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/m², HbA_1c 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?1c 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?p?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.     

Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised,placebo-controlled study

Aims/hypothesis

Liraglutide can modulate insulin secretion by directly stimulating beta cells or indirectly through weight loss and enhanced insulin sensitivity. Recently, we showed that liraglutide treatment in overweight individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) led to greater weight loss (?7.7% vs ?3.9%) and improvement in insulin resistance compared with placebo. The current study evaluates the effects on beta cell function of weight loss augmented by liraglutide compared with weight loss alone.

Methods

This was a parallel, randomised study conducted in a single academic centre. Both participants and study administrators were blinded to treatment assignment. Individuals who were 40–70 years old, overweight (BMI 27–40 kg/m²) and with prediabetes were randomised (via a computerised system) to receive liraglutide (n?=?35) or matching placebo (n?=?33), and 49 participants were analysed. All were instructed to follow an energy-restricted diet. Primary outcome was insulin secretory function, which was evaluated in response to graded infusions of glucose and day-long mixed meals.

Results

Liraglutide treatment (n?=?24) significantly (p?≤?0.03) increased the insulin secretion rate (% mean change [95% CI]; 21% [12, 31] vs ?4% [?11, 3]) and pancreatic beta cell sensitivity to intravenous glucose (229% [161, 276] vs ?0.5% (?15, 14]), and decreased insulin clearance rate (?3.5% [?11, 4] vs 8.2 [0.2, 16]) as compared with placebo (n?=?25). The liraglutide-treated group also had significantly (p?≤?0.03) lower day-long glucose (?8.2% [?11, ?6] vs ?0.1 [?3, 2]) and NEFA concentrations (?14 [?20, ?8] vs ?2.1 [?10, 6]) following mixed meals, whereas day-long insulin concentrations did not significantly differ as compared with placebo. In a multivariate regression analysis, weight loss was associated with a decrease in insulin secretion rate and day-long glucose and insulin concentrations in the placebo group (p?≤?0.05), but there was no association with weight loss in the liraglutide group. The most common side effect of liraglutide was nausea.

Conclusions/interpretation

A direct stimulatory effect on beta cell function was the predominant change in liraglutide-augmented weight loss. These changes appear to be independent of weight loss.

Trial registration

ClinicalTrials.gov NCT01784965

Funding

The study was funded by the ADA.     

Human preferences for sexually dimorphic faces may be evolutionarily novel

A large literature proposes that preferences for exaggerated sex typicality in human faces (masculinity/femininity) reflect a long evolutionary history of sexual and social selection. This proposal implies that dimorphism was important to judgments of attractiveness and personality in ancestral environments. It is difficult to evaluate, however, because most available data come from large-scale, industrialized, urban populations. Here, we report the results for 12 populations with very diverse levels of economic development. Surprisingly, preferences for exaggerated sex-specific traits are only found in the novel, highly developed environments. Similarly, perceptions that masculine males look aggressive increase strongly with development and, specifically, urbanization. These data challenge the hypothesis that facial dimorphism was an important ancestral signal of heritable mate value. One possibility is that highly developed environments provide novel opportunities to discern relationships between facial traits and behavior by exposing individuals to large numbers of unfamiliar faces, revealing patterns too subtle to detect with smaller samples.Inspired by evidence from nonhuman species indicating that exaggerated sex-typical traits (e.g., large antlers, peacock tails) are often attractive to mates or intimidating to rivals (1, 2), morphological sex typicality in humans (masculinity in men and femininity in women) has been the focus of considerable research into attractiveness judgments (3, 4). Facial attractiveness research has been revolutionized by this explanatory framework from the biological sciences, which proposes that attractive human faces honestly signaled mate value within ancestral environments.An influential proposal is that facial femininity is a signal of fertility in human female faces (4–9) because, within same-age women, it is associated with estrogens (10), which, in turn, are related to measures of reproductive health (11). Like ovarian function, facial femininity declines with age in adulthood (12, 13). The proposal that fertile women should be attractive to men is seemingly uncontroversial because males who discriminatively mate with fertile females should achieve a straightforward reproductive advantage over those males who do not, with all other factors being equal (6). Although direct associations between facial femininity and fertility have not been demonstrated, the consensus from Western preferences, and from the limited cross-cultural data available, is that femininity is attractive, as predicted by the fertility hypothesis (14–17). In environments where fertility is high and variable, this relationship should be even more apparent.In male faces, masculinity has been variously proposed to signal heritable disease resistance (“good genes” or “immunocompetence”) (4, 15, 18–22) and/or perceived as a cue of aggressiveness and, consequently, intrasexual competitiveness (22, 23). The “honesty” of face shape as an indicator of immunocompetence is proposed to be the result of an immunosuppressive effect of testosterone. Because testosterone influences the growth of sex-typical traits in many species (24, 25), masculine facial shape is proposed to be a costly, and thus honest, signal of male quality (22). The hypothesis that cues of heritable health should be attractive to females is widely accepted (26), although the evidence for a link between heritable health and masculinity in humans is tentative at best (22).Support for a link between masculinity and aggression is largely indirect, and it consists of an association between testosterone and both aggressive behavior (27, 28) and face shape (25), in addition to the fact that honest signaling of dominance is commonly observed in nonhuman species (3). Masculine faces are perceived as aggressive in those groups (i.e., urban, Western) where the relationship has been tested (29). Because masculinity may signal both (desirable) immunity and (potentially costly) aggression in humans, some authors have proposed that preferences for masculinity reflect women trading-off benefits of traits putatively associated with health against those traits associated with prosocial behaviors, such as parental investment (23, 30, 31).Consistent with both of these proposals, data indicate that preferences for masculinity are stronger in circumstances where indirect benefits (heritable quality) can be realized without accompanying direct costs (aggression and low paternal investment). Such circumstances include judging attractiveness in the context of a short-term (vs. a long-term) relationship (32) and in the follicular phase of the menstrual cycle when conception following intercourse is most likely (33). Masculinity is also reported to be more strongly preferred in environments with relatively high pathogen burdens (19, 30) and in environments with higher local homicide rates (23), which has been interpreted as a response to variation in the benefits of heritable disease resistance (19) and in the net benefits conferred by aggressive males under varying levels of male–male competition (23).All of this supporting evidence comes with a very important caveat; although there has been some cross-cultural work in this area (34), the majority of studies have been conducted in Western, often student, populations characterized by high levels of development and urbanization [Western, educated, industrialized, rich, and democratic; so-called WEIRD participants (35)]. Research on preferences in other groups is scant and methodologically inconsistent, using Internet-based designs or a limited cross-cultural component (7, 15–18). Because there are differences between Western/non-Western and industrial/small-scale societies in many behaviors, including aspects of visual perception and mate choice (35), this over-representation greatly limits generalizability. Perhaps most importantly, large-scale (post)industrial societies present inhabitants with large numbers of unfamiliar faces and provide venues for the efficient exchange of (visual) social information (e.g., posters, television, Internet); these factors may be instrumental in the acquisition and reinforcement of preferences (36–39). It is possible therefore that rather than being a legacy of ancestral selection pressures, preferences for dimorphism emerge in large urban groups as a byproduct of the information-processing strategies used to process large amounts of social information or in response to arbitrary cultural norms.Development also introduces an increased presence of highly differentiated social roles that arise from a greater division of labor, along with opportunities to acquire prestige without strength or aggression. Because partner preferences have been proposed to develop in response to sex-typical social roles (40, 41), it is possible that increasingly differentiated roles could influence masculinity preferences if desirable social roles not present in less developed groups are associated with facial appearance.We assessed preferences for, and trait attributions made to, faces varying in dimorphism in a cross-cultural sample of 12 groups, including non-Western, nonstudent, and small-scale societies (n = 962; Tables S1 and S2). We tested the predictions, derived from the immunocompetence handicapping hypothesis, that (i) preferences for dimorphism will be stronger in less developed groups and (ii) masculine faces would be perceived as aggressive in all populations, with perceptions in low-development groups at least as strong as in groups with high development. We estimated social development with the Human Development Index (HDI), which is a composite indicator compiled by the United Nations Development Program. To investigate which aspects of development were associated with variation in perception of our facial stimuli, we took the World Health Organization measures of years lost to disease and United Nations (UN) measures of homicide rates as proxy measures of disease burden and male intrasexual competition, respectively (both log-transformed), and UN measures of levels of urbanization. Using these national statistics almost certainly underestimates disease burden in the small-scale societies in our sample, which is a conservative estimate with regard to our hypotheses.

Table 1.

Summary information for the groups tested

Interventions in the management of infection in the foot in diabetes: a systematic review

The optimal approaches to managing diabetic foot infections remain a challenge for clinicians. Despite an exponential rise in publications investigating different treatment strategies, the various agents studied generally produce comparable results, and high‐quality data are scarce. In this systematic review, we searched the medical literature using the PubMed and Embase databases for published studies on the treatment of diabetic foot infections as of June 2018. This systematic review is an update of previous reviews, the first of which was undertaken in 2010 and the most recent in 2014, by the infection committee of the International Working Group of the Diabetic Foot. We defined the context of literature by formulating clinical questions of interest, then developing structured clinical questions (PICOs) to address these. We only included data from controlled studies of an intervention to prevent or cure a diabetic foot infection. Two independent reviewers selected articles for inclusion and then assessed their relevant outcomes and the methodological quality. Our literature search identified a total of 15 327 articles, of which we selected 48 for full‐text review; we added five more studies discovered by means other than the systematic literature search. Among these selected articles were 11 high‐quality studies published in the last 4 years and two Cochrane systematic reviews. Overall, the outcomes in patients treated with the different antibiotic regimens for both skin and soft tissue infection and osteomyelitis of the diabetic foot were broadly equivalent across studies, except that treatment with tigecycline was inferior to ertapenem (±vancomycin). Similar outcomes were also reported in studies comparing primarily surgical and predominantly antibiotic treatment strategies in selected patients with diabetic foot osteomyelitis. There is insufficient high‐quality evidence to assess the effect of various adjunctive therapies, such as negative pressure wound therapy, topical ointments or hyperbaric oxygen, on infection related outcomes of the diabetic foot. In general, the quality of more recent trial designs are better in past years, but there is still a great need for further well‐designed trials to produce higher quality evidence to underpin our recommendations.