Purpose of Review
In recent years, the recommendation for and use of patient-reported outcome measures (PROMs) in routine diabetes care has significantly increased. We review recent evidence and ...highlight key opportunities and challenges related to the active clinical use of PROMs to support person-centered diabetes care and focus areas for future research in the area.
Recent Findings
Recent pragmatic studies support that integration of multi-dimensional PROMs for diabetes in clinical care as part of a care improvement strategy can be acceptable for and valued by people with diabetes (PWD) and healthcare professionals (HCPs) and may improve multiple aspects of quality of care, including screening, medical care monitoring and decision support, individualization of self-management support and goal-setting, and broader benefits related to active patient participation and person-centred diabetes care. We identify multiple intervention, individual, and care setting characteristics, which influence acceptability, feasibility, implementation, and effectiveness of PROMs in routine care. Recent clinical PROM studies highlight the value of mixed methods research and systematic involvement of PWD, clinicians, and other stakeholders in the design and implementation of questionnaires for patient input in routine diabetes care.
Summary
We identified a new significant trend towards participatory development of multi-dimensional PROMs with the aim of IT-enabled integration into routine diabetes care to facilitate multiple components of person-centered diabetes care and better clinical, quality of life, and cost outcomes. While results from large-scale randomized controlled studies are still limited, a growing number of pragmatic implementation studies support that user-centric PROM interventions have the potential to facilitate significant improvements in care for PWD.
Aims/hypothesis The aim of the study was to determine the loss of muscle volume in the lower leg and foot in long-term diabetic patients in relation to the presence of neuropathy. Methods We ...re-examined 26 type 1 diabetic patients who had participated in magnetic resonance imaging (MRI) studies on muscle volume in the lower leg and foot 9 to 12 years earlier. Re-examination involved MRI, isokinetic dynamometry, clinical examination, electrophysiological studies and quantitative sensory examinations. Results Annual loss of muscle volume of ankle dorsal and plantar flexors was 4.5 (5.5-3.9)% (median range) and 5.0 (7.0-4.2)% in neuropathic patients, 1.9 (3.2-1.0)% and 1.8 (2.6-1.3)% in non-neuropathic patients, and 1.7 (2.8-0.8)% and 1.8 (2.4-0.8)% in controls, respectively (p < 0.01). Annual change of volume and strength correlated for ankle dorsal flexors (r s = 0.73, p < 0.01) and for ankle plantar flexors (r s = 0.63, p < 0.05) in diabetic patients. In addition, annual change of muscle volume for dorsal and plantar flexors was related to the combined score of all measures of neuropathy (r s = -0.68, p < 0.02 and r s = -0.73, p < 0.01, respectively). Foot muscle volume declined annually by 3.0 (3.4-1.0)% in neuropathic patients and by 1.1 (4.0-0.2)% in non-neuropathic patients, both values being significantly different from controls (0.2 -2.5 to 2.4%). Loss of foot muscle volume was related to severity of neuropathy assessed at clinical evaluation (r s = -0.6, p < 0.05). Conclusions/interpretation Muscular atrophy in long-term diabetic neuropathy occurs early in the feet, progresses steadily in the lower legs, relates to severity of neuropathy and leads to weakness at the ankle.
Systemic inflammatory processes plausibly contribute to the development of cardiovascular complications, causing increased morbidity and mortality in type 2 diabetes. Circulating inflammatory ...markers, i.e., interleukin (IL)-6 and tumour necrosis factor-α, are associated with neurocardiac measures. We examined a broad panel of various inflammatory and inflammation-related serum markers to obtain more detailed insight into the possible neuro-immune interaction between cardiovascular regulation and systemic level of inflammation.
Serum samples from 100 participants with type 2 diabetes were analysed. Heart rate variability, cardiovascular autonomic reflex tests, and cardiac vagal tone tests were performed based on electrocardiographic readings. Data regarding covariates (demographic-, diabetes-, and cardiovascular risk factors) were registered.
Increased serum levels of IL-12/IL-23p40 (p < 0.01) and intercellular adhesion molecule (ICAM)-1 (p < 0.007) were associated with diminished heart rate variability measures. After all adjustments, the associations between IL-12/23p40, SDANN and VLF persisted (p = 0.001). Additionally, serum levels of vascular endothelial growth factor (VEGF)-C were associated with response to standing (p = 0.005).
The few but robust associations between neurocardiac regulation and serum markers found in this study suggest systemic changes in proinflammatory, endothelial, and lymphatic function, which collectively impacts the systemic cardiovascular function. Our results warrant further exploration of IL-12/IL-23p40, ICAM-1, and VEGF-C as possible cardiovascular biomarkers in T2D that may support future decisions regarding treatment strategies for improved patient care.
To evaluate if diffusion-tensor-imaging MR-Neurography (DTI-MRN) can detect lesions of peripheral nerves due to polyneuropathy in patients with type 2 diabetes.
Ten patients with type 2 diabetes with ...polyneuropathy (DPN), 10 patients with type 2 diabetes without polyneuropathy (nDPN) as well as 20 healthy controls (HC) were included. DTI-MRN covered proximal (sciatic nerve) and distal regions (tibial nerve) of the lower extremity. Fractional-anisotropy (FA) and diffusivity (mean (MD), axial (AD) and radial (RD)) were calculated and compared to neuropathy severity. Conventional T2-relaxation-time and proton-spin-density data were obtained from a multi-echo SE sequence. Furthermore, we evaluated sensitivity and specificity of DTI-MRN from receiver operating characteristics (ROC).
The proximal and distal FA was lowest in patients with DPN compared with nDPN and HC (p < 0.01). Likewise, proximal and distal RD was highest in patients with DPN (p < 0.01). MD and AD were also significantly different though less pronounced. ROC curve analyses of DTI separated nDPN and DPN with area-under-the-curve values ranging from 0.65 to 0.98. T2-relaxation-time and proton-spin-density could not differentiate between nDPN and DPN.
DTI-MRN accurately detects DPN by lower nerve FA and higher RD. These alterations are likely to reflect both proximal and distal nerve fiber pathology in patients with type 2 diabetes.
•Magnetic resonance imaging (MRI) of peripheral nerves is able to detect peripheral nerve lesions in patients with type 2 diabetes.•We demonstrate that MRI enables detection of abnormalities in the sciatic and tibial nerve in type 2 diabetic patients.•Finally, the study show early nerve involvement in the peripheral nerves in type 2 diabetes when evaluating radial diffusivity MRI.•Later stages of diabetic complications have a massive effect on way of life and healthcare costs. These findings indicate that MRI might be a useful tool for detection of early nerve involvement in patients with type 2 diabetes.
Background
TZP‐102, a potent, oral, ghrelin receptor agonist, improved diabetic gastroparesis symptoms in Phase 2a.
Methods
Patients with type 1 or 2 diabetes, delayed gastric half‐emptying (T1/2), ...and ≥3 months gastroparesis symptoms randomized 1 : 1 : 1 to double‐blind placebo, 10‐mg, or 20‐mg TZP‐102 once daily for 12 weeks (Study TZP‐102‐CL‐G003). Study TZP‐102‐CL‐G004 patients randomized 1 : 1 to 10‐mg TZP‐102:placebo three‐times‐daily. Primary endpoint was change‐from‐baseline through Weeks 11–12 in Daily Diary of Gastroparesis Symptoms Questionnaire (GSDD) via electronic Patient Recorded Outcome device: worst severity of nausea, early satiety, bloating, and upper abdominal pain in 24 h (0 = none‐to‐5 = very severe). GSDD Composite Score for eligibility was ≥2.5 (Day‐14‐to‐baseline). Patient Overall Treatment Evaluation (OTE) provided an anchor‐based minimal clinically important difference (MCID) for GSDD Composite Score.
Key Results
Study TZP‐102‐CL‐G003 enrolled 201 outpatients: females 72%; Caucasians 87%; type 2 diabetes 61%; insulin‐dependent 65%; age mean ± SD 53 ± 11.3 years; HbA1c 7.8 ± 1.5%; GCSI 3.4 ± 0.7; GSDD Composite 3.6 ± 0.6; gastric T1/2 131 ± 32 min; n = 69 (10‐mg), n = 66 (20‐mg), n = 66 (placebo). Primary endpoint (GSDD): significant improvement in all arms, although not for TZP‐102 vs placebo: mean change‐from‐baseline −1.7, −1.4, −1.5 (10‐mg, 20‐mg, placebo); Gastroparesis Cardinal Symptom Index −1.8, −1.6, −1.5, respectively. The OTE (all patients) at Week‐12 was: Patient 3.7 ± 3.2 and Physician 3.6 ± 3.0 with median score for both of 5.0 = important on scale of improvement; individual MCID was 1.61 and 0.94 for group analyses, greater than expected. Study TZP‐102‐CL‐G004 with similar demographic/disease characteristics was prematurely terminated for efficacy futility (n = 64 with Week‐4 assessments).
Conclusions & Inferences
Efficacy of TZP‐102 was not demonstrated compared with placebo in diabetic gastroparesis; however, there was substantial symptom improvement in all arms (ClinicalTrials.gov NCT01452815/NCT01664637).
Diabetic ketoacidosis is an infrequent but life-threatening acute complication of diabetes, affecting predominantly patients with type 1 diabetes, children, and pregnant women, where ketosis is ...usually associated with marked hyperglycemia. Recently, an increasing number of cases have been reported of euglycemic diabetic ketoacidosis in patients with type 2 diabetes receiving sodium-glucose cotransporter 2 inhibitor treatment in routine practice. There is a minor, but not negligible diabetic ketoacidosis risk associated with this drug class, which was not seen in randomized clinical trials. However, sodium-glucose cotransporter2 inhibitors increase the risk of ketosis by increasing glucagon secretion in the pancreas and decreasing the renal excretion of 3-hydroxybutyrate and acetoacetate. When used in addition to insulin, any insulin dose reduction required to avoid hypoglycemia may lead to insufficient suppression of lipolysis and ketogenesis. sodium-glucose cotransporter2 inhibitor-induced loss of urinary glucose encourages euglycemia. Normo-glycemic or near-normoglycemic diabetic ketoacidosis represents a major threat to the health and well-being of a patient, because it may occur undetected and without any indicative hyperglycemia. In consequence, patients on sodium-glucose cotransporter2 inhibitors are recommended to perform regular blood ketone tests since they are not alerted to incipient diabetic ketoacidosis by glucose testing alone. This option is offered by several blood glucose meters that can also measure ketones with a separate ketone strip or in one case by an automatic parallel ketone assessment from the same strip. The need for extra testing and the associated costs may be a barrier to patient acceptance of this risk mitigation procedure. However, patients who are at risk for euglycemic diabetic ketoacidosis when being treated with sodium-glucose cotransporter2 inhibitors should be specially advised to monitor blood ketone levels on a regular basis.
Aims/hypothesis
There is limited evidence on how multifactorial treatment improves outcomes of diabetes when initiated in the lead time between detection by screening and diagnosis in routine ...clinical practice. Cardiac autonomic neuropathy (CAN) in people with diabetes indicates widespread damage to the autonomic nervous system, which may severely affect health and quality of life. We examined effects of early detection and subsequent intensive treatment of type 2 diabetes in primary care on the prevalence of CAN at the 6-year follow-up examination in a pragmatic cluster-randomised parallel group trial.
Methods
One hundred and ninety general practices were randomised to deliver either intensive multifactorial treatment (IT) or routine care (RC) as recommended by national guidelines to patients with type 2 diabetes, identified through a stepwise screening programme in the primary care setting. 1533 people (IT,
n
= 910; RC,
n
= 623) were identified and included. At the 6-year follow-up examination, measures of CAN were applied in an unselected subsample of 777 participants using heart rate variability analysis and standard tests of CAN.
Results
At the 6-year follow-up examination, the prevalence of early CAN was 15.1% in the RC group and 15.5% in the IT group, while manifest CAN was present in 7.1% and 7.3%, respectively. We found no statistically significant effect of intensive treatment on the prevalence of CAN compared with routine care.
Conclusions/interpretation
In the Danish arm of the ADDITION Study, signs of CAN were highly prevalent 6 years after a screening-based diagnosis of type 2 diabetes. Intensive multifactorial treatment did not significantly affect the prevalence of CAN compared with routine care. However, at follow-up the level of medication was also high in the RC group.
Background Gastroparesis causes significant morbidity and treatment options are limited. TZP‐102 a novel, macrocyclic, selective, oral ghrelin receptor agonist, was evaluated in a randomized, ...double‐blind, placebo‐controlled trial in patients with diabetic gastroparesis.
Methods A total of 92 outpatients were randomized to once‐daily administrations of 10‐mg (n = 22), 20‐mg (n = 21), 40‐mg (n = 23) TZP‐102 or placebo (n = 26). The primary endpoint was the change from baseline in gastric half‐emptying time (T½) utilizing 13C‐breath test methodology and secondary endpoints included symptom improvement using patient‐reported gastroparesis symptom scores (PAGI‐SYM questionnaire) and patient and physician overall treatment evaluations (OTE).
Key Results Gastric T½ changes were not statistically significant between TZP‐102 and placebo after 28 days of treatment at any dose. Clinical improvements (−1.0 to −1.4 point mean decrease in symptom severity) occurred in the Gastroparesis Cardinal Symptom Index (GCSI) component of the PAGI‐SYM, which was significant vs placebo for all TZP‐102 doses combined. Improvements became evident after 1 week of treatment. Significantly, more patients given TZP‐102 (any dose) had a 50% reduction in baseline GCSI score (28.8%vs 7.7% placebo). Safety profiles were similar across groups. All TZP‐102 doses were well‐tolerated with no adverse cardiac, weight, or glucose control outcomes.
Conclusions & Inferences TZP‐102 for 28 days, at doses of 10–40 mg once daily, was well‐tolerated and resulted in a reduction in symptoms of gastroparesis. The lack of correlation between symptom improvement and gastric emptying change is consistent with previous studies in diabetic gastroparesis, and emphasizes the value of patient‐defined outcomes in determining therapeutic benefit.
Summary
Background TZP‐101 is a synthetic, selective ghrelin agonist in development for gastroparesis.
Aim To assess safety and effects of TZP‐101 in diabetes patients with symptomatic ...gastroparesis.
Methods Adults with type 1 or type 2 diabetes mellitus received placebo and TZP‐101 (80, 160, 320 or 600 μg/kg) infusions in a cross‐over manner following a radiolabelled meal. Blood glucose levels were stabilized using a hyperinsulinemic‐euglycemic clamp. Primary endpoints were gastric half emptying and latency times. Secondary measures included assessment of gastroparesis symptoms and endocrine responses.
Results Ten patients with type 1 (n = 7) or 2 (n = 3) diabetes, moderate‐to‐severe gastroparesis symptoms and ≥29% retention 4 h after a radiolabelled solid meal were enrolled. TZP‐101 produced significant reductions in solid meal half‐emptying (20%, P = 0.043) and latency (34%, P = 0.037) times vs. placebo. Reductions in overall postmeal symptom intensity (24%) and postprandial fullness (37%) following TZP‐101 infusion were not statistically significant. Most adverse events were mild and self‐limiting and there were no identifiable differences in numbers or types of adverse events between TZP‐101 and placebo.
Conclusions This proof‐of‐concept study demonstrates that the ghrelin agonist TZP‐101 is well‐tolerated in diabetes patients with moderate‐to‐severe chronic gastroparesis and shows statistically significant improvements in gastric emptying.
Aliment Pharmacol Ther 2011; 33: 679–688
Summary
Background Limited therapeutic options exist for severe gastroparesis, where severe nausea and vomiting can lead to weight loss, dehydration and ...malnutrition due to inadequate caloric and fluid intake. TZP‐101 (ulimorelin) is a ghrelin receptor agonist that accelerates gastric emptying and improves upper gastrointestinal symptoms in diabetic patients with gastroparesis.
Aim To assess effects of TZP‐101 in diabetic gastroparesis patients with severe nausea/vomiting and baseline severity scores of ≥3.5 (range: 0–5) on the Gastroparesis Cardinal Symptom Index (GCSI) Nausea/Vomiting subscale.
Methods Patients were hospitalised and received four single daily 30‐min infusions of one of six TZP‐101 doses (range 20–600 μg/kg) or placebo. Efficacy was assessed by symptom improvement.
Results At baseline, 23 patients had a mean severity score for GCSI Nausea/Vomiting of 4.45 ± 0.44. Statistically significant improvements over placebo occurred in the 80 μg/kg group for end of treatment changes from baseline in GCSI Nausea/Vomiting subscale (reduction in score of −3.82 ± 0.76, P = 0.011) and the GCSI Total score (−3.14 ± 0.78, P = 0.016) and were maintained at the 30‐day follow‐up assessment (−2.02 ± 1.63, P = 0.073 and −1.99 ± 1.33, P = 0.032 respectively). The proportion of days with vomiting was reduced significantly (P = 0.05) in the 80 μg/kg group (mean of 1.2 days of vomiting for four treatment days) compared with placebo (mean of 3.2 days of vomiting across 4 treatment days).
Conclusions TZP‐101 substantially reduced the frequency and severity of nausea and vomiting as well as overall gastroparesis symptoms. The results are consistent with gastrointestinal motility effects of TZP‐101, supporting further investigation of TZP‐101 in the management of severe gastroparesis.
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