Tirzepatide: A Novel Glucose-Dependent Insulinotropic Polypeptide/Glucagon-Like Peptide 1 Receptor Agonist for the Treatment of Type 2 Diabetes: The First Twincretin Free

Tirzepatide was approved by the U.S. Food and Drug Administration (FDA) on 13 May 2022 and is being sold under the brand name Mounjaro (Eli Lilly and Company, Indianapolis, IN) (15). Tirzepatide is an agonist of both GIP and GLP-1 receptors, mimicking the body’s natural incretin hormones, and is the first agent in a new class known as twincretins. It increases insulin secretion, reduces glucagon secretion, increases insulin sensitivity, and slows gastric emptying to reduce fasting and postprandial glucose levels, as well as body weight. It is a once-weekly injection that is administered from a device identical to that used for the GLP-1 receptor agonist dulaglutide and is indicated for reducing glucose in adult patients with type 2 diabetes in whom diet and exercise alone have not been successful. Patients begin with a low initial dose of 2.5 mg weekly with or without food, which is not meant to be therapeutic but rather to ensure tolerability. The dose may be titrated every 4 weeks in 2.5-mg increments to a maximum of 15 mg, yielding six dosing options (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg) for individualization of treatment and tolerability. There are no recommended dose adjustments for renal or hepatic impairments. Preferred administration sites include the abdomen, thigh, or upper arm, and rotating injection sites is recommended.

Adverse effects seem to be similar to those of GLP-1 receptor agonists and include primarily GI effects such as nausea (12–18%), diarrhea (12–17%), decreased appetite (12–17%), vomiting (5–9%), constipation (6–7%), dyspepsia (5–8%), and abdominal pain (5–6%). Also, like GLP-1 receptor agonists, tirzepatide has a boxed warning regarding thyroid C-cell tumors and is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or MENS-2 because of occurrences in rodent studies. Warnings include pancreatitis, hypoglycemia with concurrent use of insulin secretagogues or insulin, hypersensitivity reactions, acute kidney injury (as a result of dehydration resulting from GI symptoms), GI disease such as gastroparesis, diabetic retinopathy, and acute gallbladder disease, all of which are relevant to GLP-1 receptor agonists and some of which (pancreatitis and gastroparesis) have not yet been studied for tirzepatide specifically. Hypoglycemia incidences are greater in patients taking tirzepatide with insulin secretagogues or insulin (15).

The SURPASS program of international phase 3 clinical trials provided data on safety and efficacy to support FDA approval of tirzepatide’s use in patients with type 2 diabetes. The five SURPASS trials ranged in length from 40 to 52 weeks and studied tirzepatide as monotherapy; add-on therapy to metformin, sulfonylureas, and/or sodium–glucose cotransporter 2 inhibitors; and add-on therapy to basal insulin with or without metformin. Tirzepatide was compared with control groups taking placebo, semaglutide 1 mg, insulin degludec, and insulin glargine (15). The SURPASS trials are summarized below.

The SURPASS-1 trial (16) investigated the dose-dependent efficacy of tirzepatide versus placebo in a 40-week, randomized, double-blind, placebo-controlled, parallel group, phase 3 trial. Adults with a confirmed diagnosis of type 2 diabetes that was considered inadequately controlled (A1C 7–9.5%), with a BMI ≥23 kg/m² with stable weight for 90 days, and who were naive to diabetes injectable therapies were eligible. Participants (n = 478) were randomly assigned (1:1:1:1) to once-weekly injections of tirzepatide 5-, 10-, or 15-mg doses or placebo. The primary outcome was mean change from baseline A1C in tirzepatide groups versus placebo. Secondary outcomes included change from baseline A1C; proportions of participants achieving an A1C <7%, <6.5%, and <5.7%; and mean change in weight from baseline and proportion of participants achieving weight loss. Adverse events and discontinuation of therapy due to adverse events were safety end points.

All three tirzepatide doses were superior to placebo in primary outcomes. Compared with a mean A1C reduction of 0.04% from a baseline of 7.94% with placebo, tirzepatide 5-, 10-, and 15-mg doses reduced A1C 1.87, 1.89, and 2.07%, respectively (all P <0.0001). The estimated treatment difference (ETD) of A1C versus placebo was −1.91% (95% CI −2.18 to −1.63%; P <0.0001), −1.93% (95% CI −2.21 to −1.65%; P <0.0001), and −2.11% (95% CI −2.39 to −1.83%; P <0.0001) for tirzepatide 5-, 10-, and 15-mg doses, respectively. Tirzepatide at all doses was superior to placebo in the proportion of patients achieving A1C targets of <7% (87–92%, odds ratio [OR] 80.4, 95% CI 31.8–203.2, P <0.0001), <6.5% (81–86%, OR 105.8, 95% CI 41.3–271.4, P <0.0001), or <5.7% (31–52%, OR 85.1, 95% CI 16.4–443.1, P <0.0001) (Figure 1).

Participants using tirzepatide experienced a dose- dependent weight reduction of 7.0 kg on the 5-mg dose, 7.8 kg on 10 mg, and 9.5 kg on 15 mg, while those taking placebo lost 0.7 kg. The ETD versus placebo was −6.3, −7.1, and −8.8 kg, respectively (all P <0.0001). Tirzepatide 5-, 10-, and 15-mg doses were each superior versus insulin degludec for body weight loss from baseline of ≥5% (all P <0.0001), ≥10% (all P <0.0001), and ≥15% (P = 0.011, 0.0063, and 0.0016, respectively). Results were dose-dependent, and at the 15-mg dose, 77% achieved ≥5% loss, 47% achieved ≥10% loss, and 27% achieved ≥15% loss. Noteworthy adverse effects of tirzepatide versus placebo included mild-to-moderate GI effects such as nausea (12–18%), vomiting (2–6%), and diarrhea (12–15%). Clinically significant hypoglycemia (blood glucose <54 mg/dL) was not observed.

The SURPASS-2 trial (17) investigated the dose-dependent efficacy of tirzepatide versus semaglutide in a 40-week, randomized, open-label, active-controlled, parallel-group, phase 3 trial. The main eligibility criteria included adults with a confirmed diagnosis of type 2 diabetes considered inadequately controlled (A1C 7–10.5%), BMI ≥25 kg/m², and a stable weight for 90 days and who were taking oral metformin ≥1,500 mg daily. Participants (n = 1,879) were randomly assigned (1:1:1:1) to once-weekly tirzepatide 5-, 10-, or 15-mg dose or semaglutide 1 mg. The primary outcome was mean change from baseline A1C in tirzepatide groups versus semaglutide. Secondary outcomes included change from baseline A1C; proportions of participants achieving an A1C <7%, <6.5%; or <5.7%; and mean change in weight from baseline and proportion of participants achieving weight loss. Adverse events and discontinuation of therapy due to adverse events were safety end points.

All three tirzepatide doses were superior to placebo in primary outcomes. Compared with a mean A1C reduction of 1.86% from a baseline of 8.28% with semaglutide, tirzepatide 5-, 10-, and 15-mg doses reduced A1C 2.01, 2.24, and 2.30%, respectively. The ETD of A1C versus semaglutide was −0.15% (95% CI −0.28 to −0.03, P = 0.02), −0.39% (95% CI −0.51 to −0.26, P <0.001), and −0.45% (95% CI −0.57 to −0.32, P <0.001) for tirzepatide 5, 10, and 15 mg, respectively. More recipients of tirzepatide versus semaglutide acquired an A1C <7.0% (82–86% vs. 79%, P <0.05), <6.5% (69–80% vs. 64%), and <5.7% (27–46% vs. 19%, P <0.001). For participants with an A1C >8.5%, the 15-mg tirzepatide dose achieved a greater reduction than 1 mg semaglutide (−3.22 vs. −2.86%) (Figure 1).

From a baseline of 93.8 kg, participants using tirzepatide experienced a dose-dependent weight reduction of 7.6 kg on the 5-mg dose, 9.3 kg on 10 mg, and 11.2 kg on 15 mg, while those taking semaglutide lost 5.7 kg. The ETD versus semaglutide was statistically significant at all doses: −1.9, −3.6, and −5.5 kg, respectively (all P <0.001). More participants using tirzepatide 5, 10, or 15 mg versus semaglutide reached body weight loss targets of ≥5% (65–80% vs. 54%), ≥10% (34–57% vs. 24%), and ≥15% (15–36% vs. 8%) from baseline.

Noteworthy adverse effects of tirzepatide versus semaglutide included mild-to-moderate GI effects such as nausea (17–22% vs. 18%), vomiting (6–10% vs. 8%), and diarrhea (13–16% vs. 12%). Clinically significant hypoglycemia (<54 mg/dL) was reported with tirzepatide 5 mg (three patients, 0.6%), 10 mg (one patient, 0.2%), and 15 mg (eight patients, 1.7%) and with 1 mg semaglutide (two patients, 0.4%). Two events of severe hypoglycemia requiring therapy intervention were found in tirzepatide patients (5- and 15-mg doses), and persistent hypoglycemia requiring therapy intervention was found in both the tirzepatide (1.3–1.5%) and semaglutide (2.8%) groups.

The SURPASS-3 trial (18) investigated the efficacy and safety of once-weekly tirzepatide compared with once-daily insulin degludec in a 52-week, randomized, open-label, parallel-group, multicenter, phase 3 trial. Adult men and women with a confirmed diagnosis of type 2 diabetes who were insulin-naive and whose diabetes was inadequately controlled on treatment with metformin alone or in combination with a sodium–glucose cotransporter 2 (SGLT2) inhibitor were eligible. Participants (n = 1,444) were randomly assigned (1:1:1:1) to a once-weekly subcutaneous regimen of tirzepatide 5, 10, or 15 mg or once-daily insulin degludec titrated to a fasting blood glucose level <90 mg/dL. The primary outcome was mean change from baseline A1C in the tirzepatide groups compared with insulin degludec. Secondary outcomes included change from baseline A1C; proportions of participants achieving an A1C target of <7%, <6.5%, and <5.7%; and mean change in weight from baseline and proportion of participants achieving weight loss.

All three tirzepatide doses were superior to insulin degludec in the primary outcome. Compared with a mean A1C reduction of 1.34% from a baseline of 8.17% with insulin degludec, tirzepatide 5, 10, and 15 mg reduced A1C by 1.93, 2.2, and 2.37%, respectively (all P <0.001). The ETD in A1C for tirzepatide compared with insulin degludec was −0.59% (95% CI −0.73 to −0.45%, P <0.0001) for the 5-mg dose, −0.86% (95% CI −1.00 to −0.72%, P <0.0001) for the 10-mg dose, and −1.04% (95% CI −1.17 to −0.90%, P <0.0001) for the 15-mg dose. Tirzepatide at all doses was superior to insulin degludec in the proportion of patients achieving A1C targets of <7% (82–93% vs. 61%, OR 10.79, 95% CI 6.65–17.48, P <0.0001), <6.5% (71–85% vs. 44%, OR 9.9, 95% CI 6.48–14.19, P <0.0001), or <5.7% (26–48% vs. 5%, OR 22.09, 95% CI 13.02–37.47, P <0.0001) (Figure 1).

Participants using tirzepatide experienced a dose- dependent weight reduction of 7.5 kg on 5 mg, 10.7 kg on 10 mg, and 12.9 kg on 15 mg, whereas those using insulin degludec gained 2.3 kg. The ETD in weight versus insulin degludec was −9.8, −13.0, and −15.2 kg, respectively (all P <0.0001). Tirzepatide 5, 10, and 15 mg were each superior to insulin degludec for body weight loss of ≥5, ≥10, and ≥15% from baseline (all P <0.0001). Results were dose-dependent, and, at the 15-mg dose, 88% achieved ≥5% weight loss, 69% achieved ≥10% weight loss, and 43% achieved ≥15% weight loss. Noteworthy adverse effects of tirzepatide versus insulin degludec included mild-to-moderate GI effects such as nausea (12–24% vs. 2%), vomiting (6–10% vs. 1%), diarrhea (15–16% vs. 4%), and decreased appetite (6–12% vs. 1%). Clinically significant hypoglycemia (blood glucose <54 mg/dL) was observed in 1–2% of participants in the tirzepatide groups versus 7% in the insulin degludec group.

The SURPASS-4 trial (19) investigated the efficacy and cardiovascular safety of tirzepatide compared with once-daily insulin glargine in a 52-week, randomized, open-label, parallel-group, multicenter, phase 3 trial. Adult men and women with a confirmed diagnosis of type 2 diabetes who were taking any combination of metformin, sulfonylurea, and/or SGLT2 inhibitor with established CVD, a high risk of cardiovascular events, or CKD were eligible. Participants (n = 2,002) were randomly assigned (1:1:1:3) to a once-weekly regimen of subcutaneous tirzepatide 5, 10, or 15 mg or once-daily insulin glargine titrated to reach a fasting blood glucose <100 mg/dL. The primary outcome was change from baseline A1C in the tirzepatide groups versus insulin glargine. Secondary outcomes included proportions of participants achieving an A1C target of <7%, <6.5%, and <5.7% and mean change from baseline body weight. Cardiovascular risk comparison between tirzepatide and insulin glargine was a prespecified safety objective.

All three tirzepatide doses were superior to insulin glargine in the primary outcome. From a mean baseline A1C of 8.52%, tirzepatide 5 mg lowered A1C by 2.24%, the 10-mg dose lowered A1C by 2.43%, and the 15-mg dose lowered A1C by 2.58%. The ETD in A1C of tirzepatide versus insulin glargine was −0.80% (95% CI −0.92 to −0.685, P <0.0001), −0.99% (95% CI −1.11 to −0.87%, P <0.0001), and −1.14% (95% CI −1.26 to −1.02%, P <0.0001) for tirzepatide 5, 10, and 15 mg, respectively. All tirzepatide doses were superior to insulin glargine in reaching A1C targets of <7% (81–91% vs. 51%, OR 11.87, 95% CI 7.88–17.89, P <0.0001), <6.5% (66–81% vs. 32%, OR 11.84, 95% CI 8.52–16.45, P <0.0001), or <5.7% (23–43% vs. 3%, OR 26.53, 95% CI 17.53–40.56, P <0.0001) (Figure 1).

Participants using tirzepatide experienced a dose-dependent weight reduction of −7.1 kg on a 5-mg dose, −9.5 kg on 10 mg, and −11.7 kg on 15 mg, whereas those using insulin glargine gained 1.9 kg. The ETD for weight loss with tirzepatide versus insulin glargine was −9.0, −11.4, and −13.5 kg, respectively, for 5, 10, and 15 mg. Tirzepatide 5, 10, and 15 mg were each superior versus insulin glargine for ≥5, ≥10, and ≥15% body weight loss from baseline (all P <0.0001). Results were dose-dependent, and, at the 15-mg dose, 85% achieved ≥5% loss, 66% achieved ≥10% loss, and 37% achieved ≥15% loss.

Noteworthy adverse effects of tirzepatide versus insulin glargine included mild-to-moderate GI effects such as nausea (12–23% vs. 4%), vomiting (5–9% vs. 1%), diarrhea (13–22% vs. 4%), and decreased appetite (9–11% vs. <1%). Dose-dependent reductions in serum triglycerides (up to −23%), LDL cholesterol (up to −8%), and non-HDL cholesterol (up to −12%) were seen with tirzepatide compared with marginal changes with insulin glargine. At the 52-week mark, mean systolic (−2.8 to −4.8 mmHg) and diastolic (−0.8 to −1.0 mmHg) blood pressure decreased with tirzepatide and increased (systolic +1.3 mmHg and diastolic +0.7 mmHg) with insulin glargine.

Comparison of cardiovascular risk between groups by assessing the incidence of a four-point MACE composite (cardiovascular death, myocardial infarction, stroke, and hospitalization for unstable angina) was a prespecified safety objective. Four-point MACE events were similar between groups (hazard ratio [HR] 0.74 [95% CI 0.51–1.08]). Tirzepatide was noninferior to insulin glargine with regard to cardiovascular risk.

The SURPASS-5 trial (20) investigated the efficacy of tirzepatide compared with placebo when added to once-daily insulin glargine with or without metformin. This was a 40-week, randomized, double-blind, parallel, multicenter, placebo-controlled, phase 3 trial. Adults with a confirmed diagnosis of type 2 diabetes, an A1C of 7–10.5%, and a BMI ≥23 kg/m² who were receiving consistent doses of insulin glargine (>20 units/day or >0.25 units/kg/day) with or without metformin (≥1,500 mg/day) were eligible. Participants (n = 475) were randomized (1:1:1:1) to receive a once-weekly subcutaneous injection of tirzepatide 5, 10, or 15 mg or a volume-matched dose of placebo. The primary outcome was mean change in A1C from baseline of the tirzepatide groups versus placebo. Secondary outcomes included the proportions of participants achieving A1C targets of <7%, <6.5%, and <5.7% and mean change in baseline body weight.

The addition of any tirzepatide dose to insulin glargine with or without metformin produced statistically significant reductions of A1C compared with placebo. From the mean baseline A1C of 8.31%, tirzepatide 5 mg lowered A1C by 2.11%, 10 mg lowered A1C by 2.40%, and 15 mg lowered A1C by 2.34%, whereas placebo lowered A1C by 0.86%. The ETD in A1C was −1.24% (95% CI −1.48 to −1.10%, P <0.001), −1.53% (95% CI −1.77 to −1.30%, P <0.001), and −1.47%, (95% CI −1.71 to −1.23%, P <0.001) for 5, 10, and 15 mg tirzepatide, respectively, versus placebo. All tirzepatide doses were superior to insulin glargine in reaching A1C targets of <7% (84.7–89.6% vs. 34.5%, OR 19.5, 95% CI 9.2–41.3, P <0.001), <6.5% (74.3–85.9% vs. 17.3%, OR 29.5, 95% CI 14.4–60.6, P <0.001), and <5.7% (24.4–49.6% vs. 2.7%, OR 30.7, 95% CI 10.1–93.6, P <0.001) (Figure 1). These significant improvements in glycemic control were accompanied by significantly less insulin glargine use in each tirzepatide group compared with the group receiving placebo plus insulin glargine (P <0.001). The percentage of change in insulin glargine dose from baseline to week 40 was +13% for tirzepatide 5 mg, +8.1% for 10 mg, and −11.4% for 15 mg compared with a change of +75% for those taking the placebo plus insulin glargine.

Participants using tirzepatide experienced a dose- dependent weight reduction of −5.4 kg with 5 mg, −7.5 kg with 10 mg, and −8.8 kg with 15 mg, whereas those receiving placebo gained 1.6 kg. The ETD for body weight versus placebo was −7.1, −9.1, and −10.5 kg, respectively. Tirzepatide 5, 10, and 15 mg were each superior to placebo for body weight loss from baseline of ≥5% (all P <0.001), ≥10% (all P <0.001), and ≥15% (5 mg P <0.38, 10 mg P <0.002, and 15 mg P <0.002). Results were dose-dependent, and, at the 15-mg dose, 71.6% achieved a weight loss of ≥5% loss, 40.7% achieved a loss of ≥10%, and 22.9% achieved a loss of ≥15%. Noteworthy adverse events in tirzepatide groups versus placebo included nausea (13–18% vs. 3%) and diarrhea (12–21% vs. 10%).

The SURPASS trials have proven tirzepatide’s ability to lower A1C levels from baseline by a statistically significant degree either as a standalone drug or as add-on therapy to other diabetes medications. A1C was lowered by 1.7–2.4% (16–20) from baseline, which is much greater than the most potent traditional noninsulin agents metformin and sulfonylureas (each with A1C reductions of 1–1.5%) (21,22) or even with GLP-1 receptor agonists, which average A1C reductions of 0.78–1.9% (13). At the maximal dose of 15 mg, tirzepatide alone reduced A1C by 1.6% more than placebo; when used in combination with basal insulin, it reduced A1C by 1.5% more than placebo. Tirzepatide outperformed properly titrated semaglutide, insulin glargine, and insulin degludec by lowering A1C 0.5, 1.0, and 0.9% more than each agent, respectively. It is also important to note that maximum A1C reduction was achieved by week 26 and remained at this plateau for the remainder of the trials, showing durability and maintenance of the effect.

The SURPASS trials additionally assessed how many patients achieved varying levels of A1C control by the conclusion of each trial (Figure 1). Baseline A1C levels across all five trials ranged from 7.9 to 8.5%. The proportion of patients achieving an A1C <7% ranged from 91 to 93%. The proportion of patients achieving an A1C <5.7% ranged from 43 to 52%. Thus, an overwhelming majority of patients using tirzepatide across all SURPASS trials achieved the general American Diabetes Association (ADA) goal A1C of <7%, and nearly half of the patients achieved an A1C below the diagnostic range of diabetes and in the normoglycemic range (<5.7%) (3). The SURPASS-3, -4, and -5 trials each used an insulin product in the arm being compared with tirzepatide. The proportions of patients in the insulin groups who achieved an A1C <7%, <6.5%, and <5.7% were remarkably lower than in the tirzepatide groups (18–20). This finding is important to note because some health care providers hold a view that early initiation of insulin is desirable because a larger A1C reduction may be achieved with insulin. However, the tirzepatide data are impressive in refuting this view, and this is especially true when viewed in the context of essentially no increased risk for hypoglycemia and highly significant weight loss in the tirzepatide arms. Additionally, SURPASS-5 revealed that significantly less insulin glargine may be needed when used in combination with tirzepatide. By the end of the trial, the insulin glargine dose in the placebo group had increased by 75%, whereas the insulin dose decreased by 11.4% in the group taking tirzepatide 15 mg (20). This finding has huge implications for the clinical care of patients with type 2 diabetes, including the potential for reduced hypoglycemia risk and improved weight loss.

Tirzepatide is not yet approved for weight loss with obesity/overweight; however, change in body weight was studied as a secondary outcome of the SURPASS trials. Many patients in the trials had obesity, with an average BMI at the time of enrollment of 32–34 kg/m². Patients in the treatment groups averaged a weight loss of 5.44–11.34 kg (12–25 lb) (16–20,23) (Figure 2). Across all trials, patients taking 5 mg of tirzepatide lost 5.4–7.6 kg (11.91–16.7 lb) or 5.64–8.22% body weight. Patients taking 10 mg lost 7.5–10.7 kg (16.53–23.59 lb) or 7.93–10.71% body weight. Patients taking 15 mg lost 8.8–12.9 kg (19.4–28.44 lb) or 9.17–13.7% body weight (Figure 3). Tirzepatide significantly outperformed the control groups for weight loss in all SURPASS trials. Patients taking the maximum dosage lost 15 lb more than those taking placebo without concomitant insulin use and 23 lb more than placebo when both groups were also using insulin. Those on tirzepatide 15 mg also lost 5.44 kg (12 lb) more than those on semaglutide, 13.15 kg (29 lb) more than those using insulin degludec, and 12.25 kg (27 lb) more than those using insulin glargine. Patients using basal insulin instead of tirzepatide tended to gain weight through the trials.

Of note, weights were still decreasing at the end of the trials and never plateaued, suggesting that the weight loss effect would have been even greater if the studies had continued longer. These are astounding results considering the weight losses observed in other weight loss studies. Weight loss drugs such as orlistat, phentermine/topiramate, and lorcaserin have shown mild reductions in weight, with an average of 5–6% body weight (24). GLP-1 receptor agonists have outperformed these agents in trials, with patients using liraglutide 3 mg losing a mean of 6.5 kg (14.33 lb) or 6.0% body weight (25), patients using dulaglutide 4.5 mg losing a mean of 4.9 kg (10.8 lb) or 4.7% body weight (26), and patients using semaglutide 2.4 mg losing a mean of 18.7 kg (41.23 lb) or 17.4% body weight (27). Weight loss with semaglutide in the STEP-4 (27) trial was impressive, and it should be noted that high-dose semaglutide 2.4 mg was used compared with the previous maximum dose of semaglutide 1 mg used in the SURPASS-2 trial.

The manufacturer is now pursuing an indication for weight loss for tirzepatide with its SURMOUNT research program. The recently published SURMOUNT-1 trial (28,29) investigated its efficacy and safety in adults with obesity or overweight who do not have diabetes but who do have at least one of the following comorbidities: hypertension, dyslipidemia, obstructive sleep apnea, and/or CVD. This trial was a 72-week, randomized, double-blind, parallel, multicenter, placebo-controlled, phase 3 trial. Patients who had prediabetes stayed enrolled in the trial for 104 weeks after the initial 72-week treatment to assess tirzepatide’s effect on body weight and progression to type 2 diabetes. Patients were randomized (1:1:1:1) to receive a once-weekly tirzepatide dose of 5, 10, or 15 mg or placebo. Primary outcomes included average body weight reduction and percentage of participants achieving a body weight reduction ≥5%. A secondary outcome measured the percentage of patients achieving a body weight reduction ≥20%.

Tirzepatide showed superior weight loss in all end points compared with placebo. The average body weight reduction for those on 5 mg was 16.0% (95% CI −16.8 to −15.2%), those on 10 mg lost 21.4% (95% CI −22.2 to −20.6%), and those on 15 mg lost 22.5% (95% CI −23.3 to −21.7%) of body weight compared with 2.4% (95% CI −3.2 to −1.6) in the placebo group (all P <0.001) (Figure 3). The proportion of patients achieving a body weight reduction ≥5% was 85% with 5 mg, 89% with 10 mg, and 91% with 15 mg compared with 35% in the placebo group (all P <0.001). The proportion of patients achieving a body weight reduction ≥20% was 30% with 5 mg, 50% with 10 mg, and 57% with 15 mg compared with 3.1% in the placebo group (all P <0.001). Patients taking tirzepatide lost up to 22.5% of their body weight (52 lb). Noteworthy adverse effects in the tirzepatide groups versus placebo included nausea (24.6–33.3% vs. 9.5%), diarrhea (18.7–23% vs. 7.3%), vomiting (8.3–12.2% vs. 1.7%), and constipation (11.7–17.1% vs. 5.8%). These results indicate that tirzepatide may be an effective treatment for patients struggling with obesity.

Several other clinical trials are underway to evaluate the safety and efficacy of tirzepatide (30). SURPASS-6 assesses effect on A1C of adding tirzepatide to basal insulin instead of prandial insulin. SUPASS-AP-Combo assesses tirzepatide versus insulin glargine in patients taking metformin with or without a sulfonylurea. SURPASS-PEDS assesses change in A1C among children aged 10–17 years with type 2 diabetes taking metformin, insulin, or both. Trials specific to Japanese/Asian markets include SURPASS J-mono, SURPASS J-combo, SURMOUNT-J, and SURMOUNT-CN. SURMOUNT-2, -3, and -4 will address weight loss in specific populations. The SUMMIT trial will assess a composite end point of mortality, heart failure events, exercise capacity, and heart failure symptoms among people with obesity and heart failure with preserved ejection fraction.

One of the most impactful and practice-changing features of GLP-1 receptor agonists was discovered through their CVOTs. Several of the agents in this class have been shown to reduce MACE outcomes (i.e., the composite of myocardial infarction, stroke, or cardiovascular death) (31–33). These findings have led the ADA and the American Association of Clinical Endocrinologists to recommend these GLP-1 receptor agonists (liraglutide, dulaglutide, and semaglutide) as first-line agents for patients with or at high risk of ASCVD (3,34). Because not every agent in this drug class has similarly proven benefits, we must wait for additional CVOTs to be completed to know whether newer agents will provide cardiovascular protection.

Twincretins like tirzepatide have many characteristics in common with GLP-1 receptor agonists with regard to safety and efficacy. SURPASS-4, the only SURPASS trial to exclusively enroll patients with or at risk for CVD, showed that the safety of tirzepatide with regard to MACE outcomes was no different than that of insulin glargine (19). It is anticipated that tirzepatide will provide cardiovascular protection to those at risk; however, we must wait for the tirzepatide CVOT to know for certain. SURPASS-CVOT began in May 2020, and its results are expected in late 2024 (35). The trial has the same basic design as all CVOTs for new diabetes medications, with MACE outcomes as the primary outcome measure and several secondary outcome measures, including impact on A1C, weight, adverse effects, and individual cardiovascular outcomes. This trial includes adults with type 2 diabetes and ASCVD who have a BMI ≥25 kg/m² and an A1C between 7 and 10.5% and compares patients using tirzepatide to those using dulaglutide, which already has proven cardiovascular benefits. SURPASS-CVOT will attempt to confirm tirzepatide’s noninferiority to comparators with regard to safety and to prove its superiority (i.e., that it provides cardiovascular benefit beyond its safety on MACE outcomes).

A prespecified subanalysis of the SURPASS-4 trial addressed effects on CKD, and data from the trial were presented at the ADA’s 82nd Scientific Sessions in June 2022 (36). Lead investigator Hiddo Heerspink noted that once-weekly tirzepatide compared with daily insulin glargine treatment meaningfully slowed decline in estimated glomerular filtration rate and reduced urine albumin-to-creatinine ratio and the risk of end-stage kidney disease, with low risk of clinically relevant hypoglycemia in participants with type 2 diabetes who were at high cardiovascular risk and had varying degrees of CKD (37). Participants using tirzepatide were ∼40% less likely to experience a decline in renal function with new-onset macroalbuminuria (HR 0.59, P <0.05). This finding implies a potential role for tirzepatide in preventing and treating CKD in people with diabetes.

One of the most influential considerations in the selection of medications is their cost. Affordability can determine the availability of agents to patients and greatly affect adherence to the treatment regimen. With a list price of $974.33 for a 1-month supply (four weekly doses), the annual cost of tirzepatide is expected to be approximately $12,666. Although this price seems daunting, it is on par with current pricing of semaglutide, a competitor GLP-1 receptor agonist. The manufacturer’s discount programs can bring the out-of-pocket price down to $25/month (38). The high list price may lead some health care providers to assume that many of their patients will not be able to afford this new and valuable medication. This belief may perpetuate the under-usage of recommended and beneficial new drug classes among patients with diabetes, many of whom are in underserved populations and minority groups with high rates of cardiovascular risk and obesity, further perpetuating health care disparities.

The dual action of the tirzepatide molecule to stimulate both GIP and GLP-1 receptors provides a more thorough enhancement of incretin activity than GLP-1 receptor agonists or DPP-4 inhibitors. The full role and place in therapy of twincretins remain to be determined, but these agents have the potential to be considered a “better” GLP-1 receptor agonist and to fit into therapy in a way similar to GLP-1 receptor agonists, but with improved results. Tirzepatide’s adverse effect profile is similar to that of the GLP-1 receptor agonists and primarily includes gastrointestinal effects such as nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain (15), which are often well tolerated and transient as a result of strategies for gradual dose titration. The tirzepatide delivery pen is identical to the delivery pen for dulaglutide. Many patients and providers will recognize this familiar device and easily adopt its use. The needle is kept within the device until the moment of injection and is not visible to the patient. This feature may be desirable for patients who fear needles or the anticipation of an injection. Providers do not need to prescribe pen needles for this device, so this step will not be forgotten (which is common with other injection devices), decisions about needle length and gauge will not be necessary, and patients will not have to pick up and pay for this separate prescription. Additionally, the built-in needle is 29 gauge and 5 mm in length, which is very fine and short (15). Once-weekly injections could improve adherence compared with once-daily products (39), which may in turn lead to improved glucose control and outcomes and reduced polypharmacy. These characteristics make tirzepatide a desirable agent with great potential.

With superior A1C and weight reduction compared with other glucose-lowering drugs, tirzepatide is primed to transcend currently recommended first-line agents for type 2 diabetes management. If tirzepatide’s CVOT results prove benefit with regard to MACE outcomes and further data support renal benefits, this agent will become a powerful new weapon against hyperglycemia and related comorbidities. Patients with type 2 diabetes are at an increased risk of obesity, CVD, dyslipidemia, and CKD. This GIP/GLP-1 receptor agonist can target elevated glucose levels, obesity, dyslipidemia, and renal dysfunction, and its use may even reduce polypharmacy in select populations in lieu of using additional drugs for weight loss, glucose control, lipid-lowering, and heart failure treatment. The age of twincretins is upon us, and tirzepatide leads the way.

No potential conflicts of interest relevant to this article were reported.

A.V.F. conducted literature searches and wrote and edited the manuscript. B.K.C. wrote reviews of trials, created figures, and edited the manuscript. M.C.G. wrote reviews of trials and edited the manuscript. J.L.J. conducted literature searches, wrote the manuscript, created figures, and edited the manuscript. J.L.J. is the guarantor of this work and, as such, takes responsibility for the integrity and accuracy of the contents.