Key Conclusion
If "glucose-lowering efficacy in head-to-head randomized controlled trials" is the sole criterion, tirzepatide (a dual GIP/GLP-1 receptor agonist) is currently the peptide hormone with the highest efficacy for blood glucose control. An updated network meta-analysis involving 5,199 participants showed that tirzepatide 15 mg ranked highest in reducing HbA1c (P-score 0.99), achieving a reduction 0.73% greater than that of semaglutide 1.0 mg (MD −0.73%, 95% CI −0.85 to −0.61, p<0.001).
However, being "most effective at controlling blood glucose" does not equate to being "most suitable for all patients." Single-target GLP-1 receptor agonists (such as semaglutide) remain irreplaceable for specific patient populations; meanwhile, pramlintide-used as an adjunct to insulin therapy-offers a distinct pathway for glycemic control through entirely different mechanisms (delaying gastric emptying and inhibiting glucagon). The choice depends on treatment goals, patient characteristics, and risk tolerance.
I. Why tirzepatide excels in glucose-lowering efficacy
Mechanistic basis: Dual-receptor synergy
Tirzepatide simultaneously activates both GLP-1 and GIP receptors. GLP-1 receptor agonism promotes glucose-dependent insulin secretion, inhibits glucagon release, and delays gastric emptying via the cAMP/PKA pathway. The addition of GIP receptor activation further amplifies these effects-particularly regarding the enhancement of insulin secretion and the regulation of lipid metabolism-creating a synergistic effect unattainable by single-target drugs.
Head-to-head evidence
The SURPASS-2 trial directly compared the effects of tirzepatide versus semaglutide 1.0 mg in patients with type 2 diabetes. A network meta-analysis integrating this direct evidence with indirect evidence from the STEP trial series yielded a clear conclusion: among all active comparator drugs, the 15 mg dose of tirzepatide achieved the greatest reduction in HbA1c. Notably, the analysis also found that regarding weight loss, semaglutide 2.4 mg ranked highest (P-score 0.97), with tirzepatide 15 mg ranking a close second (P-score 0.93). This discrepancy in rankings-glucose lowering versus weight loss-suggests that the drug with the highest efficacy depends on the specific therapeutic goal.
II. The Irreplaceable Value of Single-Target GLP-1 Receptor Agonists
Tirzepatide's superiority in glucose lowering does not render single-target GLP-1 drugs obsolete. A network meta-analysis involving 29 randomized controlled trials (RCTs) and 7,404 Chinese patients with type 2 diabetes and overweight/obesity showed that semaglutide had the highest probability of ranking first in reducing both HbA1c and fasting plasma glucose. The apparent contradiction between this finding and global data on tirzepatide reflects differences in study populations and comparator drugs: when the comparison is limited to the class of GLP-1 receptor agonists (GLP-1 RAs), semaglutide is the best-in-class; however, when dual-target drugs are introduced, tirzepatide demonstrates a higher efficacy ceiling.
From a clinical practice perspective, single-target GLP-1 RAs benefit from a more extensive body of long-term safety data, a more complete evidence base from cardiovascular outcome trials (CVOTs), and more mature experience in managing gastrointestinal tolerability. A systematic review clearly indicated that gastrointestinal adverse events associated with multi-receptor agonists "do not appear to be reduced compared with conventional GLP-1 RAs." This implies that the glucose-lowering advantages of dual-target drugs come with a tolerability burden that has not been alleviated.
III. An Overlooked Differentiated Pathway: Pramlintide
If the definition of "blood glucose control" extends beyond the overall reduction of HbA1c to include postprandial glucose fluctuations, pramlintide offers a completely different solution.
Pramlintide is a synthetic analogue of amylin, a hormone co-secreted with insulin by pancreatic beta cells. Its mechanism of glycemic control differs fundamentally from that of incretin-based therapies: it delays gastric emptying, suppresses postprandial glucagon secretion, and enhances satiety.
A 52-week, double-blind, randomized controlled trial involving 656 patients with type 2 diabetes treated with insulin demonstrated that pramlintide (120 μg twice daily) reduced HbA1c from baseline by 0.68% (at week 26) and 0.62% (at week 52)-results significantly superior to placebo (p<0.05). This was accompanied by a weight loss of 1.4 kg (compared to a 0.7 kg gain in the placebo group) and occurred without increasing the rate of severe hypoglycemic events. A triple-tracer study in patients with type 1 diabetes further elucidated its precise mechanism of action: pramlintide reduced the 2-hour postprandial glucose excursion (iAUC difference: 444.0 mM·min, p=0.0003) and plasma glucagon excursion (iAUC difference: 1730.6 pg/ml·min, p=0.0147), while leaving endogenous glucose production unaffected (p=0.5842).
Pramlintide is positioned as an adjunct to insulin therapy rather than a replacement. Its value lies not in achieving a greater magnitude of glucose reduction than GLP-1 receptor agonists (GLP-1 RAs), but in offering a mechanistically complementary intervention that targets postprandial glucose fluctuations-an independent risk factor. For patients who continue to experience significant postprandial hyperglycemia despite insulin therapy, pramlintide may be a superior choice to simply increasing the insulin dosage. IV. Why "Most Effective" Is a Question Requiring Contextual Qualification
Evidence regarding the blood glucose-lowering effects of three representative peptide hormones reveals a clear pattern:
Tirzepatide Dual GIP/GLP-1 agonist ~2.0–2.5% (high dose) Highest glucose-lowering efficacy Limited long-term safety data; no improvement in GI side effects
Semaglutide GLP-1 mono-agonist ~1.5–2.0% Superior weight loss; robust CVOT evidence Lower glucose-lowering ceiling than dual-target agents
Pramlintide Amylin analog ~0.4–0.7% (adjunct to insulin) Targets postprandial glucose; weight loss Requires injection; limited glucose-lowering magnitude
A Hierarchical Conclusion: If "effectiveness" is defined by the absolute reduction in HbA1c, tirzepatide currently represents the pinnacle of efficacy among peptide hormones. However, if "effectiveness" is defined as the optimal match for specific therapeutic goals (weight loss vs. glucose lowering) and patient populations (high cardiovascular risk vs. significant postprandial fluctuations), there is no single answer. Dual- and triple-target agonists (such as Retatrutide, a GLP-1/GIP/glucagon triple agonist) are further expanding this landscape; preliminary data indicate glucose-lowering and weight-loss effects that are "similar or superior," though head-to-head comparative studies are still lacking.