IMpact of flash glucose Monitoring in pEople with type 2 Diabetes Inadequately controlled with non-insulin Antihyperglycaemic ThErapy (IMMEDIATE): A randomized controlled trial.

AIM: To examine the efficacy and patient satisfaction of intermittently scanned continuous glucose monitoring (isCGM) in adults using non-insulin therapies for the management of type 2 diabetes. MATERIALS AND METHODS: The IMMEDIATE study was a multisite, open label, randomized controlled trial with follow-up at 16 weeks. Adults with type 2 diabetes using at least one non-insulin therapy, with an HbA1c of 7.5% or higher (≥ 58 mmol/mol), were randomized 1:1 to receive an isCGM device plus diabetes self-management education (isCGM + DSME) or DSME alone. Enrolment occurred from 8 September 2020 to 24 December 2021. The primary outcome was percentage mean time in range (TIR), in the final 2-week period, measured via blinded CGM. RESULTS: One hundred and sixteen participants were randomized (mean age, 58 years; diabetes duration, 10 years; mean HbA1c, 8.6% [70 mmol/mol]). At 16 weeks of follow-up, the isCGM and DSME arm had a significantly greater mean TIR by 9.9% (2.4 hours) (95% CI, -17.3% to -2.5%; P < .01), significantly less time above range by 8.1% (1.9 hours) (95% CI, 0.5% to 15.7%; P = .037), and a greater reduction in mean HbA1c by 0.3% (3 mmol/mol) (95% CI, 0% to 0.7%; P = .048) versus the DSME arm. Time below range was low and not significantly different between groups and hypoglycaemic events were few in both groups. Glucose monitoring satisfaction was higher among isCGM users (adjusted difference -0.5 [95% CI, -0.7 to -0.3], P < .01). CONCLUSIONS: The IMMEDIATE study has shown that among non-insulin-treated individuals with type 2 diabetes, use of isCGM is associated with an improvement in glycaemic outcomes.

Goal achievement of HbA1c and LDL-cholesterol in a randomized trial comparing colesevelam with ezetimibe: GOAL-RCT.

AIM: To compare the efficacy and safety of colesevelam and ezetimibe as second-line low density lipoprotein-cholesterol (LDL-c)-lowering options in type 2 diabetes (T2D). MATERIALS AND METHODS: GOAL-RCT is a 24-week, open-label, randomized, pragmatic clinical trial. Subjects with T2D with uncontrolled HbA1c (7.1%-10%) and LDL-c (>2.0 mmol/L) were randomized 1:1 to colesevelam 3.75 g or ezetimibe 10 mg daily. The primary composite outcome was the proportion of participants achieving an LDL-c target of ≤2.0 mmol/L and HbA1c target of ≤7.0%. Intention to treat analysis was performed. RESULTS: Two hundred subjects were enrolled: mean age 59 ± 10 years; mean HbA1c 8.0%; mean LDL-c 2.5 mmol/L; 97% on statin therapy. The primary composite outcome was achieved by similar proportions of participants with colesevelam (14.6%) and ezetimibe (10.5%) (Pnon-inferiority < .001, Psuperiority = .41). LDL-c reduction from baseline was less with colesevelam compared with ezetimibe (14.0% vs. 23.2%, P < .01), as was the proportion of subjects achieving an LDL-c target of ≤2.0 mmol/L (47.6% and 67.0%, respectively; P = .007). Mean HbA1c was reduced with colesevelam (-0.26 ± 0.10%), while no change was observed with ezetimibe (difference P = .06). Adverse events and discontinuation rates were higher for colesevelam (20.2% and 31.1%) compared with ezetimibe (7.2% and 6.2%), respectively. CONCLUSIONS: Among subjects with T2D, the initiation of colesevelam or ezetimibe led to similar achievement of primary composite outcome (LDL-c and HbA1c within target), with ezetimibe recording a greater LDL-c reduction and better tolerability than colesevelam.

Randomized Comparison of Initiating the Fixed-Ratio Combination of iGlarLixi or Biosimilar Insulin Glargine Together With Gliclazide in Participants of South Asian Origin With Type 2 Diabetes: VARIATION 2 SA Trial.

OBJECTIVES: The objective of this study was to compare initiation of a fixed-ratio combination of insulin glargine and lixisenatide (iGlarLixi) vs insulin glargine U100 (iGlar) along with gliclazide, exclusively in people of South Asian origin with type 2 diabetes (T2D). METHODS: The Variability of glucose Assessed in a Randomized trial comparing the Initiation of A Treatment approach with biosimilar basal Insulin analog Or a titratable iGlarLixi combinatioN in type 2 diabetes among South Asian participants (VARIATION 2 SA) trial (ClinicalTrials.gov identifier: NCT03819790) randomized insulin-naïve adults with T2D having glycated hemoglobin (A1C) 7.1% to 11% to initiate either iGlarLixi or iGlar + gliclazide. Insulin doses were titrated similarly to a prebreakfast glucose target of 4.0 to 5.5 mmol/L. Average time in range (TIR) on a masked continuous glucose monitor (CGM), A1C, fasting plasma glucose (FPG) and weight were assessed at the end of the 12-week treatment period. RESULTS: Mean baseline characteristics for the 104 randomized participants were similar between treatment groups, including the following: age, 59±11 years; diabetes duration, 13.7±7.3 years; and A1C, 8.5%±1.2%. Coprimary outcomes of average TIRs within 24- and 12-h (6 am to 6 pm) periods at the end of trial were 70.5%±16.8% and 72.9%±17.6% for iGlarLixi, whereas these TIRs were 65.6%±21.6% and 67.3%±20.7% for the iGlar + gliclazide regimen, respectively, with no significant differences between groups (p=0.35 for 24-h TIR and p=0.14 for 12-h TIR). No significant difference in secondary outcomes was observed between treatment groups. Self-reported hypoglycemic events throughout the trial period and CGM-reported hypoglycemia (<4 and <3 mmol/L) were similar between randomized treatments. CONCLUSIONS: Initiation of iGlarLixi resulted in similar TIR, A1C, FPG, weight and hypoglycemia compared with the more affordable option of starting iGlar + gliclazide in adults of South Asian origin with T2D.

Patient Reported Outcomes following initiation of Glucagon-like peptide-1 Receptor agonists in patients with type 2 Diabetes in a specialist endocrinology practice of the LMC diabetes registry: The PROGRESS-Diabetes study.

AIMS: To compare patient-reported outcomes and clinical outcomes in patients who initiated dulaglutide or liraglutide as part of usual clinical therapy. METHODS: This observational study enrolled adults with type 2 diabetes who initiated dulaglutide or liraglutide between April 2017 and January 2018. A prospective patient cohort completed questionnaires at baseline and at their usual follow-up visit three to six months later. Clinical outcomes were assessed in a post-hoc retrospective analysis using propensity score matching. RESULTS: In the per-protocol analysis, 146 dulaglutide and 79 liraglutide patients had similar significant improvements in diabetes treatment satisfaction scores (dulaglutide 9.6 ±â€¯1.1, p < 0.001; liraglutide 10.6 ±â€¯1.4, p < 0.001) and follow-up scores for diabetes device satisfaction. Only dulaglutide had significant improvements in medication adherence scores. In the overall cohort, 754 matched patients showed similar reductions in A1C (dulaglutide -0.8% [9 mmol/mol]; liraglutide -0.7% [8 mmol/mol]). Liraglutide patients had a greater reduction in weight than those initiating dulaglutide (-2.8 kg vs. -1.8 kg; p < 0.001). CONCLUSIONS: Patients who initiated dulaglutide or liraglutide in a real-world specialist practice had similar improvements in diabetes medication satisfaction and diabetes device satisfaction. Only dulaglutide patients had significant improvements in medication adherence scores. Both treatment cohorts had similar patterns of A1C change, and liraglutide had significantly greater weight loss, which are similar to findings from clinical trials.

Diabetes Canada Position Statement for People With Types 1 and 2 Diabetes Who Fast During Ramadan.

OBJECTIVE: Fasting from dawn to dusk during Ramadan, including abstaining from water and food, is 1 of the pillars of Islam and is observed by the majority of Muslims. Most research concerning diabetes and fasting during Ramadan originates from Middle Eastern or South Asian countries; however, differences exist in hours of work and fasting, pharmacotherapy and blood glucose monitoring between these countries and Canada. METHODS: An expert forum of 7 Canadian experts and 1 international expert collaborated to develop Canadian guidelines using the same evidence-based principles, with the exception of an independent methods review used for the Diabetes Canada clinical practice guidelines. Diabetes Canada scientific leadership and Canadian health-care providers performed independent external reviews. Religious leaders endorsed the position statement and provided letters of support. An informed patient participated in the position-statement development. Each recommendation was approved with 100% consensus of the expert forum. RESULTS: Recommendations for risk stratification, education, pharmacotherapy and blood glucose monitoring for adults with type 1 and type 2 diabetes who intend to fast during Ramadan have been developed. CONCLUSIONS: This is the first Canadian position statement on the topic of Ramadan fasting and diabetes. It was developed by an expert faculty and endorsed by Diabetes Canada, and provides guidance about pharmacotherapy and glucose monitoring for health-care providers so that they can assist Canadian Muslims living with diabetes to observe fasting during Ramadan safely.

Proinflammatory and proapoptotic effects of methylglyoxal on neutrophils from patients with type 2 diabetes mellitus.

OBJECTIVE: To determine the effect of methylglyoxal (MG) on cytokine production by, and apoptosis of, neutrophils from type 2 diabetes mellitus (T2DM) patients. DESIGN AND METHODS: The levels of plasma MG, cytokines released by isolated neutrophils and the apoptotic status of neutrophils were determined. RESULTS: The higher level of plasma MG in T2DM patients was correlated positively with glycated hemoglobin levels, fasting plasma glucose levels and urine albumin/creatinine ratios. The basal levels of cytokines released from neutrophils were markedly higher in patients. MG treatment of the neutrophils isolated from diabetic patients either did not alter, or decreased, the production of cytokines. In contrast, MG induced the release of cytokines from neutrophils of non-diabetics. Moreover, the neutrophils from T2DM patients showed a greater proclivity for apoptosis, which was further increased by in vitro MG treatment. CONCLUSION: MG stimulated neutrophils to release more cytokines, which might play a role in the development of infection in T2DM.

Lowest Glucose Variability and Hypoglycemia Are Observed With the Combination of a GLP-1 Receptor Agonist and Basal Insulin (VARIATION Study).

OBJECTIVE: There is a dearth of published literature comparing glucose variability (GV) between different insulin regimens in type 2 diabetes. This cohort study compares GV using continuous glucose monitoring (CGM) in patients with well-controlled type 2 diabetes using four common insulin regimens: basal insulin + oral drugs (BO), basal insulin + glucagon-like peptide 1 receptor agonist (GLP-1 RA) (BGLP), premixed insulin (PM), and basal-bolus insulin (BB). RESEARCH DESIGN AND METHODS: Consecutive patients from three endocrinology clinics who met study criteria-type 2 diabetes, age 18 to 80 years, BMI ≤ 45 kg/m2, stable insulin regimen for a minimum of 6 months, and stable A1C value ≤7.5% (58 mmol/mol) before study enrollment-underwent 6-day masked CGM. Hypoglycemia was defined as a sensor glucose concentration <70 mg/dL on CGM. RESULTS: A total of 160 patients with comparable baseline characteristics formed four equal insulin regimen cohorts. The daily glucose SD (the primary outcome) was significantly lower in the BGLP cohort versus the BO, PM, and BB cohorts (P = 0.03, P = 0.01, and P < 0.01, respectively), and remained so after adjusting for age, BMI, type 2 diabetes duration, and A1C. Similarly, daily hypoglycemia outcomes on CGM were least for the BGLP cohort. CONCLUSIONS: The lowest GV and lowest hypoglycemia were observed in patients using the combination of basal insulin with a GLP-1 RA, supporting the complementary glycemic action of these agents in type 2 diabetes. These observed benefits in GV and hypoglycemia may contribute to the cardiovascular outcome reduction seen with GLP-1 RA therapy and should be investigated further.

Reversible hypercalcemia and hyperparathyroidism associated with lithium therapy: case report and review of literature.

OBJECTIVE: To present a case of reversible hypercalcemia and hyperparathyroidism associated with lithium therapy and to discuss the pathophysiology and management of this condition. METHODS: The clinical and laboratory findings in a patient with lithium-induced hypercalcemia are presented. A PubMed search for associated English language articles (with use of the key words lithium, hypercalcemia, and hyperparathyroidism) was conducted, and the relevant literature to date was reviewed. An approach to the management of patients with lithium-induced hypercalcemia is suggested. RESULTS: A 56-year-old man was referred for management of incidentally discovered hypercalcemia. The serum parathyroid hormone (PTH) level was increased; serum phosphorus and 24-hour urine calcium excretion were both normal. For 5 years, he had been treated with lithium carbonate for bipolar affective disorder. The laboratory features were consistent with lithium-induced primary hyperparathyroidism. Discontinuation of lithium treatment resulted in normalization of serum calcium and PTH levels. Review of the literature suggests that hypercalcemia and hyperparathyroidism are common consequences of lithium therapy. CONCLUSION: Hypercalcemia associated with lithium-induced hyperparathyroidism is a common, but underrecognized, complication of lithium therapy. Most patients have mild asymptomatic hypercalcemia. The long-term consequences of mild lithium-induced hypercalcemia are unknown. After discontinuation of lithium, the hypercalcemia may not always resolve; thus, parathyroidectomy may be necessary in some cases. Measurement of the serum calcium and PTH levels before and periodically after the initiation of lithium treatment is advisable. The appropriate monitoring of patients with lithium-induced hypercalcemia and decisions regarding parathyroidectomy are unclear. The decision to continue lithium therapy in the presence of hypercalcemia should be individualized.

Acromegaly as an endocrine form of myopathy: case report and review of literature.

OBJECTIVE: To describe a case of muscle weakness in a patient with acromegaly and to review the pathophysiologic features of this disorder. METHODS: We present the clinical, laboratory, electromyographic, and muscle biopsy findings in our patient and review related reports in the literature. RESULTS: A 58-year-old woman with acromegaly presented with complaints of bilateral hip pain, weakness, and instability 8 months after transsphenoidal resection of a growth hormone (GH)-secreting pituitary macroadenoma. She had biochemically normal thyroid and adrenal function and no evidence of any neuropathy, inflammatory myopathy, or rheumatologic disorder to explain her symptoms. Investigations revealed increased levels of GH, insulin-like growth factor-I, serum creatine kinase (CK), and the MB fraction of CK, normal results of nerve conduction studies, and nonspecific findings on electromyography and muscle biopsy. A review of the literature revealed that although muscle weakness is a well-recognized feature of acromegaly, only a few cases similar to ours have been reported since acromegaly was first described in the late 1800s. Little is known about the natural history, best diagnostic approach, and optimal therapy for this debilitating complication. CONCLUSION: Muscle weakness in acromegaly is common and may result from a combination of the direct effect of GH excess on muscle and other metabolic derangements (hypothyroidism, hypoadrenalism, or diabetes). Mechanical factors may also contribute, such as joint laxity in conjunction with hypermobility. Affected patients may benefit from a reduction in GH levels and physiotherapy for adaptive training. Persistently increased serum CK levels in a patient with diabetes, for whom no other cause is found, should prompt an investigation for acromegaly. More research into this aspect of acromegaly is needed for enhancement of our understanding of, and therapy for, this debilitating condition.

Evaluation and treatment of osteoporosis in patients with a fragility hip fracture.

OBJECTIVE: To determine whether patients with fragility hip fractures underwent assessment and treatment of osteoporosis during initial hospitalization or recommendations for such intervention were made to the primary care provider (PCP) at the time of hospital dismissal. METHODS: A review of medical records of patients admitted with a low-impact hip fracture to the Royal University Hospital in Saskatoon, Saskatchewan, Canada, was performed to determine whether recommendations were made to evaluate for or treat osteoporosis. In addition, a questionnaire was sent to the orthopedic surgeons practicing at the hospital to help identify barriers to widespread diagnosis and treatment of osteoporosis in such patients. RESULTS: Between January and December 2004, 174 patients with fragility hip fractures were admitted to the Royal University Hospital. The mean age of these patients was 82.5 +/- 9.8 years. Evaluation for treatment of osteoporosis was recommended in only 9 patients (5%). We found no significant differences in the intervention rates between male and female patients, between patients with and those without a prior history of osteoporosis or fracture, between patients who were previously taking osteoporosis medications and those who were not, and between patients who were seen by a medical consultant and those who were not. Most orthopedic surgeons believed that they were primarily responsible for the surgical care of these patients, and because they did not see these patients in regular follow-up, the management of osteoporosis was considered the responsibility of the PCP. CONCLUSION: The results of this study indicate that only a small number of patients with fragility hip fractures receive appropriate evaluation or treatment for underlying osteoporosis either during initial hospitalization or at the time of dismissal from the hospital. In this study, most orthopedic surgeons believed that evaluation and treatment of osteoporosis were the responsibility of the PCP. Because these patients have an increased risk for future fractures, barriers to the diagnosis and treatment of osteoporosis need to be removed, and health-care professionals need to be educated about appropriate risk factor modification in these patients.

Multiple myeloma presenting with recurrent hypercalcemia in a patient with a history of primary hyperparathyroidism: report of case and review of literature.

OBJECTIVE: To report a case of primary hyperparathyroidism (PHPT) that presented with recurrent hypercalcemia due to multiple myeloma after successful parathyroidectomy. METHODS: The initial manifestations, investigations, and postoperative follow-up of a case of hypercalcemia due to PHPT are described. The studies performed for evaluation for recurrent hypercalcemia and the subsequent diagnosis of multiple myeloma are discussed. The association between these disorders and reports of similar cases in the literature are reviewed. RESULTS: A 72-year-old woman was referred for incidentally discovered hypercalcemia. She had no history of kidney stones or fractures. Further investigations revealed a high parathyroid hormone (PTH) level, hypercalciuria, and low bone mass, particularly at the cortical sites. Parathyroidectomy was performed, and a right inferior parathyroid adenoma was removed. Postoperatively, both the calcium and PTH levels normalized. She presented 9 months later with a 3-week history of pain in her left hip, polyuria, nausea, and vomiting. The patient had severe hypercalcemia and a suppressed PTH level. Further investigations revealed multiple bony lytic lesions, abnormalities on serum protein electrophoresis, and features consistent with multiple myeloma on a bone marrow biopsy specimen. CONCLUSION: Hypercalcemia can occur in patients with PHPT and multiple myeloma; however, the occurrence of both disorders in the same patient is rare. Review of the literature revealed only a few cases similar to ours. Evidence in the literature suggests that monoclonal gammopathies occur more often in patients with PHPT than in the general population; therefore, screening for monoclonal gammopathy may be warranted in patients with PHPT.

Lipid lowering inefficacy of high-dose statin therapy due to concurrent use of phenytoin.

HMG-CoA reductase inhibitors ("statins") are the most commonly prescribed lipid lowering agents. Most of the statins are metabolized by the CYP450 cytochrome system. A number of medications either induce or inhibit this system which leads to changes in the bioavailability of the statins and the potential for either an increase in adverse effects or reduction in efficacy. Phenytoin induces the CYP3A4 isoform of the CYP450 system and can reduce the bioavailability, and thus the efficacy of the statins metabolized by this enzyme, including atorvastatin and lovastatin. A case of a patient on multiple lipid-lowering medications, including high-dose atorvastatin whose LDL cholesterol improved significantly after discontinuation of phenytoin is presented, and a review of the literature for similar cases is discussed.

Macroprolactinemia in a patient with infertility and hyperprolactinemia.

A significant number of patients with hyperprolactinemia have macroprolactinemia, a condition characterized by the preponderance of big-big prolactin with normal levels of free prolactin. As macroprolactin does not have biologic activity, such patients do not require further investigations or treatment for hyperprolactinemia. The case of a patient with hyperprolactinemia diagnosed during investigation of secondary infertility is presented. She was treated for over 2 years with dopamine agonists, with which her prolactin level normalized, but she remained infertile. Subsequent investigations demonstrated that she suffered from macroprolactinemia, not true hyperprolactinemia. The patient is currently not on dopamine agonist therapy, and although her total prolactin levels remain significantly elevated, her free prolactin levels have been in the normal range. Physicians should familiarize themselves with this entity and consider testing for it in patients with hyperprolactinemia to avoid an inappropriate diagnosis and unnecessary treatment.

Celiac disease occurring in a patient with hypoparathyroidism and autoimmune thyroid disease.

Patients with an underlying autoimmune endocrine disorder are at an increased risk of developing other autoimmune diseases. We describe a patient with idiopathic autoimmune hypoparathyroidism who developed hyperthyroidism due to Graves disease and subsequently was diagnosed with celiac disease. Malabsorption of L-thyroxine was the only clue regarding the presence of celiac disease. This particular association of these three autoimmune disorders occurring in the same patient has not, to our knowledge, been previously reported. The presentation, investigations performed, and treatment provided are discussed and the literature pertaining to similar cases is reviewed.

Low serum alkaline phosphatase activity and pathologic fracture: case report and brief review of hypophosphatasia diagnosed in adulthood.

OBJECTIVE: To describe an elderly patient with low serum alkaline phosphatase (ALP) activity detected after a pathologic fracture and to characterize hypophosphatasia in adult patients. METHODS: We present a case report of a 64-year-old woman, who was referred after sustaining an atraumatic femoral fracture treated successfully with intramedullary nailing. Clinical, biochemical, radiologic, and molecular studies explore the differential diagnosis of her hypophosphatasemia, and the features, diagnosis, and management of the adult form of hypophosphatasia are reviewed. RESULTS: Physical examination of our patient was revealing only for short stature. Bone mineral density evaluated by dual-energy x-ray absorptiometry was unremarkable. Biochemical investigations showed normal calcium, elevated inorganic phosphate, and low ALP levels in serum. In light of the hypophosphatasemia and pathologic fracture, the serum pyridoxal 5'-phosphate concentration was measured and found to be considerably elevated, a substantiation of the diagnosis of hypophosphatasia. Analysis of the gene encoding the "tissue-nonspecific" isoenzyme of ALP (TNSALP) demonstrated a novel, heterozygous, missense mutation causing her disorder. CONCLUSION: Hypophosphatasia is a rare inborn error of metabolism due to a deactivating mutation (or mutations) of the gene encoding TNSALP, in turn leading to global deficiency of TNSALP activity and inadequate skeletal mineralization and fractures. Our patient illustrates the importance of low serum ALP activity in the assessment of patients with fractures. No established treatment exists for hypophosphatasia, but the correct diagnosis should help to avoid the use of traditional therapies for osteoporosis or osteomalacia, which would be ineffective or potentially harmful.

A case of congestive heart failure due to reversible dilated cardiomyopathy caused by hyperthyroidism.

Thyrotoxicosis is an uncommon cause of low-output congestive heart failure. The case of a 41-year-old male who presented with severe symptomatic congestive heart failure, and was subsequently diagnosed with dilated cardiomyopathy secondary to hyperthyroidism, is presented. The cause of his hyperthyroidism was Graves disease. Despite an initial left ventricular systolic ejection fraction of 20% and evidence of global hypokinesis on echocardiography, treatment with antithyroid agents led to rapid improvement in his clinical status and normalization of his ejection fraction. The proposed mechanisms underlying the development of systolic dysfunction in thyrotoxicosis are discussed, and the literature on similar cases previously reported is reviewed.

Adrenomyeloneuropathy as a cause of primary adrenal insufficiency and spastic paraparesis.

Adrenomyeloneuropathy is a varient of adrenoleukodystrophy, both of which are rare inherited disorders of peroxisomes characterized by the accumulation of very-long-chain fatty acids in plasma, the central and peripheral nervous systems, adrenal glands and testes, which leads to dysfunction of these organs and systems. In this article, we describe an illustrative case of adrenomyeloneuropathy and discuss the clinical presentation, diagnosis and management of the 2 disorders.