- Src: Chia(2008)JCEM:Incretin-based Tx in T2DM
- "Incretins":
- GLP-1=glucagon-like peptide-1 (from L cells)
- GIP=glucose-dependent insulinotropic polypeptid (from K cells)
- secreted from enteroendocrine cells pp'ly in response to ingested nutrients (but not IV glucose) [NB: MF, orlistat, alpha-glucosidase inhibitors icr GLP-1]
- increase insulin secretion through activation of specific receptors
- in T2DM
- in early T2DM: nml [/icrd] levels of GLP-1 and GIP.
- in long-standing T2DM: dcrd GLP-1 response, GIP nml.
- in T2DM: 3-5fold dcrd insulin response to exog GLP-1 but allows nmlization of insulin and glucose, whereas exog GIP (even supraphysiol doses) with little/no effect
- NB GLP-1 can achieve nm FPB even if no longer responsive to SU and MF
- other Tx GLP-1 effects
- dcr glucagon secretion in hi/nm-glycemia: better insul sensitivity and glyc control
- slower gastric emptying and gut motility: better gluc pp'ly, icrd satiety: less food intake: wt loss: better insulin sensitivity
- GLP-1 sc bolus preprandially [or similarly sc cont for 12wk]: improved beta-cell fx and restoration of first-phase insulin secretion
- GLP-1 in animals: icr islet size, icr beta-cell proliferation, dcr beta-cell apoptosis
- T1/2=2min through degradation by dipeptidyl peptidase (DPP) 4 and hydrolysis by neutral endopeptidase (NEP) 24.11
- Tx approaches: GLP-1 mimetics (GLP-1R agonists) with longer T1/2 (exenatide, liraglutide); or DPP4 inhibitors (sitagliptin, vildagliptin)
- GLP-1 mimetics:
- Exenatide
- (synthetic exendin-4, 39AA): binds and activates GLP-1R, but not substrate for DPP4 and less susceptible to NEP hydrolysis
- T1/2=3.3-4h, needs sc admin, in plasma after 15h, biolog. effect 8h after dosing, elim by renal glom filtr
- efficacy: 10mcg bd as adjuv Tx ~50% achieved A1c<=7% (cf vs 10% with placebo, 50% with glargine, 25% biphasic insulin aspart); dcr HbA1c of 0.8-1.1% for up to 3yr
- progressive wt loss 1.6-2.8kg at 30wk, 5.3 at 3yr
- antiexenatide antibodies in 45% (but no effect on glyc contr)
- SE: severe hypoglyc rare; mild/mod hypoglyc 16/17% (esp if on SU); N&V (57% & 17%) esp initial 8wks; withdrawal rates 4% bo GI SE [aj: pancreatitis?!]
- Liraglutide
- icrd binding to albumin, dcrd renal clearance, dcrd sc absorption rate
- Unresolved:
- effects on beta-cell mass in humans;
- mechanism of lowering the icrd glucagon levels (fasting/pp) in T2DM (?direct effect on alpha-cells, ?!paracrine effects, ?via ANS)
- DPP4 Inhibitors:
- Sitagliptin
- selective DPP4 inhibitor: peak plasma 1-6h after dosing, T1/2 8-14h, bioavail 87% (with/without food); 80% renally excreted (unchanged) in 2-4h, 15% metab by liver (CYP); at 100mg od [dcr to 50|25mg if GFR<50|30] inhibits >80% DPP4 activity
- efficacy: HbA1c dcrd 1.9% with sitagliptin+MF after 24wk (vs 1.1% with MF vs 0.6% sitagliptin); adjuvant Tx with MF/glipizide/pioglitazone: A1c dcr 0.6% (vs placebo) up to 52wk (although nadir at ~27wk!)
- SE: nasopharyngitis [, UTI, headache]; wt neutral, and no effect on gastric emptying
- Vildagliptin
- selective reversible competitive DPP4 inhibitor; shorter T1/2 of 2h; at 100mg od inhibits 98%|60% of DPP4 activity after 45min|24h; 85% hydrolyzed in liver; 15% excreted by kidneys; no apparent effects of liver impairment; max HbA1c dcr after ~27wk, then gradual icr; similar efficacy as rosiglit 8mg od, but less than MF 1g bd; as adjuvant Tx dcr A1c by 0.6% with SU, 0.9% with MF, 1.0% with TZD, 0.5% with insulin
- Unresolved:
- ?effect on beta-cell mass in humans
- ?additional modulating effects other than the modest icr in active GLP-1 levels [NB: no changes in insulin and C-peptide levels]
- Summary:
- Exenatide [|Liraglutide?]
- sustained 1.0[|1.5?]% A1c dcr, improved beta-cell fx and wt loss; drawback sc inj, but a/w LA (wkly) formulations
- Sitagliptin[|Vildagliptin]
- oral monotherapy 0.6% A1c dcr after 54wk [|1.2% after 24wk, but return to pre-Tx A1c after 108wk]; need long-term results and Ix of ?DPP4 substrates
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