Cost-Utility of Liraglutide Plus Standard of Care Versus Standard of Care in People with Type 2 Diabetes and Cardiovascular Risk in Thailand.

INTRODUCTION: Liraglutide has demonstrated a significant reduction in the primary major composite cardiovascular (CV) outcome (CV death, non-fatal myocardial infarction, non-fatal stroke). This study aimed to determine the cost-utility of adding liraglutide to the standard of care (SoC) for treating type 2 diabetes (T2D) in Thailand for three cohorts: people with atherosclerotic cardiovascular disease (ASCVD), with no ASCVD, and all people with T2D. METHODS: A Markov model was developed to capture the long-term costs and outcomes under the perspective of the healthcare system. Costs were based on local data, the transitional probabilities were derived from the LEADER trial, and utilities were derived from published studies. Future costs and outcomes were discounted at 3% annually. A series of sensitivity analyses were performed. RESULTS: Compared to SoC, adding liraglutide incurred higher costs and gained more quality-adjusted life-years (QALYs), yielding incremental cost-effectiveness ratios (ICERs) of above 1 million Thai baht (THB) for the three cohorts. The most influential parameter was the discount rate. When the annual cost of liraglutide reduced from 87,874 to 30,340 THB, 30,116 THB, and 31,617 THB for all people with T2D, people with ASCVD, and people without ASCVD, respectively, the ICER fell below the local threshold of 160,000 THB/QALY. Compared to the SoC treatment, the liraglutide group acquired more clinical benefit in terms of fewer CVD. Sensitivity analyses revealed that with an increase in the level of willingness-to-pay (WTP) threshold, adding liraglutide had an increased chance of being a cost-effective strategy. CONCLUSION: Compared to the SoC treatment, adding liraglutide at the current cost is not cost-effective at the local WTP. People with T2D with ASCVD would have the most potential gain from adding liraglutide treatment compared to other populations.

CAPTURE: a multinational, cross-sectional study of cardiovascular disease prevalence in adults with type 2 diabetes across 13 countries.

BACKGROUND: There is a paucity of global data on cardiovascular disease (CVD) prevalence in people with type 2 diabetes (T2D). The primary objective of the CAPTURE study was to estimate the prevalence of established CVD and its management in adults with T2D across 13 countries from five continents. Additional objectives were to further characterize the study sample regarding demographics, clinical parameters and medication usage, with particular reference to blood glucose-lowering agents (GLAs: glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors) with demonstrated cardiovascular benefit in randomized intervention trials. METHODS: Data were collected from adults with T2D managed in primary or specialist care in Australia, China, Japan, Czech Republic, France, Hungary, Italy, Argentina, Brazil, Mexico, Israel, Kingdom of Saudi Arabia, and Turkey in 2019, using standardized methodology. CVD prevalence, weighted by diabetes prevalence in each country, was estimated for the overall CAPTURE sample and participating countries. Country-specific odds ratios for CVD prevalence were further adjusted for relevant demographic and clinical parameters. RESULTS: The overall CAPTURE sample included 9823 adults with T2D (n = 4502 from primary care; n = 5321 from specialist care). The overall CAPTURE sample had median (interquartile range) diabetes duration 10.7 years (5.6-17.9 years) and glycated hemoglobin 7.3% (6.6-8.4%) [56 mmol/mol (49-68 mmol/mol)]. Overall weighted CVD and atherosclerotic CVD prevalence estimates were 34.8% (95% confidence interval [CI] 32.7-36.8) and 31.8% (95% CI 29.7-33.8%), respectively. Age, gender, and clinical parameters accounted for some of the between-country variation in CVD prevalence. GLAs with demonstrated cardiovascular benefit were used by 21.9% of participants, which was similar in participants with and without CVD: 21.5% and 22.2%, respectively. CONCLUSIONS: In 2019, approximately one in three adults with T2D in CAPTURE had diagnosed CVD. The low use of GLAs with demonstrated cardiovascular benefit even in participants with established CVD suggested that most were not managed according to contemporary diabetes and cardiology guidelines. Study registration NCT03786406 (registered on December 20, 2018), NCT03811288 (registered on January 18, 2019).

Patient motivation to lose weight: Importance of healthcare professional support, goals and self-efficacy.

BACKGROUND: People with obesity (PwO) often struggle to achieve and maintain weight loss. This can perpetuate and/or be influenced by feelings of low motivation. This analysis from ACTION-IO data identified factors associated with PwO motivation to lose weight. METHODS: PwO completed an online survey in 11 countries. Exploratory multinomial logistic regression analyses identified independent variables associated with self-report of feeling motivated versus not motivated to lose weight. RESULTS: Data from 10,854 PwO were included (5,369 motivated; 3,312 neutral; 2,173 not motivated). Variables associated with feeling motivated versus not motivated included (odds ratio [95% confidence interval]): acknowledgement of healthcare professional (HCP) responsibility to contribute to weight loss (2.32 [1.86-2.88]), comfort in talking to their HCP about weight (1.46 [1.24-1.72), agreement that it is easy to lose weight (1.73 [1.30-2.31]), and a goal of reducing risks from excess weight (1.45 [1.22-1.73]). Conversely, if PwO considered obesity less important than other diseases they were less likely to report feeling motivated (0.49 [0.41-0.58]). PwO who reported being motivated to lose weight were more likely to exercise ≥5 times a week versus <1 time a week (2.77 [2.09-3.68]) than those who reported they were not motivated. CONCLUSIONS: Positive interactions with HCPs, self-efficacy, setting goals and knowledge of the importance of weight management, in addition to regular exercising, may increase PwO motivation for weight loss. Appropriate HCP support may help PwO who are ready to engage in weight management. CLINICAL TRIAL REGISTRATION: NCT03584191.

The 3Ds - Discussion, diagnosis and direction: Elements for effective obesity care by healthcare professionals.

BACKGROUND: The care of people with obesity is often suboptimal due to both physician and patient perceptions about obesity itself and clinical barriers. Using data from the ACTION-IO study, we aimed to identify factors that might improve the quality of obesity care through adoption of the 3D approach (Discussion, Diagnosis and Direction [follow-up]) by healthcare professionals (HCPs). METHODS: An online survey was completed by HCPs in 11 countries. Exploratory beta regression analyses identified independent variables associated with each component of the 3D approach. RESULTS: Data from 2,331 HCPs were included in the statistical models. HCPs were significantly more likely to initiate weight discussions and inform patients of obesity diagnoses, respectively, if (odds ratio [95% confidence interval]): they recorded an obesity diagnosis in their patient's medical notes (1.59, [1.43-1.76] and 2.16 [1.94-2.40], respectively); and they were comfortable discussing weight with their patients (1.53 [1.39-1.69] and 1.15 [1.04-1.27]). HCPs who reported feeling motivated to help their patients lose weight were also more likely to initiate discussions (1.36 [1.21-1.53]) and schedule follow-up appointments (1.21 [1.06-1.38]). By contrast, HCPs who lacked advanced formal training in obesity management were less likely to inform patients of obesity diagnoses (0.83 [0.74-0.92]) or schedule follow-up appointments (0.69 [0.62-0.78]). CONCLUSION: Specific actions that could improve obesity care through the 3D approach include: encouraging HCPs to record an obesity diagnosis; providing tools to help HCPs feel more comfortable initiating weight discussions; and provision of training in obesity management. CLINICAL TRIAL REGISTRATION: NCT03584191.

Understanding Patients' Willingness to Pay for Biphasic Insulin Aspart 30/70 in a Pen Device for Type 2 Diabetes Treatment in an Out-of-Pocket Payment Market.

OBJECTIVE: Our objective was to investigate willingness to pay (WTP) for biphasic insulin aspart 30/70 (BIAsp 30) in patients with type 2 diabetes mellitus (T2DM) in India. METHODS: A multicenter, prospective, non-interventional, preference study was conducted that assessed WTP for BIAsp 30 in an insulin pen (FlexPen® or Penfill® device) in patients in India with T2DM previously treated with biphasic human insulin (BHI) in vials and believed to be able to pay for treatment. The primary endpoint was the proportion of patients willing to continue to pay for BIAsp 30 after 12 weeks' treatment. Secondary endpoints included the change from baseline in treatment and device satisfaction and patient preferences for treatment attributes as assessed by a nested discrete-choice experiment. RESULTS: Overall, 54.9% (n = 277/505) of participants were male; the mean age was 56.4 years; diabetes duration was 10.9 years; 63.8% had a body mass index ≥ 25 kg/m2; > 75% had an annual household income > 150,000 Indian rupees (INR). After 12 weeks' treatment, 96.4% of patients were willing to pay for BIAsp 30. Mean treatment and device satisfaction significantly improved from baseline (p < 0.0001). Patients were willing to pay INR3576 (95% confidence interval [CI] 2755-4398) for improved glycemic control, INR688 (95% CI 383-994) for a device upgrade (vial/syringe to an insulin pen), or INR327 (95% CI 95-560) to avoid major hypoglycemia. Patients would need to be compensated INR44 (95% CI 56-32) per minor hypoglycemic event. CONCLUSIONS: In India, patients with T2DM previously treated with BHI were willing to pay for BIAsp 30 in an insulin pen. Furthermore, treatment and device satisfaction improved after this therapeutic switch. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03374774.

Gaps to bridge: Misalignment between perception, reality and actions in obesity.

AIMS: Despite increased recognition as a chronic disease, obesity remains greatly underdiagnosed and undertreated. We aimed to identify international perceptions, attitudes, behaviours and barriers to effective obesity care in people with obesity (PwO) and healthcare professionals (HCPs). MATERIALS AND METHODS: An online survey was conducted in 11 countries. Participants were adults with obesity and HCPs who were primarily concerned with direct patient care. RESULTS: A total of 14 502 PwO and 2785 HCPs completed the survey. Most PwO (68%) and HCPs (88%) agreed that obesity is a disease. However, 81% of PwO assumed complete responsibility for their own weight loss and only 44% of HCPs agreed that genetics were a barrier. There was a median of three (mean, six) years between the time PwO began struggling with excess weight or obesity and when they first discussed their weight with an HCP. Many PwO were concerned about the impact of excess weight on health (46%) and were motivated to lose weight (48%). Most PwO (68%) would like their HCP to initiate a conversation about weight and only 3% were offended by such a conversation. Among HCPs, belief that patients have little interest in or motivation for weight management may constitute a barrier for weight management conversations. When discussed, HCPs typically recommended lifestyle changes; however, more referrals and follow-up appointments are required. CONCLUSIONS: Our international dataset reveals a need to increase understanding of obesity and improve education concerning its physiological basis and clinical management. Realization that PwO are motivated to lose weight offers an opportunity for HCPs to initiate earlier weight management conversations.

A Retrospective Database Study of Liraglutide Persistence Associated with Glycemic and Body Weight Control in Patients with Type 2 Diabetes.

INTRODUCTION: In both randomized controlled trials and real-world studies, liraglutide has demonstrated glycemic and body weight benefits in patients with type 2 diabetes. However, persistence with diabetes medication can be challenging. This study compared glycated hemoglobin (HbA1c) and other outcomes in patients with type 2 diabetes who continued treatment with liraglutide for over 12 months with those who discontinued treatment earlier, in a real-life setting. METHODS: This is a retrospective study of adult patients with type 2 diabetes from Maccabi Healthcare Services in Israel, who initiated treatment with liraglutide from 2010 to 2015. Mean HbA1c and body weight change from initiation to after 24 months was compared between patients who received liraglutide for at least 12 months ("continuers") and those who discontinued within the first year ("discontinuers"). Adjustment for HbA1c, body weight, and other potentially confounding factors was performed using 1:1 propensity score matching. RESULTS: The 3580 patients comprised 2695 continuers and 885 discontinuers; 882 patients per group were matched. A significant (p < 0.001) reduction in HbA1c (- 0.80% vs - 0.32%) was seen in continuers compared with discontinuers, despite higher insulin usage (70.2% vs 59.0%; p < 0.001), and a higher proportion of patients using ≥ 3 oral glucose-lowering drugs (20.6% vs 6.2%; p < 0.001) at 24 months among discontinuers. Mean body weight reduction was greater in continuers than discontinuers (3.57 vs 1.25 kg; p < 0.001). CONCLUSION: In a real-world setting, persistent use of liraglutide was associated with good glycemic and body weight control. FUNDING: Novo Nordisk Health Care AG.

Guanylin and uroguanylin mRNA expression is increased following Roux-en-Y gastric bypass, but guanylins do not play a significant role in body weight regulation and glycemic control.

AIM: To determine whether intestinal expression of guanylate cyclase activator 2A (GUCA2A) and guanylate cyclase activator 2B (GUCA2B) genes is regulated in obese humans following Roux-en-Y gastric bypass (RYGB), and to evaluate the corresponding guanylin (GN) and uroguanylin (UGN) peptides for potentially contributing to the beneficial metabolic effects of RYGB. METHODS: Enteroendocrine cells were harvested peri- and post-RYGB, and GUCA2A/GUCA2B mRNA expression was compared. GN, UGN and their prohormones (proGN, proUGN) were administered subcutaneously in normal-weight mice to evaluate effects on food intake and glucose regulation. The effect of pro-UGN or UGN overexpression, using adeno-associated virus (AAV) vectors, was assessed in diet-induced obese (DIO) mice. Intracerebroventricular administration of GN and UGN was performed in rats for assessment of putative centrally mediated effects on food intake. GN and UGN, as well as their prohormones, were evaluated for effects on glucose-stimulated insulin secretion (GSIS) in rat pancreatic islets and perfused rat pancreas. RESULTS: GUCA2A and GUCA2B mRNA expression was significantly upregulated in enteroendocrine cells after RYGB. Peripheral administration of guanylins or prohormones did not influence food intake, oral glucose tolerance, and GSIS. Central administration of GN and UGN did not affect food intake in rats. Chronic AVV-mediated overexpression of UGN and proUGN had no effect on body weight or glucose homeostasis in DIO mice. CONCLUSION: GN and UGN, as well as their prohormones, do not seem to play a significant role in body weight regulation and glycemic control, suggesting that guanylin-family peptides do not show promise as targets for the treatment of obesity or diabetes.

Enteroendocrine K and L cells in healthy and type 2 diabetic individuals.

AIMS/HYPOTHESIS: Enteroendocrine K and L cells are pivotal in regulating appetite and glucose homeostasis. Knowledge of their distribution in humans is sparse and it is unknown whether alterations occur in type 2 diabetes. We aimed to evaluate the distribution of enteroendocrine K and L cells and relevant prohormone-processing enzymes (using immunohistochemical staining), and to evaluate the mRNA expression of the corresponding genes along the entire intestinal tract in individuals with type 2 diabetes and healthy participants. METHODS: In this cross-sectional study, 12 individuals with type 2 diabetes and 12 age- and BMI-matched healthy individuals underwent upper and lower double-balloon enteroscopy with mucosal biopsy retrieval from approximately every 30 cm of the small intestine and from seven specific anatomical locations in the large intestine. RESULTS: Significantly different densities for cells positive for chromogranin A (CgA), glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, peptide YY, prohormone convertase (PC) 1/3 and PC2 were observed along the intestinal tract. The expression of CHGA did not vary along the intestinal tract, but the mRNA expression of GCG, GIP, PYY, PCSK1 and PCSK2 differed along the intestinal tract. Lower counts of CgA-positive and PC1/3-positive cells, respectively, were observed in the small intestine of individuals with type 2 diabetes compared with healthy participants. In individuals with type 2 diabetes compared with healthy participants, the expression of GCG and PYY was greater in the colon, while the expression of GIP and PCSK1 was greater in the small intestine and colon, and the expression of PCSK2 was greater in the small intestine. CONCLUSIONS/INTERPRETATION: Our findings provide a detailed description of the distribution of enteroendocrine K and L cells and the expression of their products in the human intestinal tract and demonstrate significant differences between individuals with type 2 diabetes and healthy participants. TRIAL REGISTRATION: NCT03044860.

Weight loss experiences and willingness to intervention with pharmacotherapy among obese and very obese Danish people.

OBJECTIVES: Obesity is a growing issue with increasing impact on healthcare budgets, yet very little is known about weight loss experiences of people with body mass index (BMI)≥30kg/m(2) and their willingness to try and pay for weight loss interventions (WLI). The objective of this survey was to gather knowledge about weight loss experiences among obese and severely obese people. METHODS: 1,003 Danish people >18 years of age with BMI≥30 who wanted to lose weight completed an online survey. Data included demographics, experience with WLI, awareness of anti-obesity medication (AOM), and willingness to try and pay for WLI including AOM. RESULTS: Respondents had been trying to lose weight for several years (medium [25% percentile;75% percentile]);5.1[2.0;10.3] years (BMI 30-35) and 10.0 [5.0;20.0] (very obese (BMI>35) with co-morbidities (OWC). The desired weight loss was 20.0 [15.0;25.0] kg (BMI 30-35) and 35.0 [28.0;47.5] kg (OWC). Independent of educational level and gender, health concern was the main incentive for weight loss. Several WLI had been tried repeatedly, yet 60% of respondents with BMI 30-35 and 50% of the OWC were unaware of AOM. Among those who had tried AOM, side effects and lack of effectiveness were the main reasons to stop. 50-73% were willing to try AOM dependent on expected weight loss. Willingness to try and pay for new AOM was strongest for the OWC. CONCLUSION: Respondents had made repeated attempts for up to a decade to lose weight, yet remained far from their ideal weight. They had spent a substantial amount of money on WLI, had limited information of AOM, and indicated a desire for increased professional support.

Effect of Roux-en-Y gastric bypass on the distribution and hormone expression of small-intestinal enteroendocrine cells in obese patients with type 2 diabetes.

AIMS/HYPOTHESIS: We studied the impact of Roux-en-Y gastric bypass (RYGB) on the density and hormonal gene expression of small-intestinal enteroendocrine cells in obese patients with type 2 diabetes. METHODS: Twelve patients with diabetes and 11 age- and BMI-matched controls underwent RYGB followed by enteroscopy ~10 months later. Mucosal biopsies taken during surgery and enteroscopy were immunohistochemically stained for glucagon-like peptide-1 (GLP-1), peptide YY (PYY), cholecystokinin (CCK), glucose-dependent insulinotropic polypeptide (GIP) and prohormone convertase 2 (PC2) and the expression of GCG (encoding preproglucagon), PYY, CCK, GIP, GHRL (encoding ghrelin), SCT (encoding secretin), NTS (encoding neurotensin) and NR1H4 (encoding farnesoid X receptor) was evaluated. RESULTS: The density of cells immunoreactive for GLP-1, CCK and GIP increased in patients after RYGB and the density of those immunoreactive for GLP-1, PYY, CCK and PC2 increased in controls. In both groups, GHRL, SCT and GIP mRNA was reduced after RYGB while PYY, CCK, NTS and NR1H4 gene expression was unaltered. GCG mRNA was upregulated in both groups. CONCLUSIONS/INTERPRETATION: Numerous alterations in the distribution of enteroendocrine cells and their expression of hormonal genes are seen after RYGB and include increased density of GLP-1-, PYY-, CCK-, GIP- and PC2-positive cells, reduced gene expression of GHRL, SCT and GIP and increased expression of GCG.

Individual and societal consequences of hypoglycemia: A cross-sectional survey.

BACKGROUND: Hypoglycemia and fear of hypoglycemia threaten individuals' ability to work and drive. We studied the effect of hypoglycemia on the individual and society, with a focus on possible implications of new European union legislation on patients' continued ability to drive. METHODS: A cross-sectional survey of Danish Diabetes Association members was conducted to investigate individual and societal consequences of hypoglycemia. RESULTS: A total of 3117/9951 individuals with type 1 diabetes (T1DM) (32.2%) or type 2 diabetes (T2DM) (67.8%) completed the survey. The calculated incidence rates of self-reported severe and mild hypoglycemia were 2.9, 0.6 and 0.1 events per patient year (ppy) in patients with T1DM, insulin using T2DM and non-insulin using T2DM, respectively; and incidence rates of self-reported mild hypoglycemia were 99.0, 23.2 and 10.9 events ppy, respectively. Self-care strategies to avoid hypoglycemia include maintaining higher blood glucose levels (45.7%) and reducing physical activity (15.7%). Few people take sick leave as a result of hypoglycemia, but prolonged mental recovery ≥4 h following an episode of mild or severe hypoglycemia was reported by 8.7 and 31.0%, respectively. 26.5% of patients holding a valid driving license reported having ever had at least one episode of severe hypoglycemia. Patients considering underreporting of hypoglycemia to maintain their driving license were more likely to have experienced severe hypoglycemia (odds ratio [OR]: 3.03; 95% CI: 2.42-3.79; p < 0.0001). CONCLUSION: A high proportion of insulin-treated patients experience hypoglycemia resulting in fear of hypoglycemia and changes in self-care behavior that may compromise glycemic control. Many patients with a history of severe hypoglycemia consider underreporting hypoglycemic events through concern over retaining their driving license.

The use of double-balloon enteroscopy in retrieving mucosal biopsies from the entire human gastrointestinal tract.

OBJECTIVE: The aim of this explorative study was to evaluate double-balloon enteroscopy (DBE) as a new tool for collecting mucosal biopsies from well-defined parts of the entire small and large bowel in patients with type 2 diabetes and in matched healthy subjects. MATERIAL AND METHODS: Twelve subjects with type 2 diabetes and 12 body mass index and age-matched healthy subjects underwent anterograde and retrograde DBE under nurse-administered propofol sedation on two separate days. We attempted to collect two mucosal biopsies from every 30 cm from pylorus to rectum. RESULTS: A mean of 21 biopsy sites were sampled in the diabetic group versus 25 in the healthy group. In 4 out of 24 patients (2 [17%] from each group) sampling from the entire gastrointestinal system was possible. Mean depth of maximal insertion (anterograde) was 478 ± 32 cm in patients with type 2 diabetes versus 465 ± 44 cm in healthy subjects (p = 0.81) and with retrograde access 230 ± 36 cm (type 2 diabetes) versus 207 ± 26 cm (healthy subjects). CONCLUSIONS: DBE is a minimally invasive way of collecting fresh biopsies from the entire gastrointestinal tract and, thus provides research and clinical communities with a new possibility to access hitherto unexplored human anatomy and physiology.