Treatment escalation options for patients with type 2 diabetes after failure of exenatide twice daily or glimepiride added to metformin: results from the prospective European Exenatide (EUREXA) study.

AIMS: To evaluate third-line thiazolidinedione (TZD) or glimepiride therapy in patients inadequately controlled on metformin + exenatide twice daily, and third-line exenatide twice daily in patients inadequately controlled on metformin + glimepiride. METHODS: In this randomized, open-label, multicentre trial, 144 patients with type 2 diabetes inadequately controlled [glycated haemoglobin (HbA1c) >9% (75 mmol/mol) after 3 months' treatment or >7% (53 mmol/mol) at two consecutive visits 3 months apart, after 6 months' treatment] on metformin + exenatide twice daily were re-randomized to add-on TZD or glimepiride, and 166 patients inadequately controlled on metformin + glimepiride received add-on exenatide twice daily. Changes in HbA1c, body mass index (BMI), lipids, hypoglycaemia and vital signs were evaluated. RESULTS: The median duration of triple therapy was ∼2 years. In patients inadequately controlled on metformin + exenatide twice daily, add-on TZD decreased HbA1c levels significantly better than add-on glimepiride: 130-week difference 0.48% [95% confidence interval (CI) 0.19-0.77] or 5.2 mmol/mol (95% CI 2.1-8.4; p = 0.001), but with significantly increased BMI and systolic blood pressure. The ratio of documented symptomatic (blood glucose ≤70 mg/dl [3.9 mmol/l]) hypoglycaemia rates for add-on glimepiride to add-on TZD was 8.48 (p < 0.0001). Add-on exenatide twice daily after metformin + glimepiride significantly reduced HbA1c levels: mean [standard deviation (s.d.)] change from baseline -0.35 (0.89)% [-3.8 (9.7) mmol/mol] and BMI: mean (s.d.) change from baseline -0.82 (1.9) kg/m(2) at 130 weeks, with a slightly increased rate of documented symptomatic hypoglycaemia from metformin + glimepiride (ratio 1.49). CONCLUSIONS: TZD, but not glimepiride, was an effective and well tolerated third-line therapy in patients without glycaemic control after long-term therapy with metformin + exenatide twice daily. Exenatide twice daily was an effective and well tolerated third-line therapy in patients inadequately controlled on metformin + glimepiride.

A placebo-controlled trial of exenatide twice-daily added to thiazolidinediones alone or in combination with metformin.

AIM: To test the hypothesis that glycaemic control with exenatide added to thiazolidinediones (TZDs) with or without metformin was superior to placebo. METHODS: A 26-week, multi-country (Canada, Mexico, Romania, South Africa and the USA), randomized, double-blind, placebo-controlled study compared exenatide twice-daily vs. placebo in 165 subjects suboptimally controlled with TZDs with or without metformin [HbA(1c) 8.2% (s.d. 0.9), fasting serum glucose 9.1 (2.6) mmol/l, body weight 93.9 (17.8) kg, diabetes duration 6.4 (4.3) years]. After a 2-week, single-blind, lead-in period, subjects were randomly assigned (2 : 1) to add exenatide or placebo to current regimens. The primary endpoint was HbA(1c) change at endpoint (Week 26 or last-observation-carried-forward). RESULTS: Only 8 subjects were treated with concomitant TZD alone. Exenatide reduced HbA(1c) significantly more than placebo [-0.84% (s.e. 0.20) vs. -0.10% (0.23), treatment difference -0.74% (0.16), p < 0.001)]. Mean reductions in body weight were similar in both treatments at endpoint [exenatide, -1.4 (s.e. 0.6) kg vs. placebo, -0.8 (0.7) kg, p = 0.176)]. Nearly 71% of subjects had both a reduction in HbA(1c) and body weight with exenatide compared with 54% with placebo. The most common adverse events (exenatide vs. placebo) were nausea (12% vs. 2%, p = 0.037), vomiting (8% vs. 0%, p = 0.031) and headache (4% vs. 4%). Confirmed (blood glucose <3.0 mmol/l) minor hypoglycaemia was experienced by 4 and 2% of subjects treated with exenatide and placebo, respectively. Incidence of hypoglycaemia was not significantly different between groups. CONCLUSIONS: Exenatide added to TZDs alone or in combination with metformin significantly improved glycaemic control as determined by significant improvement in HbA(1c) without associated hypoglycaemia.

Normokalemic thyrotoxic periodic paralysis: a new therapeutic strategy.

An unusual presentation of periodic paralysis in a Mexican man with thyrotoxicosis is presented. The patient suffered paralysis of the lower extremities without apparent precipitating factors such as hypokalemia, exercise, carbohydrate or alcohol ingestion. Hyperthyroidism was managed first with a thyroid suppressant (methimazole) and propranolol. Prednisone was added after another episode of paralysis. Definitive treatment of hyperthyroidism was achieved with radioactive iodine, which subsequently required substitution therapy with thyroxine. A moderate dose of thyroxine (100 microg) caused muscular weakness. Treatment of thyrotoxicosis and flaccid paralysis as well as the effects of glucocorticoids on thyroid function are discussed.