Tirzepatide results published in The Lancet show superior A1C and body weight reductions compared to insulin glargine type 2 diabetes with increased cardiovascular risk.

At 52 weeks, the highest dose of tirzepatide led to an A1C reduction of 2.58 percent and reduced body weight by 11.7 kg (-25.8 lb., -13.0 percent) compared to results for those treated with insulin glargine (A1C reduction of 1.44 percent and weight gain of 1.9 kg [+4.2 lb., +2.2 percent]) for the efficacy estimand.

SURPASS-4 is the largest and longest clinical trial completed to date of the phase III program studying tirzepatide as a potential treatment for type 2 diabetes. The primary endpoint was measured at 52 weeks, with participants continuing treatment up to 104 weeks or until study completion. The completion of the study was triggered by the accrual of major adverse cardiovascular events (MACE) to assess CV risk. In newly published data from the treatment period after 52 weeks, participants taking tirzepatide maintained A1C and weight control for up to two years.The overall safety profile of tirzepatide, assessed over the full study period, was consistent with the safety results measured at 52 weeks, with no new findings up to 104 weeks. Gastrointestinal side effects were the most commonly reported adverse events, usually occurring during the escalation period and then decreasing over time.

SURPASS-4 was an open-label global trial comparing the safety and efficacy of three tirzepatide doses (5 mg, 10 mg and 15 mg) to titrated insulin glargine in 2,002 adults with type 2 diabetes with increased CV risk who were treated with between one and three oral antihyperglycemic medicines (metformin, a sulfonylurea or an SGLT-2 inhibitor). Of the total participants randomized, 1,819 (91%) completed the primary 52-week visit and 1,706 (85%) completed the study on treatment. The median study duration was 85 weeks and 202 participants (10%) completed two years. Study participants had a mean duration of diabetes of 11.8 years, a baseline A1C of 8.52 percent and a baseline weight of 90.3 kg. More than 85 percent of participants had a history of cardiovascular events. In the insulin glargine arm, the insulin dose was titrated following a treat-to-target algorithm with the goal of fasting blood glucose below 100 mg/dL. The starting dose of insulin glargine was 10 units per day, and the mean dose of insulin glargine at 52 weeks was 43.5 units per day.

Results:SURPASS-4 achieved each of its primary and key secondary endpoints. All three doses of tirzepatide (5 mg, 10 mg and 15 mg) led to statistically significant and superior A1C and body weight reductions compared to insulin glargine for both estimands at 52 weeks (the primary endpoint). Specifically, the efficacy estimand results showed: i A1C reduction: -2.24% (5 mg), -2.43% (10 mg), -2.58% (15 mg), -1.44% (insulin glargine). ii. Weight change: -7.1 kg (-8.1%, 5 mg), -9.5 kg (-10.7%, 10 mg), -11.7 kg (-13.0%, 15 mg), +1.9 kg (+2.2%, insulin glargine) iii. Percent of participants achieving A1C <7%: 81% (5 mg), 88% (10 mg), 91% (15 mg), 51% (insulin glargine). iv. percent of participants achieving a1c><5.7% (not controlled for type 1 error): 23% (5 mg), 33% (10 mg), 43% (15 mg), 3% (insulin glargine).></5.7%></7%:>

For the treatment-regimen estimand, all three doses of tirzepatide led to superior A1C and weight reductions at 52 weeks. Specifically, results showed: i.A1C reduction: -2.11% (5 mg), -2.30% (10 mg), -2.41% (15 mg), -1.39% (insulin glargine). ii. Weight change: -6.4 kg (5 mg), -8.9 kg (10 mg), -10.6 kg (15 mg), +1.7 kg (insulin glargine). iii. Percent of participants achieving A1C <7%: 75% (5 mg), 83% (10 mg), 85% (15 mg), 49% (insulin glargine).></7%:>

Participants taking tirzepatide maintained A1C and weight control for up to two years in exploratory analyses. The mean A1C values at 52 and 104 weeks were: i. At 52 weeks (N=1,750): 6.3% (5 mg), 6.1% (10 mg), 6.0% (15 mg), 7.1% (insulin glargine).ii. At 104 weeks (N=199): 6.4% (5 mg), 6.1% (10 mg), 6.1% (15 mg), 7.5% (insulin glargine).

The changes in body weight at 52 and 104 weeks were: i. At 52 weeks (N=1,755): -7.1 kg (-8.1%, 5 mg), -9.5 kg (-10.7%, 10 mg), -11.7 kg (-13.0%, 15 mg), +1.9 kg (+2.2%, insulin glargine). ii. At 104 weeks (N=202): -5.8 kg (-8.6%, 5 mg), -10.4 kg (-10.8%, 10 mg), -11.1 kg (-12.8%, 15 mg), +2.3 kg (+2.3%, insulin glargine).

Hypoglycemia less than 54 mg/dL was reported in 8.8 percent (5 mg), 6.1 percent (10 mg) and 8.0 percent (15 mg) of participants in the tirzepatide arms and in 19.1 percent of participants in the insulin glargine arm over the full study period. Episodes of hypoglycemia were seen more often in participants who had a background therapy of a sulfonylurea. In an additional exploratory endpoint, all three doses of tirzepatide led to favorable changes from baseline in fasting lipids at 52 weeks. Specifically, at the highest dose of tirzepatide (15 mg): total cholesterol was reduced by 5.6 percent, triglycerides were reduced by 22.5 percent, low-density lipoprotein (LDL) cholesterol was reduced by 7.9 percent, very low-density lipoprotein (VLDL) cholesterol was reduced by 21.8 percent, and high-density lipoprotein (HDL) cholesterol was increased by 10.8 percent.

The most commonly reported adverse events over the full study period in the tirzepatide arms were gastrointestinal-related and generally mild to moderate in severity. For study participants treated with tirzepatide (5 mg, 10 mg and 15 mg, respectively), nausea (12 percent, 16 percent, 23 percent), diarrhea (13 percent, 20 percent, 22 percent) and vomiting (5 percent, 8 percent, 9 percent) were more frequently experienced compared to insulin glargine (2 percent [nausea], 4 percent [diarrhea], 2 percent [vomiting]). Treatment discontinuation rates due to adverse events over the full study period were 7.3 percent (tirzepatide 5 mg), 7.9 percent (tirzepatide 10 mg) and 8.9 percent (tirzepatide 15 mg), compared to 1.9 percent (insulin glargine). A safety analysis evaluated adjudicated MACE-4, a composite endpoint of death from cardiovascular causes, myocardial infarction, stroke and hospitalization for unstable angina. Within SURPASS-4, comparing pooled tirzepatide to insulin glargine, no increased cardiovascular risk was identified with tirzepatide; a hazard ratio of 0.74 (95% confidence interval, 0.51 to 1.08) was observed..

See- "Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase III trial". Prof Stefano Del Prato, MD, Prof Steven E Kahn, MBChB Imre Pavo, MD Govinda J Weerakkody, PhD. et al. Published :October 18, 2021DOI:https://doi.org/10.1016/S0140-6736(21)02188-7.The Lancet.