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)
Albiglutide 30 mg weekly -0.7% -16 N/A N/A
Albiglutide 50 mg weekly -0.9% -25 N/A N/A
Dulaglutide 0.75 mg weekly -0.7% -26 -0.9% -30
Dulaglutide 1.5 mg weekly -0.8% -29 -1.1% -41
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
Albiglutide 30 mg once weekly for 52 weeks 0.88 lbs (0.4 kg)
Albiglutide 50 mg once weekly for 52 weeks 1.98 lbs (0.9 kg)
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)
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)




HARMONY Trial - Albiglutide vs Placebo for Secondary Prevention of CVD, Lancet (2018) [PubMed abstract]
  • The HARMONY trial enrolled 9463 diabetics with a history of CVD
Main inclusion criteria
  • Type 2 diabetes
  • HgA1C > 7%
  • One of the following: documented CAD, previous stroke, documented carotid artery disease, or documented PAD
Main exclusion criteria
  • GFR < 30 ml/min
  • Personal history of pancreatitis or risk factors
  • Current use of GLP-1 analog
Baseline characteristics
  • Average age 64 years
  • Average duration of diabetes - 14 years
  • Average HgA1C - 8.7%
  • Average BMI - 32
  • Average BP - 135/77
  • Qualifying condition: CAD - 70%, Stroke - 17%, PAD - 25%
  • Receiving statin - 84%
  • Receiving insulin - 59%
Randomized treatment groups
  • Group 1 (4731 patients) - Albiglutide 30 - 50 mg once weekly
  • Group 2 (4732 patients) - Placebo once weekly
  • Patients were treated to a glycemic goals based on local guidelines
  • All other diabetes medications were allowed except GLP-1 analogs
Primary outcome: Composite of death from cardiovascular causes, myocardial infarction, or stroke
Results

Duration: Median of 1.6 years
Outcome Albiglutide Placebo Comparisons
Primary outcome 7% 9% HR 0.78, 95%CI [0.68 - 0.90], p=0.0006
Myocardial infarction 4% 5% HR 0.75, 95%CI [0.61 - 0.90], p=0.003
Stroke 2% 2% HR 0.86, 95%CI [0.66 - 1.14], p=0.30
Overall mortality 4% 4% HR 0.95, 95%CI [0.79 - 1.16], p=0.644
Pancreatitis <1% <1% HR 1.43, 95%CI [0.54 - 3.75]
Pancreatic cancer <1% <1% HR 1.20, 95%CI [0.37 - 3.93]
Medullary thyroid carcinoma 0 cases 0 cases N/A
  • HgA1C values were significantly lower in Group 1 throughout the trial. At 8 months, the average difference was 0.63%, and at 16 months, it was 0.52%.
  • Weight loss was significantly greater in Group 1 than in Group 2. At 16 months, the mean difference was 1.8 lbs (0.83 kg)

Findings: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes.
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 Group 1 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 Group 1 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 Group 1 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
Summary
  • Albiglutide, dulaglutide, liraglutide, and Ozempic all were superior to placebo for their respective composite CVD outcomes while exenatide and Rybelsus were not. Dulaglutide and liraglutide were also superior to placebo for preventing progression to macroalbuminuria.
  • In all of the trials, the GLP-1 analog-treated groups achieved significantly lower HgA1C values than the placebo groups. The difference in most of the trials was around 0.50% with an absolute risk reduction in the primary outcome of < 2%. In the Ozempic trial, the A1C difference was > 1% and the absolute risk reduction was 2.3%. The differences in A1C values between treatment groups and placebo groups likely accounted for much of the observed effect.






  • 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


Gastrointestinal (GI) side effects
Overview
  • Gastrointestinal side effects are the most common side effects with GLP-1 analogs
  • In trials, up to 48% of patients have experienced some type of GI side effect
  • To minimize the effects, starting doses should be low and increased gradually

  • 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%

Low blood sugar (hypoglycemia)

Injection site reactions

Hypersensitivity reactions

GLP-1 analog antibodies
Overview
  • GLP-1 analogs have the potential to induce an immune response
  • The immune response can lead to the production of antibodies against the GLP-1 analog
Albiglutide (Tanzeum™)
  • In a 30-week trial, albiglutide induced anti-albiglutide antibodies in 5.5% of subjects
  • Anti-albiglutide antibodies were not associated with reduced efficacy [14]
Dulaglutide (Trulicity™)
  • In dulaglutide trials, 1.6% of patients developed anti-drug antibodies to the active ingredient in dulaglutide
  • Of these patients, about half developed dulaglutide-neutralizing antibodies, and half developed antibodies against native GLP-1 [16]
Exenatide (Byetta®, Bydureon®)
  • In a 30-week trial, a small amount of antibody to exenatide developed in 38% of patients. A large amount of antibody to exenatide developed in 6% of patients - half the patients with a large amount of antibody (3% of total patients) had a decreased response to exenatide [1]
Liraglutide (Victoza®)
  • In a 26-week trial, antibody to liraglutide developed in 9.8% of patients. Antibodies did not appear to affect the response to liraglutide [6]
  • In other trials, liraglutide antibodies have been found to cross-react with endogenous GLP-1 [2]
Lixisenatide (Adlyxin®)
  • In 9 trials, antibody to lixisenatide developed in 70% of patients
  • A higher incidence of allergic reactions and injection site reactions occurred in antibody positive patients
  • In a subset of patients (2.4%) with the highest antibody titers, a reduced effect on blood sugars was seen
  • Antibody characterization studies have demonstrated the potential for the development of antibodies that cross-react with endogenous GLP-1 and glucagon [21]
Semaglutide (Ozempic®)
  • In trials, 1% (32 patients) of semaglutide-treated patients developed anti-semaglutide antibodies. Of the 32 patients that developed antibodies, 19 patients (0.6% of the overall population) developed antibodies cross-reacting with native GLP-1.
  • The effect of cross-reacting antibodies on efficacy and hypersensitivity reactions is unknown
Semaglutide (Rybelsus®)
  • In Rybelsus trials, 0.5% of Rybelsus-treated patients developed anti-semaglutide antibodies. Of these patients, 50% had antibodies that cross-reacted with endogenous GLP-1.
  • The effect of cross-reacting antibodies on efficacy and hypersensitivity reactions is unknown
Summary
  • It is not uncommon for biologic medications to induce antibodies
  • The overall significance of this effect with GLP-1 analogs is not well-defined
  • Based on current information, some patients may experience a decrease in glycemic control if they develop GLP-1 antibodies. Antibodies may also increase the risk of hypersensitivity reactions.
  • GLP-1 analog antibodies also have the potential to cross-react with endogenous GLP-1

Pancreatitis
Overview
  • Pancreatitis is a painful condition where the pancreas becomes inflamed. Severe pancreatitis can be life-threatening.
  • After exenatide was released, the FDA began to receive case reports of pancreatitis in patients taking exenatide
  • After reviewing a large amount of data from clinical trials, observational studies, and animal studies, the FDA published a paper in 2014 that stated there was no definitive link between GLP-1 analogs and an increased risk of pancreatitis
  • The paper went on to state that the FDA will continue to monitor studies for a possible link [13]
Clinical trials
  • In the CVD trials detailed above (see clinical outcomes), the risk of pancreatitis was not significantly greater in the GLP-1 analog-treated patients when compared to placebo-treated patients
Manufacturer recommendations
  • The prescribing information for GLP-1 analogs state the following:
    • Patients prescribed GLP-1 analogs should be monitored for signs of pancreatitis (severe abdominal pain that may or may not radiate to the back, nausea, vomiting)
    • If patients develop pancreatitis while taking GLP-1 analogs, the drugs should be stopped and should not be restarted
    • GLP-1 analogs should be prescribed with caution in patients with a history of pancreatitis, and other diabetes medications should be considered [1,2,14]
Summary
  • The FDA has reviewed a large amount of information regarding GLP-1 analogs and pancreatitis, and no definitive link has been found
  • It is unlikely that GLP-1 analogs increase the risk of pancreatitis

Decreased kidney function

Gallbladder disease
Overview
  • In some trials, patients receiving GLP-1 analogs have had a higher incidence of gallbladder disease than placebo-treated patients. In the LEADER trial, the incidence of acute gallstone disease was higher in liraglutide-treated patients than in placebo-treated patients (Liraglutide - 3.1%, Placebo - 1.9% (p<0.001). In Saxenda® trials, higher incidences of gallbladder disease have also been observed in liraglutide-treated patients.
  • In semaglutide trials, cholelithiasis was reported in 1.5% and 0.4% of patients treated with Ozempic 0.5 mg and 1 mg, respectively. In Rybelsus trials, 1% of patients treated with Rybelsus 7 mg developed cholelithiasis. Cholelithiasis was not observed in placebo-treated patients.
STUDY
Association of Bile Duct and Gallbladder Diseases With the Use of Incretin-Based Drugs in Patients with Type 2 Diabetes, JAMA intern med (2016) [PubMed abstract]
  • A cohort study (N=71,369) compared the risk of bile duct and gallbladder disease among type 2 diabetics who were using DPP-4 inhibitors and/or GLP-1 analogs to diabetics who were not using these drugs
  • During 227,994 person-years of follow-up, the following was seen
    • Current use of DPP-4 inhibitors was not associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral antidiabetic drugs (3.6 vs 3.3 per 1000 person-years; adjusted HR, 0.99; 95%CI [0.75-1.32])
    • Current use of GLP-1 analogues was associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral antidiabetic drugs (6.1 vs 3.3 per 1000 person-years; adjusted HR, 1.79; 95%CI [1.21-2.67])
    • GLP-1 analogues were also associated with an increased risk of cholecystectomy (adjusted HR, 2.08; 95% CI, 1.08-4.02)
Summary
  • GLP-1 analogs may cause a slight increase in the risk of gallbladder disease. It's unclear if the effect is drug-related or secondary to weight loss which is also a risk factor for gallstone formation. [19,20]

Thyroid cancer
Overview
  • In toxicology studies, an increased incidence of malignant and benign thyroid medullary tumors has been observed in rats and mice receiving GLP-1 analogs
  • This prompted the FDA to place a boxed warning on semaglutide, exenatide, liraglutide, albiglutide, and dulaglutide about the potential risk of medullary thyroid cancer with GLP-1 analog use in humans
  • The FDA is requiring the manufacturer of liraglutide to conduct a 5-year epidemiological study using healthcare databases to compare trends in thyroid cancers between patients prescribed liraglutide and patients prescribed other diabetes medications
  • GLP-1 analogs (except lixisenatide) are also contraindicated in patients with a history of multiple endocrine neoplasia 2 (a condition that increases the risk for medullary thyroid cancer)
Clinical trials
  • In the CVD trials detailed above (see clinical outcomes), the risk of thyroid cancer was not significantly greater in the GLP-1 analog-treated patients when compared to placebo-treated patients
Summary
  • It is unclear if GLP-1 analogs increase the risk for thyroid cancer
  • If an increased risk does exist, it is likely very small

Pancreatic cancer
Overview
  • Because GLP-1 analogs stimulate the pancreas, theoretical concerns about an increased risk of pancreatic cancer have been raised
FDA review
  • In March 2013, the FDA released a warning about the possible association of GLP-1 analogs and DPP-4 inhibitors with pancreatic duct metaplasia and pancreatitis
  • In 2014, the FDA published a paper stating that after having reviewed a large amount of data from clinical trials, observational studies, and animal studies, they found no definitive link between pancreatic cancer and GLP-1 analogs
  • The paper went on to say that the FDA will continue to monitor studies for a possible link [13]
STUDY
Incretin based drugs and the risk of pancreatic cancer, nested case-control study, BMJ (2016) [PubMed abstract]
  • A nested case-control study compared the risk of pancreatic cancer among patients exposed to incretin mimetics (GLP-1 analogs and DPP-4 inhibitors) and those exposed to sulfonylureas. The study included 639 cases of pancreatic cancer who were matched with 8651 controls.
  • The study found no increased risk of pancreatic cancer among patients exposed to incretin mimetics (GLP-1 analogs and DPP-4 inhibitors) when compared to those exposed to sulfonylureas (adjusted HR 1.02, 95%CI [0.84 - 1.23])
  • For DPP-4 inhibitors alone, no increased risk was found (adjusted HR 1.02, 95%CI [0.84 - 1.24])
  • For GLP-1 analogs alone, no increased risk was found (adjusted HR 1.13, 95%CI [0.38 - 3.38])
  • No association of risk with length of use was observed
Clinical trials
  • In the CVD trials detailed above (see clinical outcomes), the risk of pancreatic cancer was not significantly greater in the GLP-1 analog-treated patients when compared to placebo-treated patients
Summary
  • There is no clear evidence that GLP-1 analogs increase the risk of pancreatic cancer. If a risk exists, it is likely very small.

Diabetic retinopathy (semaglutide)

Pancreatic enzyme elevations (semaglutide)






Kidney disease
Albiglutide (Tanzeum™)
  • CrCl ≥ 15 ml/min: No dose adjustment necessary
  • GI side effects may increase in patients with decreased kidney function. Use caution. [14]
Dulaglutide (Trulicity™)
  • No dose adjustment is recommended in patients with renal impairment including end-stage renal disease
  • Gastrointestinal side effects may be worse in patients with kidney disease [16]
Exenatide (Byetta®)
  • CrCl > 50 ml/min: No dosage adjustment necessary
  • CrCl 30 - 50 ml/min: Starting dose 5 mcg twice a day. Caution should be used if increasing to 10 mcg.
  • CrCl < 30 ml/min: DO NOT USE [1]
Exenatide (Bydureon®)
  • CrCl > 50 ml/min: No dosage adjustment necessary
  • CrCl 30 - 50 ml/min: Use caution
  • CrCl < 30 ml/min: DO NOT USE [15]
Liraglutide (Victoza®)
  • No dose adjustment is recommended in patients with renal impairment
  • Use caution in patients with dehydration [2]
Lixisenatide (Adlyxin®)
  • CrCl ≥ 60 ml/min: No dosage adjustment necessary
  • CrCl 30 - 60 ml/min: No dose adjustment recommended. Monitor for increased GI and renal side effects.
  • CrCl 15 - 30 ml/min: Very limited data. No dose adjustment recommended. Monitor for increased GI and renal side effects.
  • CrCl < 15 ml/min: DO NOT USE
Semaglutide (Ozempic®)
  • No dose adjustment is necessary for any degree of renal impairment [22]
Semaglutide (Rybelsus®)
  • No dose adjustment is necessary for any degree of renal impairment [24]

Liver disease
Albiglutide (Tanzeum™)
  • The prescribing information states that liver disease is not expected to affect the elimination of albiglutide, although no studies have evaluated this specifically [14]
Dulaglutide (Trulicity™)
  • Dulaglutide systemic exposure decreased by 23, 33 and 21% for mild, moderate and severe hepatic impairment groups, respectively, compared to subjects with normal hepatic function
  • No dose adjustment is necessary. Has not been studied extensively in liver disease [16]
Exenatide (Byetta®)
  • The manufacturer states that no studies have been performed on patients with significant liver disease
  • Because exenatide is cleared primarily by the kidneys, liver disease is not expected to affect its clearance [1]
Exenatide (Bydureon®)
  • The manufacturer states that no studies have been performed on patients with significant liver disease
  • Because exenatide is cleared primarily by the kidneys, liver disease is not expected to affect its clearance [15]
Liraglutide (Victoza®)
  • The prescribing information states that liraglutide should be used with caution in patients with liver disease
  • The manufacturer does not recommend adjusting the dose in liver disease [2]
Lixisenatide (Adlyxin®)
  • Has not been studied
  • Hepatic dysfunction is not expected to affect the pharmacokinetics of lixisenatide [21]
Semaglutide (Ozempic®)
  • No dose adjustment is necessary for any degree of hepatic impairment [22]
Semaglutide (Rybelsus®)
  • No dose adjustment is necessary for any degree of hepatic impairment [24]

Stomach disorders



All GLP-1 analogs


Exenatide (Byetta®)

  • Oral contraceptives - Exenatide can affect the absorption of oral contraceptive pills (see gastric emptying below). Oral contraceptives should be taken at least one hour before exenatide is injected. [1]

Lixisenatide (Adlyxin®)

  • Oral contraceptives - Lixisenatide can affect the absorption of oral contraceptives. Oral contraceptives should be taken at least 1 hour before lixisenatide administration or at least 11 hours after the last dose of lixisenatide. [21]

Gastric emptying
Overview
  • When a person consumes food or medications, they are partially digested in the stomach
  • The stomach then "empties" food and medications into the small intestine
  • GLP-1 analogs slow the process of stomach emptying
  • Since most medications are absorbed in the small intestine, slowing of stomach emptying by GLP-1 analogs may affect the absorption of some medications
  • In many cases, the overall effect on the drug's therapeutic effect is not significant
  • The large number of possible interaction has not been studied extensively
  • The effect of the medications listed below may be altered by decreased gastric emptying caused by GLP-1 analogs
Antibiotics
  • Antibiotics require rapid absorption to achieve their desired therapeutic effect
  • GLP-1 analogs may alter their absorption
  • Antibiotics should be taken at least 1 hour before GLP-1 analogs
Drugs with a narrow therapeutic index
  • Drugs with narrow therapeutic index may be affected by GLP-1 analogs
  • Taking these drugs at least 1 hour before GLP-1 analogs may help prevent an interaction

Metabolism and clearance