Microalbuminuria as a marker of silent myocardial ischaemia in IDDM patients

Summary Insulin-dependent diabetic (IDDM) subjects with microalbuminuria have an increased long-term risk of overt cardiovascular disease; however, the early exposure to cardiovascular risk factors may increase their predisposition to current silent myocardial ischaemia. The frequency of silent myocardial ischaemia detected by stress echocardiography and electrocardiography was significantly greater in 32 asymptomatic IDDM patients with microalbuminuria compared to 32 normoalbuminuric IDDM patients (25 % [n = 8] vs 6.3 % [n = 2]; p = 0.03, odds ratio [95 % CI] 6.3 [1.2, 37.8]). Elective coronary artery bypass grafting was required in 1 patient with microalbuminuria and silent myocardial disease. Microalbuminuria and poorer autonomic function were independently associated with silent myocardial ischaemia in multivariate analysis (p = 0.03 and p = 0.02, respectively). Screening for silent myocardial ischaemia using these non-invasive tests may be warranted in microalbuminuric IDDM which patients could be of considerable clinical importance. [Diabetologia (1996) 39: 854–856] Received: 16 February 1996 and in revised form: 13 March 1996     

The natural history of somatosensory and autonomic nerve dysfunction in relation to glycaemic control during the first 5 years after diagnosis of Type 1 (insulin-dependent) diabetes mellitus

Summary The natural evolution of neural dysfunction was studied prospectively over 5 years following diagnosis of Type 1 (insulin-dependent) diabetes in 32 patients aged 12–36 years. Motor and sensory nerve conduction velocities, heart rate variation at rest and during deep breathing, and pupillary function were measured at diagnosis and after 3,12, 24,48, and 60 months. Thermal and vibration sensation thresholds were determined after 24, 48, and 60 months of diabetes. Mean HbA₁ levels of months 3–60 within the normal range of <8.3% (7.3±0.2%) were observed in 13 patients (Group 1), while a mean HbA₁ of months 3–608.3% (10.0±0.3%) was found in 19 patients (Group 2). Mean nerve conduction was significantly diminished in Group 2 as compared with Group 1 in at least 4 out of 6 nerves tested during months 12–60 (p<0.05). Both tests of heart rate variation were significantly impaired in Group 2 as compared with Group 1 after 24 and 60 months (p<0.05), but no differences in pupillary function were observed between the groups. Thermal discrimination but not vibration perception thresholds on the foot were significantly higher in Group 2 than in Group 1 at 40 and 60 months (p<0.05). Abnormalities in nerve conduction, thermal discrimination, and heart rate variation, but not vibration perception threshold and the pupillary function tests were significantly more frequent in Group 2 than in Group 1 at 60 months (p<0.05). After 60 months, none of the patients of Group 1, but 6 and 4 patients of Group 2 developed subclinical or symptomatic neuropathy, respectively (p<0.05). These findings suggest that the evolution of subclinical and symptomatic neuropathy during the first 5 years after diagnosis of Type 1 diabetes may be predicted by poor glycaemic control and prevented by near-normoglycaemia.     

Progression of subclinical polyneuropathy in young patients with Type 1 (insulin-dependent) diabetes: associations with glycaemic control and microangiopathy (microvascular complications)

Summary The progression of subclinical polyneuropathy over 2.5 years has been studied in a representative group of 75 young patients with Type 1 (insulin-dependent) diabetes (initial age 16–19 years). The relationships between changes in nerve function, glycaemic control and concurrently developing microvascular complications (retinopathy, microproteinuria) were investigated. Deterioration of motor, sensory and autonomic nerve function, retinopathy and microproteinuria was related to poor glycaemic control. In addition, there was an association between developing neural and microvascular complications which was not diminished when their common relationship to hyperglycaemia was taken into account. These findings suggest that, although poor glycaemic control is an essential permissive factor in the early development of diabetic polyneuropathy, other influences, shared with microvascular complications, must also be important.     

Ethnic differences in glycaemic control in adult Type 2 diabetic patients in primary care: a 3-year follow-up study.

OBJECTIVE: To evaluate ethnic differences and characteristics related to glycaemic control in patients with Type 2 diabetes in primary care. RESEARCH DESIGN AND METHODS: Prospective cohort study; 500 adult patients with Type 2 diabetes, who were not on insulin therapy, were followed up annually for 3 years. HbA(1c) at baseline and 3-year changes and subsequent insulin therapy were related to baseline characteristics. RESULTS: Malay patients had significantly higher HbA(1c) (mean 8.7% +/- sd 1.66) compared with Chinese (8.2 +/- sd 1.67) and Indian (8.2 +/- sd 1.55) (P = 0.032) at baseline, and consistently for all years of HbA(1c) assessment (P = 0.017). At baseline, Malay patients were significantly more obese than Chinese or Indians (P < 0.001); fewer of them received structured shared-care intervention (P = 0.001), but they had a significantly higher glucose control educational score (P < 0.05). Multivariable analyses showed that HbA(1c) at baseline was significantly related to age (P = 0.001), BMI (P = 0.031) and ethnicity (P = 0.002). HbA(1c) declined significantly over 3 years in the whole population and in all ethnic groups. Significantly greater HbA(1c) declines were associated with higher baseline HbA(1c), structured shared-care intervention and non-insulin therapy. Correcting for differences on these factors, the decline in HbA(1c) in Malays was significantly less than in the Chinese. Insulin therapy was associated with higher baseline HbA(1c) and higher BMI. CONCLUSIONS: Malay ethnicity was associated with persistently poor glycaemic control. Sociocultural and behavioural factors should be addressed in improving care for patients with poorly controlled diabetes.     

[13C]0ctanoic acid breath test for non-invasive assessment of gastric emptying in diabetic patients: Validation and relationship to gastric symptoms and cardiovascular autonomic function

Summary Since there is a need for a widely applicable non-invasive test to assess gastric emptying in diabetic patients, we evaluated the sensitivity, specificity, and reproducibility of the [¹³C]octanoic acid breath test as compared with scintigraphy. Moreover, we examined the relationship between the breath test indices and gastric symptoms, cardiovascular autonomic function, and metabolic parameters. Forty healthy control subjects and 34 diabetic patients were studied. Three indices of gastric emptying, assessed by the breath test, were computed: half-emptying time (t_1/2breath), gastric emptying coefficient (GEC), and lag phase. Furthermore, the half-emptying time, measured by scintigraphy (t_1/2scint), was calculated and gastric symptoms and cardiovascular autonomic neuropathy (CAN) were scored. The coefficients of variation of day-to-day reproducibility in 10 healthy subjects were 29.6 % for t_1/2breath, 7.4 % for GEC, and 46.5 % for lag phase. An abnormal delay for t_1/2scint (> 100 min) or t_1/2breath (> 200 min) was noted in 12 patients. Based on the results for t_1/2scint, the sensitivity of t_1/2breath and GEC was 75 % and the specificity was 86 %. Both t_1/2breath (r _s = 0.523; p < 0.05) and GEC (r ₂ = − 0.594; p < 0.05) were significantly associated with the gastric symptom score. A significant relationship to the CAN score was demonstrated for t_1/2breath (r _s = 0.448; p < 0.05), GEC (r _s = − 0.467; p < 0.05), and t_1/2scint (r _s = 0.602; p < 0.05). There were no significant associations of the breath test indices with the blood glucose levels during the test, HbA_1c, age, and duration of diabetes. In patients with abnormal t_1/2scint (n = 12) not only was t_1/2breath significantly prolonged and GEC reduced, but also the scores of CAN and gastric symptoms were significantly increased as compared with those who had a normal t_1/2scint (n = 22). We conclude that the [¹³C]octanoic acid breath test represents a suitable measure of delayed gastric emptying in diabetic patients which is associated with the severity of gastric symptoms and CAN but not affected by the blood glucose level. [Diabetologia (1996) 39: 823–830]     

Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes

AIM: The aim of this study was to assess the effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on 24-h glucose control when added to the regimen of patients with type 2 diabetes who had inadequate glycaemic control on metformin therapy. METHODS: In a double-blind, randomized, placebo-controlled, two-period crossover study, patients with type 2 diabetes with inadequate glycaemic control on metformin monotherapy (i.e. on a stable dose of > or = 1500 mg/day for > or = 6 weeks prior to the screening visit and an haemoglobin A(1c) (HbA(1c)) > or = 6.5% and <10% and fasting plasma glucose (FPG) < or = 240 mg/dl) were recruited for participation. A total of 28 patients (baseline HbA(1c) range = 6.5-9.6%) receiving metformin were randomized into one of two treatment sequences: the addition of placebo for 4 weeks followed by the addition of sitagliptin 50 mg twice daily (b.i.d.) for 4 weeks, or vice versa. At the end of each treatment period, patients were domiciled for frequent blood sampling over 24 h. The primary endpoint was 24-h weighted mean glucose (WMG) and secondary endpoints included change in FPG, mean of 7 daily self-blood glucose measurements (MDG) and fructosamine. beta-cell function was assessed from glucose and C-peptide concentrations were measured during the 5-h period after a standard breakfast meal by using the C-peptide minimal model. RESULTS: Despite a carryover effect from period 1 to period 2, the combined period 1 and period 2 results for glycaemic endpoints were statistically significant for sitagliptin relative to placebo when added to ongoing metformin therapy. To account for the carryover effect, the period 1 results were also compared between the groups. Following period 1, there were significant least-squares (LS) mean reductions in 24-h WMG of 32.8 mg/dl, significant LS mean reduction from baseline in MDG of 28 mg/dl, FPG of 20.3 mg/dl and fructosamine of 33.7 mmol/l in patients treated with sitagliptin relative to placebo (p < 0.05). When added to ongoing metformin therapy, parameters of beta-cell function were significantly improved with sitagliptin compared with placebo. No weight gain or increases in gastrointestinal adverse events or hypoglycaemia events were observed with sitagliptin relative to placebo during this study. CONCLUSIONS: In this study, the addition of sitagliptin 50 mg b.i.d. to ongoing metformin therapy improved 24-h glycaemic control and beta-cell function, and was generally well tolerated in patients with type 2 diabetes.     

Evaluation of risk factors for the development of nephropathy in patients with IDDM: insertion/deletion angiotensin converting enzyme gene polymorphism, hypertension and metabolic control

Summary Diabetic nephropathy represents a major complication in patients with insulin-dependent diabetes mellitus (IDDM). Intervention trials using angiotensin-converting enzyme (ACE) inhibitors have pointed towards the important pathogenetic role of the renin-angiotensin system. Recently an insertion/deletion (I/D) polymorphism for the gene encoding the ACE has been described, the deletion type being associated with higher plasma ACE levels. As the intrarenal renin-angiotensin system might also be activated in this setting, we determined the ACE genotype together with other risk factors for the development of diabetic nephropathy in 122 patients with IDDM from a single centre with (n = 63) and without (n = 59) nephropathy. Long-term glycaemic control was evaluated using mean HbA_1c values from the last 10 years. The two patient group were comparable with regard to duration of diabetes and glycaemic control as assessed by current HbA_1c values. However, mean long-term HbA_1c values were significantly higher in patients with diabetic nephropathy as was systemic blood pressure. The DD genotype was more prevalent in patients with renal disease. In the subgroup of patients who had had diabetes for more than 20 years (n = 90), the DD genotype was even more frequent in patients with nephropathy, and blood pressure and long-term HbA_1c values were also higher in patients with renal disease. Logistic regression analysis revealed long-term glycaemic control, blood pressure and the ACE genotype to be independent risk factors for the prevalence of diabetic nephropathy. [Diabetologia (1997) 40: 327–331] Received: 1 July 1996 and in final revised form: 20 November 1996     

Effect of metabolic control on homocysteine levels in type 2 diabetic patients: a 3-year follow-up

OBJECTIVES: Hyperhomocysteinaemia has emerged as a novel risk factor for cardiovascular disease. The determinants of total homocysteine (tHcy) levels in type 2 diabetic patients (D2p) have not been studied in detail. We examined prospectively the effect of different degrees of metabolic control on plasma tHcy in D2p with preserved kidney function. SUBJECTS AND MAIN OUTCOME MEASUREMENTS: Ninety-five D2p were studied. Clinical parameters, fasting plasma glucose, HbA1c, serum lipids, blood urea nitrogen (BUN) and creatinine, vitamin B12 and folate and tHcy were measured at the baseline and after 36 months. The methylentetrahydrofolate reductase (MTHFR) C677T polymorphism was also determined. Subjects were categorized according to deltaHbA1c into group A (+/-1 point), B (>1 point increase) or C (>1 point decrease). RESULTS: Total homocysteine was reduced in subjects whose HbA1c decreased with time, whilst patients showing a worsened metabolic control had an increased tHcy in respect to baseline. A larger response to the improved metabolic control in terms of tHcy reduction was noted in wild type patients versus those homozygous for the mutation. A multivariate analysis revealed MTHFR polymorphism and HbA1c as strong determinants of changes in tHcy with time. CONCLUSIONS: The findings suggest that in D2p tHcy decreases even with modest improvement of glycaemic control; moreover patients homozygous for the MTHFR C677T mutation show the largest changes in tHcy levels with concomitant changing of HbA1c. These results define a further mechanism through which hyperglycaemia might promote cardiovascular damage in diabetic patients.     

The effect of 8 years of strict glycaemic control on peripheral nerve function in IDDM patients: the Oslo study

Summary We have investigated the effect of long-term strict glycaemic control on peripheral and autonomic nerve function in 45 IDDM patients (age 18–42 years, diabetes duration 7–23 years) without clinical signs of neuropathy or other neurological disease. They were randomly assigned to treatment either with continuous insulin infusion, multiple injections (4–6 times daily), or conventional treatment (twice daily) for 4 years and followed prospectively for 8 years. Motor and sensory nerve conduction velocities were measured at the start and after 8 years. Autonomic nerve function tests were performed only once, after 8 years. A significant reduction of nerve conduction velocity was observed during 8 years in patients with mean HbA₁ more than 10% (n=12, group mean 10.9%, range 10.1–13.2%) compared to patients with HbA₁ less than 10% (n=33, group mean 9.0%, range 7.5–9.9%). Change of motor nerve conduction velocity in the peroneal nerve was: –4.8±4.9 (SD) vs –2.2±5.3 m/s (p<0.01). Change of motor nerve conduction velocity in the posterior tibial nerve was: –6.8±5.7 vs –3.9±5.1 m/s (p<0.05). No significant changes were observed in the ulnar nerve. Change of sensoric nerve conduction velocity in the sural nerve was: –8.9±8.0 vs –4.6±5.3 m/s (p<0.05). Multiple regression analysis showed that a change in HbA₁ of 1% resulted in a 1.3 m/s change in nerve conduction velocity during 8 years. A significantly lowered heart-rate variation during deep breathing (p<0.05) and heart-rate response to standing (p<0.01) was found in patients with HbA₁ more than 10% compared to patients with HbA₁ less than 10%. This study confirms that the long-term lowering of blood glucose retards the deterioration in nerve conduction velocity observed in the diabetic nerve.Abbreviations IDDM Insulin-dependent diabetes mellitus     

Effects of asynchronous ventricular activation on myocardial adrenergic innervation in patients with permanent dual-chamber pacemakers; an I(123)-metaiodobenzylguanidine cardiac scintigraphic study.

AIMS: To evaluate myocardial sympathetic innervation abnormalities in patients with DDD pacemakers for complete heart block. METHODS: We studied 39 patients, chronically paced in DDD mode because of complete atrioventricular block. Twenty-three healthy individuals served as a control group. All patients underwent planar and single-photon emission computed tomography (SPECT) myocardial imaging 4 h after intravenous infusion of 185 MBq I(123)-MIBG. The heart to mediastinum ratio was calculated to quantify cardiac I(123)-MIBG accumulation, while the SPECT study was performed to investigate the regional distribution of adrenergic innervation. All patients underwent a SPECT thallium(201)myocardial study during the same week as the I(123)-MIBG study. RESULTS: The heart to mediastinum ratio was significantly smaller in paced patients than in the controls (P<0.001). 89.7% of paced patients had regional abnormalities of I(123)-MIBG uptake, mainly in the inferior (92.3%) and apical (38.5%) wall. 46.2% of paced patients had regional perfusion defects, also mainly in the inferior (46.2%) and apical (10.3%) wall. Neither the I(123)-MIBG abnormalities nor the perfusion defects were related to the duration of pacing. CONCLUSIONS: Stimulation from the apex of the right ventricle leads to regional disturbances of the adrenergic innervation of the left ventricular myocardium, as assessed by I(123)-MIBG activity.     

Prognostic significance of cardiac 123I metaiodobenzylguanidine imaging for mortality and morbidity in patients with chronic heart failure: a prospective study

OBJECTIVE—To determine whether cardiac iodine-123 metaiodobenzylguanidine (¹²³I MIBG) imaging is useful in predicting the prognosis of patients with chronic heart failure.
DESIGN—Cardiac ¹²³I MIBG imaging was done on entry to the study. The cardiac MIBG washout rate was calculated from anterior chest view images obtained 20 and 200 minutes after injection of the isotope. Study patients were divided into two groups with washout rates above and below 27% (the mean value + 2 SD obtained in 20 normal subjects), and were then followed up.
SETTING—Tertiary referral centre.
PATIENTS—79 patients with chronic heart failure in whom the left ventricular ejection fraction was less than 40%.
RESULTS—There were 37 patients in group 1 (washout rate of  27%) and 42 in group 2 (< 27%). During a follow up period of between 1 and 52 months, eight patients died suddenly and five died of worsening heart failure in group 1, while none died in group 2; 13 patients in group 1 and four in group 2 were admitted to hospital for progressive heart failure. Kaplan-Meier analysis showed that group 1 had a significantly higher mortality and morbidity (p = 0.001 and p < 0.001, respectively) than group 2.
CONCLUSIONS—Cardiac ¹²³I MIBG washout rate seems to be a good predictor of prognosis in patients with chronic heart failure.


Keywords: chronic heart failure; sudden death; cardiac adrenergic nerve activity     

Lack of synergism between long-term poor glycaemic control and three gene polymorphisms of the renin angiotensin system on risk of developing diabetic nephropathy in Type I diabetic patients

Aims/hypothesis. Reports on a putative synergism between poor glycaemic control and carriage of the angiotensin II type 1 receptor (AGTR1) C¹¹⁶⁶-allele and risk of diabetic nephropathy have been conflicting. Therefore, we investigated the interaction between long-term glycaemic control and three polymorphisms in the genes coding for AGTR1 (A¹¹⁶⁶→C), angiotensin converting enzyme (ACE/ID) and angiotensinogen (M235T) on risk of developing diabetic nephropathy. Furthermore, we investigated the relation between a random measurement and long-term measurements of haemoglobin A_{1 c} (HbA_{1 c}).¶Methods. We studied Caucasian patients with Type I (insulin-dependent) diabetes mellitus and nephropathy (120 men 74 women, age 41.1 ± 9.6 years, diabetes duration 28 ± 8 years) and long-standing Type I diabetic patients with persistent normoalbuminuria (112 men 69 women, age 42.5 ± 10.0 years, diabetes duration 27 ± 9 years). Genotyping was PCR-based and metabolic control estimated from all measurements of HbA_{1 c} done in each patient [average (range) n = 31 (6–74)]. The median observation time (range) was 13.5 (2–14) years.¶Results. Type I diabetic patients with a history of poor glycaemic control (HbA_{1 c} above the median, 8.7 %) had an increased risk of diabetic nephropathy compared with patients with a better metabolic control, OR (95 % CI): 9.2 (5.8–14.7). The magnitude of this risk was similar in carriers and non-carriers of the mutations. The risk of nephropathy in patients with HbA_{1 c} above compared with below the median in carriers of the mutant C¹¹⁶⁶-allele, D-allele, or T235-allele were 7.6 (95 % CI: 3.9–14.8), 10.4 (6.0–17.8) and 9.8 (5.4–17.9), respectively. A significant correlation (r = 0.74, p < 0.001) existed between a random and long-term measurements of HbA_{1 c} with a small mean difference (limits of agreement) [0.2 (–1.8 to 2.1) %] between the two estimates.¶Conclusion/interpretation. Poor metabolic control is a major risk factor for diabetic nephropathy in Caucasian Type I diabetic patients. This risk was similar in carriers and non-carriers of the mutant alleles of the AGTR1(A¹¹⁶⁶→C), ACE/ID and angiotensinogen-M235T polymorphisms. The HbA_{1 c} value measured at random reflects rather closely average long-term HbA_{1 c} values. [Diabetologia (2000) 43: 794–799]     

E-Selectin plasma concentration is influenced by glycaemic control in NIDDM patients: possible role of oxidative stress

Summary Although elevated levels of soluble E-selectin and intercellular cell adhesion molecules-1 (ICAM-1) have been reported in non-insulin-dependent diabetes mellitus (NIDDM), it is not clear by what mechanism this elevation occurs and whether or not it is related to glycaemic control. In this study we analyse: 1) the relation of glycaemic control with the concentrations of E-selectin, vascular cell adhesion molecules-1 (VCAM-1) and ICAM-1 in NIDDM patients; 2) whether metabolic control can affect the oxidative stress (as measured by plasma hydroperoxide concentration and susceptibility of LDL to in vitro oxidation) and hence the adhesion molecule plasma concentrations. Thirty-four (19 males and 15 females) poorly controlled NIDDM patients were studied. All parameters were evaluated at the beginning of the study and after 90 days of dietary and pharmacological treatment. The treatment decreased HbA_1C (p < 0.001), E-selectin (p < 0.001), plasma hydroperoxides (p < 0.003) and the susceptibility of LDL to in vitro oxidation (lag phase) (p < 0.0001). Before treatment HbA_1C, lag phase and lipid hydroperoxides correlated with E-selectin plasma concentration (r = 0.51, –0.57 and 0.54, respectively, p < 0.01). There was also a correlation between HbA _1C and lag phase (p < 0.01) and between HbA _1C and lipid hydroperoxides (p < 0.01). In addition, the variations of HbA _1C, lag phase and lipid hydroperoxide values correlated with those for E-selectin concentration after 90 days' treatment (r = 0.54, –0.64 and 0.61, respectively, p < 0.01). In multiple linear correlation analysis, however, the partial correlation coefficients of HbA _1C (basal and variations) with E-selectin concentration (basal and variations) fell to non-significant values (r = 0.12 and 0.25, respectively) when LDL lag phase and plasma hydroperoxides were kept constant. The results indicate that the improvement of metabolic control in NIDDM patients is associated with a decrease of E-selectin plasma levels; they also suggest that glycaemic control per se is not directly implicated in determining E-selectin plasma concentration; glycaemic control could affect E-selectin concentration through its effect on oxidative stress. [Diabetologia (1997) 40: 584–589] Received: 31 October 1996 and in revised form 23 January 1997     

Detection of myocarditis during the first year after discovery of a dilated cardiomyopathy by endomyocardial biopsy and gallium-67 myocardial scintigraphy: prospective multicentre French study of 91 patients

The purpose of this study was to assess the frequency of inflammatorylesions in the myocardium of subjects with dilated cardiomyopathyand to determine if there was any correlation between the resultsof two methods of evaluation, one (endomyocardial biopsy) invasiveand the other (gallium-67 scintigraphy) noninvasive. Of 115subjects recruited in seven centres, 91 met the inclusion criteria(left ventricular dilatation 100 ml m^–2 and ejectionfraction <55% with normal coronary arteriography) and hadendomyocardial biopsy (mean five specimens) and Ga-67 myocardialscintigraphy after several days. Scanning was considered doubtful19 times and positive 13 times. The histologic count of mononuclearcells in the myocardial interstitium in 20 fields was greaterthan 5 cells field^–1 in only four cases. No correlationwas found between the two methods. Subjectivity in the choiceof the criterion of positivity of Ga-67 scintigraphy and difficultiesin identifying lymphocytes upon pathological examination werethe major problems encountered. Despite limitations, both techniquessuggest that cellular infiltrates are minimal and quite infrequentin dilated cardiomyopathy.     

The effect of the availability of inhaled insulin on glycaemic control in patients with Type 2 diabetes failing on oral therapy: the evaluation of Exubera® as a therapeutic option on insulin initiation and improvement in glycaemic control in clinical practice (EXPERIENCE) trial

Aim To examine the impact of inhaled human insulin (Exubera®, EXU) on patient or physician willingness to adopt insulin after oral glucose‐lowering agent failure. Methods During a randomized controlled trial in primary, secondary and tertiary care in Europe and North America, 739 patients using ≥ 2 oral glucose‐lowering agents with glycated haemoglobin (HbA_1c) ≥ 8.0% were assigned to two treatment groups: Group 1 (standard care with the option of EXU) or Group 2 (standard care only). Standard care included adjusting oral therapy (optimizing current regimen or adding/omitting agents) and/or initiating subcutaneous (s.c.) insulin. The primary endpoint was difference in HbA_1c between randomized groups at 26 weeks. Secondary outcomes included differences in the rate of uptake of insulin therapy, proportion achieving satisfactory glycaemic control, treatment satisfaction and safety outcomes. Results At baseline, insulin was initiated by more [odds ratio 6.0; 95% confidence interval (CI) 4.2 to 8.8; P < 0.0001] patients in Group 1 (86.2%; 76.7% EXU plus 9.5% s.c.) than Group 2 (50.7%; s.c. insulin only). At 26 weeks, mean (sd ) changes in HbA_1c from baseline were –2.0% (1.2%) and –1.7% (1.3%) in Groups 1 and 2, respectively, a difference of –0.2% (95% CI: –0.1% to –0.4%; P = 0.004). In Group 1, 45% of patients achieved an HbA_1c≤ 7.0% by 26 weeks compared with 39% in Group 2 (P = 0.02). Conclusion The availability of EXU may increase initiation of insulin, thereby contributing to improved overall glycaemic control in patients with Type 2 diabetes inadequately controlled on two or more oral glucose‐lowering agents.