Novel and emerging diabetes mellitus drug therapies for the type 2 diabetes patient

Table 1 Emerging classes of medications and approaches[8]

SGLT inhibitors

11β-HSD-1 inhibitors

GKA

AMPK agonists

SIRT activators

PTP-1B inhibitors

GCGR antagonists

GR antagonists

Novel insulin sensitizers

GPR119 agonists

Other drugs augmenting GLP-1 secretion: GPR40, G-protein coupled bile acid receptor (TGR5) agonists

Acyl-CoA: DGAT1 inhibitors

FGF-21-receptor agonists

Ranolazine

Other glucometabolic approaches

Other metabolic approaches

Anti-inflammatory approaches

Induction of immune tolerance

Pancreatic beta cell protection and regeneration

Pancreatic islet cell transplantation

Various antidiabetic approaches

SGLT: Sodium-dependent glucose co-transporter; 11beta-HSD-1: 11beta-hydroxysteroid dehydrogenase type 1; GKA: Glucokinase activators; AMPK: Adenosine monophosphate activated protein kinase; SIRT: Sirtuin; PTP-1B: Protein tyrosine phosphatase-1B; GCGR: Glucagon receptor; GR: Glucocorticoid receptor; GPR119: G-protein coupled receptor 119; GLP-1: Glucagon like peptide-1; Acyl-CoA: Acyl-coenzymeA; DGAT1: Diacylglycerol acyltransferase1; FGF-21: Fibroblast growth factor-21.

Table 2 Results of phase 3, CANagliflozin treatment and trial analysis-metformin plus SUIphonylurea, n = 469[14]

Parameters	Canagliflozin 100 mg	Canagliflozin 300 mg	Placebo	Comments
A1c (%) week 26	-0.85	-1.06	-0.13	P < 0.001
A1c (%) week 52	-0.74	-0.96	-0.01	P < 0.001
% Patients with A1c < 7% week 26	43.2	56.6	18.0	P < 0.001
% Patients with A1c < 7% week 52	39.4	52.6	18.7	P < 0.001
FPG (mg/dL) week 26	-21.6	-34.2	-	P < 0.001
FPG (mg/dL) week 52	-28.8	-37.8	-	P < 0.001
Weight	-1.10	-1.7	-	P < 0.001
Change in systolic blood pressure (mmHg)	-2.20	-1.6	-	Non significant
Change in pulse (beats/min)	0.90	-1.2	-0.4	Non significant

A1c: Hemoglobin A1c; FPG: Fasting plasma glucose.

Table 3 Results of canagliflozin compared with sitagliptin for patients with type 2 diabetes: (n = 755)[16]

Parameters	Canagliflozin 300 mg	Sitagliptin 100 mg	Comments
A1c (%) week 52	-1.03	-0.66	Non inferiority to sitagliptin (upper limit of the 95%CI < 0.3%) and superiority to sitagliptin (upper limit of the 95%CI < 0.0%)
Percent (%) of patients with A1c < 7% at week 52	47.6	35.3	Not significant
Percent (%) of patients with A1c < 6.5% at week 52	22.5	18.9	Not significant
FPG (mg/dL) week 26	-29.9	-5.9	P < 0.001
Weight (kg)	-2.3	-0.1	P < 0.001
Change in systolic blood pressure (mmHg)	-5.1	0.9	P < 0.001
Change in diastolic blood pressure (mmHg)	-3.0	-0.3	Not significant

A1c: Hemoglobin A1c; FPG: Fasting plasma glucose.

Table 4 Dapagliflozin in combination with metformin[24]

	Study 1			Study 2
Parameters	DAPA 5 ± MET	DAPA 5 ± PBO	MET ± PBO	DAPA 10 ± MET	DAPA 10 ± PBO	MET ± PBO
A1c at 24 wk (%)
Baseline (n)	9.21 (185)	9.14 (196)	9.14 (195)	9.1 (202)	9.03 (216)	9.03 (203)
A1c (%) at 24 wk (baseline change)	7.13 (-2.05)	7.96 (-1.19)	7.79 (-1.35)	7.1 (-1.98)	7.59 (-1.45)	7.6 (-1.44)
DAPA ± MET vs DAPA	-0.86 (-1.11, -0.62)			-0.53 (-0.74, -0.32)
P value	< 0.0001			< 0.0001
DAPA ± MET vs MET	-0.70 (-0.94, -0.45)			-0.43 (-0.75, -0.33)
P value	< 0.0001			< 0.0001
Patients with A1c < 7% at 24 wk
n (%)	96/185 (52.4%)	46/196 (22.5%)	68/195 (34.6%)	92/202 (46.6%)	69/216 (31.7%)	72/203 (35.2%)
DAPA ± MET vs DAPA	29.9	22.5		14.9
P value	< 0.0001			0.0012
DAPA ± MET vs MET	17.8			11.3
P value	< 0.0001			0.0165
Plasma glucose at 24 wk (mg/dL)
Baseline FPG (mg/dL)	193.14 (n = 192)	190.62 (n = 203)	196.56 (n = 200)	189.36 (n = 209)	197.28 (n = 216)	189.72 (n = 207)
FPG after 24 wk (baseline change)	132.3 (-61.02)	150.3 (-41.94)	161.1 (-33.48)	130.86 (-60.3)	147.6 (-46.44)	156.42 (-34.74)
DAPA ± MET vs DAPA	-19.08			-13.86
P value	< 0.0001			< 0.0001
DAPA ± MET vs MET	-27.54			-25.56
P value	< 0.0001			< 0.0001
Total body weight at 24 wk (kg)
Baseline weight (n)	84.24 (192)	86.20 (203)	85.75 (200)	88.56 (209)	88.53 (219)	87.24 (208)
Change from baseline	-2.66 (-3.14, -2.19)	-2.61 (-3.07, -2.15)	-1.29 (-1.76, -0.82)	-3.33 (-3.80, -2.86)	-2.73 (-3.19, -2.27)	-1.36 (-1.83, -0.89)

DAPA: Dapagliflozin; MET: Metformin; PBO: Placebo; FPG: Fasting plasma glucose; A1c: Hemoglobin A1c.

Table 5 Efficacy assessment of INCB13739 in combination with metformin[30]

	Placebo	5 mg	15 mg	50 mg	100 mg	200 mg
Baseline A1c (%)	8.3 ± 1	8.2 ± 1	8.3 ± 1	8.3 ± 1	8.2 ± 1	8.2 ± 1
LS mean change A1c (%) from baseline	0.09 ± 1	-0.21 ± 1be	-0.11 ± 1	-0.09 ± 2	-0.38 ± 1ae	0.47 ± 1dh
A1c > 8% (n)	-0.10 ± 0.2 (23)	-0.39 ± 0.2e (23)	-0.24 ± 0.2 (18)	-0.65 ± 0.3be (11)	-0.72 ± 0.2ae (16)	0.65 ± 0.2 (19)
A1c (%) for BMI > 30 mg/m2 (n)	0.17 ± 0.1 (29)	-0.24 ± 0.2bf (23)	-0.10 ± 0.2 (26)	-0.25 ± 0.2b (18)	-0.36 ± 0.2a (26)	-0.76 ± 0.2dh (18)
Baseline FPG (mg/dL)	179 ± 51	172 ± 41	175 ± 44	178 ± 53	170 ± 64	165 ± 41
LS mean change from baseline (mg/dL)	12.6 ± 6.1	6 ± 6.3	2.3 ± 6.4	-4.7 ± 7.2b	-1.6 ± 6.1b	-11.5 ± 6.2df
Weight (kg)	-0.2 ± 0.3	-0.5 ± 0.38	-0.6 ± 0.4e	0 ± 0.4	-1.1 ± 0.3be	-0.9 ± 0.3h
HOMA-IR	0.25 ± 0.4	-0.29 ± 0.4	0.33 ± 0.4	-0.42 ± 0.5	0.51 ± 0.4	-1.06 ± 0.4ae

Data are placebo adjusted least-squares (LS) mean change from baseline: mean ± SE.

^aP < 0.05,

^bP < 0.01,

^dP < 0.01, active vs Placebo,

^eP < 0.05,

^fP < 0.01,

^hP < 0.01, week 12 vs baseline. A1c: Hemoglobin A1c; FPG: Fasting plasma glucose; LS: Least squares; BMI: Body mass index; HOMA-IR: Homeostatic model assessment-insulin resistance.