Reference: Diabetologia. 2022 May 17 early online
Managing diabetes is tricky. Despite the ever-growing artillery of non-insulin treatment options, many clinicians take the “metformin first, and whatever insurance will cover and the patient will tolerate next” approach. Well, buckle up: a new treatment for type 2 diabetes has the potential to become your first choice for a second-line agent.
Tirzepatide (Mounjaro) is a novel injectable diabetes medication with dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) properties. It was approved by the FDA on May 18th, 2022. This week, rather than our usual Focus on a single study, we’re going to take you through the STEPS (Safety, Tolerability, Effectiveness, Price, and Simplicity) for evaluating a new drug, an anti-bias approach first published in American Family Physician by Slawson and Shaughnessy.
Safety: How safe is the new medication? Tirzepatide is contraindicated for patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia (MEN) type 2. It is also associated (rarely) with pancreatitis, acute kidney injury, worsening of diabetic retinopathy, and acute gallbladder disease. When taken with insulin, an increased risk of hypoglycemia has been reported, but this finding was not demonstrated in the recent meta-analysis described below. Tirzepatide is not recommended for patients who are pregnant or lactating due to limited data.
Tolerability: Are there any side effects bad enough that would make patients stop taking it? (Think drop-out rates.) Nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain are reported in more than 5% of people completing follow-up, although 32% of those enrolled in the SURPASS trial dropped out in the first 3 weeks of a run-in period because they couldn’t tolerate tirzepatide. In a recent meta-analysis, more participants stopped treatment due to adverse effects when tirzepatide was dosed at 15 mg/week compared to the other agents; when compared to placebo, more of those using the 10 mg/week dose also stopped treatment due to adverse events.
Effectiveness: What’s the number of people who need to be treated (NNT) with tirzepatide for a certain period of time to help one additional person achieve a certain clinical outcome? (In this case, lowering their A1c to a target of less than 7%.) In the SURPASS-1 trial, after 40 weeks the rates of participants achieving HbA1c < 7% (with mean baseline HbA1c of 7.9%) ranged from 87%-92% with tirzepatide compared to 19% with placebo, giving an NNT of 2 over 40 weeks.
- Just a little more on effectiveness: A recent systematic review and meta-analysis analyzed the data from all randomized trials of at least 12 weeks duration comparing once-weekly tirzepatide at a maintenance dose of 5, 10, or 15 mg with any other glucose-lowering medication or placebo. The researchers identified 7 randomized trials with 6,609 participants. The comparator drugs used in the various trials included once-weekly semaglutide 1 mg, once-weekly dulaglutide 1.5 mg, basal insulin, or placebo. Amongst participants, the mean HbA1c at baseline was 8.2%, the mean body weight was 91.5 kg, and the mean age was 58 years. In most trials, participants were already taking metformin.
- Compared with placebo, there was a greater reduction in HbA1c with tirzepatide (1.62% more with 5 mg dose and 2.06% more with 15 mg dose), and all doses were superior to placebo for achieving various HbA1c goals. In addition, when compared to other glucose lowering agents, there was again greater HbA1c lowering with tirzepatide, although not as great as the magnitude of reduction when compared to placebo.
- There were also dose-dependent reductions in weight compared to placebo, ranging from 6.3 kg with 5 mg dosing to 9.4 kg with 15 mg dosing. Additionally, there was greater weight loss with tirzepatide compared to the GLP-1 RA medications, though less than that seen versus placebo. The weight loss seen compared to basal insulin was comparable to the differences vs. placebo.
Price: How much does the drug cost, including the cost of supplies and testing (think insulin supplies or INR testing with warfarin)? One month’s supply of tirzepatide is about $500 with GoodRx. Information regarding insurance coverage is limited at this time, but it will likely take some time to make it onto most formularies. For comparison, a month’s supply of Ozempic is about $1,000 and Trulicity is about $775 (all in the US).
Simplicity: How easy is it to take? Tirzepatide is injected subcutaneously once-weekly with a dose titration over time.
While this may not be a complete literature review, going through these STEPS is a practical way to approach decision-making around new medications that can keep you from relying on drug reps. In this case, tirzepatide is a once-weekly injectable medication for patients with type 2 diabetes shown in high quality trials to be more effective at lowering HbA1c and achieving weight loss than both insulin and other non-insulin agents on the market. It has a safety and tolerability profile similar to other agents (although dose-dependent GI side effects are a problem) and appears to cost about half as much. While we will certainly await more data on potential cardiovascular benefit and hope to see these results repeated in additional trials, based on these data this may be a first STEP towards “metformin first, tirzepatide next”.
For more information, see the topic Glucagon-like Peptide-1 (GLP-1) Receptor Agonists for Diabetes Mellitus in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School, and Katharine DeGeorge, MD, MS, Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Dan Randall, MD, Deputy Editor at DynaMed; Carina Brown, MD, Assistant Professor at Cone Health Family Medicine Residency; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Senior Medical Writer at DynaMed; and Sarah Hill, MSc, Associate Editor at DynaMed.