Natalia McInnes

Aims: When administered in early type 2 diabetes (T2DM), the strategy of ‘induction’ with short‐term intensive insulin therapy (IIT) followed by ‘maintenance’ with metformin thereafter can yield outstanding glycaemic control, with some patients achieving A1c in the normal range of its assay. We thus sought to identify determinants of sustained normalisation of A1c in response to this treatment strategy. Materials and Methods: In this study, adults with T2DM of mean duration 1.7 ± 1.4 years received induction IIT (glargine, lispro) for 3 weeks, followed by metformin maintenance either with or without periodic 2‐week courses of IIT every 3 months for 2 years. Sustained glycaemic normalisation was defined by A1c p = 0.02; waist circumference: p = 0.02), hepatic insulin resistance (HOMA‐IR: p = 0.02) and ALT ( p = 0.005), coupled with relative stabilisation of beta‐cell function and glycaemia. On logistic regression analyses, significant independent predictors of normalisation of A1c at 2 years were baseline A1c (adjusted odds ratio [aOR] = 0.01 [95% CI 0.001–0.16], p = 0.001) and the changes in waist circumference (aOR = 0.77 [0.63–0.94], p = 0.012) and ALT (aOR = 0.90 [0.82–0.98], p = 0.019) during maintenance therapy from 3 weeks to 2 years. Conclusions: While lower baseline A1c and greater reduction in central adiposity predicted A1c <6.0% at 2 years as anticipated, the emergence of greater reduction in ALT as a concomitant determinant highlights the role of the liver in the achievement of sustained glycaemic normalisation.

OBJECTIVE: Alleviation of unrecognized glucotoxicity, with resultant recovery of β-cell function, could amplify the glucose-lowering effect of pharmacotherapy and contribute to the variable therapeutic response observed among patients with type 2 diabetes (T2D). However, clinical evidence supporting this concept is lacking. Short-term intensive insulin therapy (IIT) can ameliorate glucotoxicity and improve β-cell function in early T2D. Thus, for evidence of recovery of glucotoxicity-associated β-cell dysfunction, we sought to determine whether there exists a baseline fasting glucose threshold above which the post-IIT improvement in both β-cell function and glycemia is amplified. RESEARCH DESIGN AND METHODS: IIT (glargine, lispro) was administered for 3 weeks to 108 adults with T2D (mean duration 1.8 ± 1.4 years). Oral glucose tolerance tests before and after IIT enabled assessment of β-cell function by Insulin Secretion-Sensitivity Index-2 and insulinogenic index/HOMA-insulin resistance. For each level of baseline fasting glycemia from 6.0 to 10.5 mmol/L, we modeled the difference in IIT-induced percentage change in β-cell function between those at/above the indicated glucose level and those below it. RESULTS: The relationship between baseline fasting glucose and the differential change in β-cell function was nonlinear. Instead, this relationship was best fit by a cubic regression model with inflection (amplification) at fasting glucose at 9.3 mmol/L. Moreover, baseline fasting glucose at 9.3 mmol/L also identified the inflection point at which nonlinear reductions in fasting glucose and 2-h glucose, respectively, were both amplified. CONCLUSIONS: The respective improvements in β-cell function and glycemia in response to short-term IIT are amplified in those in whom baseline fasting glucose exceeds a defined threshold, consistent with reversal of glucotoxicity.

Aim: To evaluate the effect on type 2 diabetes remission of short‐term intensive metabolic intervention consisting of frequent dietary, exercise and diabetes management coaching, metformin and fixed‐ratio insulin degludec/liraglutide. Methods: In a multicentre open‐label randomized controlled trial, insulin‐naïve participants within 5 years of diabetes diagnosis were assigned to a 16‐week remission intervention regimen or standard care, and followed for relapse of diabetes and sustained remission for an additional year after stopping glucose‐lowering drugs. Results: A total of 159 participants aged 57 ± 10 years, with diabetes duration 2.6 ± 1.5 years, body mass index 33.5 ± 6.5 kg/m ² , and glycated haemoglobin (HbA1c) level 53 ± 7 mmol/mol were randomized and analysed (79 intervention, 80 control). At the end of the 16‐week intervention period, compared to controls, intervention participants achieved lower HbA1c levels (40 ± 4 vs. 51 ± 7 mmol/mol; p < 0.0001), and lost more weight (3.3 ± 4.4% vs. 1.9 ± 3.0%; p = 0.02). There was a lower hazard of diabetes relapse overall in the intervention group compared to controls (hazard ratio 0.63, 95% confidence interval [CI] 0.45, 0.88; p = 0.007), although this was not sustained over time. Remission rates in the intervention group were not significantly higher than in the control group at 12 weeks (17.7% vs. 12.5%, relative risk [RR] 1.42, 95% CI 0.67, 3.00; p = 0.36) or at 52 weeks (6.3% vs. 3.8%, RR 1.69, 95% CI 0.42, 6.82) following the intervention period. Conclusions: An intensive remission‐induction intervention including fixed‐ratio insulin degludec/liraglutide reduced the risk of type 2 diabetes relapse within 1 year without sustained remission.

Hematologic malignancies are rare causes of sellar masses and hypopituitarism. We report 2 cases of hypopituitarism due to sellar masses from hematologic malignancies. The first patient was found to have hypopituitarism but initial non-gadolinium-enhanced magnetic resonance imaging (MRI) sella did not demonstrate a mass. Subsequent gadolinium-enhanced MRI and transsphenoidal biopsy confirmed a diagnosis of intravascular lymphoma. Treatment with systemic chemotherapy resulted in resolution of abnormalities on MRI. The second patient had a known diagnosis of chronic lymphocytic leukemia, and sellar involvement contributing to hypopituitarism was confirmed on biopsy. Treatment with ibrutinib, acalabrutinib, and stereotactic radiosurgery resulted in resolution of abnormalities on MRI. Both patients were treated with hormone replacement for hypopituitarism. These cases highlight that hematologic malignancies should be suspected as causes of sellar masses/hypopituitarism in patients with concurrent symptoms atypical for a pituitary adenoma (eg, constitutional symptoms), known diagnoses of hematologic malignancies, or rapid tumor growth and invasion on imaging. Gadolinium-enhanced MRI should be pursued if nonenhanced MRI is nondiagnostic. Transsphenoidal biopsy can be considered for diagnosis. Malignancy-directed systemic therapy may improve hypopituitarism and radiographic abnormalities on MRI.

Aim: Non‐surgical options for inducing type 2 diabetes remission are limited. We examined whether remission can be achieved by combining lifestyle approaches and short‐term intensive glucose‐lowering therapy. Methods: In this trial, 160 patients with type 2 diabetes on none to two diabetes medications other than insulin were randomised to (a) an intervention comprising lifestyle approaches, insulin glargine/lixisenatide and metformin, or (b) standard care. Participants with glycated haemoglobin (HbA1c) p = .002). Complete or partial diabetes remission was achieved in 30 (38.0%) intervention group participants versus 16 (19.8%) controls at 24 weeks and 25 (31.6%) versus 14 (17.3%) at 36 weeks [relative risk 1.92 (95% confidence interval 1.14‐3.24) and 1.83 (1.03‐3.26), respectively]. The relative risk of diabetes remission in the intervention versus control group was 1.88 (1.00‐3.53) at 48 weeks and 2.05 (0.98‐4.29) at 64 weeks. Conclusions: A 12‐week intensive intervention comprising insulin glargine/lixisenatide, metformin and lifestyle approaches can induce remission of diabetes.

OBJECTIVE The aim of the study was to evaluate remission of type 2 diabetes following a short-term intervention with insulin glargine, sitagliptin/metformin, and lifestyle approaches. RESEARCH DESIGN AND METHODS In this open multicenter trial, 102 patients with type 2 diabetes were randomized to 1) a 12-week intervention with sitagliptin/metformin, insulin glargine and lifestyle therapy, or 2) control group. Participants with HbA_1c <7.3% (10 mmol/L over 1 week, and reinitiation of diabetes medications with or without abnormal fasting plasma glucose (FPG) or 2-h plasma glucose on an oral glucose tolerance test (OGTT). Time-to-relapse analysis was conducted to compare the treatment groups with (primary analysis) and without (supplementary analysis) FPG/OGTT relapse criteria. RESULTS With the FPG/OGTT relapse criteria included, the hazard ratio (HR) of relapse was 0.72 (95% CI 0.47–1.10) in the intervention group compared with the control group (primary analysis), and the number of participants remaining in remission was not significantly different between treatment groups at 24, 36, 48, and 64 weeks. In the supplementary analyses without these criteria, HR of relapse was 0.60 (95% CI 0.39–0.95), and the number of participants remaining in remission was significantly higher (26 vs. 10%) in the intervention group at 36 weeks. CONCLUSIONS Although our primary outcome was not statistically significant, the tested approach deserves further study with further optimization of its components.

Objective To examine diabetes remission following a short-term intensive metabolic intervention combining lifestyle and glucose-lowering approaches. Methods We conducted an open-label, randomized controlled trial in 154 patients with type 2 diabetes up to 8 years in duration on 0 to 2 glucose-lowering medications. Participants were randomized to (a) a 12-week intensive intervention comprising lifestyle approaches and treatment with insulin glargine, metformin, and dapagliflozin or (b) standard diabetes care. At 12 weeks, diabetes medications were discontinued in participants with hemoglobin A_1c (HbA_1C) < 7.3% (56 mmol/mol). Participants were then followed for diabetes relapse until 64 weeks. The primary outcome was complete or partial diabetes remission (HbA_1C < 6.5% [48 mmol/mol] off chronic diabetes drugs) at 24 weeks. Main secondary outcomes were complete or partial diabetes remission at 36, 48, and 64 weeks. Results The primary outcome was achieved in 19 (24.7%) intervention group participants and 13 (16.9%) control group participants at 24 weeks (relative risk [RR] 1.5; 95% confidence interval [CI], 0.8-2.7). The relative risks of remission at 36, 48, and 64 weeks were 2.4 (95% CI, 1.2-5.0), 2.1 (95% CI, 1.0-4.4), and 1.8 (95% CI, 0.7-4.7), respectively. In an exploratory analysis, the intervention reduced the hazard of diabetes relapse with overt hyperglycemia by 43% (hazard ratio 0.57; 95% CI, 0.39-0.81). Conclusions Our primary outcome of diabetes remission at 24 weeks was not statistically significantly different. However, our overall results suggest that some patients with early type 2 diabetes are able to achieve sustained diabetes remission following a short-term intensive intervention. Further studies are needed to optimize the combined therapeutic approach used.