Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes 

Design

International, randomized, open-label, 40-week, parallel-group, active-controlled phase 3 trial

N= 1,878

Objective

To compare the efficacy and safety of once-weekly tirzepatide (doses 5 mg, 10 mg, and 15 mg) subcutaneous injection with semaglutide (1 mg) in Type 2 diabetics inadequately controlled on metformin monotherapy

Study Groups

Tirzepatide 5 mg (n= 470)

Tirzepatide 10 mg (n= 469)

Tirzepatide 15 mg (n= 470)

Semaglutide 1 mg (n= 469)

Inclusion Criteria

Age ≥ 18 years old, type 2 diabetes inadequately controlled on metformin at dose of ≥ 1500 mg/d, glycated hemoglobin (HbA1c) 7.0 to 10.5%, body mass index (BMI) ≥ 25 kg/m², stable weight (± 5%) during previous 3 months

Exclusion Criteria

Type 1 diabetes, eGFR < 45 mL/min/1.73m², history of pancreatitis, history of any of the following: non-proliferative diabetic retinopathy that warranted urgent treatment, proliferative diabetic retinopathy, or diabetic maculopathy

Methods

Patients were randomized 1:1:1:1 to receive once weekly injections of tirzepatide 5 mg, 10 mg, or 15 mg or semaglutide 1 mg. Safety follow-up occurred after 4 weeks. The initial dose of tirzepatide was 2.5 mg once weekly, increased by 2.5 mg every 4 weeks until the assigned dose was reached. The initial dose of semaglutide was 0.25 mg, doubled every 4 weeks until the assigned 1 mg dose was reached. 

Duration

July 30, 2019 to February 15, 2021

Intervention: 40 weeks

Safety Followup: 4 weeks 

Outcome Measures

Primary: change in HbA1c levels from baseline to week 40

Secondary: change in body weight from baseline to week 40, attainment of HbA1c target levels < 7.0% and < 5.7%

Safety: adverse events (AEs), discontinuation of tirzepatide or semaglutide due to adverse events

Baseline Characteristics

Tirzepatide 5 mg

(n= 470)

Tirzepatide 10 mg

(n= 469)

Tirzepatide 15 mg

(n= 470)

Semaglutide 1 mg

(n= 469)

Age, years

Female

Race

American Indian/Alaska Native

Asian

Black

White

53 (11.3%)

6 (1.3%)

28 (6.0%)

382 (81.3%)

53 (11.3%)

11 (2.3%)

21 (4.5%)

376 (80.2%)

57 (12.1%)

5 (1.1%)

15 (3.2%)

392 (83.4%)

45 (9.6%)

3 (0.6%)

15 (3.2%)

401 (85.5%)

Glycated hemoglobin level, %

≤ 8.5%

> 8.5%

8.32  ± 1.08

293 (62.3%)

177 (37.7%)

8.30 ± 1.02

294 (62.7%)

175 (37.3%)

8.26 ± 1.00

303 (64.5%)

167 (35.5%) 

8.25 ± 1.01

302 (64.4%)

167 (35.6%)

Fasting serum glucose level, mg/dL

173.8 ± 51.87

174.2 ± 49.79

172.4 ± 54.37

171.4 ± 49.77

BMI, kg/m²

Weight, kg

Results

Endpoint

Tirzepatide 5 mg

(n= 470)

Tirzepatide 10 mg

(n= 469)

Tirzepatide 15 mg

(n= 470)

Semaglutide 1 mg

(n= 469)

Change in HbA1c

Baseline to week 40, % 

Difference vs. semaglutide, %  (95% CI)

p-value

-2.01

-0.15 (-0.28 to -0.03)

0.02

-2.24

-0.39 (-0.51 to -0.26)

< 0.001

-2.30

-0.45 (-0.57 to -0.32)

< 0.001

-1.86

—

—

Body weight reduction

Baseline to week 40, kg 

Difference vs. semaglutide, kg (95% CI)

p-value 

-7.6 

-1.9 (-2.8 to -1.0)

< 0.001

-9.3 

-3.6 (-4.5 to -2.7)

< 0.001

-11.2 

-5.5 (-6.4 to -4.6)

< 0.001

-5.7 

—

—

Target HbA1c at 40 weeks

< 7.0%

≤ 6.5%

< 5.7%

82%

69%

27%

86%*

77%

40%**

86%*

80%

46%**

79%

64%

19%

Adverse events

Patients with ≥ 1 AE 

Patients with ≥ 1 serious AE

Lead to discontinuation

All gastrointestinal AEs

299 (63.6%)

33 (7.0%)

28 (6.0%)

188 (40.0%)

322 (68.7%)

25 (5.3%)

40 (8.5%)

216 (46.1%)

324 (68.9%)

27 (5.7%)

40 (8.5%)

211 (44.9%)

301 (64.2%)

13 (2.8%)

19 (4.1%)

193 (41.2%)

*p< 0.05 vs. semaglutide

**p< 0.001 vs. semaglutide

Adverse Effects

Most common AEs included mild to moderate gastrointestinal effects (nausea, 17 to 22% tirzepatide and 18% semaglutide; diarrhea, 13 to 16% and 12%; vomiting, 6 to 10% and 8%). Serious AEs occurred in 5 to 7% of tirzepatide and 3% of semaglutide patients, including COVID-19 related pneumonia (0.4% and 0.9%) and acute cholecystitis (0.2 to 0.4% and 0). 

In patients with type 2 diabetes who were receiving metformin, the novel once-weekly dual glucose-dependent insulinotropic polypeptide–GLP-1 receptor agonist tirzepatide was noninferior and superior to the selective GLP-1 receptor agonist semaglutide (at a dose of 1 mg) with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks.

InpharmD Researcher Critique

Maximum dose of semaglutide (2mg weekly) was not utilized. About twice as many patients discontinued higher doses of tirzepatide 10 mg and 15 mg due to adverse events compared to semaglutide and tirzepatide 5 mg which may also translate to higher discontinuation rates in the general population. Although African Americans are at a higher risk for diabetes, they had low representation in this study.

Tirzepatide versus Insulin Glargine in Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4): A Randomized, Open-Label, Parallel-Group, Multicentre, Phase 3 Trial

Design

Randomized, open-label, parallel-group, multicentre, phase 3 trial

N= 1,995

Objective

To compare the efficacy and safety of three doses of tirzepatide (5 mg, 10 mg, and 15 mg) versus glargine titrated to fasting glucose of less than 100 mg/dL in people with type 2 diabetes and high cardiovascular risk inadequately controlled on oral glucose-lowering medications

Study Groups

Tirzepatide 5 mg (n= 329)

Tirzepatide 10 mg (n= 328)

Tirzepatide 15 mg (n= 338)

Insulin glargine (n= 1,000)

Inclusion Criteria

Aged 18 years or older, had type 2 diabetes treated with any combination of metformin, sulfonylurea, or sodium-glucose co-transporter-2 inhibitor, a baseline glycated hemoglobin (HbA1c) of 7.5–10.5% (58–91 mmol/mol), body-mass index of 25 kg/m2 or greater, and established cardiovascular disease or a high risk of cardiovascular events

Exclusion Criteria

Type 1 diabetes, history of pancreatitis, proliferative diabetic retinopathy or diabetic maculopathy, ketoacidosis or hyperosmolar state/coma, one or more episodes of severe hypoglycemia and/or 1 or more episodes of hypoglycemia unawareness within the 6 months prior to Visit 1, New York Heart Association Functional Classification IV congestive heart failure, acute myocardial infarction, cerebrovascular accident (stroke), or hospitalization for CHF within 2 months prior to visit 1

Methods

Participants were randomly assigned (1:1:1:3) via an interactive web-response system to subcutaneous injection of either once-per-week tirzepatide (5 mg, 10 mg, or 15 mg) or glargine (100 U/mL), titrated to reach fasting blood glucose of less than 100 mg/dL.

All participants were treated for at least 52 weeks, with treatment continued for a maximum of 104 weeks or until study completion to collect and adjudicate major adverse cardiovascular events (MACE). Key secondary objectives, controlled for type I error, included non-inferiority and superiority of tirzepatide 5 mg compared with glargine relative to HbA1c, and superiority of all doses of tirzepatide versus glargine relative to weight and the proportion of participants achieving HbA1c of less than 7.0%.

Duration

From November 20, 2018 to December 30, 2019

Intervention: 52 weeks

Outcome Measures

Primary: change in HbA1c

Secondary: change in bodyweight, achievement of HbA1c target of less than 7.0%, achievement of bodyweight loss target  

Baseline Characteristics

Overall population (N= 1,995)

Age, years

Female

White

Median duration of diabetes (IQR), years

Body-mass index, kg/m²

History of cardiovascular disease

Coronary artery disease

Myocardial infarction

Coronary revascularization procedure

Hospitalization for unstable angina

Hospitalization for heart failure S

Stroke

Transient ischemic attack

Peripheral artery disease

1,738 (87%)

880 (44%)

646 (32%)

644 (32%)

164 (8%)

140 (7%)

241 (12%)

98 (5%)

606 (30%)

Antidiabetic medications

SGLT2 inhibitor 

Sulfonylurea

Metformin

501 (25%)

1,086 (54%)

1,893 (95%)

Demographics and clinical characteristics were similar across groups.

IQR, interquartile range

Results

Endpoint

Tirzepatide 5 mg (n= 326)

Tirzepatide 10 mg (n= 321)

Tirzepatide 15 mg (n= 334)

Insulin glargine (n= 978)

Change from baseline at week 52^*¶

HbA1c, %

p-value vs. insulin glargine

–2.43 ± 0.053

<0.001

Change from baseline at week 52^¶

Bodyweight, kg

p-value vs. insulin glargine

–7.1 ± 0.34

<0.001

–9.5 ± 0.34

<0.001

–11.7 ± 0.33

<0.001

1.9 ± 0.19

--

Achieved HbA1c <7% at week 52^¶

p-value vs. insulin glargine

264 (81%)

<0.001

283 (88%)

<0.001

303 (91%)

<0.001

496 (51%) 

--

Achieved bodyweight loss targets at week 52

≥5% loss

≥10% loss

≥15% loss

249 (78%)

170 (53%)

77 (24%)

285 (85%)

219 (66%)

122 (37%)

78 (8%)

15 (2%)

5 (<1%)

TEAEs with at least 5% frequency 

Diarrhea

Nausea

COVID-19

Nasopharyngitis

Decreased appetite

Vomiting

Dyspepsia

Lipase increase

Constipation

20%

16%

4%

5%

11%

8%

8%

4%

4%

22%

23%

6%

5%

10%

9%

8%

6%

4%

4%

2%

6%

7%

<1%

2%

1%

2%

<1%

*Tested for non-inferiority, controlled for type I error.

^¶Tested for superiority, controlled for type I error.

Adverse Events

Common Adverse Events: See results

Serious Adverse Events: 15% vs. 17% vs. 12% vs. 19%

Percentage that Discontinued due to Adverse Events: 11% vs. 9% vs. 11% vs. 5%

Study Author Conclusions

In people with long-standing type 2 diabetes and high cardiovascular risk, tirzepatide demonstrated superiority and sustainability in overall glycaemic control and weight reduction compared with glargine. Given the progressive nature of type 2 diabetes,35 evaluating the durability of glycaemic and weight effects of dual incretin receptor agonists like tirzepatide is important to determine the expected therapeutic benefits. The improvement in cardiovascular risk profile and distribution of cardiovascular events between treatment groups suggests that tirzepatide is safe from a cardiovascular perspective.

InpharmD Researcher Critique

Despite several strengths such as the large sample size and selection of glargine as a comparator group, this study was limited based on its non-blinding fashion. Moreover, long-term safety data beyond 52 weeks period was not attainable for all patients.

Once-weekly Tirzepatide versus Once-Daily Insulin Degludec as Add-on to Metformin with or without SGLT2 Inhibitors in Patients with Type 2 Diabetes (SURPASS-3): A Randomized, Open-Label, Parallel-Group, Phase 3 Trial

Open-label, parallel-group, multicenter, multinational, active-controlled, phase 3 study

N= 1,437

Objective

To assess the efficacy  and safety of tirzepatide versus titrated insulin degludec in people with type 2 diabetes inadequately controlled by metformin with or without SGLT2 inhibitors 

Study Groups

Tirzepatide 5 mg group (n= 358)

Tirzepatide 10 mg group (n= 360)

Tirzepatide 15 mg group (n= 359)

Insulin degludec group (n= 360)

Inclusion Criteria

Aged ≥ 18 years, insulin naive, uncontrolled type 2 diabetes (HbA1c 7.0 - 10.5%) on stable treatment with metformin alone or in combination with an SGLT2 inhibitor for at least 3 months before screening, body mass index ≥ 25 kg/m², and stable weight (no change outside of 5%) during the previous 3 months

Exclusion Criteria

Type 1 diabetes, history of pancreatitis, history of proliferative diabetic retinopathy or maculopathy (or non-proliferative diabetic retinopathy requiring acute treatment, an estimated glomerular filtration rate (eGFR) < 45 mL/min per 1.73 m²

Methods

Eligible patients were randomized (1:1:1:1) to receive tirzepatide subcutaneously (5, 10, or 15 mg) with a single-dose pen on the same day and time once weekly; or insulin degludec subcutaneously with a prefilled pen containing 3 mL (U100/mL) once daily ideally at bedtime for 52 weeks. Tirzepatide was initially given at 2.5 mg and escalated by 2.5 mg every 4 weeks until reached the assigned dose. De-escalation of dosage was allowed to a tolerated maintenance dose of 5 mg or 10 mg, whereas it was not allowed in patients randomly allocated at 5 mg of tirzepatide or after the escalation period (week 24). Insulin degludec was initially given at 10 U per day and was titrated once weekly to a fasting self-monitored blood glucose of < 5.0 mmol/L (​< 90 mg/dL) for 52 weeks. Rescue therapy such as initiation of new antihyperglycemic medications except for pramlintide was allowed during the study and safety follow-up period (4 weeks). 

Duration

Intervention: 52 weeks

Follow-up period: 4 weeks 

Primary: non-inferiority of tirzepatide 10 mg or 15 mg, or both, versus insulin degludec in mean change from baseline in HbA1c at week 52

Secondary: non-inferiority of tirzepatide 5 mg versus insulin degludec in mean change from baseline in HbA1c at week 52, superiority of all doses of tirzepatide versus insulin degludec in mean change from baseline in HbA1c and bodyweight, and proportion of participants achieving HbA1c of less than 7.0%, adverse events

Baseline Characteristics

Tirzepatide 5 mg (n= 358)

Tirzapatide 10 mg (n= 360) 

Age, years

Sex 

Male

Female 

200 (56%)

158 (44%)

195 (54%)

165 (46%)

194 (54%)

165 (46%)

213 (59%)

147 (41%) 

Race

American Indian/Alaska Native

Asian

Black/African American

Native Hawaiian/Pacific Islander

White 

0  

20 (6%)

13 (4%)

1 (<1%)

323 (90%)

1 (<1%)

19 (5%)

12 (3%)

0

328 (91%)

1 (<1%)

20 (6%)

8 (2%)

2 (1%)

327 (91%)

2 (1%)

17 (5%)

11 (3%)

1 (<1%)

329 (91%)

Duration of diabetes, years 

HbA1c conc.

Values in %

Patients with ≤8.5%

Patients with >8.5%

8.17 ± 0.89

248 (69%)

110 (31%)

8.18 ± 0.89

249 (69%)

111 (31%)

8.21 ± 0.94

252 (70%)

107 (30%)

8.12 ± 0.94

256 (71%)

104 (29%)

Fasting serum glucose conc.

Values in mmol/L

Values in mg/dL

9.53 ± 2.66

171.7 ± 47.9

9.46 ± 2.64

170.4 ± 47.6

9.35 ± 2.55

168.4 ± 46.0

9.26 ± 2.33

166.7 ± 41.9

Diabetes medication 

Metformin alone

Metformin + SGLT2 inhibitor

246 (69%)

112 (31%)

242 (67%)

118 (33%)

247 (69%)

112 (31%)

244 (68%)

116 (32%)

Body mass index (BMI), kg/m²

33.6 ± 5.9

Urine albumin:creatinine ratio, g/kg

< 30

≥ 30 to ≤ 300

> 300

250 (70%)

88 (25%)

19 (5%)

274 (76%)

67 (19%)

19 (5%)

250 (70%)

98 (27%)

11 (3%)

258 (72%)

85 (24%)

15 (4%)

Results

Endpoint

Tirzepatide 5 mg (n= 358)

Tirzapatide 10 mg (n= 360)

Tirzepatide 15 mg (n= 359)

HbA1c, %

Change from baseline at Wk 52

ETD vs. degludec (95% CI)

p-value

-1.93% ± 0.05 

-0.59% (-0.73 to -0.45)

p< 0.0001

-2.20% ± 0.05 

-0.86% (-1.00 to -0.72)

p< 0.0001

-2.37% ±0.05

-1.04% (-1.17 to -0.90)

p< 0.0001

-1.34% ± 0.05

---

HbA1c target at Wk 52 

< 7.0% (< 53 mmol/mol)

OR vs. insulin degludec

p-value

≤ 6.5% (≤ 48 mmol/mol)

OR vs. insulin degludec 

p-value

≤ 5.7% (≤ 39 mmol/mol)

OR vs. insulin degludec 

p-value

291 (82%)

3.45 (2.38 to 5.01)

p< 0.0001

252 (71%)

3.62 (2.59 to 5.06)

p< 0.0001 

91 (26%)

7.11 (4.17 to 12.12)

p< 0.0001

314 (90%)

7.02 (4.55 to 10.84)

p< 0.0001

281 (80%)

6.63 (4.42 to 9.14)

p< 0.0001

135 (39%)

14.14 (8.34 to 23.96)

p< 0.0001

327 (93%)

10.79 (6.65 to 17.48)

p< 0.0001

301 (85%)

9.59 (6.48 to 14.19)

p< 0.0001

171 (48%) 

22.09 (13.02 to 37.47)

p< 0.0001

215 (61%)

---

156 (44%)

---

19 (5%)

---

Fasting serum glucose, mmol/L

Change from baseline at Wk 52 

ETD vs. insulin degludec

p-value

-2.68 ± 0.10

0.41 (0.14 to 0.69)

p= 0.0036

-3.04 ± 0.10

0.05 (-0.24 to 0.33)

p= 0.7510

-3.29 ± 0.10

-0.20 (-0.48 to 0.08)

p= 0.1682

-3.09 ± 0.10

---

Fasting serum glucose, mg/dL

Change from baseline at Wk 52 

ETD vs. insulin degludec 

p-value

-48.2 ± 1.8

7.5 (2.4 to 12.5)

p= 0.0036

-54.8 ± 1.9 

0.8 (-4.3 to 5.9)

p=0.7310 

-59.2 ± 1.9 

-3.6 (-8.7 to 1.5)

p=0.1682  

-55.7 ± 1.8 

---

Bodyweight (BW), kg

Change from baseline at Wk 52 

ETD vs. insulin degludec 

p-value

-7.5 ± 0.4

-9.8 (-10.8 to -8.8)

p< 0.0001 

-10.7 ± 0.4

-13.0 (-14.0 to -11.9)

p< 0.0001  

-12.9 ± 0.4

-15.2 (-16.2 to -14.2)

p< 0.0001

2.3 ± 0.4

---

BW loss targets at Wk 52

≥5% loss

OR vs. insulin degludec 

p-value

≥10% loss

OR vs. insulin degludec 

p-value

≥15% loss

OR vs. insulin degludec

p-value

233 (66%)

29.78 

p< 0.0001

132 (37%)

20.61 

p< 0.0001

44 (13%)

104.50 

p< 0.0001

293 (84%)

79.88 

p< 0.0001

195 (56%)

44.67 

p< 0.0001

99 (28%)

293.07 

p< 0.0001

310 (88%)

110.77 

p< 0.0001

245 (69%)

82.26 

p< 0.0001

150 (43%)

564.49 

p< 0.0001

22 (6%)

---

10 (3%)

---

0

---

Any serious adverse event (AE)

Deaths

AEs leading to discontinuation

Nausea

Vomiting

Diarrhea

Decreased appetite

Decreased weight

25 (7%)

3 (1%)

3 (1%)

4 (1%)

1 (<1%)

1 (<1%)

37 (10%)

7 (2%)

6 (2%)

1 (<1%)

4 (1%)

1 (<1%)

39 (11%)

9 (3%)

3 (1%)

3 (1%)

1 (<1%)

4 (1%)

5 (1%)

1 (<1%)

0

0

0

0

TEAEs occurring in ≥ 5% 

Nausea

Diarrhea

Decreased appetite

Vomiting

Dyspepsia

Increased lpase

Nasopharyngitis

Abdominal pain

Hypertension 

41 (12%)

55 (15%)

22 (6%)

21 (6%)

15 (4%)

21 (6%)

11 (3%)

7 (2%)

11 (3%)

81 (23%)

60 (17%)

37 (10%)

34 (9%)

32 (9%)

16 (4%)

14 (4%)

17 (5%)

7 (2%)

85 (24%)

56 (16%)

43 (12%)

36 (10%)

18 (5%)

20 (6%)

15 (4%)

23 (6%)

11 (3%)

6 (2%)

14 (4%)

2 (1%)

4 (1%)

0

7 (2%)

22 (6%)

4 (1%)

21 (6%)

Adverse Events

See Results

]Study Author Conclusions

In patients with type 2 diabetes, tirzepatide (5, 10, and 15 mg) was superior to titrated insulin degludec, with greater reductions in HbA1c and bodyweight at week 52 and a lower risk of hypoglycaemia. Tirzepatide showed a similar safety profile to that of GLP-1 receptor agonists.

InpharmD Researcher Critique

The study adopted an open-label design due to different dosing frequency, titration scheme, and injection device of insulin degludec. Gastrointestinal adverse events self-reported by patients are susceptible to subjectivity and nocebo effect. Despite the nature of the multinational (13 centuries) study, there is a clear racial preponderance of White among included participants. 

Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial

Design

Multi-center, phase 3, randomized, double-blind, parallel, placebo-controlled study 

N= 475

Objective

To assess the efficacy and safety of tirzepatide added to insulin glargine in patients with type 2 diabetes with inadequate glycemic control

Study Groups

Tirzepatide 5 mg (n= 116)

Tirzepatide 10 mg (n= 119)

Tirzepatide 15 mg (n= 120)

Placebo (n= 120)

Inclusion Criteria

Adults with type 2 diabetes, baseline glycated hemoglobin A1c (HbA1c) of 7.0% to 10.5% (53-91 mmol/mol) inclusive, and body mass index (BMI) of at least 23 receiving stable doses of once-daily insulin glargine (> 20 IU/d or > 0.25 IU/kg/d) with or without metformin (≥ 1500 mg/d)

Exclusion Criteria

Type 1 diabetes, history of pancreatitis, nonproliferative diabetic retinopathy requiring acute treatment, proliferative diabetic retinopathy, diabetic maculopathy, hepatitis, hypoglycemia unawareness, gastroparesis, estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m² (or < 45 mL/min/1.73 m² for patients receiving metformin), and use of any other antihyperglycemic medication in the 3 months before screening

Methods

Eligible patients were randomized (1:1:1:1) to receive once-weekly subcutaneous injections of 5 mg, 10 mg, or 15 mg tirzepatide or a volume-matched placebo over 40 weeks following a 4-week safety follow-up. Tirzepatide was initiated at 2.5 mg/week and escalated by 2.5 mg every 4 weeks until the assigned dose was achieved to improve gastrointestinal tolerability. All patients continue to receive insulin glargine once daily, and those with HbA1c ≤ 8.0% at randomization were required to reduce the dose of insulin glargine by 20% to minimize the risk of hypoglycemia. 

Duration

August 30, 2019, to March 20, 2020

Follow-up: completed January 13, 2021

Outcome Measures

Primary: mean change from baseline in HbA1c at week 40

Secondary: mean change in body weight and percentage of patients achieving < 7% HbA1c levels

Baseline Characteristics

Tirzepatide 5 mg (n= 116)

Tirzepatide 10 mg (n= 119)

Tirzepatide 15 mg
(n= 120)

Age, years

Female

White

Body mass index, kg

Duration of diabetes, years

Used metformin

Metformin dose, mg/d

99 (85.3%)

2,018 ± 397

99 (83.2%)

2,077 ± 416

97 (80.8%)

2,046 ± 392

99 (82.5%)

2,051 ± 411

Insulin glargine dose (IQR), IU/kg/d

HbA1c (mean), %

Fasting serum glucose, mg/dL

8.30 ± 0.88

162.9 ± 53.9

8.36 ± 0.83

162.3 ± 52.0

8.23 ± 0.86

160.3 ± 54.2

8.37 ± 0.84

164.1 ± 45.0

86.1 ± 18.1

87.1 ± 18.2

84.1 ± 17.2

84.7 ± 17.8

IQR, interquatile range

Results

Endpoint

Tirzepatide 5 mg
(n= 116)

Tirzepatide 10 mg (n= 119)

Tirzepatide 15 mg
(n= 120)

Placebo
(n= 120)

HbA1c Change at week 40 (95% CI), %

Difference vs placebo (95% CI)

p-value

−2.11 (−2.28 to −1.94)

−1.24 (−1.48 to −1.01

< 0.001

−2.40 (−2.56 to −2.23)

−1.53 (−1.77 to −1.30)

< 0.001

−2.34 (−2.51 to −2.16)

−1.47 (−1.71 to −1.23)

< 0.001 

−0.86 (−1.03 to −0.70)

-

- 

Patients met HbA1c <7.0% at week 40

Odds ratio vs placebo (95% CI)

p-value

101 (87.3%) 

14.7 (7.0 to 30.6)

< 0.001

106 (89.6%)

19.5 (9.2 to 41.3)

< 0.001

100 (84.7%)

11.5 (5.6 to 23.3)

< 0.001

41 (34.5%)

-

-

Bodyweight change at week 40 (95% CI), kg

≥5% loss

Odds ratio vs placebo (95% CI)

p-value*

−5.4 (−6.6 to −4.3)

56 (47.9%)

13.8 (6.0 to 31.4)

< 0.001

−7.5 (−8.6 to −6.3)

68 (57.9%)

20.9 (9.2 to 47.8)

< 0.001

−8.8 (−10.0 to −7.7)

85 (71.6%)

38.5 (16.5 to 89.8)

< 0.001

1.6 (0.5 to 2.8)

7 (6.0%)

-

-

Treatment-emergent adverse events ≥5% 

Nasopharyngitis

Nausea

Diarrhea

Decrease appetite

Vomiting

Dyspepsia

Constipation

Back pain

Eructation

Arthralgia

Lipase increase

18 (15.5%)

15 (12.9%)

14 (12.1%)

8 (6.9%)

8 (6.9%)

8 (6.9%)

7 (6.0%)

6 (5.2%)

6 (5.2%)

6 (5.2%)

4 (3.4%)

8 (6.7%)

21 (17.6%)

15 (12.6%)

15 (12.6%)

9 (7.6%)

10 (8.4%)

8 (6.7%)

6 (5.0%)

4 (3.4%)

4 (3.4%)

2 (1.7%)

15 (12.5%)

22 (18.3%)

25 (20.8%)

17 (14.2%)

15 (12.5%)

6 (5.0%)

8 (6.7%)

4 (3.3%)

7 (5.8%)

3 (2.5%)

10 (8.3%)

23 (19.2%)

3 (2.5%)

12 (10.0%)

2 (1.7%)

3 (2.5%)

2 (1.7%)

2 (1.7%)

7 (5.8%)

1 (0.8%)

2 (1.7%)

2 (1.7%)

CI, confidence interval

*Significant results for ≥ 10% weight loss (p-value: <0.001 vs <0.001 vs <0.001) as well as ≥ 15% weight loss (p-value: 0.038 vs. 0.002 vs. 0.002)

Adverse Events

Common Adverse Events: See results

Serious Adverse Events: 7.8% vs. 10.9% vs. 7.5% vs. 8.3%

Percentage that Discontinued due to Adverse Events: 6.0% vs. 8.4% vs. 10.8% vs. 2.5%

Study Author Conclusions

Among patients with type 2 diabetes and inadequate glycemic control despite treatment with insulin glargine, the addition of subcutaneous tirzepatide, compared with placebo, to titrated insulin glargine resulted in statistically significant improvements in glycemic control after 40 weeks.

InpharmD Researcher Critique

The results of the study are not generalizable to the patients using antihyperglycemic medications other than insulin glargine and/or metformin. Additionally, the insulin dose unadjusted during the first 4 weeks of treatment may have affected the results, favoring the patients receiving tirzepatide. 

Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial

Design

Multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 trial

N= 478 

Objective

To assess efficacy, safety, and tolerability of novel dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist tirzepatide monotherapy versus placebo in people with type 2 diabetes inadequately controlled by diet and exercise alone

Study Groups

Tirzepatide 5 mg (n= 121)

Tirzepatide 10 mg (n= 121)

Tirzepatide 15 mg (n= 121)

Placebo (n= 115)

Inclusion Criteria

Adult participants (≥ 18 years) with type 2 diabetes inadequately controlled with diet and exercise alone and who were naive to injectable diabetes therapy, had glycated hemoglobin (HbA1c) of 7.0% or more to 9.5% or less, body-mass index ≥ 23 kg/m² and stable weight (no change outside of 5%) during the previous 3 months, agreement to not initiate a new diet or exercise program during the study

Exclusion Criteria

Type 1 diabetes, history of pancreatitis, history of proliferative diabetic retinopathy, diabetic maculopathy, or nonproliferative diabetic retinopathy that requires acute treatment, estimated glomerular filtration rate < 30 mL/min/1.73 m², use of any oral antihyperglycemic medication for 3 months before screening

Methods

Participants were randomized (1:1:1:1) to receive once-weekly tirzepatide (5 mg, 10 mg, or 15 mg) or volume matching placebo in a single dose pen injection. After a screening and lead-in period, participants then received subcutaneous injections of tirzepatide, followed by a safety follow-up period. Patients started at 2.5 mg injections and were tapered up by 2.5 mg every 4 weeks until they reached their assigned maintenance dose. 

Vital signs were assessed with the patients in a fasting state, with the exception of the first visit, and taken prior to obtaining an electrocardiogram tracing and before blood sample collections at each visit, when required. Initiation of new antihyperglycemic medications was allowed if persistent hyperglycemia occurred, patients required permanent discontinuation of study drug, but remained in the study, or patients needed additional glycemic control during the safety follow-up period.

Duration

Enrollment: June 3, 2019 to October 28, 2020

Screening or lead-in period: 3 weeks

Treatment period: 40 weeks

Safety follow-up: 4 weeks

Outcome Measures

Primary: mean change from baseline in HbA1c at 40 weeks

Secondary: mean change from baseline in fasting serum glucose; proportion of participants with HbA1c target values < 7.0% and < 5.7%; mean change from baseline in bodyweight; proportion of participants with an HbA1c target ≤ 6.5%; proportion of patients reaching HbA1c ≥ 5%, ≥ 10%, and ≥ 15% weight loss

Baseline Characteristics

Tirzepatide 5 mg (n= 121)

Tirzepatide 10 mg (n= 121)

Tirzepatide 15 mg (n= 121)

Age, years

Female

65 (54%)

49 (40%)

58 (48%)

59 (51%)

Race/Ethnicity

White

Asian

Black

White

Hispanic or Latino

31 (26%)

45 (37%)

7 (6%)

38 (31%)

50 (41%)

31 (26%)

43 (36%)

4 (3%)

43 (36%)

54 (45%)

30 (25%)

42 (35%)

6 (5%)

43 (36%)

55 (45%)

26 (23%)

38 (33%)

5 (4%)

46 (40%)

48 (42%)

HbA1c concentration, %

≤ 8.5%

> 8.5%

7.97 ± 0.84

95 (79%)

26 (21%)

7.90 ± 0.78

98 (81%)

23 (19%)

7.85 ± 1.02

98 (81%)

23 (19%)

8.05 ± 0.80

87 (76%)

28 (24%)

Fasting serum glucose concentration, mg/dL

153.7 ± 37.3

152.6 ± 41.7

153.3 ± 40.4

154.8 ± 40.3

Body-mass index, kg/m²

32.2 ± 7.0

32.2 ± 7.6

31.5 ± 5.5

31.7 ± 6.1

Weight, kg

Vitals

SBP, mm Hg

DBP, mm Hg

HR, beats/min

128.2 ± 15.7

79.9 ± 9.0

72.7 ± 9.3

127.8 ± 12.6

78.7 ± 8.2

73.0 ± 9.8

126.8 ± 13.8

79.2 ± 8.8

74.3 ± 8.3

127.8 ± 14.1

79.7 ± 9.3

74.9 ± 10.0

Previous oral antihyperglycemic use

55 (45%)

53 (44%)

56 (46%)

55 (48%)

SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate

Results

Endpoint

Tirzepatide 5 mg (n= 121)

Tirzepatide 10 m (n= 121)

Tirzepatide 15 mg (n= 121)

HbA1c, %

Baseline

Change from baseline

Versus placebo

7.97 ± 0.08

-1.87 ± 0.09

-1.91 (-2.18 to -1.63)

-

< 0.0001

< 0.0001

7.88 ± 0.08

-1.89 ± 0.10

-1.93 (-2.21 to -1.65)

-

< 0.0001

< 0.0001

7.88 ± 0.08

-2.07 ± 0.10

-2.11 (-2.39 to -1.83)

-

< 0.0001

< 0.0001

8.08 ± 0.08

0.04 ± 0.11

-

-

0.72

-

Weight, kg

Baseline

Change from baseline

Versus placebo

87.0 ± 1.8

-7.0 ± 0.5

-6.3 (-7.8 to -4.7)

-

< 0.0001

< 0.0001

85.7 ± 1.8

-7.8 ± 0.5

-7.1 (-8.6 to -5.5)

-

< 0.0001

< 0.0001

85.9 ± 1.8

-9.5 ± 0.5

-8.8 (-10.3 to -7.2)

-

< 0.0001

< 0.0001

84.4 ± 1.9

-0.7 ± 0.6

-

-

0.22

-

Patients reaching HbA1c < 7.0%

Versus placebo

105 (87%)

49.0 (21.1 to 113.7)

-

< 0.0001

108 (92%)

80.4 (31.8 to 203.2)

-

< 0.0001

102 (88%)

52.9 (22.3 to 125.7)

-

< 0.0001

22 (19%)

-

-

-

Fasting serum glucose, mg/dL

Baseline

Change from baseline

Versus placebo

153.7 ± 3.7

-43.6 ± 3.4

-56.5 (-66.8 to -46.1)

-

< 0.0001

< 0.0001

152.6 ± 3.7

-45.9 ± 3.5

-58.8 (-69.2 to -48.4)

-

< 0.0001

< 0.0001

154.6 ± 3.7

-49.3 ± 3.6

-62.1 (-72.7 to -51.5)

-

< 0.0001

< 0.0001

155.2 ± 3.8

12.9 ± 4.0

-

-

0.0014

-

Patients reaching HbA1c < 5.7%

Versus placebo 

41 (34%)

40.3 (7.7 to 209.7)

-

< 0.0001

36 (31%)

34.1 (6.5 to 178.2)

-

< 0.0001

60 (52%)

85.1 (16.4 to 443.1)

-

< 0.0001

1 (1%)

-

-

-

Patients reaching HbA1c ≤ 6.5%

Versus placebo 

99 (82%)

74.8 (30.6 to 183.0)

-

< 0.0001

96 (81%)

69.1 (28.5 to 167.6)

-

< 0.0001

100 (86%)

105.8 (41.3 to 271.4)

-

< 0.0001

11 (10%)

-

-

-

Patients with ≥ 5% weight loss

Versus placebo 

81 (67%)

12.4 (6.4 to 23.9)

-

< 0.0001

92 (78%)

21.1 (10.6 to 42.2)

-

< 0.0001

89 (77%)

20.1 (10.1 to 40.0)

-

< 0.0001

16 (14%)

-

-

-

Patients with ≥ 10% weight loss

Versus placebo 

37 (31%)

34.9 (6.8 to 180.5)

-

< 0.0001

47 (40%)

50.6 (9.8 to 260.4)

-

< 0.0001

55 (47%)

71.5 (13.9 to 368.4)

-

< 0.0001

1 (1%)

-

-

-

Patients with ≥ 15% weight loss

Versus placebo 

16 (13%)

35.6 (2.2 to 565.3)

-

0.011

20 (17%)

46.5 (3.0 to 733.2)

-

0.0063

31 (27%)

83.6 (5.4 to > 999.0)

-

0.0016

0

-

-

-

*Baseline and change from baseline at 40 weeks data are least squares mean (standard error) and treatment differences are LSM (95% confidence interval [CI]), except for HbA1c targets and weight loss of 5% or more, 10% or more, or 15% or more versus placebo, which are n (%) or odds ratio (95% CI).

Adverse Events

Common Adverse Events: nausea (12% vs. 13% vs. 18% vs. 6%), diarrhea (12% vs. 14% vs. 12% vs. 8%), hyperglycemia (3% vs. 4% vs. 2% vs. 27%), nasopharyngitis (6% vs. 7% vs. 7% vs. 9%), dyspepsia (9% vs. 7% vs. 6% vs. 3%)), decreased appetite (4% vs. 7% vs. 8% vs. 1%), hypoglycemia (< 70 mg/dL; 6% vs. 7% vs. 7% vs. 1%)

Serious Adverse Events: 4% vs. 2% vs. 1% vs. 3%

Percentage that Discontinued due to Adverse Events: gastrointestinal disorder (2% vs. 5% vs. 7% vs. 1%), diarrhea (0 vs. 2% vs. 2% vs. 0), nausea (0 vs. 2% vs. 1% vs. 0), abdominal discomfort (0 vs. 0 vs. 2% vs. 0)

Study Author Conclusions

Tirzepatide once a week, a novel dual GIP and GLP-1 receptor agonist, at doses of 5, 10, and 15 mg as monotherapy for type 2 diabetes, showed robust reductions compared with placebo in glycemic control with 31–52% of participants reaching normoglycemia (HbA1c < 5.7% [< 39 mmol/mol]), and meaningful reductions in bodyweight, without increased risk of clinically significant (< 54 mg/dL [< 3 mmol/L]) or severe hypoglycemia, and a safety profile consistent with GLP-1 receptor agonists, indicating a potential use of tirzepatide as an option for type 2 diabetes treatment.

InpharmD Researcher Critique

This study lasted for 40 weeks, which is relatively a short duration in terms of weight loss; a longer study duration would be ideal to examine the full weight loss effects of using tirzepatide. The gastrointestinal adverse events were self-reported by the patients, therefore, side effects could be the result of other factors.