While not appropriate as primary therapy, the effect of the GLP-1 agonists on blood pressure and of the GLP-1 agonists and DPP-4 inhibitors on the lipid profile could be an added benefit for all patients with T2DM because of the strong association between T2DM and cardiovascular disease. This can be seen in all 3 of our cases: Case 1 (hypertriglyceridemia), Case 2 (essential hypertension), and Case 3 (peripheral arterial disease).
TABLE 1
Selected studies with GLP-1 agonists and DPP-4 inhibitors assessing cardiovascular end points4,8-12,17,22,30,31
| Agent/clinical trial | Concomitant treatment; duration (wk) | Change from baseline | |||
|---|---|---|---|---|---|
| Systolic blood pressure (mm Hg) | LDL cholesterol (mg/dL) | HDL cholesterol (mg/dL) | Triglycerides (mg/dL) | ||
| Exenatide (E) | |||||
| Moretto, 200830 | Diet/exercise; | ||||
| E, 5 μg BID | 24 | -4 | NR | NR | NR |
| E, 10 μg BID | -4 | NR | NR | NR | |
| Placebo | 0 | NR | NR | NR | |
| Blonde, 20068 | MET + SU; | ||||
| E, 5 μg BID | 82 wk | -1 | -2 | +5 | -39 |
| E, 10 μg BID | -1 | -2 | +5 | -39 | |
| Nauck, 200731 | MET + SU; | ||||
| E, 10 μg BID | 52 wk | -5 | NC | NR | NC |
| Premix aspart 70/30 BID | +1 | NC | NR | NC | |
| Zinman, 20079 | TZD ± MET; | ||||
| E, 10 μg BID | 16 wk | NC | NC | NC | NC |
| Placebo | NC | NC | NC | NC | |
| Liraglutide (L) | |||||
| Garber, 20094 | None; 52 wk | ||||
| L, 1.2 mg OD | -2 | NR | NR | NR | |
| L, 1.8 mg OD | -4 | NR | NR | NR | |
| Glimepiride, 8 mg OD | -1 | NR | NR | NR | |
| Russell-Jones, 200910 | MET + GLIM; | ||||
| L, 1.8 mg OD | 26 wk | -4 | NR | NR | NR |
| Insulin glargine | +1 | NR | NR | NR | |
| Placebo | -1 | NR | NR | NR | |
| Zinman, 200911 | MET + ROSI; | ||||
| L, 1.2 mg OD | 26 wk | -7 | -11 | -1 | -34 |
| L, 1.8 mg OD | -6 | -9 | -1 | -29 | |
| Placebo | -1 | -4 | -1 | -5 | |
| Buse, 200912 | MET, SU, MET + SU; | ||||
| L, 1.8 mg OD | -3 | -17 | -2 | -36 | |
| E, 10 μg BID | 26 wk | -2 | -15 | -2 | -20 |
| Sitagliptin (Si) | |||||
| Scott, 200717 | Diet/exercise; | ||||
| Si, 25 mg BID | 12 wk | NR | 0 | +1 | -3 |
| Si, 50 mg BIDa | NR | +1 | +1 | 0 | |
| Glipizide, 5 mg OD | NR | 0 | 0 | +3 | |
| Placebo | NR | 0 | 0 | +16 | |
| Saxagliptin (Sa) | |||||
| Hollander, 200922 | TZD; | ||||
| Sa, 2.5 mg OD | 24 wk | NR | +4 | -1 | -1 |
| Sa, 5 mg OD | NR | +9 | +2 | -4 | |
| Placebo | NR | +3 | 0 | -1 | |
| aDose not included in currently approved prescribing information. | |||||
| DPP, dipeptidyl peptidase; GLIM, glimepiride; GLP, glucagon-like peptide; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MET, metformin; NC, no difference between baseline and study end; NR, not reported; OD, once daily; ROSI, rosiglitazone; SBP, systolic blood pressure; SU, sulfonylurea; TZD, thiazolidinedione. | |||||
Favorable safety profile
Overview
In general, GLP-1 agonists and DPP-4 inhibitors are well tolerated. Because of concerns about hypoglycemia with glucose-lowering agents, signs and symptoms of hypoglycemia have been closely monitored in clinical trials. The low incidence and mild to moderate severity of hypoglycemia are important attributes of the GLP-1 agonists and DPP-4 inhibitors.
Other than hypoglycemia, the most common adverse reaction reported in ≥5% of patients and more commonly than with placebo are shown in TABLE 2.33-36 Other medication-specific side effects are seen infrequently but bear mentioning. An increased international normalized ratio, sometimes with bleeding, has been noted with combined use of exenatide and warfarin.33 Immune-related events (eg, urticaria) have been reported with exenatide33 and have been observed to occur more frequently with liraglutide than with comparator agents.34 Peripheral edema is more common when a thiazolidinedione is administered with saxagliptin than with placebo.36
While experience with GLP-1 agonists and DPP-4 inhibitors indicates that they have favorable safety profiles, some concerns have surfaced with 1 or more of these agents during clinical trials or from postmarketing reports. These include gastrointestinal side effects (principally nausea), acute pancreatitis, and hypersensitivity reactions. In addition, new standards recently adopted by the US Food and Drug Administration (FDA) are requiring further investigation of several issues for newly approved glucose-lowering drugs and those in development. These issues are discussed next.
TABLE 2
Most common side effectsa of the GLP-1 agonists and DPP-4 inhibitors33-36
| Agent | Side effects |
|---|---|
| Exenatide | Nausea, vomiting, diarrhea, feeling jittery, dizziness, headache, dyspepsia |
| Liraglutide | Nausea, diarrhea, headache |
| Sitagliptin | Upper respiratory tract infection, nasopharyngitis, headache |
| Saxagliptin | Upper respiratory tract infection, urinary tract infection, headache |
| DPP, dipeptidyl peptidase; GLP, glucagon-like peptide. | |
| aOccurring in ≥5% of patients and more frequently than with placebo. | |
Hypoglycemia
In contrast to other glucose-lowering drugs that stimulate insulin secretion, incretin-based therapies have a glucose-dependent mechanism of action that minimizes the risk of hypoglycemia. Preclinical investigation showed that GLP-1 acts on islet α-cells to strongly inhibit postprandial glucagon secretion.37,38 These observations were subsequently supported by early clinical investigations showing that administration of GLP-1 to healthy volunteers and people with T2DM augmented insulin secretion and decreased glucagon secretion in a glucose-dependent manner.39,40 Similar effects were also observed with a DPP-4 inhibitor.25 At the same time, GLP-1 has been shown not to suppress glucagon secretion at a plasma glucose level <65 mg/dL.41 This mechanism is believed to maintain the counterregulatory hormone response that serves to prevent hypoglycemia.
Accordingly, severe hypoglycemia has not been observed in monotherapy trials of exenatide,6,30 liraglutide,4,42 sitagliptin,17,19 or saxagliptin.21 Mild to mod erate hypoglycemia has been observed in 4% to 9% of patients treated with exenatide monotherapy6,30 and 0% to 12% of patients treated with liraglutide monotherapy4,42; by comparison, the incidence was 24% in patients treated with glimepiride monotherapy.4 Mild to moderate hypoglycemia has been found to be less frequent with sitagliptin and saxagliptin. In monotherapy and combination studies, 0% to 4% of patients treated with sitagliptin and 0% to 2% administered placebo experienced mild to moderate hypoglycemia.17,18,43-45 Mild to moderate hypoglycemia has not been observed in patients treated with saxagliptin monotherapy at doses of 2.5 mg to 40 mg.21 When saxagliptin was added to metformin, hypoglycemia was reported by 5.7% of patients compared with 5.0% of patients who added placebo to metformin.46