Which is the eligible patient to be treated with pioglitazone? The expert view.

Pioglitazone has an important role in the treatment of patients with Type 2 diabetes. The drug can help patients to achieve sustained glycemic control and may delay the requirement for insulin. Pioglitazone may provide benefits beyond its effects on glycemia, with data suggesting it may confer anti-atherosclerotic and cardioprotective properties. Attention should be given to possible side effects relating to class effects of TZD, and selection of appropriate patients to be prescribed pioglitazone will enable optimum benefits to be derived from pioglitazone treatment.

Comparing the actions of older and newer therapies on body weight: to what extent should these effects guide the selection of antidiabetic therapy?

BACKGROUND: Type 2 diabetes patients are usually overweight or obese. Further weight gain induced by antidiabetic treatment should be avoided if possible. Much attention has been focussed recently on the potential for GLP-1 mimetics, in particular, to reduce weight. AIMS: Effects on weight are but one of several important criteria in selecting antidiabetic therapy, however. This review explores the effects on weight of older classes of antidiabetic agents (metformin, sulfonylureas, thiazolidinediones) and the newer drugs acting via the GLP-1 system. Other aspects of their therapeutic profiles and current therapeutic use are reviewed briefly to place effects on weight within a broader context. FINDINGS: Comparative trials demonstrated weight neutrality or weight reduction with metformin, and weight increases with a sulfonylurea or thiazolidinedione. There was no clinically significant change in weight with DPP-4 inhibitors and a small and variable decrease in weight (about 3 kg or less) with GLP-1 mimetics. Improved clinical outcomes have been demonstrated for metformin and a sulfonylurea (cardiovascular and microvascular benefits, respectively, in the UK Prospective Diabetes Study), and secondary endpoints improved modestly with pioglitazone in the PROactive trial. No outcome benefits have been demonstrated to date with GLP-1-based therapies, and these agents exert little effect on cardiovascular risk factors. Concerns remain over long-term safety of these agents and this must be weighed against any potential benefit on weight management. CONCLUSIONS: Considering effects on weight within the overall risk-benefit profile of antidiabetic therapies, metformin continues to justify its place at the head of current management algorithms for type 2 diabetes, due to its decades-long clinical evidence base, cardiovascular outcome benefits and low cost.

Effects of early use of pioglitazone in combination with metformin in patients with newly diagnosed type 2 diabetes.

BACKGROUND: Type 2 diabetes is characterised by a progressive decline in HbA1c control over time. Early combination therapy, rather than sequential introduction of individual oral glucose-lowering agents, has been proposed to prevent this gradual rise in HbA1c. This observational study assessed the effect of early dual combination oral glucose-lowering therapies within 6 months of diagnosis in newly diagnosed, drug-naïve patients with type 2 diabetes. PATIENTS AND METHODS: This was an observational, open-label, non-randomised study in newly diagnosed patients with type 2 diabetes, aged 35-70 years, with HbA1c levels > 8.0% at diagnosis or > 7.0% at the 3-6-month follow-up. Patients were allocated to dietary management alone if the HbA1c level was 7.0-8.0% at diagnosis. Metformin combined with gliclazide, repaglinide, or pioglitazone was given at diagnosis if the HbA1c was > 8.0%. Similar treatments were introduced at 3-6 months if the HbA1c was > 7.0%. Over a 3-year period, HbA1c was measured at 3-monthly intervals. All patients underwent regular dietetic review. Target HbA1c was < or = 7.0%. RESULTS: 416 patients were considered eligible for inclusion, with a mean (+/- SD) age of 54.1 +/- 9.2 years, BMI of 33.5 +/- 6.1 kg/m2, and baseline HbA1c of 8.6 +/- 1.7%. A mixed model analysis of variance on the 178 patients who started with combination therapy, either immediately or after a 3-6 month period on diet, showed that metformin plus gliclazide, repaglinide, or pioglitazone was associated with a gradual increase in HbA1c values. Amongst those patients treated with the metformin/pioglitazone combination there was an estimated 0.1% increase in HbA1c/year. This was much less pronounced than the rises seen in HbA1c/year of 0.5% with the metformin/gliclazide and metformin/repaglinide combinations. CONCLUSIONS: This preliminary analysis of an observational, non-randomised, open-label ongoing study has shown that early use of combination therapy at time of diagnosis or within the first 3-6 months following diagnosis with metformin plus pioglitazone in newly diagnosed type 2 diabetes results in a slower deterioration in glycaemic control than that with metformin combined with either gliclazide or repaglinide. This may be due to the beta-cell protective properties of pioglitazone. These results need to be confirmed by further studies with a more robust design and methodology.

Nateglinide--current and future role in the treatment of patients with type 2 diabetes mellitus.

Therapy for type 2 diabetes mellitus should aim to control not only fasting, but also postprandial glucose levels. Nateglinide, a d-phenylalanine derivative, restores postprandial early phase insulin secretion in a transient and glucose-sensitive manner without affecting basal insulin levels. As nateglinide is administered immediately before meals it provides greater lifestyle flexibility than agents that require patients to eat to avoid hypoglycemic events (e.g. long-acting sulfonylureas). In randomised, double-blind trials in patients with type 2 diabetes, nateglinide monotherapy (mealtime treatment of 120 mg three times daily) significantly improved long-term glycaemic control by significantly reducing glyated haemoglobin (HbA 1c) and preventing mealtime glucose spikes. The combination of nateglinide with insulin-sensitising agents, for example, metformin and thiazolidinediones, addresses the dual defects of loss of insulin secretion and insulin resistance to provide optimal management of type 2 diabetes, and more patients achieve HbA 1c goal with nateglinide combination therapy rather than with monotherapy with other oral agents. Nateglinide also restores early insulin secretion and reduces postprandial hyperglycaemia in prediabetic subjects with impaired glucose tolerance (IGT) and appears similarly effective in elderly and non-elderly populations with type 2 diabetes. It has an excellent safety and tolerability profile, with a low propensity to cause hypoglycaemia due to its transient, selective effect on early phase insulin secretion. Nateglinide as monotherapy or combination therapy is an effective option to reduce mealtime glucose in patients with type 2 diabetes. The results of ongoing research into its potential role in delaying progression to overt diabetes, and protecting against cardiovascular events, in prediabetic patients with IGT are awaited.

The Clinical Significance of PPAR Gamma Agonism.

Insulin resistance is a principal underlying defect in type 2 DM along with beta-cell dysfunction, and this insulin resistance underpins many of the abnormalities associated with the metabolic syndrome. Peroxisome-proliferator-activated receptor gamma agonists (PPARgamma agonists), also known as glitazones or thiazolidinediones (TZDs) are powerful insulin sensitisers with recent evidence suggesting that they also have a potential to improve pancreatic beta-cell function. TZDs cause a major redistribution of body fat with a decrease in visceral and hepatic fat content with a resultant increase in insulin sensitivity. The glucose lowering effects of TZDs are similar to those seen with the well-established sulphonylureas and metformin. TZDs have a small reducing effect on blood pressure and have been shown to reduce microalbuminuria independent of their blood glucose lowering effect. Both TZDs in clinical practice, pioglitazone and rosiglitazone, reduce small dense LDL-cholesterol and increase HDL-cholesterol levels but pioglitazone would appear to have a more pronounced benefit on these two parameters with a greater reduction in plasma triglycerides. TZDs improved the pro-coagulant state and show benefits in improving endothelial dysfunction and reducing 'non-traditional' inflammatory cytokines and increasing adiponectin levels. The greatest benefit for the TZDs is to directly influence atherogenesis itself and the potential that these so-called pleiotrophic effects of TZDs to reduce cardiovascular events in type 2 DM will be tested when the results of outcome trials are published in the next few years. If the results are positive for the reduction in vascular end-points, then TZDs will represent a major advance in improving the prognosis of type 2 DM subjects with the metabolic syndrome.

Long-term glycaemic control with pioglitazone in patients with type 2 diabetes.

Patients with type 2 diabetes have dual defects: insulin resistance and beta-cell dysfunction. Thiazolidinediones (TZDs), a new class of oral drugs used for the treatment of type 2 diabetes, reduce insulin resistance via an action on peroxisome proliferator-activated receptors. There is also growing evidence that TZDs may preserve beta-cell function. Pioglitazone is a TZD that provides appropriate monotherapy or combination treatment for patients with type 2 diabetes. Studies of up to 32-week duration have shown that pioglitazone significantly reduces HbA1c and fasting plasma glucose when used alone or in combination with another glucose-lowering agent. Four recently published 52-week clinical trials, involving over 3700 patients with type 2 diabetes, show that pioglitazone is an effective long-term treatment, both as monotherapy and in combination with metformin or sulphonylurea. As well as maintaining glycaemic control over the long term, pioglitazone also confers benefits in terms of improvements in fasting insulin, lipid parameters, C-peptide and 32,33-split proinsulin (independent predictors of cardiovascular risk) and hypoglycaemia compared with other monotherapies or combination therapies. It is well tolerated, with a low incidence of adverse events. These long-term data support the concept that pioglitazone should be used earlier in the treatment of type 2 diabetes, either as monotherapy or as add-on therapy.

Hashimoto's encephalopathy presenting as an acute medical emergency.

Three cases are described of a reversible encephalopathy, all presenting with marked neurological disturbance. In all three, the diagnosis was not clear at the time of presentation but eventually it was felt all of the cases were consistent with Hashimoto's encephalopathy. The diagnosis of Hashimoto's encephalopathy should be considered in any case of unexplained encephalopathy. Common features are high anti-thyroid peroxidase antibody titres, an abnormal EEG and an elevated CSF protein concentration. The encephalopathy is independent of thyroid hormonal status. Treatment with corticosteroids leads to a prompt resolution of symptoms and long-term low dose steroid therapy prevents further neurological recurrence.

Incidence of blindness due to diabetic eye disease in Fife 1990-9.

AIMS: In the light of goals for reducing blindness due to diabetes, published in the St Vincent Declaration, 1989, the aim of this study was to find the incidence and prevalence of blindness in the diabetic population of Fife. METHODS: All blind registrations for the period 1990-9 were studied. Those with diabetes as the first or main diagnosis were included as new diabetic blind. The prevalence of diabetes was studied in a large sample population and extrapolated to the estimated population of Fife. RESULTS: The incidence of blindness due to diabetes was 64 (SD 24, 95% CI 49-79) per 100 000 diabetic population/year. The point prevalence of blindness due to diabetes on 31 December 1999 was 210 per 100 000 diabetic population. CONCLUSION: The incidence of blindness due to diabetes, in a diabetic population, is now known. Without this benchmark it is impossible to assess the implementation of the St Vincent Declaration.

Sex hormones induce insulin resistance in 3T3-L1 adipocytes by reducing cellular content of IRS proteins.

AIM/HYPOTHESIS: Numerous studies have suggested a relation between sex hormones and insulin sensitivity but the ability of sex hormones to directly influence insulin action in peripheral tissues has not been investigated. METHODS: We have examined the effects of estriol, estradiol and estrone on insulin action in cultured 3T3-L1 adipocytes, a useful model of adipocytes. RESULTS: Treatment of these cells with each of these sex hormones resulted in a statistically significant reduction in the ability of insulin to stimulate glucose transport independently of a reduction in total cellular GLUT-4 content. This diminished ability of insulin to stimulate glucose transport was accompanied by a reduction in the total cellular content of insulin receptor substrates -1 and -2 and the p85alpha subunit of phosphatidylinositol 3'-kinase. By contrast, cellular content of protein kinase B was unchanged by hormone treatment but the magnitude of insulin-stimulated kinase activity was statistically significantly reduced after incubation with each of the sex hormones tested. We have further shown that treatment of 3T3-L1 adipocytes with these hormones alters the subcellular distribution of insulin receptor substrate proteins such that the particulate and soluble pools of these proteins were differentially affected by hormone treatment. CONCLUSION/INTERPRETATION: These data show that sex hormones can directly induce a state of insulin resistance in 3T3-L1 adipocytes in culture. The mechanism of this defect seems to be at least in part due to decreased cellular content and altered subcellular distribution of insulin receptor substrate proteins which in turn results in a reduction in proximal insulin-stimulated signalling cascades.

Antidiabetic drugs present and future: will improving insulin resistance benefit cardiovascular risk in type 2 diabetes mellitus?

Results from the United Kingdom Prospective Diabetes Study showed that intensive treatment of type 2 (non-insulin-dependent) diabetes mellitus, with sulphonylureas or insulin, significantly reduced microvascular complications but did not have a significant effect on macrovascular complications after 10 years. Insulin resistance plays a key role in type 2 diabetes mellitus and is linked to a cluster of cardiovascular risk factors. Optimal treatment for type 2 diabetes mellitus should aim to improve insulin resistance and the associated cardiovascular risk factors in addition to achieving glycaemic control. Treatment with sulphonylureas or exogenous insulin improves glycaemic control by increasing insulin supplies rather than reducing insulin resistance. Metformin and the recently introduced thiazolidinediones have beneficial effects on reducing insulin resistance as well as providing glycaemic control. There is evidence that, like metformin, thiazolidinediones also improve cardiovascular risk factors such as dyslipidaemia and fibrinolysis. Whether these differences will translate into clinical benefit remains to be seen. The thiazolidinediones rosiglitazone and pioglitazone have been available in the US since 1999 (with pioglitazone also being available in Japan). Both products are now available to physicians in Europe.

Bilateral optic atrophy following diabetic ketoacidosis.

Diabetic ketoacidosis (DKA) can result in neuropathic abnormalities of the somatic and the autonomous nervous systems. We report the case of a 50-year-old man with Type 1 diabetes of 20-year duration who after severe DKA lost vision in his right eye and only retain partial vision in his left. This case demonstrates that optic neural tissue is vulnerable to haemodynamic and metabolic complications of DKA.

Overlap of IGF- and heparin-binding sites in rat IGF-binding protein-5.

Using site-directed mutagenesis, we have undertaken a study of a potential IGF-binding site in the C-terminal domain of rat IGFBP-5, lying close to or within a previously described heparin-binding domain (residues 201-218) in this protein. After analysis of binding activity using three different methods - ligand blotting, solution phase equilibrium binding and biosensor measurement of real-time on- and off-rates - we report that the mutation of two highly conserved residues within this region (glycine 203 and glutamine 209) reduces the affinity of the binding protein for both IGF-I and IGF-II, while having no effect on heparin binding. In addition, we confirm that mutation of basic residues within the heparin-binding domain (R201L, K202E, K206Q and R214A) results in a protein that has attenuated heparin binding but shows only a small reduction in affinity for IGF-I and -II. Previous findings have described the reduction in affinity of IGFBP-5 for IGFs that occurs after complexation of the binding protein with heparin or other components of the extracellular matrix (ECM) and have postulated that such an interaction may result in conformational changes in protein structure, affecting subsequent IGF interaction. Our data suggesting potential overlap of heparin- and IGF-binding domains argue for a more direct effect of ECM modulation of the affinity of IGFBP-5 for ligand by partial occlusion of the IGF-binding site after interaction with ECM.