Pharmacotherapy of type 2 diabetes: An update.

Type 2 diabetes (T2DM) is a leading cause of morbidity and mortality worldwide and a major economic burden. The prevalence of T2DM is rising, suggesting more effective prevention and treatment strategies are necessary. The aim of this narrative review is to summarize the pharmacologic treatment options available for patients with T2DM. Each therapeutic class is presented in detail, outlining medication effects, side effects, glycemic control, effect on weight, indications and contraindications, and use in selected populations (heart failure, renal insufficiency, obesity and the elderly). We also present representative cost for each antidiabetic category. Then, we provide an individualized guide for initiation and intensification of treatment and discuss the considerations and rationale for an individualized glycemic goal.

GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial.

AIMS/HYPOTHESIS: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome). METHODS: In 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrolment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days, and 1.8 mg for 3 days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (functional MRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center. RESULTS: Immunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide -0.47 ± 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation. CONCLUSIONS/INTERPRETATION: For the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3 mg) recently approved for obesity. TRIAL REGISTRATION: ClinicalTrials.gov NCT01562678 FUNDING : The study was funded by Novo Nordisk, NIH UL1 RR025758 and 5T32HD052961.

Omentin-1 levels are reduced by pharmacologic doses of leptin, but remain unaffected by energy deprivation and display no day-night variation.

OBJECTIVE: To study the day-night variation of omentin-1 levels and assess whether leptin and/or short- and long-term energy deprivation alter circulating omentin-1 levels via cytokines. DESIGN AND METHODS: Omentin-1 levels were measured hourly in serum samples from six healthy men to evaluate for day-night variation. To study effects of acute energy deprivation and of leptin administration, eight healthy subjects were studied in the fasting state for 72 h with administration of either placebo or metreleptin (recombinant human leptin) in physiologic replacement doses. We evaluated the effect of leptin in pharmacologic doses on serum omentin-1 and cytokine levels, as well as on omentin-1 levels in ex vivo omental adipose tissue, in 15 healthy volunteers. To study the effect of chronic energy deprivation and weight loss on omentin-1 levels, we followed 18 obese subjects for 12 months who underwent bariatric surgery. RESULTS: There is no day-night variation in omentin-1 levels. Short-term and chronic energy deprivation, as well as ex vivo leptin administration and physiologic replacement doses of leptin, do not alter omentin-1 levels; pharmacologic doses of metreleptin reduce omentin-1 levels, whereas levels of tumor necrosis factor-α receptor II and interleukin-6 tend to increase. CONCLUSIONS: Omentin-1 levels are reduced by pharmacologic doses of metreleptin independent of effects on cytokine levels.

Circulating fetuin-A levels are not affected by short and long-term energy deprivation and/or by leptin administration.

OBJECTIVE: Fetuin-A may mediate cross-talk between the liver and adipose tissue. We studied the physiologic regulation of fetuin-A and explored its potential regulation by leptin. DESIGN AND METHODS: Fetuin-A levels were measured in three interventional studies as well as in in vitro experiments. Study 1: 15 lean subjects received placebo or physiologic replacement-dose recombinant human leptin (metreleptin) following short term complete caloric deprivation to induce severe hypoleptinemia; Study 2: 7 women with relative leptin deficiency due to strenuous exercise or low weight received 3 months of metreleptin; Study 3: 17 women with relative leptin deficiency were randomized to receive metreleptin or placebo over 9 months. In study 4 human hepatoma Hep G2 cells were treated with leptin. Fetuin-A mRNA expression and secretion were measured. RESULTS: Complete caloric deprivation significantly decreased leptin but had no effect on fetuin-A levels. Normalizing leptin levels with metreleptin in hypoleptinemic subjects had no effect on circulating fetuin-A levels. Leptin treatment had no effect on fetuin-A mRNA expression and secretion in vitro. CONCLUSIONS: Circulating fetuin-A levels are not affected by short and long-term energy deprivation. Furthermore, both in vivo and in vitro experiments confirm that fetuin-A is not regulated by leptin.

Early life adversity is associated with elevated levels of circulating leptin, irisin, and decreased levels of adiponectin in midlife adults.

CONTEXT: Early-life adversity, defined as physical, emotional, or sexual abuse and neglect before 18 years of age, is associated with metabolic syndrome, obesity, and type 2 diabetes mellitus in adult life. However, the underlying mechanism is not fully understood, and whether adipomyokines are associated with early-life adversity independent of other factors such as body mass index, psychosocial risks, and health behaviors is not known. OBJECTIVES: The objective of the study was to evaluate the association between early-life adversity and circulating the levels of the adipomyokines such as leptin, adiponectin, and irisin and the inflammatory marker, C-reactive protein (CRP). DESIGN/SUBJECTS/SETTING: This study was a cross-sectional study of 95 adults at a university-based research center. We collected venous blood from participants and analyzed serum for leptin, adiponectin, irisin, and CRP. RESULTS: Circulating leptin, irisin, and CRP levels were significantly higher in the highest adversity tertile group compared with low and middle tertile groups (P < .001 for leptin, P = .01 for irisin, and P = .02 for CRP). Adiponectin levels were lower in the highest tertile group compared with the low and middle tertile groups (P = .03). After adjusting for demographic variables, physical activity, diet, current mental health, and body mass index, the associations between early-life adversity leptin, irisin, and did not change. However, adiponectin and CRP levels were no longer significantly related to early life adversity. CONCLUSION: Early-life adversity is directly associated with elevated circulating leptin and irisin, and indirectly associated with elevated CRP and decreased adiponectin. These findings suggest that these adipomyokines may play a role in the pathogenesis of metabolic abnormality in a population with significant early life adversity.

Circulating irisin in relation to insulin resistance and the metabolic syndrome.

CONTEXT: Irisin, a recently identified hormone, has been proposed to regulate energy homeostasis and obesity in mice. Whether irisin levels are associated with risk of the metabolic syndrome (MetS), cardiometabolic variables, and cardiovascular disease (CVD) risk in humans remains unknown. OBJECTIVE: Our objective was to assess the associations between baseline serum irisin levels and MetS, cardiometabolic variables, and CVD risk. DESIGN, SETTING, AND SUBJECTS: We conducted a comparative cross-sectional evaluation of baseline circulating levels of the novel hormone irisin and the established adipokine adiponectin with MetS, cardiometabolic variables, and CVD risk in a sample of 151 subjects. RESULTS: Baseline irisin levels were significantly higher in subjects with MetS than in subjects without MetS. Irisin was associated negatively with adiponectin (r = -0.4, P < .001) and positively with body mass index (r = 0.22, P = .008), systolic (r = 0.17, P = .04) and diastolic (r = 0.27, P = .001) blood pressure, fasting glucose (r = 0.25, P = .002), triglycerides (r = 0.25, P = .003), and homeostasis model assessment for insulin resistance (r = 0.33, P < .001). After adjustment for potential confounders, including body mass index, subjects in the highest tertile of irisin levels were more likely to have MetS (odds ratio [OR] = 9.44, 95% confidence interval [CI] = 2.66-33.44), elevated fasting blood glucose (OR = 5.80, 95% CI = 1.72-19.60), high triglycerides (OR = 3.89, 95% CI = 1.16-13.03), and low high-density lipoprotein cholesterol (OR = 3.30, 95% CI = 1.18-9.20). Irisin was independently associated with homeostasis model assessment for insulin resistance and general Framingham risk profile in multiple linear regression analyses after adjustment for confounders. Adiponectin demonstrated the expected associations with outcomes. CONCLUSIONS: Irisin is associated with increased risk of MetS, cardiometabolic variables, and CVD in humans, indicating either increased secretion by adipose/muscle tissue and/or a compensatory increase of irisin to overcome an underlying irisin resistance in these subjects.

Gender dimorphism and lack of day/night variation or effects of energy deprivation on undercarboxylated osteocalcin levels in humans.

OBJECTIVE: Undercarboxylated osteocalcin (ucOC) is a bone marker with potent metabolic effects. Leptin regulates Esp gene expression and osteocalcin carboxylation in animal models. We aim to elucidate day/night patterns of ucOC levels, whether short-term and/or chronic energy deprivation alters ucOC levels, and whether leptin may mediate these changes in humans. DESIGN AND METHODS: Twelve healthy males and females were studied for 72 h in the fed state to study day/night pattern of ucOC. The six female subjects were also studied in a crossover interventional study in the fasting state for 72 h with administration of either placebo or metreleptin in physiological doses. Blood samples were obtained hourly from 0800 a.m. on day 3 until 0800 a.m. on day 4. In a separate study, eleven obese subjects who underwent bariatric surgery were followed for 24 weeks to examine the effects of postsurgery weight loss on ucOC levels. RESULTS: Males have higher ucOC levels compared to females. There is no day/night variation pattern of circulating ucOC in humans. Short-term and chronic energy deprivation or leptin administrations do not alter ucOC levels. CONCLUSIONS: The hypothesis that ucOC plays a role in energy homeostasis or of leptin in regulating ucOC in humans is not supported.

Metformin and sulfonylureas in relation to cancer risk in type II diabetes patients: a meta-analysis using primary data of published studies.

INTRODUCTION: Accumulating evidence suggests that patients with type 2 diabetes mellitus (T2DM) and hyperinsulinemia are at increased risk for developing malignancies. It remains to be fully elucidated whether use of metformin, an insulin sensitizer, and/or sulfonylureas, insulin secretagogues, affect cancer incidence in subjects with T2DM. MATERIAL & METHODS: We performed a meta-analysis using PubMed, of randomized control trials (RCTs), cohorts, and case-control studies published through July 2012 that assess effects of metformin and/or sulfonylurea sulfonylureas on cancer risk at any site, in subjects with T2DM. Fixed and random effects meta-analysis models were used, and the effect size was summarized as relative risk (RR) for RCTs/cohorts and as odds ratio (OR) for the case-control studies. RESULTS: Analysis of 24 metformin studies in subjects with T2DM showed that metformin use is associated with reduced risk for the development of cancer, in both cohort (RR=0.70 [95% CI=0.67-0.73]) and case-control studies (OR=0.90 [95% CI=0.84-0.98]), but this finding was not supported by RCTs (RR=1.01[95% CI=0.81-1.26]). Data from 18 sulfonylurea studies in subjects with T2DM showed that sulfonylurea use is associated with an increase in all-cancer risk, in cohort studies (RR=1.55 [95% CI=1.48 -1.63]), though data from RCTs (RR=1.17 [95% CI=0.95-1.45]) and case-control studies (OR=1.02 [95% CI=0.93-1.13]) failed to demonstrate a statistically significant effect. CONCLUSIONS: This analysis using pooled primary data demonstrates that metformin use reduces, while sulfonylurea use may be associated with an increased cancer risk in subjects with T2DM. These findings need to be confirmed in large-scale RCTs before they are translated into clinical practice.