Tirzepatide: Because Who Needs Diet and Exercise When You Have a Needle?

Here is Lilly’s headline to investors

“Tirzepatide reduced the risk of developing type 2 diabetes by 94% in adults with prediabetes and obesity or overweight.”

Here is what researchers reported in the NEJM.

The study was the phase 3 double-blind, randomized, controlled trial of tirzepatide involving 2,539 adults aged 18 or older with a body-mass index (BMI) of 30 or more or a BMI of 27 or more with at least one weight-related complication (such as hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease), who had reported unsuccessful dietary efforts to lose weight. Participants were randomly assigned to receive once-weekly, subcutaneous injections of tirzepatide or a placebo.

The study participants were generally similar across treatment groups in terms of demographic and clinical baseline characteristics. The average age was 44.9 years, with a majority being female (67.5%) and White (70.6%). The mean body weight was 104.8 kg, BMI averaged 38.0, and waist circumference was 114.1 cm. Most participants (94.5%) had a BMI of 30 or higher, indicating obesity, with an average duration of obesity of 14.4 years. At baseline, 40.6% had prediabetes, and nearly two-thirds had one or more weight-related complications.

• Treatment with all three doses of tirzepatide resulted in significantly more significant weight reduction compared to placebo.
• There was a dose-response in mean weight reduction and, therefore, efficacy compared to placebo, between 5mg and 10mg of tirzepatide. The dose-effect appeared to have plateaued between 10 and 15 mg doses.
• At 72 weeks:
  • 5 mg tirzepatide dose reduced weight by 35 pounds
  • 10 mg tirzepatide dose reduced weight by 49 pounds
  • 15 mg tirzepatide dose reduced weight by 52 pounds 
  • Placebo reduced weight by 5 pounds
• Significant reductions in waist circumference were anticipated with this degree of weight loss.
• There were significant reductions in systolic and diastolic blood pressure and lipid levels
• Slightly more participants receiving tirzepatide reported an “adverse” event than those taking placebo (80% versus 72%). Most commonly, GI symptoms associated with changing transit times, e.g., nausea, diarrhea, and constipation. The safety profile of tirzepatide showed a low overall incidence of serious adverse events, with no unexpected safety concerns emerging from the study.

“95.3% of participants with prediabetes reverted to normoglycemia, compared to 61.9% in the placebo group.”

Tirzepatide was initially approved for treating Type 2 diabetes, marketed as Mounjaro. It was subsequently approved for weight loss and is now sold as Zepbound. This is identical to the marketing of semaglutide, such as Ozempic, for diabetes and Wegovy for weight loss. This study, reported in the NEJM, supports tirzepatide’s impact on weight loss and points to an additional benefit for diabetes. This is not surprising. The additional advantage, and here we may well be talking from a marketing rather than clinical perspective, is that terzepatide is a medication that functions as a dual agonist, targeting both the GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptors. These receptors play a crucial role in regulating blood sugar levels.

The ground truth is that tirzepatide appears to be protective for individuals with prediabetes progressing to type 2 diabetes. However, nearly two-thirds of those participants who used the placebo, in conjunction with diet and exercise, also saw a return to normoglycemia. The effect of tirzepatide, therefore, would be about another 30% of participants being returned to normoglycemia, which is not negligible but certainly not the highlighted 95.3%. 

In a study looking at older adults within the Atherosclerosis Risk in Communities (ARIC) study, fewer than 12% of individuals went from prediabetes to diabetes during a six-year interval. As with the current tirzepatide study, participants were urged to choose a better diet and more exercise, but here, the researchers concluded:

“Given the low risk of diabetes progression in this study (especially relative to mortality risk), it is unlikely that pharmacologic intervention or other aggressive approaches to diabetes prevention in older age will provide large benefits and could have unintended harmful effects…” [emphasis added]

To counterbalance this claim, we should also consider that eating better and exercising more is easier said than done. Moreover, in a study of physician behavior at one of our best health systems, Johns Hopkins, physicians faced with elevated HgA1c or fasting blood sugars rarely coded a diagnosis of prediabetes and even less frequently recommended nutritional consultation or medication (at the time of the study, metformin was the go-to agent). So, from a practical point of view, prescribing tirzepatide may be the easiest twofer, reducing weight without the need for pesky dieting and exercise and reducing the risk of diabetes. 

At the end of the day, while tirzepatide is a convenient shortcut for those who find diet and exercise too much of a hassle, let’s not pretend it’s a magic wand. After all, two-thirds of those on placebo managed just fine with old-fashioned lifestyle changes. But, if injecting yourself with a pricey drug sounds results in better health outcomes, who are we to judge? 

Source: Tirzepatide Once Weekly for the Treatment of Obesity NEJM DOI: 10.1056/NEJMoa2206038