The placebo response of injectable GLP-1 receptor agonists vs. oral DPP-4 inhibitors and SGLT-2 inhibitors: a systematic review and meta-analysis.

AIMS: The size of the placebo response in type 2 diabetes (T2DM) treatment and its relation to the route of drug administration have not been systematically reviewed. We aimed to determine weight loss, change in HbA1c and incidence of adverse events after treatment with injectable placebo GLP-1 receptor agonist (GLP-1ra), compared with oral placebo DPP-4 inhibitor (DPP-4i) and placebo SGLT-2 inhibitor (SGLT-2i). METHODS: PubMed, EMBASE and Central were searched up to September 2014 for randomized placebo controlled trials investigating GLP-1ra, DPP-4i or SGLT2-i. Data on placebo groups were extracted and pooled using a generic inverse variance random effects model. RESULTS: Sixty-seven trials were included, involving 2522, 5290 and 2028 patients randomized to placebo GLP-1ra, placebo DPP-4i and placebo SGLT-2i, respectively. Body weight decreased by -0.67 kg (95% CI -1.03, -0.31) after treatment with placebo GLP-1ra (-0.76 kg [95% CI -1.10, -0.43] with placebo short acting GLP-1ra and -0.32 kg [95% CI -1.75, 1.10] with placebo long acting GLP-1ra) and by -0.31 kg (95% CI -0.64, 0.01) with placebo DPP-4i (P = 0.06 for difference with placebo short acting GLP-1ra). Placebo SGLT-2i resulted in an intermediate -0.48 kg (95% CI -0.81, -0.15) weight loss. Weight loss with placebo showed a strong correlation with the active comparator drug (r(2)  = 0.40-0.78). HbA1c changed little with placebo treatment (-0.23%, 0.10% and -0.13% for placebo GLP-1ra, DPP-4i and SGLT-2i). Adverse events occurred frequently with placebo, were often similar to the active comparator drug and led to drop-out in 2.0-2.7% of cases. CONCLUSIONS: The response to placebo treatment was related to its active comparator, with injectable placebo GLP-1ra showing a relevant response on weight, whereas oral placebo DPP4i showed no significant response. These findings may suggest that subjective expectations influence T2DM treatment efficacy, which can possibly be employed therapeutically.

Liraglutide reverses pronounced insulin-associated weight gain, improves glycaemic control and decreases insulin dose in patients with type 2 diabetes: a 26 week, randomised clinical trial (ELEGANT).

AIMS/HYPOTHESIS: The best treatment strategy for a patient with type 2 diabetes who shows pronounced weight gain after the introduction of insulin treatment is unclear. We determined whether addition of a glucagon-like peptide-1 (GLP-1) analogue could reverse pronounced insulin-associated weight gain while maintaining glycaemic control, and compared this with the most practised strategy, continuation and intensification of standard insulin therapy. METHODS: In a 26-week, randomised controlled trial (ELEGANT), conducted in the outpatient departments of one academic and one large non-academic teaching hospital in the Netherlands, adult patients with type 2 diabetes with ≥ 4% weight gain during short-term (≤ 16 months) insulin therapy received either open-label addition of liraglutide 1.8 mg/day (n = 26) or continued standard therapy (n = 24). A computer-generated random number list was used to allocate treatments. Participants were evaluated every 4-6 weeks for weight, glycaemic control and adverse events. The primary endpoint was between-group weight difference after 26 weeks of treatment (intention to treat). RESULTS: Of 50 randomised patients (mean age 58 years, BMI 33 kg/m(2), HbA1c 7.4% [57 mmol/mol]), 47 (94%) completed the study; all patients were analysed. Body weight decreased by 4.5 kg with liraglutide and increased by 0.9 kg with standard therapy (mean difference -5.2 kg [95% CI -6.7, -3.6 kg]; p < 0.001). The respective changes in HbA1c were -0.77% (-8.4 mmol/mol) and +0.01% (+0.1 mmol/mol) (difference -0.74% [-8.1 mmol/mol]) ([95% CI -1.08%, -0.41%] [-11.8, -4.5 mmol/mol]; p < 0.001); respective changes in insulin dose were -29 U/day and +5 U/day (difference -33 U/day [95% CI -41, -25 U/day]; p < 0.001). In five patients (19%), insulin could be completely discontinued. Liraglutide was well tolerated; no severe adverse events or severe hypoglycaemia occurred. CONCLUSIONS/INTERPRETATION: In patients with pronounced insulin-associated weight gain, addition of liraglutide to their treatment regimen reverses weight, decreases insulin dose and improves glycaemic control, and hence seems a valuable therapeutic option compared with continuation of standard insulin treatment. Trial registration ClinicalTrials.gov NCT01392898. Funding The study was funded by Novo Nordisk.

Incorrect performance of the breath hold method in the old underestimates cerebrovascular reactivity and goes unnoticed without concomitant blood pressure and end-tidal CO(2) registration.

BACKGROUND AND PURPOSE: The breath hold maneuver is a convenient and frequently used method to assess cerebrovascular reactivity (CR). This study aimed to assess feasibility and reproducibility of this method in healthy older persons. METHODS: Twenty-five healthy volunteers, aged 75 (SD 4) years, performed 2 consecutive breath holds after careful instruction. Blood pressure (BP-Finapres), cerebral blood flow velocity (CBFV-Transcranial Doppler), and end-tidal CO(2) (capnography) were measured continuously. As reference standard, CR was determined by hyperventilation and CO(2) -inhalation. These measurements were repeated after 3 months in 11 randomly selected subjects. RESULTS: Despite apparent compliance with instructions during performance of breath holding, only 29 of the 50 breath holds (58%) had been accurately executed, which was identified only from BP and end-tidal CO(2) measurements. Incorrect breath holds led to underestimation of CR. For valid breath holds, reproducibility was comparable to the reference method (coefficient of variation 19.4% and 17.6%, respectively). CONCLUSION: The number of inaccurate breath holds was unacceptably high, moreover, these could not be identified from CBFV registrations alone. Therefore, reports of CR based on breath holds in older subjects without coregistration of BP and either end-tidal CO(2) or chest-expansion should no longer be acceptable.