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ForumsDosing & ProtocolsDose-response curves — need advice

Dose-response curves — need advice

Dr.PulmRoch Sat, Jun 29, 2024 at 12:40 AM 8 replies 1,746 viewsPage 1 of 2
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Dr.PulmRoch
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Jun 29, 2024 at 2:05 AM#1

I'm currently at 1.7mg semaglutide and getting great results — down 38 lbs in 5 months, appetite well-controlled, minimal side effects. My provider is suggesting I titrate up to 2.4mg "because that's the target dose."

But I'm paying out of pocket for compounded semaglutide and going from 1.7mg to 2.4mg is a 41% increase in drug usage. That's not trivial when each vial costs real money.

The question: is there actually meaningful additional benefit going from 1.7 to 2.4? What does the data say about the dose-response curve at the higher end? Or is this a case of diminishing returns where the last 0.7mg adds cost and side effects without proportional benefit?

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LarryQC_SD
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Jun 29, 2024 at 2:22 AM#2

This is a great question and the data actually gives us a reasonable answer.

The STEP 1 trial used 2.4mg as the target dose. But SUSTAIN trials and dose-ranging studies give us comparison data across doses. Here's what we know:

Weight loss by dose (approximate, from pooled data):

  • 0.5mg: ~5–7% body weight loss
  • 1.0mg: ~7–10%
  • 1.7mg: ~10–13%
  • 2.4mg: ~12–17%

So going from 1.7mg to 2.4mg adds roughly 2–4 percentage points of additional weight loss. For someone starting at 250 lbs, that's the difference between losing ~28 lbs and ~35 lbs. Meaningful? Perhaps. But the dose-response curve IS flattening at the higher end.

The STEP 2 trial in patients with T2D showed the difference was even smaller for glycemic outcomes — 1.0mg and 2.4mg produced similar A1c reductions.

Bottom line: the incremental benefit of 2.4mg over 1.7mg is real but modest. If you're getting excellent results at 1.7mg with good tolerance and the cost matters, staying at 1.7mg is a completely defensible choice.

[1] O'Neil PM, et al. "Efficacy and safety of semaglutide compared with liraglutide and placebo for weight management in adults with overweight or obesity (STEP 8)." Lancet. 2022;400(10348):229-237.

[2] Davies M, et al. "Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2)." Lancet. 2021;397(10278):971-984.

Last edited: Jun 29, 2024 at 3:22 AM
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pete_manc_UK
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Jun 29, 2024 at 2:39 AM#3
Previously posted:
the dose-response curve IS flattening at the higher end

This is a critical concept. The dose-response relationship for most GLP-1 receptor agonists follows a sigmoidal (S-shaped) curve. At low doses, each increment produces a large effect. At higher doses, you're approaching the plateau where receptor occupancy is near-maximal and additional drug produces diminishing returns.

For semaglutide, the steepest part of the curve appears to be between 0.5mg and 1.0mg. By the time you're at 1.7mg, you've captured the majority of the drug's effect. The jump from 1.7 to 2.4 sits on the flatter part of the curve.

This doesn't mean 2.4mg is pointless — for some patients, that extra few percent of weight loss is clinically meaningful, and some patients only achieve adequate appetite suppression at the highest dose. But it's a valid clinical discussion, not an automatic "you must go to the max dose."

Last edited: Jun 29, 2024 at 8:39 AM
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mel_PDX
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Jun 29, 2024 at 2:56 AM#4

This is incredibly helpful. So if I'm doing the math right — I'm already getting maybe 80–85% of the maximum effect at 1.7mg, and going to 2.4mg would squeeze out another 15–20% of benefit while increasing my drug cost by 41% and potentially adding more GI side effects. That's a pretty clear cost-benefit analysis for me.

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mark_tokyo
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Jun 29, 2024 at 3:13 AM#5

I'll offer the other perspective. I was at 1.7mg for 3 months and my weight loss had completely stalled. Still had decent appetite suppression but wasn't losing. Went to 2.4mg and within 3 weeks the scale started moving again — lost another 12 lbs over the next 2 months. For me, that last bump was absolutely worth it.

Different bodies, different responses. The population averages are useful but your individual response may differ.

Last edited: Jun 29, 2024 at 6:13 AM
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