Basal insulin analogues in the management of diabetes mellitus: What progress have we made?

Insulin remains the most effective and consistent means of controlling blood glucose levels in diabetes. Since 1946, neutral protamine Hagedorn (NPH) has been the predominant basal insulin in clinical use. However, absorption is variable due to the need for resuspension and the time-action profile (peak activity 4-6 h after subcutaneous administration) confers an increased propensity for between-meal and nocturnal hypoglycaemia. In the 1980s, recombinant DNA technology enabled modifications to the insulin molecule resulting in the soluble long-acting insulin analogues, glargine and detemir. Both exhibit a lower risk of hypoglycaemia compared with neutral protamine Hagedorn due to improved time-action profiles and reduced day-to-day glucose variability. Glargine is indicated for administration once daily and detemir once or twice daily. Degludec is the latest prolonged-acting insulin which forms long subcutaneous multi-hexamers that delay absorption. Recent phase III trials in type 1 and type 2 diabetes show that degludec was non-inferior to comparators (predominantly glargine) with a minimal although inconsistent reduction in overall hypoglycaemia and a small absolute difference in nocturnal hypoglycaemia. Newer developmental agents include LY2605541 and glargine U300. LY2605541 comprises insulin lispro combined with polyethylene glycol, thereby increasing its hydrodynamic size and retarding absorption from the subcutaneous tissue. Glargine U300 is a new formulation of glargine resulting in a flatter and more prolonged time-action profile than its predecessor. This article reviews recent advances in basal insulin analogues, including a critical appraisal of the degludec trials.

Clinical Characteristics and Outcomes of Patients With Diabetes Admitted for COVID-19 Treatment in Dubai: Single-Centre Cross-Sectional Study.

BACKGROUND: Recent studies have shown that diabetes is a major risk factor that contributes to the severity of COVID-19 and resulting mortality. Poor glycemic control is also associated with poor patient outcomes (eg, hospitalization and death). OBJECTIVE: This study aimed to describe the clinical characteristics and outcomes of patients with diabetes who were admitted to our hospital for COVID-19 treatment. METHODS: This cross-sectional, observational study comprised patients with diabetes admitted with COVID-19 to Mediclinic Parkview Hospital in Dubai, United Arab Emirates, from March 30 to June 7, 2020. We studied the differences among characteristics, length of hospital stay, diabetes status, comorbidities, treatments, and outcomes among these patients. RESULTS: Of the cohort patients, 25.1% (103/410) had coexistent diabetes or prediabetes. These patients represented 17 different ethnicities, with 59.2% (61/103) from Asian countries and 35% (36/103) from Arab countries. Mean patient age was 54 (SD 12.5) years, and 66.9% (69/103) of patients were male. Moreover, 85.4% (88/103) of patients were known to have diabetes prior to admission, and 14.6% (15/103) were newly diagnosed with either diabetes or prediabetes at admission. Most cohort patients had type 2 diabetes or prediabetes, and only 2.9% (3/103) of all patients had type 1 diabetes. Furthermore, 44.6% (46/103) of patients demonstrated evidence suggesting good glycemic control during the 4-12 weeks prior to admission, as defined arbitrarily by admission hemoglobin A1c level <7.5%, and 73.8% (76/103) of patients had other comorbidities, including hypertension, ischemic heart disease, and dyslipidemia. Laboratory data (mean and SD values) at admission for patients who needed ward-based care versus those who needed intensive care were as follows: fibrinogen, 462.8 (SD 125.1) mg/dL vs 660.0 (SD 187.6) mg/dL; D-dimer, 0.7 (SD 0.5) µg/mL vs 2.3 (SD 3.5) µg/mL; ferritin, 358.0 (SD 442.0) mg/dL vs 1762.4 (SD 2586.4) mg/dL; and C-reactive protein, 33.9 (SD 38.6) mg/L vs 137.0 (SD 111.7) mg/L. Laboratory data were all significantly higher for patients in the intensive care unit subcohort (P<.05). The average length of hospital stay was 14.55 days for all patients, with 28.2% (29/103) of patients requiring intensive care. In all, 4.9% (5/103) died during hospitalization-all of whom were in the intensive care unit. CONCLUSIONS: Majority of patients with diabetes or prediabetes and COVID-19 had other notable comorbidities. Only 4 patients tested negative for COVID-19 RT-PCR but showed pathognomonic changes of COVID-19 radiologically. Laboratory analyses revealed distinct abnormal patterns of biomarkers that were associated with a poor prognosis: fibrinogen, D-dimer, ferritin, and C-reactive protein levels were all significantly higher at admission in patients who subsequently needed intensive care than in those who needed ward-based care. More studies with larger sample sizes are needed to compare data of COVID-19 patients admitted with and without diabetes within the UAE region.

Challenges in developing drugs for the metabolic syndrome.

Metabolic syndrome refers to a clustering of established and emerging cardiovascular disease (CVD) risk factors within a single individual. The established risk factors--such as obesity, diabetes, dyslipidemia, hypertension--and other emerging risk factors are closely related to central obesity (especially intra-abdominal adiposity). Insulin resistance is also an important factor in this syndrome's etiology. However, despite the potential use of having all the CVD risk factors under an umbrella diagnosis of metabolic syndrome, debate continues about the very existence of the metabolic syndrome. Despite the controversies, many existing therapies and new drugs in development are targeting the metabolic syndrome. To date, no drugs are approved specifically for treating the metabolic syndrome. This article discusses some of the challenges in developing therapies for the metabolic syndrome.

Safe and Effective Use of the Once Weekly Dulaglutide Single-Dose Pen in Injection-Naïve Patients With Type 2 Diabetes.

BACKGROUND: This 4-week, phase 3b, multicenter, open-label, single-arm, outpatient study demonstrated the safe and effective use of the dulaglutide single-dose pen containing 0.5 mL of placebo for subcutaneous injection in injection-naïve adult patients with type 2 diabetes (T2D), with A1C ≤ 8.5% (69 mmol/mol), BMI ≥ 23 kg/m2 and ≤ 45 kg/m(2). METHOD: Patients completed a modified self-injecting subscale of the Diabetes Fear of Injecting and Self-Testing Questionnaire (mD-FISQ) and were trained to self-inject with the single-dose pen. Patients completed the initial self-injection at the site, injected at home for 2 subsequent weeks, and returned to the site for the final injection. The initial and final self-injections were evaluated for success; the final (initial) self-injection success rate was the primary (secondary) outcome measure, and the primary (secondary) objective was to demonstrate this success rate as being significantly greater than 80%. Patients recorded their level of pain after each injection. After the final injection, patients completed the mD-FISQ and the Medication Delivery Device Assessment Battery (MDDAB) to assess their perceptions of the single-dose pen, including ease of use and experience with the device. RESULTS: Among 211 patients (mean age: 61 years), the primary objective was met, with a final injection success rate of 99.1% (95% CI: 96.6% to 99.7%). Among 214 patients, the initial injection success rate was 97.2% (95% CI: 94.0% to 98.7%), meeting the key secondary objective. Overall, most patients (>96%) found the device easy to use, were satisfied with the device, and would be willing to continue to use the single-dose pen after the study. There was a significant reduction (P < .001) from baseline to study end in patients' fear of self-injecting, as measured by the mD-FISQ. CONCLUSIONS: The dulaglutide single-dose pen was found to be a safe and effective device for use by patients with T2D who were injection-naïve. A positive injection experience is an important factor for patients and providers when initiating injectable therapy.

Hyperuricemia as an independent predictor of vascular complications and mortality in type 2 diabetes patients: a meta-analysis.

BACKGROUND: Recent data have suggested that serum uric acid (SUA) level is positively associated with the development of type 2 diabetes (T2DM). Whether SUA is also independently associated with the development of vascular complications and mortality in T2DM is controversial. METHODS: A computerized literature search of MEDLINE, Embase and PubMed database was conducted and the odds ratio (OR) or hazard ratio (HR) for per 0.1 mmol/l increase in SUA in each study was calculated. Cochrane's Q and I(2) statistics were used to evaluate heterogeneity among studies and pooling OR and HR with 95% confidence intervals (CIs) were calculated using random-effects models and fixed-effects models. The pooled analysis was performed using Stata 10.0. RESULTS: Our search yielded 9 eligible articles (16 ORs and HRs) including 20,891 T2DM patients. Pooled estimates for the relationship suggested that each 0.1 mmol/l increase in SUA resulted in a 28% increase in the risk of diabetic vascular complications and a 9% increase in the risk of diabetic mortality. In stratification-analysis, the positive relationship between SUA and vascular complications remained significant irrespective of mean age, adjustment for metabolic variables and medications. However, it was inconsistent in different populations (significantly positive in the Asian but not in Australian and Italian population) and sample sizes (significantly positive in the relatively large sample size [≥1000] but non-significant in the small sample size [<1000]). CONCLUSIONS: Results of this meta-analysis supported elevated SUA as an independent predictor of vascular complications and mortality in T2DM patients. SUA-lowering therapies might be helpful for prevention and treatment of vascular complications in this population.

Recommendations for standardizing glucose reporting and analysis to optimize clinical decision making in diabetes: the Ambulatory Glucose Profile (AGP).

Abstract Underutilization of glucose data and lack of easy and standardized glucose data collection, analysis, visualization, and guided clinical decision making are key contributors to poor glycemic control among individuals with type 1 diabetes. An expert panel of diabetes specialists, facilitated by the International Diabetes Center and sponsored by the Helmsley Charitable Trust, met in 2012 to discuss recommendations for standardization of analysis and presentation of glucose monitoring data, with the initial focus on data derived from CGM systems. The panel members were introduced to a universal software report, the Ambulatory Glucose Profile (AGP), and asked to provide feedback on its content and functionality, both as a research tool and in clinical settings. This paper provides a summary of the topics and issues discussed during the meeting and presents recommendations from the expert panel regarding the need to standardize glucose profile summary metrics and the value of a uniform glucose report to aid clinicians, researchers, and patients.

Recommendations for standardizing glucose reporting and analysis to optimize clinical decision making in diabetes: the ambulatory glucose profile.

Underutilization of glucose data and lack of easy and standardized glucose data collection, analysis, visualization, and guided clinical decision making are key contributors to poor glycemic control among individuals with type 1 diabetes mellitus. An expert panel of diabetes specialists, facilitated by the International Diabetes Center and sponsored by the Helmsley Charitable Trust, met in 2012 to discuss recommendations for standardizing the analysis and presentation of glucose monitoring data, with the initial focus on data derived from continuous glucose monitoring systems. The panel members were introduced to a universal software report, the Ambulatory Glucose Profile, and asked to provide feedback on its content and functionality, both as a research tool and in clinical settings. This article provides a summary of the topics and issues discussed during the meeting and presents recommendations from the expert panel regarding the need to standardize glucose profile summary metrics and the value of a uniform glucose report to aid clinicians, researchers, and patients.

Endocrine and metabolic emergencies: hypoglycaemia.

Hypoglycaemia is rare in healthy individuals owing to the numerous elegant hormonal and neuronal mechanisms that maintain glucose homeostasis. Glucose is an obligate metabolic fuel for cerebral tissue and therefore hypoglycaemia, if uncorrected, can have disastrous consequences including death. Clinical hypoglycaemia is defined as a plasma (or serum) glucose concentration low enough to cause symptoms and/or signs, including impairment of brain function. However, no single plasma (or serum) glucose concentration categorically defines hypoglycaemia. Hypoglycaemia is probably the most common endocrine and metabolic emergency in clinical practice. The overwhelming majority of occurrences of hypoglycaemia occur in patients with diabetes, either as a result of treatment-induced hypoglycaemia and/or abnormalities that affect the normal counterregulatory response to hypoglycaemia. The differential for nondiabetes-associated hypoglycaemia is broad and includes insulinoma, drugs, hormone deficiencies, and critical illness. The acute management of hypoglycaemia is discussed along with a review of the pathophysiology and aetiology of this commonly encountered clinical problem.

Developing therapies for the metabolic syndrome: challenges, opportunities, and the unknown.

Metabolic syndrome refers to a clustering of established and emerging cardiovascular disease risk factors within a single individual. The established risk factors, such as obesity, diabetes, dyslipidaemia and hypertension, and other emerging risk factors are closely related to central obesity (especially intra-abdominal adiposity) and insulin resistance. However, debate continues about the very existence of the metabolic syndrome. Despite the controversies, many existing and new therapies are targeting the metabolic syndrome and component risk factors. To date, no therapies have been approved specifically for treating the metabolic syndrome. In this article some of the challenges and opportunities in developing therapies for the metabolic syndrome are discussed.

Endocrine and metabolic emergencies: hypocalcaemia.

Hypocalcaemia is a common electrolyte disturbance, especially in the inpatient setting. There are a wide variety of causes of hypocalcaemia and correct management depends on the underlying diagnosis. However, acute hypocalcaemia is associated with significant morbidity and mortality and should be managed as a medical emergency. Chronic care of the hypocalcaemic patient is also briefly described, as this is an important opportunity to reduce further admissions related to both hypocalcaemic and hypercalcaemic presentations.

Advances in the treatment of prediabetes.

Type 2 diabetes mellitus (T2DM) is epidemic in most developed and many developing countries. Owing to the associated morbidity, mortality and high costs of care, T2DM is an important global public health challenge and target for prevention. Patients at high risk for T2DM (referred to as having prediabetes) can be easily identified based on fasting glucose levels or responses to an oral glucose tolerance test (OGTT). More recently, glycosylated hemoglobin (i.e. HbA1c, which is also termed A1C in the US) has also been introduced as a diagnostic tool for both prediabetes and diabetes. Such patients are also at risk for cardiovascular disease (CVD). Since obesity and physical inactivity are important risk factors for T2DM, lifestyle interventions, emphasizing modest weight loss and increases in physical activity, should be recommended for most patients with prediabetes. Such interventions are safe and effective and also reduce risk factors for CVD. A number of oral antidiabetic agents have been shown to be effective at delaying onset of T2DM in patients with prediabetes. Thiazolidinediones (TZDs) are the most effective, reducing incident diabetes by up to 80%. Metformin, acarbose and orlistat also reduce incident diabetes, but their efficacy is much lower than the TZDs. Pharmacologic interventions may be appropriate for patients at particular risk for developing diabetes, but the benefits of treatment need to be balanced against the safety and tolerability of the intervention. If pharmacologic treatment is warranted, metformin should be considered first because of its favorable overall safety, tolerability, efficacy and cost profile.

Endocrine and metabolic emergencies: thyroid storm.

Thyrotoxicosis is a common endocrine condition that may be secondary to a number of underlying processes. Thyroid storm (also known as thyroid or thyrotoxic crisis) represents the severe end of the spectrum of thyrotoxicosis and is characterized by compromised organ function. Whilst rare in the modern era, the mortality rate remains high, and prompt consideration of this endocrine emergency, with specific treatments, can improve outcomes.

Endocrine and metabolic emergencies: hypercalcaemia.

Hypercalcaemia is commonly seen in the context of parathyroid dysfunction and malignancy and, when severe, can precipitate Life-threatening sequelae. The differential of hypercalcaemia is broad and can be categorized based on parathyroid hormone (PTH) Levels. The acute management of severe hypercalcaemia is discussed along with a brief review of therapeutic advances in the field.