- Pioglitazone: 15 mg, 30 mg, 45 mg.
- Fixed-dose combinations: 15 mg pioglitazone/850 mg metformin twice daily.
Dose–response relationship is weak; this, together with the variable and gradual glycemic response, reinforces the importance of the start-low, go-slow approach.
Pioglitazone is no longer licensed as monotherapy. The 2009 NICE guidelines propose the following possible combinations:
- as second-line treatment added to metformin rather than a sulphonylurea, when there is a risk of hypoglycemia or in the rare case of sulphonylurea intolerance (a minor indication with the introduction of DPP-4 inhibitors);
- as third-line treatment added to metformin and sulphonylurea when insulin is not desirable or desired;
- pioglitazone with insulin if glycemic control is poor on high-dose insulin or if there previously has been a good glycemic response to a glitazone (see below).
The logical combination of exenatide and a glitazone (with or without metformin) improves glycemic control and causes significant weight loss, at least in a short study . Another similar potential, but unlicensed, scenario for glitazones would be addition to GLP-1-containing regimens, where weight loss has been substantial but glycemic improvement limited.
Glitazone use has fallen markedly since 2007. However, in patients who respond without significant adverse effects, durability of glycemic control can be clinically striking. The trial results in secondary prevention patients – the likely benefit of pioglitazone in PROactive and that of metformin plus rosiglitazone in BARI 2D – contrasts with the limitations of their use in real life in these patient groups.
r-Glucosidase inhibitors (BNF, section 22.214.171.124)
These drugs, in vogue in the early 1990s but much less used now (they do not figure in the current NICE guidelines), inhibit enzymes that break down polysaccharides and sucrose in the small intestine, resulting in delayed absorption of glucose and lower postprandial peaks, though the total amount of glucose absorbed is unchanged. In addition, postprandial lipemia is improved. Although early studies suggested they stimulate incretins, this is probably not a significant clinical effect.
Acarbose was used in a UKPDS substudy, where it reduced HbA1c levels by about 0.5% (5 mmol/mol). This value is consistent across several studies, though in a head-to-head monotherapy comparison with the DPP-4 inhibitor vildagliptin both achieved reductions of about 1.3% (15 mmol/mol) from a mean baseline of 8.6% (70 mmol/mol), but acarbose caused greater weight loss (1.3 kg) . However, its perceived low glycemic impact, together with significant gastrointestinal side-effects, especially flatulence, has limited its use. The STOP-NIDDM trial (2002) demonstrated a powerful effect of acarbose in reducing progression of IGT to type 2 diabetes, though only while the drug was taken, a consistent finding in pharmacological compared with lifestyle interventions. Voglibose also reduces the risk of progression from IGT to diabetes. STOP-NIDDM controversially also found a reduction in cardiovascular events and new-onset hypertension. Acarbose is the only agent in use in the UK; elsewhere, voglibose and miglitol are available. Dose escalation should be slow, for example acarbose 25–50mg with the main meal of the day, increasing to 50 mg t.d.s. (100 mg t.d.s. is the maximum recommended dose and has been associated with abnormal liver function tests). Gastrointestinal side-effects decrease over the first 4–6 weeks of treatment, and do not appear to be greater even when acarbose is combined with metformin. Complete neglect of these agents is probably not justified, especially acarbose and voglibose, which are not significantly absorbed systemically; they can be added to combination therapy.
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David Levy, MD, FRCP, Consultant Physician, Gillian Hanson Centre, Whipps Cross University Hospital; Honorary Senior Lecturer
Queen Mary University of London London, UK
This edition first published 2011, © 2011 by David Levy. 1st edition 1998 (Greenwich Medical Media/Cambridge University Press) 2nd edition 2006 (Altman Publications)