I want to close this series with something I think gets underrepresented in most conversations about GLP-1 medications, which is the broader health picture. The weight loss numbers get all the attention, but some of the most important data coming out of these trials has to do with cardiovascular outcomes, metabolic markers, and long-term health. I also want to be honest about where the evidence is strong, where it is preliminary, and where there are still real gaps.
The SELECT Trial: What It Actually Showed
The SELECT trial (Lincoff et al., NEJM 2023, PMID: 37952131) was a multicenter, double-blind, randomized, placebo-controlled superiority trial enrolling 17,604 adults aged 45 or older with pre-existing cardiovascular disease, a BMI of 27 or greater, and no history of diabetes.10 Over a mean follow-up of approximately 39.8 months, once-weekly semaglutide 2.4 mg produced a 20 percent relative risk reduction in a composite cardiovascular endpoint of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, with a hazard ratio of 0.80 (95% CI 0.72 to 0.90, p<0.001). A primary cardiovascular event occurred in 6.5 percent of the semaglutide group versus 8.0 percent of the placebo group.
This is a meaningful clinical result. I also want to be precise about what it does and does not show. This is a specific population: older adults with established cardiovascular disease and overweight or obesity but without diabetes. These findings should not be extrapolated to younger people, to people without pre-existing cardiovascular disease, or to the general population. Whether GLP-1 medications reduce cardiovascular events in lower-risk populations is not yet established by an RCT.
A note on the evidence: The SELECT trial also showed a 9.4 percent mean weight reduction with semaglutide. The cardiovascular benefit appeared independent of HbA1c changes, but whether the benefit is driven primarily by weight loss, direct medication effects, or both is still being studied. Both mechanisms are plausible and likely contributing.
Tirzepatide and Cardiovascular Data
The SURPASS-CVOT trial (PMID: 41406444) was a randomized double-blind noninferiority trial in 13,299 patients with type 2 diabetes and cardiovascular disease, comparing tirzepatide to dulaglutide, which has established cardiovascular benefit.11 Tirzepatide demonstrated non-inferiority for major cardiovascular events with a hazard ratio of 0.92 (95% CI 0.81 to 1.05). This establishes cardiovascular safety and consistency with benefit, but it is not a placebo-controlled superiority trial. The evidence base for tirzepatide’s cardiovascular effects is less mature than semaglutide’s at this point, and that is worth acknowledging rather than glossing over.
Metabolic Benefits
Across both diabetic and non-diabetic populations, GLP-1 medications have consistently produced improvements in blood pressure, lipid profiles, HbA1c in those with diabetes or prediabetes, and inflammatory markers across randomized trials. These are genuine and meaningful benefits. The degree of improvement varies by individual, medication, and the specific parameter being measured.
Emerging research is also exploring potential benefits in kidney disease, fatty liver disease, and sleep apnea, with some early positive RCT data beginning to appear. I want to describe these as emerging areas rather than established benefits because the evidence base is still developing and the research is ongoing.
The Bone Health Question
The Docs Who Lift May 2026 episode with Yale-trained endocrinologist Dr. Susan Brian is one of the most useful pieces of content I have come across on this specific question. The conclusion from meta-analyses covering over two decades of GLP-1 use in type 2 diabetes is that GLP-1 use is not associated with increased fracture risk and may have bone-protective properties. At the same time, a recent retrospective cohort study in older adults on GLP-1 therapy for diabetes showed an 11 percent increased signal for fragility fractures compared to other diabetes treatments. The episode discusses this honestly rather than dismissing it.
The key practical points from that episode: the rate and magnitude of weight loss matters more than the medication itself for bone outcomes, resistance training is one of the most evidence-backed tools for maintaining bone density, and Vitamin D status should be monitored in GLP-1 users. This is a nuanced picture, not a simple reassurance, and that nuance is appropriate given where the evidence is.
What We Do Not Yet Know
I think this might be the most important section of this entire series. Long-term data beyond five years on the obesity-specific high doses is still accumulating. The optimal protocol for maintaining results when medications are reduced or stopped has not been established by large RCT evidence. The effects on fertility and pregnancy are still being studied. The long-term musculoskeletal outcomes of sustained GLP-1 use in active individuals specifically remain unclear. The Docs Who Lift podcast consistently names these gaps rather than papering over them, which is one of the reasons I trust it as a source.
What I do know is that the principles underlying long-term health have not changed. Training consistently. Eating enough protein. Building habits that can sustain you independent of any single intervention. GLP-1 medications are a meaningful development in obesity medicine that genuinely help appropriate patients. They work best when they potentiate a foundation of habits that were already there or are being built alongside the treatment. That has been true of every effective tool I have encountered in 19 years of being in this space, and I do not expect it to change now.
Train hard. Eat well. Be honest about the evidence. That is the framework I keep coming back to, whatever the conversation.
