Pathogenesis and management of postprandial hyperglycemia: role of incretin-based therapies

Figures & data

Figure 1 Relationship between increases in HbA_1c levels and increases in fasting and 2-hour postprandial glucose levels in 175 volunteers with normal glucose tolerance, impaired glucose tolerance, or type 2 diabetes mellitus.

Abbreviation: HbA_1c, glycated hemoglobin.

Figure 2 Cell mechanism linking impaired glucose utilization in type 2 diabetes and cardiovascular disease. Insulin signal transduction in individuals with normal glucose tolerance (A) and with type 2 diabetes (B). Insulin signaling through IRS-1 is impaired in type 2 diabetes, leading to decreased glucose transport/phosphorylation/metabolism and impaired NOS activation/endothelial function. Insulin resistance in the IRS-1/PI-3 kinase pathway results in compensatory hyperinsulinemia, excessive stimulation of the MAP kinase pathway, and subsequent inflammation, cell proliferation, and atherogenesis.

Abbreviations: IRS-1, insulin-receptor substrate 1; NOS, nitric oxide synthase; PI-3, phosphoinositide 3; MAP, mitogen-activated protein; SHC, Src-homology collagen.

Table 1 PPG outcomes as monotherapy: placebo-controlled trials published from 2008 to October 2012

Drug	Baseline demographics			Treatments	PPG outcome
	Patients, n	Male/female, n/n	Mean age (SD), years
GLP-1 analogs
Exenatide^Citation58	96	36/60	55 (10)	• Exenatide 5 μg bid • Matching placebo	Mean PPG at week 24 decreased to a greater extent with exenatide plus lifestyle modification versus placebo plus lifestyle modification (P<0.0001 for midday meal)
Exenatide^Citation59	232	130/102	54 (10)	• Exenatide 5 or 10 μg bid • Matching placebo	Mean decreases from baseline to week 24 in morning, evening, and daily PPG[E] significant with both doses of exenatide versus placebo (P≤0.002); however, no difference between either dose versus placebo for midday PPG[E]
Liraglutide^Citation72	18	14/4	59 (7)	• Liraglutide 0.6, 1.2, and 1.8 mg qd • Matching placebo	Mean decreases in PPG levels at steady-state significant with all three liraglutide doses versus placebo (P<0.001), except for iAUC0–5h/5 hours after the lowest dosea
Liraglutide^Citation73	• 0.1 mg, 45 • 0.3 mg, 46 • 0.6 mg, 45 • 0.9 mg, 44	• 31/14 • 32/14 • 28/17 • 31/13	• 57 (8) • 57 (9) • 60 (7) • 56 (8)	• Liraglutide 0.1, 0.3, 0.6, or 0.9 mg qd • Matching placebo	Mean decreases in PPG AUC from baseline to week 14 greater with all liraglutide doses versus placebo (P<0.0001 for linear contrast) Reductions in mean 1-hour, 2-hour, and 3-hour PPG seen with all liraglutide doses, except for 1-hour PPG with the lowest dose
Lixisenatide^Citation84	• 2-step, 120 • 1-step, 119	• 63/57 • 63/56	• 53 (10) • 54 (11)	• Lixisenatide 2-step titration (10/15/20 μg qd) or 1-step titration (10/20 μg qd) • Matching placebo 2-step or 1-step titration	Mean decreases in 2-hour PPG from baseline to week 12 were significant with lixisenatide 2-step and 1-step titration versus placebo (95% CIs −5.38 to −2.35 mmol/L and −6.29 to −3.36 mmol/L, respectively; both P<0.0001)
Albiglutide^Citation88	• 9 mg, 14 • 16 mg, 12 • 32 mg, 14	• 9/5 • 8/4 • 7/7	• 60 (46–71)b • 56 (45–65)b • 55 (30–69)b	• Albiglutide 9, 16, or 32 mg qd (2 days) • Matching placebo	Significant reductions in 4-hour PPG observed with all doses of albiglutide from day 2 to day 9
DPP-4 inhibitors
Sitagliptin^Citation111	• 25 mg, 80 • 50 mg, 72 • 100 mg, 70 • 200 mg, 68	• 51/29 • 47/25 • 36/34 • 40/28	• 60 (8) • 60 (9) • 58 (10) • 61 (8)	• Sitagliptin 25, 50, 100, or 200 mg qd • Matching placebo	Mean decreases from baseline to week 12 in 2-hour PPG significant with all doses of sitagliptin versus placebo (all P<0.001)
Sitagliptin^Citation143	102	48/54	72 (6)	• Sitagliptin 50 or 100 mg qd • Matching placebo	Mean decreases from baseline to week 24 in 2-hour PPG significant with sitagliptin versus placebo (P<0.001)
Sitagliptin^Citation110	151	95/56	55 (8)	• Sitagliptin 100 mg qd • Matching placebo	Mean decrease from baseline to week 12 in 2-hour PPG significant with sitagliptin versus placebo (P<0.001)
Saxagliptin^Citation109	• 2.5 mg, 102 • 5 mg, 106 • 10 mg, 98	• 58/44 • 54/52 • 45/53	• 53 (10) • 54 (12) • 53 (11)	• Saxagliptin 2.5, 5, or 10 mg qd • Matching placebo	Mean decreases from baseline to week 24 in 2-hour PPG and PPG AUC significantly greater with saxagliptin versus placebo (P≤0.0007), except for PPG AUC for the lowest dose (for which statistical testing was not performed as part of the prespecifed close sequential test procedure)
Saxagliptin^Citation144	284	160/124	51 (10)	• Saxagliptin 5 mg qd • Matching placebo	In drug-naive Asian patients, mean decreases from baseline to week 24 in 180-minute PPG AUC were significant for saxagliptin versus placebo (P=0.0010)
Alogliptin^Citation126	56	24/32	56 (9)	• Alogliptin 25, 100, or 400 mg qd • Matching placebo	Mean decreases from baseline to day 14 in 4-hour PPG significant with all three doses of alogliptin versus placebo after breakfast, lunch, and dinner (all P≤0.017)
Alogliptin^Citation127	480	345/135	59 (10)	• Alogliptin 6.25, 12.5, 25, or 50 mg qd • Matching placebo • Voglibose 0.2 mg tid	Mean decrease from baseline to week 12 in PPG AUC significant for all four doses of alogliptin versus placebo and for the two highest doses versus voglibose (P-values not specified)
Linagliptin^Citation108	503	243/260	56 (10)	• Linagliptin 5 mg qd • Matching placebo	Mean decrease from baseline to week 24 in 2-hour PPG levels significant with linagliptin versus placebo (P<0.0001)
Linagliptin^Citation145	77	72/5	62 (40–69)c	• Linagliptin 2.5, 5, or 10 mg qd • Matching placebo	Mean decrease from baseline to day 29 in 2-hour PPG and PPG AUC significant with all three doses of linagliptin versus placebo (P<0.025)
Dutogliptin^Citation128	• 200 mg, 174 • 400 mg, 162	• 93/81 • 87/75	• 53 (10) • 53 (10)	• Dutogliptin 200 mg or 400 mg qd • Matching placebo	Mean decreases in 2-hour PPG from baseline to week 12 were significantly greater with both doses of dutogliptin versus placebo (both P≤0.032)

Notes:

a Average incremental increase, calculated as the AUC over the fasting value from time 0 to 5 hours

b mean age (range), years

c median age (range), years.

Abbreviations: AUC, area under the curve; BID, twice daily; CI, confidence interval; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; PPG[E], postprandial glucose [excursion]; qd, once daily; SD, standard deviation; tid, three times daily.

Table 4 PPG outcomes as add-on to insulin: trials published from 2008 to October 2013

Drug	Baseline demographics			Treatments	PPG outcome
	Patients, n	Male/female, n/n	Mean age (SD), years
GLP-1 analogs
Exenatide^Citation64	137	70/67	59 (9)	• Exenatide 10 μg bid • Matching placebo	Mean decrease from baseline to week 30 in morning and evening 2-hour PPG significant with exenatide plus insulin glargine versus placebo plus insulin glargine (P<0.001); however, no significant difference in midday 2-hour PPG
Lixisenatide^Citation80	495	228/267	57 (10)	• Lixisenatide 20 μg qd • Matching placebo	Mean decrease from baseline to week 24 in 2-hour postbreakfast PPG significant with lixisenatide plus basal insulin ± metformin versus placebo plus basal insulin ± metformin (P<0.0001)
Lixisenatide^Citation85	154	69/85	59 (10)	• Lixisenatide 20 μg qd • Matching placebo	Mean decrease from baseline to week 24 in 2-hour PPG significant with lixisenatide plus basal insulin ± sulfonylurea versus placebo plus basal insulin ± sulfonylurea (P<0.0001)
DPP-4 inhibitors
Sitagliptin^Citation119	322	157/165	58 (9)	• Sitagliptin 100 mg qd • Matching placebo	Mean decrease from baseline to week 24 in 2-hour PPG significant with sitagliptin plus insulin ± metformin versus placebo plus insulin ± metformin (P≤0.001)
Saxagliptin^Citation117	304	120/184	57 (9)	• Saxagliptin 5 mg qd • Matching placebo	Mean decrease from baseline to week 24 in 180-minute and 120-minute PPG significant with saxagliptin plus insulin ± metformin versus placebo plus insulin ± metformin (P=0011 and P=0.0016, respectively)

Abbreviations: AUC, area under the curve; bid, twice daily; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; PPG, postprandial glucose; qd, once daily; SD, standard deviation; tid, three times daily.

Table 2 PPG outcomes as add-on to metformin: selected trials published from 2008 to October 2012

Drug	Baseline demographics			Treatments	PPG outcome
	Patients, n	Male/female, n/n	Mean age (SD), years
GLP-1 analogs
Exenatide^Citation60	234	48%/52%	55 (9)	• Exenatide 5 μg bid for 4 weeks and 10 μg bid for 12 weeks • Matching placebo	Mean decrease in morning, midday, and evening PPGE at week 16 significant for exenatide plus metformin versus placebo plus metformin (P<0.001)
Exenatide^Citation61,Citation62	• Exenatide, 205 • Insulin glargine, 209	• 55%/45% • 55%/45%	• 59 (9) • 57 (10)	• Exenatide 5 μg bid for 4 weeks and then 10 μg bid, with titration up to 20 μg tid if needed • Insulin glargine 10 U qd followed by self-adjusted dosing	Mean decrease in PPG AUC at weeks 26 and 52 significant for exenatide plus metformin versus insulin glargine plus metformin (P<0.001)
Exenatide^Citation63	30	11/19	53 (11)	• Exenatide 5 μg bid for 1 week and 10 μg bid for 1 week • Matching placebo	Mean morning, midday, and evening 2-hour PPG at week 2 significantly lower for exentatide plus metformin versus placebo plus metformin (P≤0.001)
Lixisenatide^Citation79	• 5 μg qd, 55 • 10 μg qd, 52 • 20 μg qd, 55 • 30 μg qd, 54 • 5 μg bid, 53 • 10 μg bid, 56 • 20 μg bid, 54 • 30 μg bid, 54	• 26/29 • 31/21 • 28/27 • 27/27 • 25/28 • 29/27 • 20/34 • 23/31	• 57 (8) • 55 (9) • 55 (10) • 57 (9) • 57 (8) • 56 (8) • 57 (8) • 55 (9)	• Lixisenatide 5, 10, 20, or 30 μg qd or bid • Matching placebo	Mean decreases in morning 2-hour PPG at week 13 significant for all doses of lixisenatide plus metformin versus placebo plus metformin (P<0.01 except for lowest dose given qd or bid [P<0.05])
DPP-4 inhibitors
Sitagliptin^Citation146	• Sitagliptin, 248 • Glipizide, 256	• 142/106 • 161/95	• 58 (9) • 57 (9)	• Sitagliptin 100 mg qd • Glipizide 5 mg qd	Mean decrease from baseline to year 2 in PPG AUC seen with sitagliptin plus metformin but not glipizide plus metformin
Saxagliptin^Citation147	93	49/44	55 (9)	• Saxagliptin 5 mg qd • Matching placebo	Mean decreases from baseline to week 4 in 2-hour and 4-hour PPG (evening meal) significant with saxagliptin plus metformin versus placebo plus metformin (P≤0.0010)
Saxagliptin^Citation113	• 2.5 mg, 192 • 5 mg, 191 • 10 mg, 181	• 83/109 • 103/88 • 95/86	• 55 (10) • 55 (10) • 54 (10)	• Saxagliptin 2.5, 5, or 10 mg qd • Matching placebo	Mean decreases from baseline to week 24 in 2-hour PPG and PPG AUC significant with all doses of saxagliptin plus metformin versus placebo plus metformin (P≤0.0001)
Saxagliptin^Citation148	• Saxagliptin + metformin, 138 • Metformin, 144	• 57/81 • 73/71	• 55 (9) • 56 (10)	• Saxagliptin 5 mg + metformin XR 1500 mg qd • Metformin XR 2000 mg qd	Mean decreases from baseline to week 18 in 2-hour PPG significant with saxagliptin plus metformin XR 1,500 mg versus metformin XR 2,000 mg (P=0.0013)
Vildagliptin^Citation122,Citation149	2,789	1,490/1,299	57 (9)	• Vildagliptin 50 mg bid • Glimepiride 6 mg qd	Mean decrease from baseline to year 2 in PPG AUC similar with vildagliptin plus metformin and glimepiride plus metformin
Linagliptin^Citation112	700	379/321	57 (10)	• Linagliptin 5 mg qd • Matching placebo	Mean decrease from baseline to week 24 in 2-hour PPG levels significant with linagliptin plus metformin versus placebo plus metformin (P<0.0001)

Abbreviations: AUC, area under the curve; bid, twice daily; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; PPG[E], postprandial glucose [excursion]; qd, once daily; SD, standard deviation; tid, three times daily; XR, extended release.

Table 3 PPG outcomes as add-on to a sulfonylurea: trials published from 2008 to October 2012

Drug	Baseline demographics			Treatments	PPG outcome
	Patients, n	Male/female, n/n	Mean age (SD), years
GLP-1 analogs
Liraglutide^Citation75	264	169/95	60 (10)	• Liraglutide 0.6 or 0.9 mg qd • Matching placebo	Mean decreases from baseline to week 24 in PPG AUC significant with both liraglutide doses versus placebo (P<0.0001), as add-on to glibenclamide, glicazide, or glimeprimide
DPP-4 inhibitors
Saxagliptin^Citation115,Citation116	• 2.5 mg, 248 • 5 mg, 253	• 113/135 • 110/143	• 55 (10) • 55 (10)	• Saxagliptin 2.5 or 5 mg qd • Matching placebo	Mean decreases from baseline to week 24 in 2-hour PPG and PPG AUC significant with saxagliptin plus uptitrated glyburide versus placebo plus uptitrated glyburide (P<0.0001); updated data at week 76 data were consistent with those at week 24
Vildagliptin^Citation123	• Vildagliptin + glimepiride, 85 • Vildagliptin + pioglitazone, 83	• 43/42 • 42/41	• 58 (5) • 59 (6)	• Vildagliptin 50 mg bid + glimepiride 2 mg tid • Vildagliptin 50 mg bid + pioglitazone 30 mg qd	Mean decreases from baseline to months 9 and 12 in PPG were significant in both groups, with no significant differences between groups
Vildagliptin^Citation124	• 50 mg qd, 132 • 50 mg bid, 132	• 78/54 • 79/53	• 59 (11) • 58 (11)	• Vildagliptin 50 mg qd or bid • Matching placebo	Mean decreases from baseline to week 24 in PPG[E] significant for vildagliptin 50 mg plus glimepiride versus placebo plus glimepiride (P=0.008; significance not reached for 100 mg dose versus placebo [P=0.085])

Abbreviations: AUC, area under the curve; bid, twice daily; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; PPG[E], postprandial glucose [excursion]; qd, once daily; SD, standard deviation; tid, three times daily.

Figure 3 Comparison of GLP-1 agonists and DPP-4 inhibitors.

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