Pubmed abstract]
• Heart failure with preserved ejection fraction (HFpEF): Like Zepbound, Wegovy has also been shown to improve HFpEF. In a 52-week study (N=529) enrolling obese adults with HFpEF, Wegovy was superior to placebo for improving heart failure symptoms and physical endurance. [Pubmed abstract]
• Secondary prevention of cardiovascular disease (CVD): In a 40-month study (N=17,604) enrolling overweight adults with a history of CVD, Wegovy was superior to placebo for reducing a composite of CVD events (6.5% vs 8%). [Pubmed abstract] Based on this study, Wegovy received FDA approval for the secondary prevention of CVD events.
• Knee osteoarthritis (OA): In a 68-week study (N=407) enrolling obese adults with moderate knee OA, Wegovy was superior to placebo for improving knee pain. [Pubmed abstract]
• Prediabetes: As discussed above, Zepbound was significantly better than placebo at preventing progression to diabetes over 3.4 years in participants with prediabetes (1.3% vs 13.3%). [Pubmed abstract]

To date, the FDA has granted two non-obesity indications for Zepbound and Wegovy: OSA for Zepbound and secondary prevention of CVD events for Wegovy. However, more are sure to come as these highly effective weight-loss drugs continue to change people's lives.

• Article on a webpage

In 2010, the ACCORD study (N=4733) was published, which found that an intensive blood pressure treatment strategy (target systolic blood pressure [SBP] < 120) did not significantly improve cardiovascular disease (CVD) outcomes compared to a standard strategy (target SBP < 140) in diabetics with hypertension. However, subsequent large trials showed that lower SBP targets (<120-130) improved CVD outcomes across a broad range of patients with and without diabetes. Given the discrepant findings, researchers decided to revisit the issue in diabetics by performing the BPROAD study, where 12,821 hypertensive type two diabetics at increased risk of CVD were randomized to an intensive (target SBP < 120) or standard (target SBP < 140) blood pressure treatment strategy; average SBP one year into the study was 122 mmHg in the intensive group and 135 mmHg in the standard group. After a median follow-up of 4.2 years, a composite of CVD events was significantly lower in the intensive group (1.65%/year vs 2.09%/year, p<0.001). [BPROAD abstract]

Contrary to the 2010 ACCORD trial, BPROAD found that a lower SBP target was beneficial in diabetics with hypertension. Possible reasons for the contradictory findings include (1) lower power in the ACCORD study due to a smaller sample size and (2) the ACCORD study design, which included another factor where patients were randomized to intensive (HgA1C < 6%) or standard (HgA1C 7 - 7.9%) glycemic targets. Other large studies, summarized below, have found that lower SBP targets modestly reduce the absolute risk of CVD events by 1 - 2% in a broad range of patients. While this effect size is small, it is meaningful when applied to large populations. Collectively, these studies support a target SBP of less than 120 mmHg in patients who can tolerate it.

• SPRINT trial (2015): The SPRINT trial (N=9361) compared a target systolic blood pressure (SBP) of <120 mm Hg to a target of <140 mm Hg in nondiabetic individuals at increased risk of CVD. The lower target reduced the incidence of a composite of CVD events by 1.6% over a median follow-up of 3.26 years (5.2% vs 6.8%, p<0.001). [PubMed abstract]
• STEP study (2021): The STEP study (N=8511) compared a target systolic blood pressure (SBP) of <130 mm Hg to a target of <150 mm Hg in Chinese patients 60 to 80 years old with hypertension. The lower target reduced the incidence of a composite of CVD events by 1.1% over a median follow-up of 3.34 years (3.5% vs 4.6%, p=0.007). [PubMed abstract]
• ESPRIT study (2024): The ESPRIT study (N=11,255) compared a target systolic blood pressure (SBP) of <120 mm Hg to a target of <140 mm Hg in Chinese patients at high risk for CVD. The lower target reduced the incidence of a composite of CVD events by 1.4% over a median follow-up of 3.4 years (9.7% vs 11.1%, p=0.028). [PubMed abstract]


• Hypertension treatment guidelines
• Article on webpage

In 2023, colchicine received FDA approval for the secondary prevention of cardiovascular disease (CVD) based on the LoDoCo2 Study (N=5522), which found that it reduced the absolute risk of a composite of CVD events by 2.8% over 29 months. [LoDoCo2 abstract] An earlier 2019 study (COLCOT trial, N=4745) also showed a beneficial effect in patients with recent myocardial infarction (MI). [COLCOT abstract] To expand on these findings, researchers conducted the CLEAR study, where 7062 patients with a recent MI who had undergone percutaneous coronary intervention (PCI) were randomized to colchicine 0.5 mg once daily or placebo. After a median follow-up of 3 years, the primary outcome (a composite of death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization) was not significantly different between groups (colchicine - 9.1%, Placebo - 9.3%, p=0.93). The study also included a second randomization to spironolactone or placebo. Results from that comparison were also negative.

Despite two prior positive studies, colchicine failed to improve CVD outcomes in the larger CLEAR study. Reasons for the discrepant findings are uncertain but may include CLEAR's high dropout rate (25%) and its two-by-two factorial design that included spironolactone. Notably, colchicine did not improve mortality in any of the trials, and in LoDoCo2, non-cardiovascular deaths were higher in the colchicine group (HR 1.51 95%CI [0.99 - 2.31]). Collectively, these studies do not make a strong case for the routine use of colchicine in CVD.

One observation from all three trials worth noting is that an increased risk of myopathy from combining colchicine with a statin - a common drug interaction warning - was not observed.

• CLEAR Study - Colchicine vs Placebo after MI, NEJM (2024) [PubMed abstract]
• Colchicine (Lodoco) review
• Article on webpage

Hip replacement surgery is the routine treatment for severe hip osteoarthritis (OA), with over 450,000 procedures performed annually in the U.S. alone. Despite its popularity, randomized trials evaluating its effectiveness are lacking. To help close the knowledge gap, researchers in Denmark randomized 109 patients 50 and older (mean age 67.6 years) with severe hip OA to total hip replacement surgery or physical therapy (PT) that included resistance training. The primary outcome was the change in the Oxford Hip Score (scale 0 to 48 with higher scores indicating less pain and better function) at 6 months; the baseline score in both groups was 25. At study conclusion, increases in the Oxford score were significantly greater in the surgery group compared to the PT group (15.9 points vs 4.5 points, p<0.001). At 6 months, 9% of patients assigned to surgery had not received it, while 21% assigned to PT had undergone hip replacement (crossovers). Despite the significant number of crossovers in the PT group, surgery was still superior in the intention-to-treat analysis.

The main weakness of the study is the lack of blinding, which would have required a sham procedure in the control group. However, simulating hip replacement surgery would be difficult given the complexities and aftercare of such a major procedure, making a sham control impractical. While entirely objective evidence does not exist, most patients experience profound pain relief and improvement in mobility after joint replacement surgery, suggesting these procedures are highly effective.

Learn more about the effects of sham procedures and crossovers on study outcomes by taking our CME course, Medical Study Analysis.

• Hip Replacement vs PT for Severe OA, NEJM (2024) [PubMed abstract]
• Reviews of orthopedic studies
• Article on webpage

Knee osteoarthritis (OA) is caused and worsened by obesity, as both mechanical stress and obesity-induced inflammation accelerate joint destruction. Weight loss improves knee OA, with studies showing a 2% improvement in the WOMAC pain, function, and stiffness scores for every 1% reduction in body weight. To evaluate the effects of Wegovy-induced weight loss on knee OA (based on clinical and X-ray findings), researchers randomized 407 patients (82% female | average age 56) with a BMI of 30 or greater and moderate knee OA to Wegovy (target dose 2.4 mg/week) or placebo. The primary outcomes were percent change in body weight and change in the WOMAC pain score (scale 0 - 100, with higher scores meaning worse outcomes) at week 68. At baseline, the average BMI was 40.3 and the average WOMAC score was 70.9. After 68 weeks, the percent decrease in body weight was 13.7% in the Wegovy group and 3.2% in the placebo group (p<0.001). Reductions in the WOMAC pain score were superior with Wegovy (41.7 vs 27.5, p<0.001), as were measures of knee function. Drug discontinuations due to adverse events were slightly higher in Wegovy-treated patients (6.7% vs 3%) [Full trial summary].

As expected, Wegovy-induced weight loss improved knee pain and function in a predominantly female population (82%) with moderate knee OA. A missed opportunity in the study was the absence of follow-up imaging to assess for changes in joint pathology.

Wegovy and Zepbound continue to rack up positive studies, as the health benefits of significant weight loss are profound. Other obesity-related conditions improved by GLP therapies include heart failure with preserved ejection fraction, cardiovascular disease, nonalcoholic steatohepatitis, and obstructive sleep apnea.

• Wegovy review
• Article with full trial summary