Long‐term efficacy of the sodium–glucose cotransporter 2 inhibitor,ipragliflozin, in a case of type A insulin resistance syndrome

Type A insulin resistance (IR) syndrome is a severe IR form caused by insulin receptor (INSR) gene defects. Antidiabetic drugs, including high‐dose insulin and insulin‐sensitizing agents, often fail to control associated hyperglycemia. Therapy with recombinant human insulin‐like growth factor 1 can be more effective, but it is expensive. We report a case of type A IR syndrome with an in‐frame INSR heterozygous deletion (ΔLeu999) that was treated with a combination of conventional therapy and ipragliflozin, a sodium–glucose cotransporter 2 inhibitor. Treatment reduced hemoglobin A1c levels (10.0–7.5%) and induced weight loss (54.4–52.0 kg) within 2 months, and the effects were sustained for >3 years. Sodium–glucose cotransporter 2 inhibitors might be useful to normalize blood glucose in type A IR syndrome by reducing bodyweight and ameliorating glucotoxicity.     

Case report of superior mesenteric artery syndrome that developed in a lean type 2 diabetes patient and was associated with rapid body weight loss after sodium–glucose cotransporter 2 inhibitor administration

A 58‐year‐old women who was diagnosed with type 2 diabetes 20 years earlier had been treated with antidiabetic medicines since she was aged 40 years. After sodium–glucose cotransporter 2 inhibitors administration, her bodyweight rapidly decreased from 40 to 30 kg over a period of 3 weeks. She had abdominal symptoms, including nausea, especially after a meal. On admission, physical examinations and laboratory data showed euglycemic ketoacidosis, dehydration and low insulin secretion levels. Additionally, abdominal contrast computed tomography showed the finding of superior mesenteric artery syndrome. This case urges caution, including rapid excessive bodyweight loss and euglycemic ketoacidosis, on the use of sodium–glucose cotransporter 2 for lean diabetes patients.     

Sodium–glucose cotransporter 2 inhibitor and sarcopenia in a lean elderly adult with type 2 diabetes: A case report

A 70‐year‐old woman with type 2 diabetes was admitted to Gifu University Hospital, Gifu, Japan, because of ketosis. She was diagnosed with type 2 diabetes at age 49 years and started insulin therapy at age 57 years, which restored glycemic control. Insulin therapy was discontinued and oral antidiabetes drugs, including sodium–glucose cotransporter 2 inhibitor dapagliflozin, were initiated at age 69 years. Thereafter, her bodyweight declined from 40.0 kg to 29.8 kg in 12 months; glycated hemoglobin remained >8.0%. On admission to our hospital, her laboratory tests and computed tomography scan showed ketosis, insulinopenia, and the presence of dehydration and bacterial pneumonia. She also lost substantial bodyweight and developed sarcopenia. The current case shows the importance of patient assessment before sodium–glucose cotransporter 2 inhibitor initiation in the elderly.     

Clinical and genetic analysis in a family with familial renal glucosuria: Identification of an N101K mutation in the sodium–glucose cotransporter 2 encoded by a solute carrier family 5 member 2 gene

We report the identification of a mutation in the solute carrier family 5 member 2 (SLC5A2) gene, which encodes sodium–glucose cotransporter 2, in a family with familial renal glucosuria. The proband was a 26‐year‐old Japanese man referred to the diabetes division with repeated glucosuria without hyperglycemia. His mother, uncle and grandfather also had a history of glucosuria. A heterozygous missense mutation (c.303T>A:p.N101K) in SLC5A2 was identified in the patient and his mother, but not in 200 chromosomes from 100 healthy and unrelated individuals, or in 3,408 Japanese individuals in the Tohoku Medical Megabank. Furthermore, bioinformatics software predicted that this lesion would be pathogenic. We infer that the mutation led to clinically relevant sodium–glucose cotransporter 2 dysfunction. The patient showed no symptoms of hypoglycemia, but continuous glucose monitoring confirmed asymptomatic hypoglycemia.     

Association between depression and concurrent Type 2 diabetes outcomes varies by diabetes regimen

Aims Although depression has weak associations with several Type 2 diabetes mellitus (DM) outcomes, it is possible that these associations are concentrated within certain patient subgroups that are more vulnerable to their effects. This study tested the hypothesis that depression is related to glycaemic control and diabetes‐related quality of life (DQOL) in patients who are prescribed injected insulin, but not those on oral glucose‐lowering agents alone. Methods Participants (103 on insulin, 155 on oral glucose‐lowering agents alone) with Type 2 DM were recruited from a large US healthcare system and underwent assessment of glycaemic control (glycated haemoglobin; HbA_1c), medication adherence and diabetes self‐care behaviours, DQOL and depression (none, mild, moderate/severe). Results There was a significant regimen × depression interaction on HbA_1c (P = 0.002), such that depression was associated with HbA_1c in patients using insulin (β = 0.35, P < 0.001) but not in patients using oral agents alone (β = –0.08, P = NS). There was a similar interaction when quality of life was analysed as an outcome (P = 0.002). Neither effect was mediated by regimen adherence. Conclusions The generally weak association between depression and glycaemic control is concentrated among patients who are prescribed insulin. Similarly, the association between depression and illness quality of life is strongest in patients prescribed insulin. Because this is not attributable to depression‐related adherence problems, psychophysiological mechanisms unique to this group ought to be carefully investigated. Clinicians might be especially vigilant for depression in Type 2 DM patients who use insulin and consider its potential impact upon their illness course.     

Effect of tofogliflozin on cardiac and vascular endothelial function in patients with type 2 diabetes and heart diseases: A pilot study

Recent studies have shown that sodium–glucose cotransporter 2 inhibitors decrease the risk of heart failure in patients with type 2 diabetes. However, the precise mechanisms of action of these drugs are not well understood. In the present study, we evaluated the effect of treatment with tofogliflozin for 6 months on cardiac and vascular endothelial function in 26 patients with type 2 diabetes and heart diseases. Tofogliflozin treatment significantly decreased left ventricular end‐diastolic dimensions and significantly increased flow‐mediated vasodilation. Although E/e′ did not significantly change after treatment, the decrease observed in the E/e′ ratio was significantly correlated with the increase in acetoacetic acid and 3‐hydroxybutyrate levels. These results suggest that sodium–glucose cotransporter 2 inhibitor might improve left ventricular dilatation and vascular endothelial function in patients with type 2 diabetes. Furthermore, it is suggested that the elevation of ketone bodies induced by sodium–glucose cotransporter 2 inhibitors might contribute to a protective effect in left ventricular diastolic dysfunction.     

Molecular changes associated with the development of resistance to imatinib in an imatinib‐sensitive canine neoplastic mast cell line carrying a KIT c.1523A>T mutation

Although imatinib has therapeutic activity for certain subsets of patients with mastocytosis, it is not always curative. Here, molecular mechanisms that confer imatinib resistance to neoplastic mast cells were investigated using an imatinib‐sensitive canine neoplastic mast cell line VI‐MC carrying a KIT c.1523A>T activating mutation. Two imatinib‐resistant sublines were established by culturing VI‐MC cells in increasing concentrations of imatinib (1 μM resistant, rVI‐MC1; 10 μM resistant, rVI‐MC10). Both sublines had a second KIT mutation c.2443G>C. Recombinant KIT with the second mutation was insensitive to 1 μM but sensitive to 10 μM imatinib. The effect of imatinib on the phosphorylation of KIT and its downstream signalling proteins was then examined using these sublines. KIT and ERK were constitutively phosphorylated in both sublines, and their phosphorylation was suppressed by 10 μM imatinib in rVI‐MC1 cells. However, KIT but not ERK phosphorylation was suppressed in rVI‐MC10 cells. The phosphorylation of ERK in rVI‐MC10 cells was also not diminished by the Src family kinase (SFK) inhibitor dasatinib. This second mutation in KIT may play an important role in imatinib resistance in neoplastic mast cells. Furthermore, KIT/SFK‐independent activation of ERK would be involved in imatinib resistance when the neoplastic cells are exposed to higher concentrations of imatinib.     

Case of ketoacidosis by a sodium‐glucose cotransporter 2 inhibitor in a diabetic patient with a low‐carbohydrate diet

We present a case of a 32‐year‐old diabetic woman with Prader–Willi syndrome who developed severe ketoacidosis caused by a sodium‐glucose cotransporter 2 (SGLT2) inhibitor, a novel class of antihyperglycemic agents, during a strict low‐carbohydrate diet. At admission, a serum glucose level of 191 mg/dL was relatively low, though laboratory evaluations showed severe ketoacidosis. This is the first report of ketoacidosis caused by a SGLT2 inhibitor. It is necessary to not only pay attention when using a SGLT2 inhibitor in patients following a low‐carbohydrate diet, but also to start a low‐carbohydrate diet in patients treated with a SGLT2 inhibitor because of a high risk for developing ketoacidosis.     

Strong association between insulin resistance in liver and skeletal muscle in non‐diabetic subjects

Objective To examine the association between insulin resistance in skeletal muscle and liver in non‐diabetic subjects. Research design and methods A total of 182 Mexican American subjects without Type 2 diabetes underwent an oral glucose tolerance test and euglycaemic–hyperinsulinaemic clamp performed with ³[H]glucose. Insulin sensitivity in skeletal muscle was measured as the insulin‐stimulated rate of total glucose disposal during the insulin clamp divided by steady‐state plasma insulin concentration (TGD/SSPI). Hepatic insulin resistance was measured as the product of basal hepatic glucose production and fasting plasma insulin concentration (HGP × FPI). Results Hepatic insulin resistance was strongly correlated (r = 0.68, P < 0.0001) with skeletal muscle insulin resistance. Thirty‐eight per cent of subjects had increased insulin resistance in both liver and skeletal muscle, while 39% were insulin sensitive in both skeletal muscle and liver. Twenty‐three per cent of subjects were discordant for muscle and hepatic insulin resistance (P < 0.0001). Subjects with increased skeletal muscle insulin resistance had a higher 2‐h plasma glucose concentration, greater incremental area under the plasma glucose concentration curve, lower fasting plasma insulin concentration and lower rate of basal hepatic glucose production compared with subjects with increased insulin resistance in liver. Conclusion In non‐diabetic subjects, insulin resistance in skeletal muscle is an important determinant of the fasting and 2‐h plasma glucose concentrations and strongly correlates with hepatic insulin resistance.     

Progenitor genotyping reveals a complex clonal architecture in a subset of CALR‐mutated myeloproliferative neoplasms

The identification of acquired CALR mutations in patients with essential thrombocythaemia (ET ) or myelofibrosis (MF ) has meant that disease‐initiating mutations can now be detected in about 90% of all patients with a myeloproliferative neoplasm (MPN ). Here, we show that only those CALR mutations that cause a +1 frameshift, thereby altering the carboxy‐terminus of calreticulin, promote cytokine independence in vitro; in‐frame deletions were not functional, and are unlikely to be the pathogenetic mutation underlying some MPN cases. Expression of the thrombopoietin receptor, MPL , was also necessary for factor‐independence. Although the CALR mutations are considered to occur only in JAK 2 V617F‐negative cases and in a heterozygous state, progenitor genotyping revealed that this is not always true. Notably, CALR mutation‐positive MPN s can be polyclonal: in one case, two distinct CALR mutation‐positive subpopulations could be identified; in another, separate populations of JAK 2 V617F‐positive and CALR ‐mutated cells were present. Mitotic recombination involving chromosome 19 in a third instance resulted in the emergence of a CALR mutation‐homozygous subclone. Collectively, our studies demonstrate that occasional patients with CALR mutation‐positive ET or MF carry other MPN ‐initiating genetic mutations (including JAK 2 V617F), acquire “secondary mutations” before or after the CALR mutation, or evolve over time to being CALR mutation‐homozygous.     

Kinetics of the interaction between anti‐FVIII antibodies and FVIII from therapeutic concentrates,with and without von Willebrand factor,assessed by surface plasmon resonance

The presence of VWF in plasma‐derived FVIII (pdFVIII/VWF) products has been pointed out as a key difference with recombinant FVIII (rFVIII) products with regard to immunogenicity. A Surface Plasmon Resonance (SPR) study was designed to characterize in detail the interaction between anti‐FVIII (IgGs) from a severe haemophilia A patient, and FVIII from concentrates of different sources. Full‐length rFVIII (preincubated or not with purified VWF), B domain‐deleted (BDD)‐rFVIII and pdFVIII/VWF were analysed. To ensure reproducible conditions for accurate determination of kinetic constants, a capture‐based assay format was developed using protein G surfaces for specific and reversible coupling of endogenous anti‐FVIII antibodies. Concentration ranges (nm ) of FVIII products tested were 9–0.03 (rFVIII) and 6–0.024 (pdFVIII/VWF). The association with antibodies was monitored for 3–5 min, whereas dissociation of the complex was followed for 5–20–240 min. A strong interaction of rFVIII and BDD‐rFVIII with patient's IgG was detected with the K _D values in the low picomolar range (5.9 ± 3.0 and 12.7 ± 6.9 pm , respectively) and very slow dissociation rates, while pdFVIII/VWF showed only marginal binding signals. The VWF complexed rFVIII displayed reduced binding signals compared with uncomplexed rFVIII, but the K _D was still in the picomolar range (4.1 ± 1.9 pm ) indicating insufficient complex formation. rFVIII, alone or bound to exogenously added VWF, showed high affinity for anti‐FVIII IgGs from a severe haemophilia A patient whereas pdFVIII/VWF did not. These results are in agreement with those studies that point towards rFVIII concentrates to be more immunogenic than pdFVIII concentrates.     

Novel PIK3R1 mutation of SHORT syndrome: A case report with a 6-month follow up

SHORT syndrome (short stature, hyperextensibility, ocular depression [deeply set eyes], Rieger anomaly and teething delay) is very rare, with a few cases reported in the literature. We report a case of SHORT syndrome with a novel PIK3R1 mutation (c.2008delT) and complicated with severe insulin resistance. Although no treatment guidelines are available to relieve insulin resistance in SHORT syndrome, our treatment plans, including lifestyle intervention combined with metformin and pioglitazone, were carried out for this patient. After the intervention, insulin resistance and hyperinsulinemia in this patient were significantly decreased during a 6-month follow up, which showed the effect of our therapeutic strategies.     

Faster insulin action is associated with improved glycaemic outcomes during closed‐loop insulin delivery and sensor‐augmented pump therapy in adults with type 1 diabetes

We aimed to evaluate the relationship between insulin pharmacodynamics and glycaemic outcomes during closed‐loop insulin delivery and sensor‐augmented pump therapy. We retrospectively analysed data from a multicentre randomized control trial involving 32 adults with type 1 diabetes receiving day‐and‐night closed‐loop insulin delivery and sensor‐augmented pump therapy over 12 weeks. We estimated time‐to‐peak insulin action (t _{max, IA} ) and insulin sensitivity ( S _I ) during both interventions, and correlated these with demographic factors and glycaemic outcomes. During both interventions, t _{max, IA} was positively correlated with pre‐ and post‐intervention HbA1c (r = 0.50‐0.52, P < .01) and mean glucose (r = 0.45‐0.62, P < .05), and inversely correlated with time sensor glucose, which was in target range 3.9 to 10 mmol/L (r = ?0.64 to ?0.47, P < .05). Increased body mass index was associated with higher t _{max, I} and lower S _I (both P < .05). During closed‐loop insulin delivery, t _{max, IA} was positively correlated with glucose variability ( P < .05). Faster insulin action is associated with improved glycaemic control during closed‐loop insulin delivery and sensor‐augmented pump therapy.     

Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: a comprehensive Argentine study of inhibitor risks

Inhibitor development against exogenous factor VIII is a severe impairment of replacement therapy affecting 18% of Argentine patients with severe haemophilia A (HA). To study the molecular predisposition for inhibitor development, we genotyped 260 HA patients with and without inhibitors, countrywide. The inhibitor‐positive population (19 transients, 15 low responders, LR and 70 high responders, HR) of 104 severe‐HA patients showed 59 Inv22 (intron 22 inversions), 18 small ins/del‐frameshifts, 12 gross deletions, 12 nonsense, one splicing defect and two missense, p.Arg531Pro and p.Leu575Pro, both LR and thought to impair FVIII A2 domain secondary structure. In addition, a patient with mild HA and HR showed the missense p.Glu1704Lys associated with two neutral intronic substitutions potentially affecting the A3 domain. A case/control study (84/143) permitted estimation of F8 genotype–specific inhibitor risks [OR; prevalence (CI)] in severe‐HA patients classifying a high‐risk group including multi‐exon deletions [3.66; 55% (19–100)], Inv22 [1.8; 24% (19–100)] and nonsense in FVIII‐LCh [1.2; 21% (7–59)]; an average risk group including single‐exon deletions, indel frameshifts and nonsense‐HCh; and a low‐risk group represented by missense defects [0.14; 3% (0.6–11)]. Analysis of inhibitor concordance/discordance in related patients indicated additional genetic factors other than F8 genotype for inhibitor formation. No significant inhibitor‐predisposing factors related to FVIII product exposure were found in age‐ and F8 genotype–stratified populations of severe‐HA patients. In conclusion, the Argentine HA patient series presents similar global and mutation‐specific inhibitor risks than the HA database and other published series. This case‐specific information will help in designing fitted therapies and follow‐up protocols in Argentina.     

Insulin degludec improves health‐related quality of life (SF‐36®) compared with insulin glargine in people with Type 2 diabetes starting on basal insulin: a meta‐analysis of phase 3a trials

Aim

To compare the effect of insulin degludec and insulin glargine on health‐related quality of life in patients with Type 2 diabetes starting on insulin therapy.

Methods

Patient‐level data from three open‐label, randomized, treat‐to‐target trials of 26 or 52 weeks' duration were pooled using a weighted analysis in conjunction with a fixed‐effects model. Insulin‐naive patients received either insulin degludec (n = 1290) or insulin glargine (n = 632) once daily, in combination with oral anti‐diabetic drugs. Glycaemic control was assessed via HbA_1c and fasting plasma glucose concentrations. Rates of hypoglycaemia, defined as plasma glucose < 3.1 mmol/l (< 56 mg/dl), were recorded. Health‐related quality of life was evaluated using the 36‐item Short Form (SF‐36^®) version 2 questionnaire. Statistical analysis was performed using a generalized linear model with treatment, trial, anti‐diabetic therapy at baseline, gender, region and age as explanatory variables.

Results

Insulin degludec was confirmed as non‐inferior to insulin glargine based on HbA_1c concentrations. In each trial comprising the meta‐analysis, fasting plasma glucose and confirmed overall and nocturnal (00.01–05.59 h) hypoglycaemia were all numerically or significantly lower with insulin degludec vs. insulin glargine. At endpoint, the overall physical health component score was significantly higher (better) with insulin degludec vs. insulin glargine [+0.66 (95% CI 0.04–1.28)], largely attributable to a difference [+1.10 (95% CI 0.22–1.98)] in the bodily pain domain score. In the mental domains, vitality was significantly higher with insulin degludec vs. insulin glargine [+0.81 (95% CI 0.01–1.59)].

Conclusions

Compared with insulin glargine, insulin degludec leads to improvements in both mental and physical health status for patients with Type 2 diabetes initiating insulin therapy.

     

Relationship between urine pH and abnormal glucose tolerance in a community‐based study

Aims/Introduction

The association between urine pH and abnormal glucose tolerance in men and women is unclear; therefore, we carried out a community‐based, cross‐sectional study to investigate sex‐specific associations between these values, possible indicators of prediabetes and type 2 diabetes.

Materials and Methods

We enrolled 4,945 Japanese individuals (2,490 men and 2,455 women), who had undergone annual health checkups. To investigate the relationship between low urine pH and abnormal glucose tolerance, participants were divided into three groups based on their fasting plasma glucose levels (<6.11 mmol/L, 6.11–6.99 mmol/L and ≥6.99 mmol/L), and three groups based on their glycated hemoglobin levels (≤44.3 mmol/mol, 44.3–47.5 mmol/mol and ≥47.5 mmol/mol). To examine the effects of urine pH on abnormal glucose tolerance, participants were categorized into five groups based on their urine pH (5.0, 5.5, 6.0, 6.5 and ≥7.0).

Results

Multivariate analysis adjusted for age, body mass index, systolic blood pressure, triglycerides, high‐density lipoprotein cholesterol, uric acid, creatinine and antidiabetic agent use showed significant associations between low urine pH and both high fasting plasma glucose and high glycated hemoglobin levels (P for trend = 0.0260, 0.0075) in men. Furthermore, after the same adjustments, prevalence rates of abnormal glucose tolerance (≥6.11 mmol/L and ≥6.99 mmol/L), increased significantly as urine pH levels decreased (P for trend = 0.0483, 0.0181) in men. In women, a similar trend was observed without a significant difference.

Conclusions

Low urine pH is significantly associated with abnormal glucose tolerance; therefore, measuring urine pH might prove useful for identifying patients at high risk for diabetes.     

Early detection of euglycemic ketoacidosis during thoracic surgery associated with empagliflozin in a patient with type 2 diabetes: A case report

We report the first case of intraoperatively detected euglycemic diabetic ketoacidosis (DKA) associated with sodium–glucose cotransporter 2 inhibitors during thoracic surgery. A 59-year-old man had a 12-year history of type 2 diabetes mellitus treated with insulin and empagliflozin. The patient developed bacterial empyema and was initiated with antibiotics at a local hospital. Owing to the persistence of his symptoms, he was transferred to our hospital after the medication of empagliflozin the day before surgery. After overnight fasting, the patient underwent thoracoscopic debridement and intrathoracic lavage surgery. During this surgery, he was noted to have euglycemic ketosis and acidosis, and diagnosed as euglycemic DKA. Immediately after the consultation in our department, the patient underwent treatment for DKA. He awoke from anesthesia normally and showed no symptoms of DKA. DKA gradually resolved over the next 24 h. Early identification and management are critical for rapid recovery from perioperative euglycemic DKA associated with sodium–glucose cotransporter 2 inhibitors, especially during thoracic surgery.     

Development and evaluation of a baseline‐event‐anticipation score for hepatitis delta

Hepatitis delta is considered the most severe form of viral hepatitis, but variables associated with disease progression are poorly defined. This study aimed to identify risk factors associated with worse clinical outcome in patients with hepatitis delta and to develop a clinical score to determine their risk of experiencing liver‐related morbidity or mortality. We followed 75 HBsAg–anti‐HDV‐positive patients with hepatitis delta for up to 16 years (median 5 years). The baseline‐event‐anticipation score (BEA score) was developed based on variables associated with the development of liver‐related clinical complications. Age, region of origin, presence of cirrhosis, albumin, INR, hyperbilirubinemia and thrombocytopenia were all associated with the development of an event in the training cohort. The BEA score included age, sex, region of origin, bilirubin, platelets and INR. Points were allocated according to hazard ratios, and three risk groups were defined: BEA‐A mild risk, BEA‐B moderate risk and BEA‐C high risk. Hazard ratios of BEA‐B and BEA‐C patients for liver‐related clinical endpoints were 9.01 and 25.27 vs BEA‐A with an area under curve of the receiving operating characteristic curve of 0.88. The accuracy of the BEA score was confirmed in two independent validation cohorts followed in Barcelona (n = 77) and Düsseldorf (n = 62). Delta hepatitis is associated with a very severe long‐term outcome. The BEA score is easy to apply and predicts with a very high accuracy the development of liver‐related complications in patients with hepatitis delta.     

Differential effects of once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide and metformin on pancreatic β‐cell and insulin sensitivity during a standardized test meal in patients with type 2 diabetes

This substudy of the AWARD‐3 trial evaluated the effects of the once‐weekly glucagon‐like peptide‐1 receptor agonist, dulaglutide, versus metformin on glucose control, pancreatic function and insulin sensitivity, after standardized test meals in patients with type 2 diabetes. Meals were administered at baseline, 26 and 52 weeks to patients randomized to monotherapy with dulaglutide 1.5 mg/week (n = 133), dulaglutide 0.75 mg/week (n = 136), or metformin ≥1500 mg/day (n = 140). Fasting and postprandial serum glucose, insulin, C‐peptide and glucagon levels were measured up to 3 h post‐meal. β‐cell function and insulin sensitivity were assessed using empirical variables and mathematical modelling. At 26 weeks, similar decreases in area under the curve for glucose [AUC_glucose (0–3 h)] were observed among all groups. β‐cell function [AUC_insulin/AUC_glucose (0–3 h)] increased with dulaglutide and was unchanged with metformin (p ≤ 0.005, both doses). Dulaglutide improved insulin secretion rate at 9 mmol/l glucose (p ≤ 0.04, both doses) and β‐cell glucose sensitivity (p = 0.004, dulaglutide 1.5 mg). Insulin sensitivity increased more with metformin versus dulaglutide. In conclusion, dulaglutide improves postprandial glycaemic control after a standardized test meal by enhancing β‐cell function, while metformin exerts a greater effect on insulin sensitivity.