Article Figures & Data
Figures
- Figure 1.
Actions of the incretins in normal glucose homeostasis: The incretins GLP1 and GIP are peptide hormones that are released from K and L cells in the small intestine following a meal. Among other actions, the incretins stimulate release of insulin from pancreatic β cells in a glucose-dependent manner, and GLP1 suppresses glucagon release from pancreatic α cells. This has a combined effect on hyperglycemia by both increasing the uptake of glucose by tissues and decreasing the release of glucose from the liver. GLP1 also affects glucose homeostasis by delaying gastric emptying. Both GLP1 and GIP are rapidly cleaved and inactivated by DPP4, resulting in a half-life of 1–2 min. In patients with T2DM, GIP’s actions in the pancreas are impaired and GLP1 production after a meal is reduced.
DPP4—dipeptidyl peptidase 4, GIP—glucose-dependent insulinotropic polypeptide, GLP1—glucagonlike peptide 1, T2DM—type 2 diabetes.
- Figure 2.
Initiating therapy for T2DM according to current CDA Guidelines3: CDA guidelines recommend a target of HbA1c ≤ 7.0% for most patients with T2D. Pharmacotherapy should be introduced and adjusted in a timely fashion in order to attain target HbA1c within 6–12 mo of diagnosis. To this end, patients who are not responding adequately to lifestyle changes or to metformin monotherapy should advance as quickly as possible to monotherapy or combination therapy with second-line agents, such as the incretin agents. Incretin agents should also be considered among the first-line options in treating patients for whom metformin is contraindicated or inappropriate. The choice among second-line options should be made on an individual basis. Among the factors to be considered are the patient’s need for postmeal vs basal glycemic control and the need to control the patient’s body weight. In general, insulin, sulfonylurea, and thiazolidinedione treatment can be associated with weight gain. In contrast, DPP4 inhibitors and glucosidase inhibitors are weight-neutral, and the GLP1 receptor agonists typically reduce body weight over a period of 2–12 mo.
CDA—Canadian Diabetes Association, DPP4—dipeptidyl peptidase 4, GLP1—glucagonlike peptide 1, HbA1c—glycated hemoglobin A1c, T2DM—type 2 diabetes.
Tables
CONSIDERATIONS GLP1 RECEPTOR AGONISTS DPP4 INHIBITORS EXENATIDE20,22,24–31 LIRAGLUTIDE18,23,32–34 VILDAGLIPTIN35,36 SITAGLIPTIN35,37 Administration SC injection Oral tablet Half-life, h 2.4 11–15 2.5 12–14 Dose 5 or 10 μg, twice daily 0.6, 1.2, or 1.8 mg, once daily 50 mg, twice daily 100 mg, once daily Origin of active incretins following treatment Exogenous and endogenous Endogenous Effect on insulin level Large increase Moderate increase Effect on glucagon level Moderate decrease Mean decrease in HbA1c vs placebo, % Approximately 0.8 0.8–1.6 Approximately 0.7 0.6–1.0 Postprandial hyperglycemia Moderate decrease Small decrease Gastric emptying Inhibited No clinically significant effect Body weight Moderate decrease Neutral Tolerability issues* Nausea Upper respiratory tract infection Incidence of hypoglycemia Low rate of hypoglycemia when administered as monotherapy in patients with T2DM; risk might increase when used in combination with sulfonylureas -
DPP4—dipeptidyl peptidase 4, GLP1—glucagonlike peptide 1, HbA1c—glycated hemoglobin A1c, SC—subcutaneous, T2DM—type 2 diabetes.
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↵* For more complete listings of adverse events, consult the respective product monographs.
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INCRETIN AGENT AND COMBINATION COMPARATOR N DURATION, WK MEAN CHANGE IN HBA1C, %* Sitagliptin • Monotherapy35,38–43 Placebo 2389 12–24 −0.44 to −0.66 • Metformin35,40,44 Placebo 1437 24 −0.67 to −1.90 • Metformin15,35 Glipizide 1172 52 −0.67 • Glimepiride with or without metformin35,45 Placebo 441 24 −0.45 • Pioglitazone35,46 Placebo 353 24 −0.85 • Metformin47 Exenatide 61 2 NA Vildagliptin • Monotherapy35,48–53 Placebo 2253 12–52 −0.20 to −0.92 • Metformin54,55 Placebo 651 12–24 −0.60 to −0.90 • Insulin56 Placebo 296 24 −0.50 • Metformin16 Pioglitazone 576 24 −0.88 • Pioglitazone57 Placebo 463 24 −1.00 • Various59 Vildagliptin vs pioglitazone vs vildagliptin and pioglitazone 607 24 −1.1 Exenatide • Sulfonylurea24 Placebo 377 30 −0.86 • Metformin25 Placebo 336 30 −0.8 • Metformin and sulfonylurea26 Placebo 733 30 −0.75† • TZD with or without metformin27 Placebo 233 16 −0.89 • Metformin and sulfonylurea20,21 Insulin glargine 689 26–32 −1.36 to −1.16 • Metformin and sulfonylurea22 Biphasic insulin 501 52 −1.04 • Monotherapy31 Placebo 232 24 −0.9 • Metformin, sulfonylurea, or both28 None 314 82 −1.1 • Metformin, sulfonylurea, or both59 Placebo 217 156 −1.0 Liraglutide • Monotherapy (LEAD-3)18 Glimepiride 746 52 −0.84 to −1.14 • Metformin (LEAD-2)33 Placebo or glimepiride 1091 26 −1.0 • Glimepiride (LEAD-1)32 Placebo or rosiglitazone 1041 26 −1.1 • Metformin and rosiglitazone (LEAD-4)34 Placebo 533 26 −1.5 • Metformin and sulfonylurea (LEAD-5)23 Insulin glargine 581 26 −1.33 • Previous oral antihyperglycemics (LEAD-6)60 Exenatide plus previous oral antihyperglycemics 464 26 −1.12 -
HbA1c—glycated hemoglobin A1c, LEAD—Liraglutide Effect and Action in Diabetes, NA—not applicable, TZD—thiazolidinedione.
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↵* Reported mean change from baseline in patients treated with incretin agents. Where several values are provided (eg, different doses of the study drug), either in a single report or in multiple reports, the range of reported mean values is shown.
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↵† Precise value not reported; reduction in HbA1c levels was shown in a figure.
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