NZ772003B2 - Method of using a gip/glp1 co-agonist for diabetes - Google Patents

Abstract

The present invention provides methods of treating type 2 diabetes (T2D), NASH, or obesity, using a novel dosing regimen of a GIP:GLP-1 Peptide having a GIP:GLP-1 receptor agonist potency ratio that is about 2.5:1 to about 10:1 GIP to GLP-1. Furthermore, the present invention provides methods of treating T2D using a novel dosing regimen of a GIP:GLP-1 Peptide having a GIP:GLP-1 receptor agonist potency ratio that is about 2.5:1 to about 5:1 GIP to GLP-1. Also, the present invention provides methods of inducing T2D remission using a novel dosing regimen of a GIP:GLP-1 Peptide.

Claims (5)

WE CLAIM:

1. Use of a compound of SEQ ID NO: 3: R X X X GTX TSDX X X X X DX X AX X X X X X X X X 1 1 2 3 6 10 11 12 13 14 16 17 19 20 21 22 23 24 25 26 27 5 X X X X 28 29 30 31 wherein: R is a modification of the N-terminal amino group wherein the modification is selected from the group consisting of Ac and absent; X is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY, 10 X is selected from the group consisting of Aib, aMeP, A, P, and D-Ala or X and X combine to form desH- ?[NHCO]-Aib; X is selected from the group consisting of E, N, Aad, and cTA; X is selected from the group consisting of F, aMeF, and aMeF(2F); X is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, Y, E, aMeF, 15 aMeF(2F), I, aMeY, Q, D-His, D-Tyr, cTA, and K(2-[2-(2-amino-ethoxy)-ethoxy]- acetyl) -( ?-Glu)-CO-(CH2)qCO2H; X is selected from the group consisting of S, aMeS, and D-Ser; X is selected from the group consisting of I, S, D-Ile, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; 20 X is selected from the group consisting of Nle, Aib, L, aMeL, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of L and K, wherein K is conjugated to a C - 14 16 fatty acid wherein said fatty acid is optionally conjugated to said K via a linker; X is selected from the group consisting of K, E, Orn, Dab, Dap, S, T, H, Aib, aMeK, R, 25 -( ?-Glu)-CO-(CH )qCO H; and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 2 X is selected from the group consisting of K, Q, I, and an amino acid conjugated to a C -C fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a 16 22 linker; X is selected from the group consisting of Q, A, and K(2-[2-(2-amino-ethoxy)-ethoxy]- 30 acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of Aib, Q, H, R, K, aMeK, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of H, Aad, D, Aib, T, A, E, I, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; 5 X is selected from the group consisting of F and aMeF; X is selected from the group consisting of I, L, A, G, F, H, E, V, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, P, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; 10 X is selected from the group consisting of Y and aMeY; is selected from the group consisting of L, aMeL, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of L, I, and K(2-[2-(2-amino-ethoxy)-ethoxy]- acetyl) -( ?-Glu)-CO-(CH )qCO H; 15 X is selected from the group consisting of E, A, S, D-Glu, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of Aib, G, A, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of C, G, G-R and K(2-[2-(2-amino-ethoxy)- 20 ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H; X is absent or is selected from the group consisting of PX X X -R (SEQ ID NO:4), 31 32 33 34 2 PX X X X X X X X -R (SEQ ID NO:5) PX X X X X X X X X -R 32 33 34 35 36 37 38 39 2 , 32 33 34 35 36 37 38 39 40 2 (SEQ ID NO:6) K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H] , 2 2 X X X -R (SEQ ID NO:7) K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO- 32 33 34 2 , 25 (CH ) -CO H] X X X X X X X X -R (SEQ ID NO:8) and K[(2-[2-(2-amino- 2 2 32 33 34 35 36 37 38 39 2 , ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H] X X X X X X X X X -R 2 2 32 33 34 35 36 37 38 39 40 2 (SEQ ID NO:9); wherein: X is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 32 2 2 X is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 33 2 2 X34 is selected from the group consisting of G, C, and K[(2-[2-(2-amino-ethoxy)-ethoxy]- acetyl) -( ?-Glu)-CO-(CH ) -CO H]; X is A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 35 2 2 5 X is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 36 2 2 X is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 37 2 2 X is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 38 2 2 X39 is selected from the group consisting of C, S, and K[(2-[2-(2-amino-ethoxy)-ethoxy]- acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 10 X is selected from the group consisting of C and K[(2-[2-(2-amino-ethoxy)-ethoxy]- acetyl) -( ?-Glu)-CO-(CH ) -CO H]; q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; and R is a modification of the C-terminal group, wherein the modification is NH or absent; or a pharmaceutically acceptable salt thereof; 15 wherein if X is G-R , then X is absent; 30 2 31 wherein no more than one of X , X , X , X , X , X , X , X , X , X X , X , X , 10 12 13 14 16 17 19 20 21 23, 24 26 27 X , X , X X X X X X X X X X and X may be a substituent that 28 29 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 contains a fatty acid; and wherein no more than one of X X X and X may be C; 30, 34, 39, 40 20 wherein if one of X X X and X is C, then none of X , X , X , X , X , X , X , 30, 34, 39, 40 10 12 13 14 16 17 19 X20, X21, X23, X24, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, and X40 is a substituent that contains a fatty acid; or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating type 2 diabetes, NASH or obesity, wherein the compound, or a pharmaceutically 25 acceptable salt thereof, has a GIP:GLP-1 receptor agonist potency ratio as measured after a 60 minute incubation using a casein cAMP assay normalized against GIP and GLP-1 that is about 2.5:1 to about 10:1, the treating comprising: a) administration of a titration dose of said medicament for a minimum of about two weeks; and thereafter 30 b) administration of a maintenance dose of said medicament; wherein the titration dose is about 50% of the maintenance dose.

2. Use of a compound of SEQ ID NO: 3: R X X X GTX TSDX X X X X DX X AX X X X X X X X X 1 1 2 3 6 10 11 12 13 14 16 17 19 20 21 22 23 24 25 26 27 X28X29X30X31 5 wherein: R1 is a modification of the N-terminal amino group wherein the modification is selected from the group consisting of Ac and absent; X1 is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY, X is selected from the group consisting of Aib, aMeP, A, P, and D-Ala 10 or X and X combine to form desH- ?[NHCO]-Aib; X is selected from the group consisting of E, N, Aad, and cTA; X is selected from the group consisting of F, aMeF, and aMeF(2F); X is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, Y, E, aMeF, aMeF(2F), I, aMeY, Q, D-His, D-Tyr, cTA, and K(2-[2-(2-amino-ethoxy)-ethoxy]- 15 acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of S, aMeS, and D-Ser; X is selected from the group consisting of I, S, D-Ile, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl) -( ?-Glu)-CO-(CH2)qCO2H; X is selected from the group consisting of Nle, Aib, L, aMeL, and K(2-[2-(2-amino- 20 ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of L and K, wherein K is conjugated to a C - 14 16 C fatty acid wherein said fatty acid is optionally conjugated to said K via a linker; X is selected from the group consisting of K, E, Orn, Dab, Dap, S, T, H, Aib, aMeK, R, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; 25 X is selected from the group consisting of K, Q, I, and an amino acid conjugated to a C -C fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a 16 22 linker; X is selected from the group consisting of Q, A, and K(2-[2-(2-amino-ethoxy)-ethoxy]- acetyl) -( ?-Glu)-CO-(CH2)qCO2H; 30 X is selected from the group consisting of Aib, Q, H, R, K, aMeK, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of H, Aad, D, Aib, T, A, E, I, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of F and aMeF; X is selected from the group consisting of I, L, A, G, F, H, E, V, and K(2-[2-(2-amino- 5 ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, P, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of Y and aMeY; X is selected from the group consisting of L, aMeL, and K(2-[2-(2-amino-ethoxy)- 10 ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; is selected from the group consisting of L, I, and K(2-[2-(2-amino-ethoxy)-ethoxy]- acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of E, A, S, D-Glu, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; 15 X is selected from the group consisting of Aib, G, A, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of C, G, G-R and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H; X is absent or is selected from the group consisting of PX X X -R (SEQ ID NO:4), 31 32 33 34 2 20 PX X X X X X X X -R (SEQ ID NO:5) PX X X X X X X X X -R 32 33 34 35 36 37 38 39 2 , 32 33 34 35 36 37 38 39 40 2 (SEQ ID NO:6), K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH2) -CO2H] X X X -R (SEQ ID NO:7) K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO- 32 33 34 2 , (CH ) -CO H] X X X X X X X X -R (SEQ ID NO:8) and K[(2-[2-(2-amino- 2 2 32 33 34 35 36 37 38 39 2 , ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH2) -CO2H] X32X33X34X35X36X37X38X39X40-R2 25 (SEQ ID NO:9); wherein: X is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 32 2 2 X is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 33 2 2 X is selected from the group consisting of G, C, and K[(2-[2-(2-amino-ethoxy)-ethoxy]- acetyl) -( ?-Glu)-CO-(CH ) -CO H]; X is A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 35 2 2 X is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 36 2 2 5 X is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 37 2 2 X is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 38 2 2 X is selected from the group consisting of C, S, and K[(2-[2-(2-amino-ethoxy)-ethoxy]- acetyl) -( ?-Glu)-CO-(CH ) -CO H]; X is selected from the group consisting of C and K[(2-[2-(2-amino-ethoxy)-ethoxy]- 10 acetyl) -( ?-Glu)-CO-(CH2) -CO2H]; q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; and R is a modification of the C-terminal group, wherein the modification is NH or absent; or a pharmaceutically acceptable salt thereof; wherein if X is G-R , then X is absent; 30 2 31 15 wherein no more than one of X , X , X , X , X , X , X , X , X , X X , X , X , 10 12 13 14 16 17 19 20 21 23, 24 26 27 X , X , X X X X X X X X X X and X may be a substituent that 28 29 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 contains a fatty acid; and wherein no more than one of X X X and X may be C; and 30, 34, 39, 40 wherein if one of X X X and X is C, then none of X , X , X , X , X , X , X , 30, 34, 39, 40 10 12 13 14 16 17 19 20 X , X , X X , X , X , X , X , X X X X X X X X X X and X 20 21 23, 24 26 27 28 29 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 is a substituent that contains a fatty acid; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating type 2 diabetes, NASH or obesity, wherein the compound, or a pharmaceutically acceptable salt thereof, has a GIP:GLP-1 receptor agonist potency ratio as measured after 25 a 60 minute incubation using a casein cAMP assay normalized against GIP and GLP-1 that is about 2.5:1 to about 10:1, the treating comprising: a) administration of a first titration dose of the medicament for a minimum of about two weeks; and thereafter b) administration of a second titration dose of the medicament for a minimum of 30 about two weeks; and thereafter c) administration of a third titration dose of the medicament for a minimum of about two weeks; and thereafter d) administration of a maintenance dose of the medicament; wherein the first titration dose is about 25% of the maintenance dose, the second 5 titration dose is about 50% of the maintenance dose and the third titration dose is about 75% of the maintenance dose.

3. Use of a compound of SEQ ID NO: 3: R1X1X2X3GTX6TSDX10X11X12X13X14DX16X17AX19X20X21X22X23X24X25X26X27 X X X X 28 29 30 31 10 wherein: R is a modification of the N-terminal amino group wherein the modification is selected from the group consisting of Ac and absent; X is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY, X2 is selected from the group consisting of Aib, aMeP, A, P, and D-Ala; 15 or X and X combine to form desH- ?[NHCO]-Aib; X is selected from the group consisting of E, N, Aad, and cTA; X is selected from the group consisting of F, aMeF, and aMeF(2F); X is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, Y, E, aMeF, aMeF(2F), I, aMeY, Q, D-His, D-Tyr, cTA, and K(2-[2-(2-amino-ethoxy)-ethoxy]- 20 acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of S, aMeS, and D-Ser; X12 is selected from the group consisting of I, S, D-Ile, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of Nle, Aib, L, aMeL, and K(2-[2-(2-amino- 25 ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of L and K, wherein K is conjugated to a C - 14 16 C fatty acid wherein said fatty acid is optionally conjugated to said K via a linker; X is selected from the group consisting of K, E, Orn, Dab, Dap, S, T, H, Aib, aMeK, R, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of K, Q, I, and an amino acid conjugated to a C -C fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a 16 22 linker; X19 is selected from the group consisting of Q, A, and K(2-[2-(2-amino-ethoxy)-ethoxy]- 5 acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of Aib, Q, H, R, K, aMeK, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of H, Aad, D, Aib, T, A, E, I, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; 10 X is selected from the group consisting of F and aMeF; X is selected from the group consisting of I, L, A, G, F, H, E, V, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, P, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; 15 X is selected from the group consisting of Y and aMeY; X is selected from the group consisting of L, aMeL, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of L, I, and K(2-[2-(2-amino-ethoxy)-ethoxy]- acetyl) -( ?-Glu)-CO-(CH )qCO H; 20 X is selected from the group consisting of E, A, S, D-Glu, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH )qCO H; X is selected from the group consisting of Aib, G, A, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl) -( ?-Glu)-CO-(CH2)qCO2H; X is selected from the group consisting of C, G, G-R and K(2-[2-(2-amino-ethoxy)- 25 ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H; X is absent or is selected from the group consisting of PX X X -R (SEQ ID NO:4), 31 32 33 34 2 PX X X X X X X X -R (SEQ ID NO:5) PX X X X X X X X X -R 32 33 34 35 36 37 38 39 2 , 32 33 34 35 36 37 38 39 40 2 (SEQ ID NO:6) K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H] , 2 2 X X X -R (SEQ ID NO:7) K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO- 32 33 34 2 , 30 (CH ) -CO H] X X X X X X X X -R (SEQ ID NO:8) and K[(2-[2-(2-amino- 2 2 32 33 34 35 36 37 38 39 2 , ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H] X X X X X X X X X -R 2 2 32 33 34 35 36 37 38 39 40 2 (SEQ ID NO:9); wherein: X is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 32 2 2 5 X is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 33 2 2 X is selected from the group consisting of G, C, and K[(2-[2-(2-amino-ethoxy)-ethoxy]- acetyl) -( ?-Glu)-CO-(CH ) -CO H]; X is A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 35 2 2 X is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 36 2 2 10 X37 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH2) -CO2H]; X is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -( ?-Glu)-CO-(CH ) -CO H]; 38 2 2 X is selected from the group consisting of C, S, and K[(2-[2-(2-amino-ethoxy)-ethoxy]- acetyl) -( ?-Glu)-CO-(CH ) -CO H]; X is selected from the group consisting of C and K[(2-[2-(2-amino-ethoxy)-ethoxy]- 15 acetyl) -( ?-Glu)-CO-(CH2) -CO2H]; q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; and R is a modification of the C-terminal group, wherein the modification is NH or absent; or a pharmaceutically acceptable salt thereof; wherein if X is G-R , then X is absent; 30 2 31 20 wherein no more than one of X , X , X , X , X , X , X , X , X , X X , X , X , 10 12 13 14 16 17 19 20 21 23, 24 26 27 X , X , X X X X X X X X X X and X may be a substituent that 28 29 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 contains a fatty acid; and wherein no more than one of X X X and X may be C; and 30, 34, 39, 40 wherein if one of X X X and X is C, then none of X , X , X , X , X , X , X , 30, 34, 39, 40 10 12 13 14 16 17 19 25 X , X , X X , X , X , X , X , X X X X X X X X X X and X 20 21 23, 24 26 27 28 29 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 is a substituent that contains a fatty acid; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating type 2 diabetes, NASH or obesity, wherein the compound, or a pharmaceutically acceptable salt thereof, has a GIP:GLP-1 receptor agonist potency ratio as measured after a 60 minute incubation using a casein cAMP assay normalized against GIP and GLP-1 that is about 2.5:1 to about 10:1, the treating comprising: a) administration of a first titration dose of the medicament for a minimum of about two weeks; and thereafter 5 b) administration of a second titration dose of the medicament for a minimum of about two weeks; and thereafter c) administration of a third titration dose of the medicament for a minimum of about two weeks; and thereafter d) administration of a fourth titration dose of the medicament for a minimum of 10 about two weeks; and thereafter e) administration of a fifth titration dose of the medicament for a minimum of about two weeks; and thereafter f) administration of a maintenance dose of the medicament; wherein the first titration dose is about 17% of the maintenance dose, the second titration 15 dose is about 33% of the maintenance dose, the third titration dose is about 50% of the maintenance dose, the fourth titration is about 66% of the maintenance dose and the fifth titration dose is about 83% of the maintenance dose.

4. The use of any one of claims 1 to 3, wherein the treating comprises administration of each of the titration doses for about four weeks before the administration of the next 20 higher dose begins.

5. Use as claimed in any one of claims 1 to 4, substantially as herein described with reference to any example thereof.