- ACRONYMS AND DEFINITIONS
- A1C - Hemoglobin A1C
- ADA - American Diabetes Association
- CAD - Coronary artery disease
- CrCl - Creatinine clearance
- CVD - Cardiovascular disease
- DM - Diabetes mellitus
- FBS - Fasting blood sugar
- GFR - Glomerular filtration rate
- GI - Gastrointestinal
- GLP-1 - Glucagon-like peptide-1
- PAD - Peripheral artery disease
- RCT - Randomized controlled trial
- SBP - Systolic blood pressure
- Thyroid C-cell tumor = Thyroid medullary tumor
- DRUGS IN CLASS
- GLP-1 analogs (injections)
- Dulaglutide (Trulicity®)
- Exenatide (Byetta®, Bydureon®, Bydureon BCise®)
- Liraglutide (Victoza®)
- Liraglutide (Saxenda®) - marketed as a weight loss drug
- Semaglutide (Ozempic®)
- Semaglutide (Wegovy®) - marketed as a weight loss drug
- GLP-1 analogs (oral)
- Semaglutide (Rybelsus®)
- Dual GLP-1/GIP agonist
- Combination products with insulin
- Soliqua® (lixisenatide + insulin glargine)
- Xultophy® (liraglutide + insulin degludec)
- MECHANISM OF ACTION
- GLP-1 analogs
- Glucagon-like peptide-1 (GLP-1) is a hormone secreted into the bloodstream by special cells in the intestine in response to food consumption. GLP-1 has the following actions: (1) slows gastric emptying; (2) stimulates insulin release and suppresses glucagon secretion in the pancreas; (3) suppresses appetite in the brain. An enzyme called dipeptidyl peptidase-4 (DPP-4) rapidly metabolizes GLP-1, rendering it inactive.
- GLP-1 analogs have a similar structure to endogenous GLP-1, mimicking its actions in the pancreas, stomach, and brain. They have also been modified so that DPP-4 cannot metabolize them.
- FDA-APPROVED INDICATIONS
- Dulaglutide (Trulicity®)
- Type two diabetes in adults
- To reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors
- Exenatide (Bydureon®, Bydureon BCise®)
- Type two diabetes in adults and pediatric patients ≥ 10 years old
- Exenatide (Byetta®)
- Type two diabetes in adults
- Liraglutide (Victoza®)
- Type two diabetes in adults and pediatric patients ≥ 10 years old
- To reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease
- Lixisenatide (Soliqua®)
- Type two diabetes in adults
- Semaglutide (Ozempic®)
- Type two diabetes in adults
- To reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease
- Semaglutide (Rybelsus®)
- Type two diabetes in adults
- TYPE 2 DIABETES
| 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 |
| Effects of GLP-1 analogs on body weight in controlled trials | |
|---|---|
| Drug | Weight loss✝ |
| Dulaglutide 0.75 mg once weekly for 26 weeks | 1.5% |
| Dulaglutide 1.5 mg once weekly for 26 weeks | 2.5% |
| Dulaglutide 3 mg once weekly for 36 weeks | 3.9% |
| Dulaglutide 4.5 mg once weekly for 36 weeks | 4.8% |
| Exenatide (Byetta) 5 mcg twice daily for 24 weeks | 3.2% |
| Exenatide (Byetta) 10 mcg twice daily for 24 weeks | 3.4% |
| Exenatide (Bydureon) 2 mg once weekly for 24 weeks | 2.4% |
| Liraglutide 1.2 mg once daily for 52 weeks | 2.3% |
| Liraglutide 1.8 mg once daily for 52 weeks | 2.7% |
| Lixisenatide 20 mcg once daily for 12 weeks | 2.2% |
| Semaglutide (Ozempic) 0.5 mg once weekly for 30 weeks | 4.2% |
| Semaglutide (Ozempic) 1 mg once weekly for 30 weeks | 4.9% |
| Semaglutide (Rybelsus) 7 mg once daily for 26 weeks | 2.6% |
| Semaglutide (Rybelsus) 14 mg once daily for 26 weeks | 4.2% |
- Cholesterol effects
- GLP-1 analogs do not appear to have a significant effect on cholesterol (lipid parameters) [3,4,5,16]
- TYPE 2 DIABETES | Clinical outcomes
- 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 |
|
|||
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.
- 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.
- 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 |
|
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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.
- 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 |
|
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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.
- 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.
- 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.
- 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 |
|
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Findings: In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral
semaglutide was not inferior to that of placebo
- ADA recommendations
- Summary
- 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.
- HEAD-TO-HEAD TRIALS
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
- SIDE EFFECTS
- Gastrointestinal (GI) side effects
- Gastrointestinal complaints are the most common type of side effect seen with GLP-1 analogs. In trials, up to 48% of patients reported some kind of GI side effect. To minimize the risk, therapy should be initiated at low doses and titrated gradually.
| Side effect | Incidence |
|---|---|
| Nausea | 12 - 40% |
| Diarrhea | 8 - 15% |
| Vomiting | 5 - 15% |
| Abdominal pain | up to 8% |
- Hypoglycemia
- GLP-1 analogs by themselves do not pose a significant risk of hypoglycemia. When they are combined with other diabetes medications, particularly insulin and insulin secretagogues, the risk of hypoglycemia is increased.
- Patients who are taking concomitant diabetes medications should monitor their blood sugars appropriately and be prepared to treat hypoglycemia if needed (see hypoglycemia for more)
- Injection site reactions
- Injection site reactions including redness, itching, bruising, and rash have occurred in some patients
- In exenatide, liraglutide, and dulaglutide trials, reactions occurred in ≤ 2% of patients [1,2]
- In lixisenatide trials, injection site reactions occurred in 4% of patients [21]
- In semaglutide trials, reactions were reported in approximately 0.2% of semaglutide-treated patients [22]
- Hypersensitivity reactions
- Serious hypersensitivity reactions including anaphylaxis, angioedema, generalized pruritus, and rash with dyspnea have been reported with GLP-1 analogs
- Use caution or avoid use in patients with a history of reactions to GLP-1 analogs
- GLP-1 analog antibodies
- 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, and in some cases, these antibodies can crossreact with endogenous GLP-1.
- Dulaglutide (Trulicity®)
- In trials, anti-dulaglutide antibodies developed in 1.6% of patients. Of these patients, about half developed dulaglutide-neutralizing antibodies, and half developed antibodies against endogenous GLP-1. [16]
- Exenatide (Byetta®, Bydureon®)
- Byetta - in a 30-week trial with Byetta, low titers of anti-exenatide antibodies developed in 38% of patients, and high titers developed in 6%. In the high-titer group, 50% of patients (3% overall) had a decreased response to exenatide. No cross-reactive antibodies to endogenous GLP-1 were detected in Byetta trials. [1]
- Bydureon - in Bydureon trials, 49% of adults developed low titers of anti-exenatide antibodies, and 12% had high titers. Low-titer patients had similar glucose control as antibody-negative patients. Half of the patients (6% overall) in the high-titer group had a decreased response to exenatide. No cross-reactive antibodies to endogenous GLP-1 were detected in Bydureon trials.
- Bydureon BCise - in Bydureon BCise trials, low titers of anti-exenatide antibodies developed in 40% of patients, and high titers developed in 34%. High-titer patients had more injection site reactions than low-titer patients (27% vs 16%). Low-titer patients had similar glucose control as antibody-negative patients. Among 133 patients with high titer antibodies, one (0.8%) was found to have cross-reactive antibodies to endogenous GLP-1 and/or glucagon. The clinical significance of these antibodies is unknown.
- Liraglutide (Victoza®)
- In a 26-week trial, anti-liraglutide antibodies developed in 9.8% of patients. Antibodies did not appear to affect the efficacy of liraglutide. [6]
- In other trials, liraglutide antibodies have been found to cross-react with endogenous GLP-1. The clinical significance of these cross-reacting antibodies is unknown. [2]
- Lixisenatide (Soliqua®)
- In 9 trials, anti-lixisenatide antibodies developed in 70% of patients. A subset of patients (2.4%) with the highest antibody titers had a reduced response to lixisenatide. Patients with anti-lixisenatide antibodies also had a higher incidence of allergic reactions and injection site reactions.
- Antibody characterization studies have demonstrated the potential for anti-lixisenatide antibodies to cross-react with endogenous GLP-1 and glucagon. The clinical significance of these cross-reacting antibodies is unknown. [21]
- Semaglutide (Ozempic®)
- In trials, 1% (32 patients) of semaglutide-treated patients developed anti-semaglutide antibodies. Of the 32 patients that developed antibodies, 19 (0.6% of the overall population) had cross-reactive antibodies to endogenous GLP-1. The clinical significance of these cross-reacting antibodies 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. In some patients, antibodies may decrease drug efficacy and increase the risk for hypersensitivity reactions. Cross-reactive antibodies to endogenous GLP-1 and glucagon have also been documented. The clinical significance of cross-reacting antibodies is unknown.
- Pancreatitis
- Pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been reported in patients receiving GLP-1 analogs. After being alerted to the issue, the FDA reviewed a large amount of data from clinical trials, observational studies, and animal studies. In 2014, it published a paper that concluded there was no definitive link between GLP-1 analogs and an increased risk of pancreatitis. The report went on to state that they will continue to monitor data for a possible link. [PMID 24571751]
- 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 reviewed a large amount of information regarding GLP-1 analogs and pancreatitis and found no definitive link
- It is unlikely that GLP-1 analogs increase the risk of pancreatitis
- Decreased kidney function
- There have been case reports of decreased kidney function in patients receiving GLP-1 analogs. In a majority of the cases, symptoms of nausea, vomiting, and/or diarrhea were present. These symptoms are common side effects of GLP-1 analogs, and they can lead to dehydration and worsening kidney function.
- In long-term clinical trials that evaluated renal outcomes (see clinical outcomes above), GLP-1 analogs did not adversely affect kidney function
- Caution should be used when prescribing GLP-1 analogs to patients with renal impairment and those taking medications that may affect kidney function (e.g. ACE inhibitors, NSAIDs, diuretics). Monitor renal function in patients who are experiencing significant gastrointestinal reactions.
- Gallbladder disease
- In some trials, patients receiving GLP-1 analogs had a higher incidence of gallbladder disease than placebo-treated patients. In the LEADER trial, the incidence of acute gallstone disease was 3.1% in liraglutide-treated patients and 1.9% in placebo-treated patients. Substantial or rapid weight loss can increase the risk of cholelithiasis, so it is unclear if GLP-1 analog-induced gallbladder disease is a primary or secondary effect.
- A cohort study that looked at the effects of GLP-1 analogs on the incidence of gallbladder disease is reviewed below.
- STUDY
- 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
- In toxicology studies, a dose-dependent and treatment-duration-dependent increase in the incidence of malignant and benign thyroid medullary tumors (C-cell tumors) was observed in rats and mice receiving clinically relevant doses of GLP-1 analogs. This prompted the FDA to place a boxed warning about medullary thyroid cancer on some GLP-1 analogs ( semaglutide, exenatide, liraglutide, dulaglutide). It is unknown if GLP-1 analogs increase the risk of tumors in humans as the incidence of these events is too low to establish causality. The FDA is requiring the liraglutide manufacturer 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 contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2, a condition that increases the risk for medullary thyroid cancer
- Pancreatic cancer
- 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. In 2014, the FDA published a paper stating that after reviewing 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 they will continue to monitor studies for a possible connection. [PMID 24571751]
- Clinical trials
- In the CVD trials detailed above (see clinical outcomes), the risk of pancreatic cancer was not significantly higher in GLP-1 analog-treated patients when compared to placebo-treated patients
- STUDY
- 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
- Summary
- There is no definitive evidence that GLP-1 analogs increase the risk of pancreatic cancer. If a risk exists, it is likely very small.
- Thrombocytopenia (Exenatide)
- Exenatide has been shown to cause drug-induced immune-mediated thrombocytopenia in the postmarketing setting. Platelet destruction occurs through exenatide-dependent anti-platelet antibodies. Exenatide-induced thrombocytopenia has led to serious bleeding in some patients.
- Exenatide should be discontinued and not restarted in patients who experience drug-induced thrombocytopenia. Patients who are receiving long-acting forms of exenatide (Bydureon, Bydureon BCise) may have thrombocytopenia that lasts up to 10 weeks after discontinuation.
- Diabetic retinopathy
- Semaglutide
- In the SUSTAIN-6 trial detailed above, significantly more diabetic retinopathy complications occurred in semaglutide-treated patients (3.0%) when compared to placebo-treated patients (1.8%). Patients with baseline retinopathy had a higher risk.
- In the PIONEER-6 trial, patients receiving oral semaglutide had a slightly higher risk of retinopathy complications when compared to placebo (7.1% vs 6.3%)
- Dulaglutide
- In the REWIND trial, diabetic retinopathy complications occurred in 1.9% of dulaglutide-treated patients and 1.5% of placebo-treated patients. Patients with baseline retinopathy had a higher risk (Dulaglutide 8.5%, placebo 6.2%).
- Summary
- Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy, so it is unclear if the effects of GLP-1 analogs on retinopathy are primary or secondary. Patients with a history of diabetic retinopathy should be monitored for worsening when receiving GLP-1 analogs.
- Pancreatic enzyme elevations (semaglutide)
- In trials, patients treated with Ozempic had an average increase from baseline in amylase of 13% and lipase of 22%. No increase was observed in placebo-treated patients.
- In Rybelsus trials, 7 mg and 14 mg caused an average increase from baseline in amylase of 10% and 13%, respectively, and lipase increases of 30% and 34%. No increase was observed in placebo-treated patients. [22,24]
- The significance of these effects is unknown
- CONTRAINDICATIONS
- All GLP-1 analogs
- History of hypersensitivity reaction to GLP-1 analogs
- All GLP-1 analogs except lixisenatide
- Personal or family history of medullary thyroid carcinoma (MTC)
- Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
- Exenatide (Byetta®, Bydureon®)
- History of drug-induced immune-mediated thrombocytopenia from exenatide products
- PRECAUTIONS
- Kidney disease
- 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 45 - 89 ml/min: exposure is increased. Monitor for adverse reactions and hypovolemia.
- CrCl < 45 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 (Soliqua®)
- CrCl 30 - 90 ml/min: no dose adjustment recommended. Monitor for increased GI and renal side effects.
- CrCl 15 - 30 ml/min: very limited data. Exposure is increased. Monitor for increased GI and renal side effects.
- CrCl < 15 ml/min: has not been studied. not recommended.
- 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
- Dulaglutide (Trulicity®)
- In a study of patients with varying degrees of liver disease, no clinically relevant change in dulaglutide pharmacokinetics was observed. However, there is limited clinical experience with dulaglutide in liver disease so caution should be used.
- 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 (Soliqua®)
- Has not been studied. Frequent glucose monitoring and dose adjustment may be necessary. [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
- Stomach disorders that slow the emptying of the stomach (ex. diabetic gastroparesis) may be worsened by GLP-1 analogs
- Caution should be used in these patients [1,2]
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- All GLP-1 analogs
- Insulin and insulin secretagogues - GLP-1 analogs may increase the risk of hypoglycemia when combined with insulin or insulin secretagogues (e.g. sulfonylureas, meglitinides). Monitor blood sugars closely and adjust medications as needed.
- Drugs affected by decreased gastric emptying - see gastric emptying below
- Drugs that alter gastrointestinal motility - Drugs that slow gastrointestinal motility may potentiate the gastric-slowing effects of 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 (Soliqua®)
- Oral contraceptives - the absorption of oral contraceptives may be reduced by lixisenatide. Take oral contraceptives at least 1 hour before or 11 hours after administering lixisenatide. [21]
- Drugs affected by gastric emptying
- Medications are partially digested in the stomach before being emptied into the small intestine, where most drug absorption occurs. GLP-1 analogs slow the process of gastric emptying, potentially altering the absorption of some drugs. In many cases, the overall effect on the medication's therapeutic action is not significant, but the efficacy of some drugs (see below) may be altered.
- Antibiotics
- Antibiotics require rapid absorption to achieve their desired therapeutic effect
- When possible, antibiotics should be taken at least 1 hour before GLP-1 analogs
- Drugs with a narrow therapeutic index
- Drugs with narrow therapeutic index may have their steady-state altered by delayed gastric emptying
- When possible, these drugs should be taken at least 1 hour before GLP-1 analogs
- Examples of drugs with a narrow therapeutic index:
- Carbamazepine (Tegretol®)
- Cyclosporine (Neoral®)
- Digoxin
- Levothyroxine (Synthroid®)
- Lithium
- Phenytoin (Dilantin®)
- Tacrolimus (Prograf®)
- Theophylline (Theo-24®)
- Warfarin (Coumadin®) [9]
- Metabolism and clearance
- GLP-1 analogs do not undergo significant liver metabolism
- DOSING
- LONG-TERM SAFETY
- The first GLP-1 analog (exenatide) was FDA-approved in 2005. When used appropriately, GLP-1 analogs appear to be safe.
- BIBLIOGRAPHY
- 1 - Exenatide PI
- 2 - Liraglutide PI
- 3 - PMID 17622601
- 4 - PMID 21975753
- 5 - PMID 19515413
- 6 - PMID 19688338
- 7 - PMID 21320263
- 8 - PMID 20682680
- 9 - North Carolina Pharmacy Practice Act. Article 4A. 90-85.28(b1).
- 10 - PMID 18931095
- 11 - PMID 19317822
- 12 - PMID 18782641
- 13 - PMID 24571751
- 14 - Albiglutide PI
- 15 - Bydureon PI
- 16 - Trulicity® PI
- 17 - PMID 25029955
- 18 - PMID 27295427 - LEADER trial
- 19 - PMID 8214980 - Weight loss and gallstones
- 20 - PMID 27063855 - Weight loss and gallstones
- 21 - Lixisenatide PI
- 22 - Semaglutide PI
- 23 - PMID 29397376 Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial, Lancet Diabetes Endocrinol (2018)
- 24 - Rybelsus® PI