GLP-1 ANALOGS


















  • All values are expressed as average change from baseline. FBS (fasting blood sugar) expressed as mg/dl.
  • Studies are from the manufacturer's package insert and ranged in length from 12 - 104 weeks
  • Baseline A1C ∼ 8% in all studies
  • Reference [1,2,14,15,16,21,22,24]
Effects of GLP-1 analogs on blood sugars in trials lasting ≥ 12 weeks
Drug A1C
(monotherapy)
FBS
(monotherapy)
A1C
(added to metformin)
FBS
(added to metformin)
Dulaglutide 0.75 mg weekly -0.7% -26 -0.9% -30
Dulaglutide 1.5 mg weekly -0.8% -29 -1.1% -41
Dulaglutide 3 mg weekly N/A N/A -1.6% -46
Dulaglutide 4.5 mg weekly N/A N/A -1.8% -51
Exenatide (Byetta) 5 mcg twice daily -0.7% -17 -0.5% -5
Exenatide (Byetta) 10 mcg twice daily -0.9% -19 -0.9% -10
Exenatide (Bydureon) 2 mg weekly -1.6% -41 -1.5% -32
Liraglutide 1.2 mg once daily -0.8% -15 -1.0% -30
Liraglutide 1.8 mg once daily -1.1% -26 -1.0% -30
Lixisenatide 20 mcg once daily -0.83% -16 -0.72% -17
Semaglutide (Ozempic) 0.5 mg once weekly -1.4% -41 N/A N/A
Semaglutide (Ozempic) 1 mg once weekly -1.6% -44 N/A N/A
Semaglutide (Rybelsus) 7 mg once daily -1.2% -28 -1.0% -21
Semaglutide (Rybelsus) 14 mg once daily -1.4% -33 -1.3% -31

  • All values are expressed as average change from baseline
  • Average baseline weight was around 200 lbs in all trials
  • Reference [1,2,14,15,16,21,22]
Effects of GLP-1 analogs on body weight in controlled trials
Drug Weight loss
Dulaglutide 0.75 mg once weekly for 26 weeks 3 lbs (1.4 kg)
Dulaglutide 1.5 mg once weekly for 26 weeks 5 lbs (2.3 kg)
Dulaglutide 3 mg once weekly for 36 weeks 8.36 lbs (3.8 kg)
Dulaglutide 4.5 mg once weekly for 36 weeks 10.12 lbs (4.6 kg)
Exenatide (Byetta) 5 mcg twice daily for 24 weeks 5.94 lbs (2.7 kg)
Exenatide (Byetta) 10 mcg twice daily for 24 weeks 6.38 lbs (2.9 kg)
Exenatide (Bydureon) 2 mg once weekly for 24 weeks 4.4 lbs (2 kg)
Liraglutide 1.2 mg once daily for 52 weeks 4.6 lbs (2.1 kg)
Liraglutide 1.8 mg once daily for 52 weeks 5.5 lbs (2.5 kg)
Lixisenatide 20 mcg once daily for 12 weeks 4.3 lbs (1.94 kg)
Semaglutide (Ozempic) 0.5 mg once weekly for 30 weeks 8.36 lbs (3.8 kg)
Semaglutide (Ozempic) 1 mg once weekly for 30 weeks 10.34 lbs (4.7 kg)
Semaglutide (Rybelsus) 7 mg once daily for 26 weeks 5.06 lbs (2.3 kg)
Semaglutide (Rybelsus) 14 mg once daily for 26 weeks 8.14 lbs (3.7 kg)




REWIND trial - Dulaglutide vs Placebo for Prevention of CVD, Lancet (2019) [PubMed abstract]
  • The REWIND trial enrolled 9901 diabetics with either documented CVD or risk factors for CVD
Main inclusion criteria
  • Age ≥ 50 years
  • Type 2 diabetes
  • HgA1C ≤ 9.5%
  • Documented CVD or at high risk for CVD
Main exclusion criteria
  • GFR < 15 ml/min
  • Severe hypoglycemia within last year
  • CVD event within 2 months
Baseline characteristics
  • Average age 66 years
  • Average BMI - 32
  • Average HgA1C - 7.3%
  • Documented CVD - 31%
  • Average GFR - 75 ml/min
  • Taking statin - 66%
  • Taking antiplatelet - 54%
Randomized treatment groups
  • Group 1 (4949 patients): Dulaglutide 1.5 mg once weekly
  • Group 2 (4952 patients): Placebo once weekly
  • Investigators were advised to promote a healthy lifestyle and to manage glucose concentrations according to local guidelines and were free to add any glucose-lowering drug apart from another GLP-1 receptor agonist or pramlintide
Primary outcome: First occurrence of any component of the composite outcome, which comprised non-fatal myocardial infarction, non-fatal stroke, and death from cardiovascular causes or unknown causes
Results

Duration: Median of 5.4 years
Outcome Dulaglutide Placebo Comparisons
Primary outcome 12% 13.4% p=0.026
Overall mortality 10.8% 12% p=0.067
Myocardial infarction 4.5% 4.7% p=0.63
Stroke 3.2% 4.1% p=0.010
Adverse GI event 47.4% 34.1% p<0.0001
Acute pancreatitis 0.5% 0.3% p=0.11
Pancreatic cancer 0.4% 0.2% p=0.22
Thyroid cancer or hyperplasia 8 cases 3 cases N/A
  • The average HgA1C was 0.61% lower in the dulaglutide group during follow-up
  • The average body weight was 3.2 lbs lower in the dulaglutide group during follow-up

Findings: Dulaglutide could be considered for the management of glycemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors.
REWIND trial - Secondary analysis of renal outcomes, Lancet (2019) [PubMed abstract]
  • A secondary analysis of the REWIND trial (see above) looked at renal outcomes
Primary outcome: First occurrence of new macroalbuminuria (albumin-to-creatinine ratio > 300 mg/g), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy
Results

Duration: Median of 5.4 years
Outcome Dulaglutide Placebo Comparisons
Primary outcome 17.1% 19.6% p=0.0004
New macroalbuminuria 8.9% 11.3% p<0.0001
GFR decline ≥ 30% 9.2% 10.1% p=0.066
Chronic renal replacement 0.3% 0.4% p=0.39

Findings: Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes.
EXSCEL study - Exenatide (Bydureon) vs Placebo for CVD Prevention, NEJM (2017) [PubMed abstract]
  • The EXSCEL trial enrolled 14,752 diabetics with or without previous CVD
Main inclusion criteria
  • Type two diabetes
  • HgA1C 6.5 - 10%
  • Enrollment was designed so that 70% of patients would have history of CVD
Main exclusion criteria
  • History of ≥ 2 episodes of severe hypoglycemia
  • GFR < 30 ml/min
  • Previous treatment with GLP-1 analog
Baseline characteristics
  • Median age 62 years
  • Median duration of DM - 12 years
  • History of CVD event - 73%
  • Median A1C - 8%
  • Median BMI - 32
Randomized treatment groups
  • Group 1 (7356 patients) - Exenatide (Bydureon) 2 mg once weekly
  • Group 2 (7396 patients) - Placebo once weekly
  • The use of open-label glucose-lowering agents (including DPP-4 inhibitors but not including GLP-1 analogs) was encouraged to promote glycemic equipoise between the two trial groups
Primary outcome: First occurrence of any component of the composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (three-component MACE outcome), in a time-to event analysis
Results

Duration: Median of 3.2 years
Outcome Exenatide Placebo Comparisons
Primary outcome 11.4% 12.2% HR 0.91, 95% CI [0.83 - 1.0], p=0.06
Overall mortality 6.9% 7.9% HR 0.86, 95% CI [0.77 - 0.97]
Myocardial infarction 6.6% 6.7% HR 0.97, 95% CI [0.85 - 1.10]
Stroke 2.5% 2.9% HR 0.85, 95% CI [0.70 - 1.03]
Pancreatitis 0.4% 0.3% N/A
Pancreatic cancer 0.2% 0.2% N/A
Medullary thyroid carcinoma <0.1% <0.1% N/A
  • The average HgA1C was 0.53% (95%CI [0.57 to 0.50]) lower in the exenatide group during follow-up
  • The average body weight was 2.8 lbs lower in the exenatide group during follow-up
  • The average SBP was 1.57 mmHg lower in the exenatide group during follow-up

Findings: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo.
LEADER trial - Liraglutide vs Placebo for CVD Prevention, NEJM (2016) [PubMed abstract]
  • The LEADER trial enrolled 9340 diabetics with either documented CVD or risk factors for CVD
Main inclusion criteria
  • Type 2 diabetes
  • HgA1C ≥ 7%
  • Documented CVD or at high risk for CVD
Main exclusion criteria
  • Use of GLP-1 analog or DPP-4 inhibitor within 3 months
  • CVD event within 14 days
  • Planned revascularization
  • NYHA class IV heart failure
Baseline characteristics
  • Average age 64 years
  • Average duration of diabetes - 13 years
  • Average HgA1C - 8.7%
  • Average BMI - 33
  • History of CVD - 81%
  • Taking statin - 72%
Randomized treatment groups
  • Group 1 (4668 patients) - Liraglutide 1.8 mg once daily added to current therapy
  • Group 2 (4672 patients) - Placebo added to current therapy
  • Patients were treated to a target HgA1C ≤ 7% or a target deemed appropriate by their doctor
  • All other diabetes meds were allowed except nonstudy GLP-1 analogs, DPP-4 inhibitors, and pramlintide
Primary outcome: Composite of death from cardiovascular causes, nonfatal (including silent) myocardial infarction, or nonfatal stroke
Results

Duration: Median of 3.8 years
Outcome Liraglutide Placebo Comparisons
Primary outcome 13% 14.9% HR 0.87, 95% CI [0.78 - 0.97], p=0.01
Myocardial infarction 6.3% 7.3% HR 0.86, 95% CI [0.73 - 1.00], p=0.046
Stroke 3.7% 4.3% HR 0.86, 95% CI [0.71 - 1.06], p=0.16
Overall mortality 8.2% 9.6% HR 0.85, 95% CI [0.74 - 0.97], p=0.02
Nausea 1.6% 0.4% p<0.001
Vomiting 0.7% <0.1% p<0.001
Diarrhea 0.6% 0.1% p<0.001
Acute gallstone disease 3.1% 1.9% p<0.001
Acute pancreatitis 0.4% 0.5% p=0.44
Pancreatic carcinoma 0.3% 0.1% p=0.06
Medullary thyroid carcinoma 0 cases 1 case p=0.32
  • HgA1C values were significantly lower in the liraglutide group throughout the trial. At 3 months, the difference was ∼ 1%. At 36 months, the average difference was 0.40% (95% CI [0.45 - 0.34]).
  • Weight loss was significantly greater in the liraglutide group throughout the trial. At 36 months, the difference in weight loss was 2.3 kg (95%CI [2.5 - 2.0]).
  • SBP was significantly lower in the liraglutide group throughout the trial. At 36 months, the difference in SBP was 1.2 mmHg (95%CI [1.9 - 0.5]).

Findings: In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo.
LEADER Trial - Secondary Analysis of Renal Outcomes NEJM (2017) [PubMed abstract]
  • A prespecified secondary analysis of the LEADER trial (see above) looked at renal outcomes
Primary outcome: Composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease
Results

Duration: Median of 3.8 years
Outcome Liraglutide Placebo Comparisons
Primary outcome 15% 19% HR 0.78, 95%CI [0.67 - 0.92], p=0.003
New-onset persistent macroalbuminuria 9% 12.1% HR 0.74, 95%CI [0.60 - 0.91], p=0.004
Persistent doubling of serum creatinine level 4.9% 5.5% HR 0.89, 95%CI [0.67 - 1.19], p=0.43
Renal-replacement therapy 3.1% 3.6% HR 0.87, 95%CI [0.61 - 1.24], p=0.44
Death due to renal disease 0.4% 0.3% HR 1.59, 95%CI [0.52 - 4.87], p=0.41

Findings: This prespecified secondary analysis shows that, when added to usual care, liraglutide resulted in lower rates of the development and progression of diabetic kidney disease than placebo.
SUSTAIN-6 trial - Semaglutide (Ozempic) vs Placebo for Prevention of CVD [PubMed abstract]
  • The SUSTAIN-6 trial enrolled 3297 patients who had type 2 diabetes and were at high risk for CVD events
Main inclusion criteria
  • Type 2 diabetes
  • HgA1C ≥ 7%
  • Age ≥ 50 years with established CVD, heart failure (NYHA II or III), or CrCl < 60 ml/min; or age ≥ 60 years with ≥ 1 CVD risk factor
Main exclusion criteria
  • DPP-4 inhibitor within 30 days
  • GLP-1 analog within 90 days
  • Insulin other than basal or premixed within 90 days
  • CVD event within 90 days
Baseline characteristics
  • Average age 65 years
  • Average A1C - 8.7%
  • Average weight - 202 lbs
  • CAD - 60% | MI - 33% | Heart failure - 24% | Stroke - 15%
Randomized treatment groups
  • Group 1 (1648 patients): Ozempic 0.5 - 1 mg SQ once weekly
  • Group 2 (1649 patients): Placebo
  • All subjects went through a titration phase of 0.25 mg for 4 weeks followed by 0.5 mg for 4 weeks. After that, patients were randomized to 0.5 mg or 1 mg. No dose adjustment of study drugs was allowed during the trial.
  • Patients were treated according to local guidelines and other diabetic medications besides GLP-1 analogs and DPP-4 inhibitors were allowed
Primary outcome: Composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction (including silent), or nonfatal stroke
Results

Duration: 104 weeks
Outcome Ozempic Placebo Comparisons
Average decrease in A1C at 104 weeks 1.1% (0.5 mg) | 1.4% (1 mg) 0.4% p<0.001
Primary outcome 6.6% 8.9% p=0.02
Overall mortality 3.8% 3.6% p=0.79
Death from CVD 2.7% 2.8% p=0.92
Nonfatal myocardial infarction 2.9% 3.9% p=0.12
Nonfatal stroke 1.6% 2.7% p=0.04
Retinopathy complications 3.0% 1.8% p=0.02
Acute pancreatitis 9 cases 12 cases N/A
Pancreatic cancer 1 cases 4 cases N/A
Gallbladder disease 58 cases 61 cases N/A

Findings: In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide.
PIONEER-6 trial - Semaglutide (Rybelsus) vs Placebo for Prevention of CVD [PubMed abstract]
  • The PIONEER-6 trial enrolled 3183 patients who had type 2 diabetes and were at high risk for CVD events
Main inclusion criteria
  • Type 2 diabetes
  • Age ≥ 50 years with established CVD or chronic kidney disease; or age ≥ 60 years with ≥ 1 CVD risk factor
Main exclusion criteria
  • DPP-4 inhibitor within 90 days
  • GLP-1 analog within 90 days
  • NYHA class IV heart failure
  • CVD event within 60 days
  • CrCl < 30 ml/min
  • Treatment for retinopathy or maculopathy
Baseline characteristics
  • Average age 66 years
  • Average HgA1C - 8.2%
  • Average BMI - 32
  • MI - 36% | Stroke/TIA - 16% | History of revascularization - 47%
Randomized treatment groups
  • Group 1 (1591 patients): Semaglutide (Rybelsus) with a target dose of 14 mg once daily
  • Group 2 (1592 patients): Placebo
  • Study drugs were titrated to target dose to limit side effects
  • Study drugs were added to patient's current meds
Primary outcome: Time from randomization to the first occurrence of a major adverse cardiovascular event, a composite of death from cardiovascular causes (including undetermined causes of death), nonfatal myocardial infarction, or nonfatal stroke
Results

Duration: Median of 15.9 months
Outcome Rybelsus Placebo Comparisons
Average decrease in A1C at end of trial 1.0% 0.3% N/A
Primary outcome 3.8% 4.8% p=0.17
Overall mortality 1.4% 2.8% HR 0.51, 95%CI [0.31–0.84]
Death from CVD 0.9% 1.9% HR 0.49, 95%CI [0.27–0.92]
Nonfatal myocardial infarction 2.3% 1.9% HR 1.18, 95%CI [0.73–1.90]
Nonfatal stroke 0.8% 1.0% HR 0.74, 95%CI [0.35–1.57)
Retinopathy complications 7.1% 6.3% N/A
Acute pancreatitis 1 cases 3 cases N/A
Malignant neoplasms 2.6% 3% N/A
  • 82% of patients in the Rybelsus group who completed the trial were taking the 14 mg dose

Findings: In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo





  • p<0.001 for difference in both outcomes
  • All values are expressed as average change from baseline
  • Baseline average A1C ∼ 8.4%
  • Reference [15]
Bydureon® vs Byetta® for 24 weeks
Outcome Bydureon 2 mg weekly (N=129) Byetta 10 mcg twice daily (N=123)
HgA1C -1.6% -0.9%
FBS (mg/dl) -25 -5

  • p<0.0001 for difference in both outcomes
  • All values are expressed as average change from baseline
  • Baseline average A1C ∼ 8.2%
  • Reference [5]
Liraglutide (Lir) vs Byetta® for 26 weeks
Outcome Lir 1.8 mg once daily (N=233) Byetta 10 mcg twice daily (N=231)
A1C -1.12% -0.79%
FBS (mg/dl) -29 -11
Body weight (lbs) -7 -6.3

  • p=0.0175 for difference in HgA1C
  • All values are expressed as average change from baseline
  • Baseline average A1C ∼ 8.0%
  • Reference [21]
Lixisenatide (Lix) vs Byetta® added to metformin for 24 weeks
Outcome Lix 20 mcg once daily (N=318) Byetta 10 mg twice daily (N=316)
HgA1C -0.73% -0.90%
FBS (mg/dl) -20 -24

  • Difference in A1C change was statistically significant (diff 0.5, 95%CI [0.7 to 0.3])
  • All values are expressed as average change from baseline
  • Baseline average A1C - 8.3%
  • Reference [22]
Ozempic vs Bydureon for 56 weeks
Outcome Ozempic 1.0 mg once weekly (N=404) Bydureon 2.0 mg once weekly (N=405)
HgA1C -1.4% -0.9%
FBS (mg/dl) -44 -34

  • Semaglutide was significantly better for all outcomes
  • All values are expressed as average change from baseline
  • Reference [23]
Ozempic vs Dulaglutide for 40 weeks
Outcome Ozempic 0.5 mg once weekly (N=301)
Ozempic 1.0 mg once weekly (N=300)
Dulaglutide 0.75 mg once weekly (N=299)
Dulaglutide 1.5 mg once weekly (N=299)
HgA1C (%) -1.5%
-1.8%
-1.1%
-1.4%
Body weight (kg) -4.6 kg
-6.5 kg
-2.3 kg
-3.0 kg

  • All values are expressed as average change from baseline
  • Patients were taking metformin +/- an SGLT2 inhibitor at baseline
  • Reference [24]
Rybelsus vs Liraglutide for 26 weeks
Outcome Rybelsus 14 mg once daily (N=285) Liraglutide 1.8 once daily (N=284)
HgA1C (%) -1.2% -1.1%
FBS (mg/dl) -36 -34
Body weight -9.7 lbs -6.8 lbs



  • Reference [1,2,3,5,16,21,22]
Side effect Incidence
Nausea 12 - 40%
Diarrhea 8 - 15%
Vomiting 5 - 15%
Abdominal pain up to 8%