diabetes and weight loss: tirzepatide outdoes semaglutide

 A recent comparative study in diabetics found that tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, outperformed the solo GLP-1 receptor agonist semaglutide both in diabetic control as well as weight loss (see dm tirzepatide vs semaglutide NEJM2021 in dropbox, or DOI: 10.1056/NEJMoa2107519)

 

Details:

-- 1879 patients were randomized to tirzepatide at doses of 5 mg, 10 mg, or 15 mg; or semaglutide 1 mg

-- mean age 57 years, 83% white/4% Black/70% Hispanic

-- mean weight 94 kg, BMI 34

-- baseline mean A1c was 8.28%, 64% had A1c <8.5%

-- eGFR 96, urine albumin-to-creatinine ratio <30 in 75%, blood pressure 131/79, 100% on metformin

-- study was conducted in 128 sites in the US, Argentina, Australia, Brazil, Canada, Israel, Mexico, and the UK, from July 30, 2019 to February 15, 2021

-- tirzepatide was initiated as a 2.5 mg weekly and increased 2.5 mg every four weeks until the randomly assigned target was reached; semaglutide was initiated at 0.25 mg once a week and doubled every four weeks until 1 mg was reached

    -- because of the different titration approaches, this was an open-label study

-- primary endpoint was change in A1c from baseline to 40 weeks

-- secondary endpoints: change in body weight from baseline to week 40 and the attainment of hemoglobin A1c <7%, as well as <5.7%

-- also measured were BMI and waist circumference, lipid levels, and the updated homeostasis model assessment insulin resistance (HOMA2-IR), a calculated entity that reflects insulin resistance

 

Results:

-- change from baseline A1c levels:

    -- semaglutide 1mg: -1.86 percentage points

    -- tirzepatide 5 mg: -2.01 percentage points

        -- difference of -0.15 percentage points vs semaglutide (-0.28 to -0.03), p=0.02

    -- tirzepatide 10 mg: -2.24 percentage points

        -- difference of -0.39 percentage points vs semaglutide (-0.51 to -0.26), p<0.001

    -- tirzepatide 15 mg: -2.30 percentage points

        -- difference of -0.45 percentage points vs semaglutide (-0.57 to -0.32), p<0.001

    -- tirzepatide at all doses was non-inferior and was superior to semaglutide

-- achieved A1c < 7.0%: 82 to 86% of patients on tirzepatide and 79% on semaglutide

-- achieved A1c <6.5%: 69 to 80% on tirzepatide and 64% on semaglutide

-- achieved A1c <5.7%: 27 to 46% on tirzepatide and 19% on semaglutide

 

-- reductions in body weight:

    -- semaglutide 1 mg: -5.7 kg

    -- tirzepatide 5 mg versus semaglutide 1 mg difference: -1.9 kg (-2.8 to -1.0)

    -- tirzepatide 10 mg versus semaglutide 1 mg difference: -3.6 kg (-4.5 to -2.7)

    -- tirzepatide 15 mg versus semaglutide 1 mg difference: -5.5 kg (-6.4 to -4.6)

    -- tirzepatide was noninferior and superior to semaglutide with p<0.001 for all comparisons

-- weight reduction of at least 5%: 65 to 80% on tirzepatide and 54% on semaglutide

-- weight reduction of at least 10%: 34 to 57% on tirzepatide and 24% on semaglutide

-- weight reduction of at least 15%: 15 to 30% on tirzepatide and 8% on semaglutide

 

-- Other endpoints:

    -- triglycerides and serum VLDL were lower on tirzepatide and the HDL was a little higher, with no significant difference in total cholesterol or LDL levels [these changes may reflect better A1c control]

    -- serum ALT decreased 22 to 30% on tirzepatide versus 22% on semaglutide; AST decreased 9 to 14% on tirzepatide and 9% on semaglutide [these are presumably from weight loss and improvement in non-alcoholic fatty liver disease, which has also been documented for the GLP-1 agonist liraglutide)

    -- blood pressure: systolic decreased 4.8 to 6.5 mmHg on tirzepatide versus 3.6 mmHg on semaglutide; diastolic decreased 1.9-2.9 mmHg on tirzepatide and 1.0 mmHg on semaglutide

-- Review of their graphs revealed that the hemoglobin A1c plateaued at about 24 weeks and was maintained for the rest of the study; body weight continued to decrease through the whole 40 weeks of the study

 

-- adverse events: mostly gastrointestinal, primarily mild-to-moderate in severity, and essentially no difference between tirzepatide and semaglutide:

    -- nausea: 17 to 22% with tirzepatide, 18% with semaglutide

    -- diarrhea: 13 to 16% with tirzepatide, 12% with semaglutide

    -- vomiting: 6 to 10% with tirzepatide, 8% with semaglutide

-- hypoglycemia (blood glucose <54 mg/dl): 0.2 to 1.7% with tirzepatide, 0.4% with semaglutide

-- adverse events leading this to discontinuation of meds: overall 7%, 6 to 9% in those on tirzepatide and 4% on semaglutide

-- serious adverse events in 5 to 7% on tirzepatide versus 3% on semaglutide. The most frequent serious adverse event was covid-19 related pneumonia in all groups and not related to the meds

-- there were 13 deaths, 4 in each of the three tirzepatide groups and 1 in the semaglutide group, none were considered to be related to the medications. Six of the deaths were related to Covid-19, 4 were cardiovascular, and 2 were indeterminate

-- pancreatitis was confirmed in 2 patients on tirzepatide and 3 on semaglutide, nonserious

-- cholelithiasis: 4 patients in each tirzepatide group and 2 on semaglutide

-- hypersensitivity reactions occurred in 1.7 to 2.8% on tirzepatide and 2.3% on semaglutide

 

Commentary:

-- semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist secreted by enteroendocrine cells in the intestinal mucosa in response to food ingestion; GLP-1 stimulates insulin secretion in hyperglycemic states, suppresses glucagon secretion, delays gastric emptying, decreases appetite, and reduces weight. Since this is secreted in response to food, there is no significant hypoglycemia

-- tirzepatide is a combo glucose-dependent insulinotropic polypeptide agonist and GLP-1 receptor agonist, the former component being the main incretin hormone in healthy persons (also secreted by these enteroendocrine cells in response to food), but is glucagonotropic in a glucose-dependent manner (ie it leads to increased glucagon and glucose levels in those with lower levels of glycemia, eg see https://pubmed.ncbi.nlm.nih.gov/27034187/ ). Its half-life is five days, allowing once weekly subcutaneous administration.

-- the actual physiologic mechanism of action of the tirzepatide vs semaglutide is not so clear (at least to me). is it based on a synergy of these two intestinal incretins working together after a meal to decrease glucose? is it just that the tirzepatide is a more potent GLP-1 receptor agonist? (it is clear that the effectiveness of the GLP-1's is related to their GLP-1 potency, with semaglutide being the leader)

-- the tirzepatide in this study was not only not inferior to semaglutide (those double negatives again), but was actually superior to the semaglutide for both A1c lowering and for weight loss

-- and, both medications were well-tolerated.

-- this study did utilize a slower up-titration algorithm for the tirzepatide,  which seems to have resulted in fewer GI adverse effects than they found in the phase 2 trial

 

-- for recent impressive results of semaglutide in weight loss in nondiabetics, leading to an FDA approval in June 2021 for its use as a weight loss agent (and it is actually much more potent than the other weight-loss medications around), see http://gmodestmedblogs.blogspot.com/2021/03/semaglutide-for-weight-loss.html . As in the study above, body weight continued to decrease over the course of this 68-week study with semaglutide without plateauing, suggesting further weight loss over time. this study utilized a higher dose of semaglutide at 2.4mg injection weekly (higher than the 1mg dose above), and found a 15% reduction in weight, with 32% achieving at least a 20% weight reduction, similar to what is achieved with the sleeve gastrectomy bariatric surgery. and this increased 2.4mg dose was well-tolerated. these results were much better than in the above study....  was is the 2.4mg dosing??  was it differences in study participants???

 

Limitations:

-- this 40-week study was actually a much shorter study than the 40 weeks noted, given the length of time it took for med up-titration (there were only 16 weeks for those on the highest dose of tirzepatide)

     -- as a result of the complexity of titration for the different participants to reach their different target dose of medications, this was an open label study, which could limit generalizability (perhaps some patients had more titrations of their doses and may have felt more attended to)

    -- and, this was especially an issue since there was no placebo group, which also limits generalizability since we do not know what changes would have taken place in baseline A1c or weight without active meds

-- though the study was done in many countries, the demographics may not be applicable generally, given the low number of Black patients for example

-- other major aspects of diabetes and weight management were not measured, such as diet and exercise, as well as socioeconomic status, stress, smoking, etc. These may limit the results to the general population.

-- the participants were pretty healthy. low A1c to start (and participants were only on metformin), not much hypertension or renal dysfunction. these limit broader generalizability

-- Also, being a study, there is a large selection bias, where participants agreed to be involved in the study and will likely include those more motivated for diabetes and weight control than the general population

so, impressive results for tirzepatide in this reasonably large study, more so than for the pretty fantastic GLP-1 receptor agonist semaglutide, and perhaps attributable to the add-on function of being a glucose-dependent insulinotropic polypeptide receptor agonist as well as a GLP-1 receptor agonist. more studies are underway to confirm its effect vs dulaglutide as well as insulin glargine. and we should also get longer term data on A1c and weight effects. We will hopefully get data on the effects of this new agent on cardiovascular and renal outcomes, which are well-documented with the GLP1's. But overall, the advent of these agents (perhaps including tirzepatide with the solo GLP-1's) has really ushered in a new and profound paradigm shift in the approach both to diabetes as well as overweight/obesity...

geoff

 

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