Pioglitazone and alogliptin combination therapy in type 2 diabetes: a pathophysiologically sound treatment

Figures & data

Figure 1 Insulin signaling system in healthy normal glucose tolerant A) and T2DM B) subjects.

Figure 2 The triumvirate: insulin resistance in liver and muscle with impaired insulin secretion represent the three core defects in T2DM. Reproduced with permission from DeFronzo RA. Lilly lecture. The triumvirate: Beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1998;37:667–687.¹⁶ Copyright © 1998 American Diabetes Association.

Figure 3 Effect of thiazolidinedione (TZD) treatment on beta cell function.

Abbreviations: PIO, pioglitazone; ROSI, rosiglitazone; SU, sulfonylurea; ISR, insulin secretion rate; AUC, area under the curve.

Figure 4 Pioglitazone positively affects the insulin signaling system resulting in improved glycemic control, generation of nitric oxide and decreased MAP kinase pathway activation.

Figure 5 Effect of thiazolidinediones (TZDs) on body fat distribution.

Figure 6 Summary of studies examining the effect of thiazolidinediones (TZDs) versus placebo or versus active-comparator on HbA_1C in type 2 diabetes subjects.

Abbreviations: PIO, pioglitazone; ROSI, rosiglitazone.

Figure 7 GLP-1 levels decline as glucose tolerance deteriorates A), whereas GIP levels are normal or elevated in patients with type 2 diabetes mellitus B).^86–88

Figure 8 Percentage (%) of subjects achieving select HbA_1c targets with alogliptin in Phase 3 trials.^135–138

Abbreviations: ALO, alogliptin; SU, sulfonylurea; MET, metformin; INS, insulin; MONO, monotherapy with alogliptin.

Table 1 Phase III alogliptin trials and alogliptin–pioglitazone combination studies

Source	Design	Background treatment	Intervention	Age (years)	BMI (kg/m^2)	A1C base (%)	A1c decrement (%)	FPG (mg/dL)	Weight (kg)
DeFronzo et al^Citation135	Run-in was SB, R, DB, PC; 26-week active treatment	Drug-naïve (no current antidiabetics, <7 days in last 3 months); 4-week single-blind placebo run-in with diet/exercise	ALO 12.5 mg (n = 133) ALO 25 mg (n = 131) Placebo (n = 64)	53.4	NR	7.9%	12.5 mg −0.56% 25 mg −0.59 Placebo −0.02	−10 −16 +11	−0.1 −0.2 +0.2
Pratley et al^Citation136	Run-in was SB, R, DB, PC; 26-week active treatment	Sulfonylurea monotherapy, placebo run-in × 4 weeks; all subjects switched to glyburide; median glyburide 10 mg daily	ALO 12.5 mg (n = 203) ALO 25 mg (n = 198) Placebo (n = 99)	56.5	30.1	8.1	12.5 mg −0.39 25 mg −0.53 Placebo −0.01	−5 −8 +2	+0.6 +0.7 −0.2
Nauck et al^Citation137	Run-in was SB, R, DB, PC; 26-week active treatment	Metformin monotherapy, placebo run-in × 4 weeks; all subjects switched to generic metformin ∼1850 mg/day	ALO 12.5 mg (n = 213) ALO 25 mg (n = 210) Placebo (n = 104)	55	32	8.0	12.5 mg −0.6 25 mg −0.6 Placebo −0.1	−9 −17 0	0.0 −0.3 versus placebo
Rosenstock et al^Citation138	Run-in was not blinded, DB, R, PC; 26-week active treatment	Insulin ± metformin, subjects given weekly dietary and exercise counseling	ALO 12.5 mg (n = 131) ALO 25 mg (n = 129) Placebo (n = 130)	55	32	9.3	12.5 mg −0.63 25 mg −0.71 Placebo −0.13	−2 −11 +5	+0.6 +0.7 +0.6
Alogliptin–pioglitazone combination studies
Pratley et al^Citation141	Run-in was SB, R, DB, PC; 26-week active treatment	Stable TZD dose months, given weekly dietary and exercise counseling. PIO dose maintained, rosiglitazone switched to equivalent dose of PIO 30 mg or 45 mg daily during run-in period. Concomitant therapy was metformin 55%, sulfonylurea 20%, none 25%	ALO 12.5 mg (n = 197) ALO 25 mg (n = 199) Placebo (n = 97)	55	32.8	8.0	12.5 mg −0.66 25 mg −0.80 Placebo −0.19	−20 −20 −6	∼ +0.6 ∼ +1.0 ∼ +1.0
*DeFronzo et al^Citation142,Citation143	R, DB, PC; 26-week active treatment	Subjects inadequately controlled on metformin For analysis, all doses of ALO monotherapy and PIO monotherapy were pooled. All PIO doses were pooled with ALO 12.5 mg and ALO 25 mg dose	ALO 12.5 mg ALO 25 mg PIO 15 mg PIO 30 mg PIO 45 mg (n = 387 for all doses) ALO 12.5 mg + PIO 15, 30, or 45 mg (n = 390) ALO 25 mg + PIO 15, 30, or 45 mg (n = 390)	NR	NR	NR	PIO any dose −0.89% ALO + any dose of PIO −1.43% ALO + any dose of PIO −1.42%	−28 −45 −44	NR
*Rosenstock et al^Citation144 *Inzucchi et al^Citation145	R, DB; 26-week active treatment	Diet and exercise only; drug-naïve	ALO 12.5 mg/PIO 30 mg ALO 25 mg/PIO 30 mg ALO 25 mg PIO 30 mg	53	31	8.8%	ALO 12.5 mg/PIO 30 mg −1.56% ALO 25 mg/PIO 30 mg 1.7% PIO −1.15% ALO −0.96%	−50 −49 −37 −26	+3.1 +2.5 +2.2 −0.3

Note:

* Available only in abstract form, numbers may change in final manscript form.

Abbreviations: BMI, body mass index; SB, single-blind; R, randomized; PC, placebo-controlled; A_1c base, HbA_1c at baseline; A_1c decrement, change in A_1c from baseline; ALO, alogliptin; PIO, pioglitazone; FPG, fasting plasma glucose ; NR, not reported.

Figure 9 Necessity for hyperglycemic rescue* in Phase III trials with alogliptin.^135–138

*see text for definitions

Abbreviations: ALO, alogliptin; SU, sulfonylurea; MET, metformin; INS, insulin; MONO, monotherapy with alogliptin.

Figure 10 The ominous octet: pathophysiologic abnormalities in type 2 diabetes mellitus.⁷

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