Glucokinase Activators for Type 2 Diabetes: Challenges and Future Developments.

Increased hepatic glucose output, the primary liver dysregulation associated with Type 2 diabetes mellitus (T2DM), is not directly or effectively targeted by the currently available classes of glucose-lowering medications except metformin. This unmet need might be addressed through activation of a specific enzyme-member of the hexokinase family, namely glucokinase (GK). GK serves as a "glucose-sensor" or "glucose receptor" in pancreatic cells, eliciting glucose-stimulated insulin secretion, and as glucose "gate-keeper" in hepatocytes, promoting hepatic glucose uptake and glycogen synthesis and storage. GK activation by small molecules present an alternative approach to restore/improve glycaemic control in patients with T2DM. GK activators (GKAs) may increase insulin secretion from the pancreas and promote glycogen synthesis in the liver, and hence reduce hepatic glucose output. Despite several setbacks in their development, interest in the GKA class has been renewed, particularly since the introduction of a novel, dual-acting full GKA, dorzagliatin, and a novel hepatoselective molecule, TTP399. In this article we provide an overview of the role, efficacy, safety and future developments of GKAs in the management of T2DM.

Switching from sitagliptin to liraglutide to manage patients with type 2 diabetes in the UK: A long-term cost-effectiveness analysis.

AIMS: The recent LIRA-SWITCH trial showed that switching from sitagliptin 100 mg to liraglutide 1.8 mg led to statistically significant and clinically relevant improvements in glycated haemoglobin (HbA1C) and body mass index (BMI). Based on these findings, the aim of the present study was to assess the long-term cost-effectiveness of switching from sitagliptin to liraglutide in patients with type 2 diabetes in the UK. MATERIALS AND METHODS: The IQVIA CORE Diabetes Model Version 8.5+ was used to project costs and clinical outcomes over patients' lifetimes. Baseline cohort characteristics and treatment effects were derived from the LIRA-SWITCH trial. Future costs and clinical benefits were discounted at 3.5% annually. Costs were accounted in pounds sterling (GBP) and expressed in 2016 values. One-way and probabilistic sensitivity analyses were performed. RESULTS: Model projections showed improved quality-adjusted life expectancy for patients with poorly controlled HbA1c upon switching from sitagliptin to liraglutide, compared with continuing sitagliptin treatment (9.18 vs 9.02 quality-adjusted life years [QALYs]). Treatment switching was associated with increased overall costs (GBP 24737 vs GBP 22362). Higher pharmacy costs were partially offset by reduced diabetes-related complication costs in patients who switched to liraglutide. Switching to liraglutide was associated with an incremental cost-effectiveness ratio of GBP 15423 per QALY gained vs continuing with sitagliptin treatment. CONCLUSIONS: Switching from sitagliptin 100 mg to liraglutide 1.8 mg in patients with poor glycaemic control was projected to improve clinical outcomes and is likely to be considered cost-effective in the UK setting and, therefore, a good use of limited NHS resources.

Type 2 diabetes in adolescents and young adults.

The prevalence of type 2 diabetes in adolescents and young adults is dramatically increasing. Similar to older-onset type 2 diabetes, the major predisposing risk factors are obesity, family history, and sedentary lifestyle. Onset of diabetes at a younger age (defined here as up to age 40 years) is associated with longer disease exposure and increased risk for chronic complications. Young-onset type 2 diabetes also affects more individuals of working age, accentuating the adverse societal effects of the disease. Furthermore, evidence is accumulating that young-onset type 2 diabetes has a more aggressive disease phenotype, leading to premature development of complications, with adverse effects on quality of life and unfavourable effects on long-term outcomes, raising the possibility of a future public health catastrophe. In this Review, we describe the epidemiology and existing knowledge regarding pathophysiology, risk factors, complications, and management of type 2 diabetes in adolescents and young adults.

Obstructive Sleep Apnea and Retinopathy in Patients with Type 2 Diabetes. A Longitudinal Study.

RATIONALE: Obstructive sleep apnea (OSA) is associated with several pathophysiological deficits found in diabetic retinopathy (DR). Hence, it's plausible that OSA could play a role in the pathogenesis of sight-threatening DR (STDR). OBJECTIVES: To assess the relationship between OSA and DR in patients with type 2 diabetes and to assess whether OSA is associated with its progression. METHODS: A longitudinal study was conducted in diabetes clinics within two U.K. hospitals. Patients known to have any respiratory disorder (including OSA) were excluded. DR was assessed using two-field 45-degree retinal images for each eye. OSA was assessed using a home-based multichannel cardiorespiratory device. MEASUREMENTS AND MAIN RESULTS: A total of 230 patients were included. STDR and OSA prevalence rates were 36.1% and 63.9%, respectively. STDR prevalence was higher in patients with OSA than in those without OSA (42.9% vs. 24.1%; P = 0.004). After adjustment for confounders, OSA remained independently associated with STDR (odds ratio, 2.3; 95% confidence interval, 1.1-4.9; P = 0.04). After a median (interquartile range) follow-up of 43.0 (37.0-51.0) months, patients with OSA were more likely than patients without OSA to develop preproliferative/proliferative DR (18.4% vs. 6.1%; P = 0.02). After adjustment for confounders, OSA remained an independent predictor of progression to preproliferative/proliferative DR (odds ratio, 5.2; 95% CI confidence interval, 1.2-23.0; P = 0.03). Patients who received continuous positive airway pressure treatment were significantly less likely to develop preproliferative/proliferative DR. CONCLUSIONS: OSA is associated with STDR in patients with type 2 diabetes. OSA is an independent predictor for the progression to preproliferative/proliferative DR. Continuous positive airway pressure treatment was associated with reduction in preproliferative/proliferative DR. Interventional studies are needed to assess the impact of OSA treatment on STDR.

Future challenges and therapeutic opportunities in type 2 diabetes: Changing the paradigm of current therapy.

Most algorithms for type 2 diabetes mellitus (T2DM) do not recommend treatment escalation until glycated haemoglobin (HbA1c) fails to reach the recommended target of 7% (53 mmol/mol) within approximately 3 months on any treatment regimen ("treat to failure"). Clinical inertia and/or poor adherence to therapy contribute to patients not reaching glycaemic targets when managed according to this paradigm. Clinical inertia exists across the entire spectrum of anti-diabetes therapies, although it is most pronounced when initiating and optimizing insulin therapy. Possible reasons include needle aversion, fear of hypoglycaemia, excessive weight gain and/or the need for increased self-monitoring of blood glucose. Studies have suggested, however, that early intensive insulin therapy in newly diagnosed, symptomatic patients with T2DM with HbA1c >9% (75 mmol/mol) can preserve beta-cell function, thereby modulating the disease process. Furthermore, postprandial plasma glucose is a key component of residual dysglycaemia, evident especially when HbA1c remains above target despite fasting normoglycaemia. Therefore, to achieve near normoglycaemia, additional treatment with prandial insulin or a glucagon-like peptide-1 receptor agonist (GLP-1 RA) is often required. Long- or short-acting GLP-1 RAs offer effective alternatives to basal or prandial insulin in patients inadequately controlled with other therapies or basal insulin alone, respectively. This review highlights the limitations of current algorithms, and proposes an alternative based on the early introduction of insulin therapy and the rationale for the sequential or fixed combination of GLP-1 RAs with insulin ("treat-to-success" paradigm).

Peripheral and Autonomic Neuropathy in South Asians and White Caucasians with Type 2 Diabetes Mellitus: Possible Explanations for Epidemiological Differences.

Objectives. To compare the prevalence of diabetic peripheral neuropathy (DPN) and that of cardiac autonomic neuropathy (CAN) between South Asians and White Caucasians with type 2 diabetes and to explore reasons for observed differences. Methods. A cross-sectional study of casually selected South Asian and White Caucasian adults attending a hospital-based diabetes clinic in the UK. DPN and CAN were assessed using the Michigan Neuropathy Screening Instrument (MNSI) and heart rate variability testing, respectively. Results. Patients (n = 266) were recruited (47.4% South Asians). DPN was more common in White Caucasians compared to South Asians (54.3% versus 38.1%, p = 0.008). Foot insensitivity as assessed by 10 g monofilament perception was more common in White Caucasians (43.9% versus 23.8%, p = 0.001). After adjustment for confounders, White Caucasians remained twice as likely to have DPN as South Asians, but the impact of ethnicity became nonsignificant after adjusting for adiposity measures or height. No difference in prevalence of standardized CAN test abnormalities was detected between ethnicities. Skin microvascular assessment demonstrated that South Asians had reduced heating flux but preserved acetylcholine response. Conclusions. South Asians with type 2 diabetes have fewer clinical signs of DPN compared to White Caucasians. Differences in adiposity (and its distribution) and height appear to explain these differences.

Prevalence and Associations of Obstructive Sleep Apnea in South Asians and White Europeans with Type 2 Diabetes: A Cross-Sectional Study.

STUDY OBJECTIVES: To assess and compare obstructive sleep apnea (OSA) prevalence in South Asians and White Europeans with type 2 diabetes mellitus (T2DM). Secondary aims included exploring possible causes for observed ethnic differences. METHODS: A cross-sectional study of patients with T2DM recruited from secondary care diabetes clinics. OSA was defined as an apnea-hypopnea index (AHI) ≥ 5 events/h using home-based, multi-channel respiratory monitoring. RESULTS: Two hundred thirty-four patients (105 South Asian and 129 White Europeans) were studied. The prevalence of mild, moderate, and severe OSA in South Asians was 36.2% (n = 38/105), 9.5% (n = 10/105), and 5.7% (n = 6/105) respectively. After adjustment, OSA was associated with a higher body mass index in South Asians. OSA was significantly less common in South Asians compared to White Europeans (51.4% [54/105] versus 75.2% [97/129], P < .001). OSA was also less severe in South Asians compared to White Europeans (median [interquartile range]: AHI 5.1 [1.4-11.5] versus 8.5 [5.0-20.7] events/h, P < .001; time spent with oxygen saturations < 90% 0.5 [0.0-2.9]% versus 4.0 [0.7-14.4]%, P < .001). Logistic regression showed that only obesity measures explained the ethnic differences in OSA. CONCLUSIONS: South Asians with T2DM are at considerable risk of OSA. OSA in South Asians was associated with obesity. However, OSA prevalence was lower in South Asians than in White Europeans. Obesity measures accounted for the observed ethnic differences. Examining factors contributing to ethnic differences will be important to inform screening and treatment strategies.

Perceptions of diabetes control among people with type 2 diabetes treated with basal insulin in Sweden, Switzerland, and the United Kingdom.

OBJECTIVE: To investigate perceptions of control among people with uncontrolled and well controlled type 2 diabetes (T2D) treated with basal insulin, as well as differences in perceptions and diabetes management practices between the two groups. RESEARCH DESIGN AND METHODS: Web surveys of 1012 people with uncontrolled T2D (HbA1c >8.0% or 64 mmol/mol) on basal insulin in Sweden, Switzerland, and the UK and 295 people with well controlled T2D (HbA1c <7.5% or 58 mmol/mol) on basal insulin in the UK were conducted. RESULTS: People with uncontrolled T2D perceived a wide range of factors as very/extremely important for deciding whether they are well controlled, including diet (80.7%), HbA1c value (78.9%), times per day insulin taken (78.8%), insulin units taken per day (77.6%), and energy levels (74.5%). Fifty-one percent of uncontrolled respondents considered the past week or more recently when thinking about control. Perceived major obstacles to control included stress (75.4%), other health issues (70.8%), medicine side effects (69.9%), food cravings (69.8%), doctor not understanding individual situation (67.6%), and life crises (66.9%). Many uncontrolled respondents reported that diabetes was very/extremely interfering with their lives, including energy level (71.0%), performance at work (70.0%), general health (69.9%), and doing what one wants (69.3%). Analyses showed significant differences between well controlled and uncontrolled UK respondents. Compared to the uncontrolled, people with well controlled T2D were significantly more likely to consider the last 24 hours/current time when thinking about control (50% vs. 21%, p < 0.001) and reported greater healthcare contact related to diabetes and more frequent glucose measurement. Study limits include potential selection bias of web surveys and possible recall bias in patient-reported data. CONCLUSIONS: The results illuminate how people with T2D treated with basal insulin perceive control and show important differences between the well controlled and uncontrolled. Findings may have implications for improving patient and physician education and diabetes management.

Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.

Health and population effects of rare gene knockouts in adult humans with related parents.

Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans.

Consequences of delaying treatment intensification in type 2 diabetes: evidence from a UK database.

OBJECTIVE: Type 2 diabetes mellitus (TD2M) treatment focuses on achieving glycemic control, with HbA1c targeted at 6.5-7.5%. Clinicians commonly delay treatment intensification despite patients failing glycemic targets. This study evaluated longitudinal clinical and cost outcomes in patients failing metformin monotherapy using electronic medical records. RESEARCH DESIGN AND METHODS: Adults with incident T2DM were identified in the UK Clinical Practice Research Datalink (CPRD) from 1 January 2000 to 31 March 2014. Patients were initiated on metformin monotherapy but had not reached target (HbA1c <7%). Patients were grouped by time to intensification of second-line therapy from first recorded HbA1c ≥7%: Group A, rapid intensification within 365 days; Group B, delayed intensification days 366-1824; Group C, never intensified. Patients were followed from day 366 for 5 years until end of study, switch to insulin, migration or death. MAIN OUTCOME MEASURES: The study evaluated baseline clinical and medication characteristics which were re-evaluated each year, including HbA1c, weight, cholesterol and concomitant prescribing. RESULTS: A total of 6710 patients were included (Group A 2647, Group B 2452, Group C 1611). Group A achieved a significant decline in HbA1c at 1 year post-index date compared to Groups B and C (-1.13% Group A; +0.26% Group B, +0.16% Group C). A significantly higher proportion of patients achieved HbA1c target < 7% in Group A (Group A [45.8%]; Group B [19.1%], p < 0.0001). Using an adjusted hazard model, Group A was found to achieve the HbA1c target from the index date significantly faster than Group B (hazard ratio 3.25 [95% CI 2.87-3.69]). The most commonly prescribed second-line medications were sulfonylureas in Groups A and B throughout observation and were associated with significant weight gain (+1.3 kg per patient) in the adjusted models. CONCLUSIONS: Patients who were rapidly intensified achieved a maintained reduction in HbA1c faster than those with delayed intensification or no second-line therapy, despite a higher baseline HbA1c.

Perceptions of diabetes control among physicians and people with type 2 diabetes uncontrolled on basal insulin in Sweden, Switzerland, and the United Kingdom.

Objective A large proportion of people with type 2 diabetes (T2D) remain uncontrolled on basal insulin. Yet, there is limited understanding of how people with uncontrolled type 2 diabetes (PWUD) perceive control and insulin intensification and whether their perceptions differ from those of physicians. The purpose of the study was to investigate perceptions of control and views on insulin intensification among physicians and PWUD. Research design and methods Web surveys of 1012 PWUD on basal insulin and 300 physicians were conducted in Sweden, Switzerland, and the United Kingdom. Results Analyses revealed significant differences between physicians and PWUD. Physicians were significantly more likely than PWUD to indicate that HbA1c (85.0% vs. 78.9%, p < 0.05), complications from diabetes (89.3% vs. 75.3%, p < 0.001), and frequency/severity of hypoglycemia (93.3% vs. 68.6%, p < 0.001) were very/extremely important for deciding whether or not diabetes is well controlled. In contrast PWUD were significantly more likely to place importance on a variety of factors, including energy levels (74.5% vs. 33.0%, p < 0.001), insulin units/day (77.6% vs. 29.0%, p < 0.001) and how predictable life is (72.1% vs. 29.3%, p < 0.001). PWUD also perceived significantly greater obstacles to control and viewed uncontrolled T2D as more interfering in their lives compared to physicians. Physicians were most reluctant to intensify insulin when there is a lack of patient agreement. Worries about weight gain and feelings of 'getting sicker' were the most frequently reported reasons why PWUD on basal insulin were reluctant to intensify insulin. Conclusions Results revealed a significant disconnect between physicians and PWUD in their perceptions of diabetes control. While physicians generally expressed a more focused and clinical view of diabetes control, patients had a broader view. Results also provide insights into PWUD and physicians' reluctance to intensify insulin. The findings suggest that physician and patient education on differing perceptions could benefit communication and improve diabetes management.

Future glucose-lowering drugs for type 2 diabetes.

The multivariable and progressive natural history of type 2 diabetes limits the effectiveness of available glucose-lowering drugs. Constraints imposed by comorbidities (notably cardiovascular disease and renal impairment) and the need to avoid hypoglycaemia, weight gain, and drug interactions further complicate the treatment process. These challenges have prompted the development of new formulations and delivery methods for existing drugs alongside research into novel pharmacological entities. Advances in incretin-based therapies include a miniature implantable osmotic pump to give continuous delivery of a glucagon-like peptide-1 receptor agonist for 6-12 months and once-weekly tablets of dipeptidyl peptidase-4 inhibitors. Hybrid molecules that combine the properties of selected incretins and other peptides are at early stages of development, and proof of concept has been shown for small non-peptide molecules to activate glucagon-like peptide-1 receptors. Additional sodium-glucose co-transporter inhibitors are progressing in development as well as possible new insulin-releasing biological agents and small-molecule inhibitors of glucagon action. Adiponectin receptor agonists, selective peroxisome proliferator-activated receptor modulators, cellular glucocorticoid inhibitors, and analogues of fibroblast growth factor 21 are being considered as potential new approaches to glucose lowering. Compounds that can enhance insulin receptor and post-receptor signalling cascades or directly promote selected pathways of glucose metabolism have suggested opportunities for future treatments. However, pharmacological interventions that are able to restore normal ß-cell function and ß-cell mass, normalise insulin action, and fully correct glucose homoeostasis are a distant vision.