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Given the continued interest in defining the optimal management of individuals with type 2 diabetes, the Editor of Diabetes Care convened a working party of diabetes specialists to examine this topic in the context of insulin therapy. This was prompted by recent new evidence on the use of insulin in such people. The group was aware of evidence that the benefits of insulin therapy are still usually offered late, and thus the aim of the discussion was how to define the optimal timing and basis for decisions regarding insulin and to apply these concepts in practice. It was noted that recent evidence had built upon that of the previous decades, together confirming the benefits and safety of insulin therapy, albeit with concerns about the potential for hypoglycemia and gain in body weight. Insulin offers a unique ability to control hyperglycemia, being used from the time of diagnosis in some circumstances, when metabolic control is disturbed by medical illness, procedures, or therapy, as well as in the longer term in ambulatory care. For those previously starting insulin, various other forms of therapy can be added later, which offer complementary effects appropriate to individual needs. Here we review current evidence and circumstances in which insulin can be used, consider individualized choices of alternatives and combination regimens, and offer some guidance on personalized targets and tactics for glycemic control in type 2 diabetes.

OBJECTIVE To evaluate the efficacy and safety of canagliflozin, a sodium glucose cotransporter 2 inhibitor, compared with sitagliptin in subjects with type 2 diabetes inadequately controlled with metformin plus sulfonylurea. RESEARCH DESIGN AND METHODS In this 52-week, randomized, double-blind, active-controlled, phase 3 study, subjects using stable metformin plus sulfonylurea (N = 755) received canagliflozin 300 mg or sitagliptin 100 mg daily. Primary end point was change from baseline in A1C at 52 weeks. Secondary end points included change in fasting plasma glucose (FPG) and systolic blood pressure (BP), and percent change in body weight, triglycerides, and HDL cholesterol. Safety was assessed based on adverse event (AE) reports. RESULTS At 52 weeks, canagliflozin 300 mg demonstrated noninferiority and, in a subsequent assessment, showed superiority to sitagliptin 100 mg in reducing A1C (−1.03% [−11.3 mmol/mol] and −0.66% [−7.2 mmol/mol], respectively; least squares mean difference between groups, −0.37% [95% CI, −0.50 to −0.25] or −4.0 mmol/mol [−5.5 to −2.7]). Greater reductions in FPG, body weight, and systolic BP were observed with canagliflozin versus sitagliptin (P < 0.001). Overall AE rates were similar with canagliflozin (76.7%) and sitagliptin (77.5%); incidence of serious AEs and AE-related discontinuations was low for both groups. Higher incidences of genital mycotic infections and osmotic diuresis–related AEs were observed with canagliflozin, which led to one discontinuation. Hypoglycemia rates were similar in both groups. CONCLUSIONS Findings suggest that canagliflozin may be a new therapeutic tool providing better improvement in glycemic control and body weight reduction than sitagliptin, but with increased genital infections in subjects with type 2 diabetes using metformin plus sulfonylurea.

Type 2 diabetes mellitus (T2DM) is a serious, chronic, and progressive disease that is rapidly increasing in prevalence. The disease now affects >10% of adults in some developed countries, increasing most in Asia. People with T2DM are two to four times more likely to develop a serious cardiovascular (CV) outcome compared with those without diabetes. The majority of patients with T2DM are insulin resistant and have associated metabolic abnormalities that are themselves significant CV risk factors. It is believed that most of this increased risk is caused by lipid abnormalities, hypertension, chronic vascular inflammation, and a proatherothrombotic state. The glycemia-related contribution is evidently lower: a long-term observational study over 18 years from Finland showed that an increase of 1% in HbA1c increased the risk of CV disease (CVD) mortality by 53% in type 1 diabetic patients but by only 7.5% in T2DM patients (1). Based on these observational data, it would be expected that a lowering of HbA1c of 1–2% would not dramatically change the absolute risk for death in people with T2DM. ### Effects of pioglitazone on CV risk factors and biomarkers Pioglitazone is known to improve insulin sensitivity, glycemic control, dyslipidemia, hypertension, and microalbuminuria in patients with T2DM. Pioglitazone decreases fasting and postprandial plasma glucose levels by improving the sensitivity of hepatic and peripheral (muscle) tissue to insulin. A large randomized controlled trial (RCT) showed that both pioglitazone and metformin reduced HbA1c by 1.5% from baseline (2). In contrast to the more commonly prescribed sulfonylureas, pioglitazone showed a significantly better durability of diabetes control in patients with T2DM (3). Similarly, pioglitazone was superior to the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin in reducing HbA1c levels in drug-naive patients (4). Pioglitazone also provides effective (lowering HbA1c by 0.5–1.5%) and durable glycemic control in combination with other oral antidiabetes drugs as well in combination with insulin …

OBJECTIVE The risk of cardiovascular death before the age of 40 is 20-fold higher in patients with type 1 diabetes mellitus (T1DM). Endothelial progenitor cells (EPCs) predict cardiovascular morbidity and mortality in patients without diabetes. We hypothesized that EPCs are modified in children with T1DM and are related to characteristics of T1DM such as glycemic control. RESEARCH DESIGN AND METHODS Children (n = 190; 156 T1DM subjects and 34 control subjects) were included in an observational cohort study and matched for age and sex. EPCs were enumerated by flow cytometry at the beginning (cross-sectional) and 1 year later (longitudinal). To analyze changes of variables during the observation, Δ values were calculated. RESULTS EPCs were significantly reduced in T1DM children versus control subjects (609 ± 359 vs. 1,165 ± 484, P < 0.001). Multivariate regression modeling revealed that glycated hemoglobin A1c (HbA1c) was the strongest independent predictor of EPCs (β = −0.355, P < 0.001). Overall glycemic control at the beginning and end of study did not differ (7.8 ± 1.2 vs. 7.8 ± 1.2 relative %, P = NS), but we observed individual HbA1c changes of −4.30/+3.10 relative %. The strongest EPC increase was observed in the patients with the most favorable HbA1c lowering during the 1-year follow-up. Accordingly, the strongest EPC decrease was demonstrated in the patients with the strongest HbA1c worsening during the time period. CONCLUSIONS This is the first prospective study demonstrating diminished EPCs in children with T1DM. The association of better glycemic control with an increase in EPC numbers within 1 year suggests that a reduction of the high cardiovascular disease burden might be mediated likewise.

OBJECTIVE Specific autoantibodies characterize type 1 diabetes in childhood but are also found in adult-onset diabetes, even when initially non–insulin requiring, e.g., with latent autoimmune diabetes (LADA). We aimed to characterize adult-onset autoimmune diabetes. RESEARCH DESIGN AND METHODS We consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30–70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A). RESULTS Of 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8A alone. More autoantibody-positive than autoantibody-negative patients were younger, leaner, on insulin (49.5 vs. 13.2%), and female (P < 0.0001 for each), though LADA patients (9.7% of total) did not show categorically distinct clinical features from autoantibody-negative type 2 diabetes. Similarly, more GADA patients with high (>200 World Health Organization IU) (n = 403) compared with low (n = 138) titer were female, lean, and insulin treated (54.6 vs. 39.7%) (P < 0.02 for each). Autoantibody-positive patients usually had GADA (541 of 598; 90.5%) and had LADA more often than type 1 autoimmune diabetes (odds ratio 3.3). CONCLUSIONS Adult-onset autoimmune diabetes emerges as a prevalent form of autoimmune diabetes. Our results indicate that adult-onset autoimmune diabetes in Europe encompasses type 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum. At diagnosis, patients with adult-onset autoimmune diabetes are usually non–insulin requiring and clinically indistinguishable from patients with type 2 diabetes, though they tend to be younger and leaner. Only with screening for autoantibodies, especially GADA, can they be identified with certainty.

About 40 years ago, the Framingham study first documented that the risk for heart failure (HF) in patients with diabetes was about twofold higher in men and fivefold in women compared with individuals without diabetes (1). The UK Prospective Diabetes Study (UKPDS) reported that the incidence of hospital admission for HF was similar to that of nonfatal myocardial infarction and nonfatal stroke (2). A more recent 6-year follow-up study of 65,619 patients with type 2 diabetes treated with insulin reported that the hospital admission rate due to HF (243 of 10,000) was higher than that due to myocardial infarction (97 of 10,000) or stroke (151 of 10,000) (3). The pathogenesis of HF in diabetes is multifactorial but can largely be attributed to four key factors: coronary artery disease (CAD), hypertension, diabetic cardiomyopathy, and extracellular fluid volume expansion (4,5). Remarkably, type 2 diabetes itself is a recognized risk factor for HF, independent of CAD and hypertension (4), suggesting that glycemic control may influence the development of HF. Hyperglycemia can exert deleterious effects on the myocardium and has been shown to increase oxidative stress, promote accumulation of advanced glycation end products, and cause interstitial fibrosis (6). Hyperglycemia has also been associated with myocardial lipotoxicity, mitochondrial dysfunction, abnormal substrate metabolism, and impaired calcium handling (7). Epidemiological evidence indicates that HbA1c and the risk of HF are significantly related. A cohort study of ∼49,000 patients with type 2 diabetes showed that each 1% increase in HbA1c was associated with an 8% increased risk of HF and that an HbA1c ≥10 relative to HbA1c

The prevalence of type 2 diabetes has markedly increased in the last decade worldwide, but in particular in Asian countries such as China and India (1–3), in strong correlation with a comparably steep increase in the prevalence of obesity (4). The primary risk factor for type 2 diabetes is obesity, and 90% of all patients with type 2 diabetes are overweight or obese. The relative risk of diabetes increases about 42-fold in men as the BMI increases from 35 kg/m2 (5) and approximately 93-fold in women as BMI increases from 35 kg/m2 (6). Type 2 diabetes is a complex major endocrine disorder in which insulin resistance in the muscle and liver as well as β-cell failure represent the core pathophysiological defects. In addition to the muscle, liver, and β-cell, the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance) all play important roles in the development of type 2 diabetes (7). The development of type 2 diabetes is strongly associated with obesity and the accumulation of abdominal and ectopic fat, which are linked to peripheral and hepatic insulin resistance, inflammation, and subsequent “lipotoxicity” of β-cells (8,9). The adipose tissue of obese subjects is characterized by increased production and secretion of a wide panel of inflammatory molecules (10) such as tumor necrosis factor-α, interleukin-6, transforming growth factor-β, monocyte chemotactic protein-1, and plasminogen activator inhibitor-1. Evidence is increasing that chronic subclinical inflammation seems to be involved in the development of type 2 diabetes. Several prospective studies demonstrated that subjects who developed type 2 diabetes during the follow-up period had elevated levels of markers of inflammatory molecules at baseline compared with those who did not develop the disease. In …

OBJECTIVE Low levels of fetuin-A, a systemic calcification inhibitor, are linked to mortality in patients on dialysis. In contrast, elevated fetuin-A is associated with cardiovascular events in non-renal patients. We investigated fetuin-A in patients with type 2 diabetes and peripheral arterial disease (PAD). RESEARCH DESIGN AND METHODS We studied fetuin-A in 76 patients with PAD and normal glucose metabolism (NGM-PAD) and in 129 patients with PAD and type 2 diabetes (type 2 diabetes–PAD). Additionally, 40 patients with diabetes without any complications (type 2 diabetes–non-PAD) were examined. RESULTS Type 2 diabetes–PAD subjects (399 ± 155 μg/ml) had significantly higher fetuin-A levels than type 2 diabetes–non-PAD subjects (247 ± 42; P < 0.001). In NGM-PAD subjects (376 ± 144), fetuin-A was significantly higher than in type 2 diabetes–non-PAD subjects (P < 0.001). Type 2 diabetes–PAD patients with mediasclerosis had lower fetuin-A than subjects without (P < 0.03). Regression analysis in type 2 diabetes–PAD subjects revealed that glycated A1C (P < 0.001) and mediasclerosis (P = 0.004) were the strongest predictors of fetuin-A. Multivariate regression revealed that a 1-SD increase in fetuin-A was associated with an odds ratio (OR) of 2.1 (95% CI 1.1–3.3; P < 0.001) for the prevalence of PAD and an OR of 1.4 (1.0–1.7, P = 0.039) for the prevalence of myocardial infarction. CONCLUSIONS In contrast to previous findings, fetuin-A was higher in type 2 diabetes–PAD patients than in type 2 diabetes–non-PAD patients. In NGM-PAD patients, fetuin-A was also higher than in type 2 diabetes–non-PAD patients. In type 2 diabetes–PAD patients, fetuin-A was inversely associated with mediasclerosis—the calcification process pathognomonic for diabetic PAD. This association persisted in multivariate regression, which is in line with the calcification inhibition in coronary heart or renal disease.

There is an epidemic of obesity throughout the developed and much of the developing world (1–3). Obesity, typically measured as BMI ≥30 kg/m2, has three subclasses: obesity 1 (30–34.9 kg/m2); obesity 2 (35–39.9 kg/m2); and extreme obesity (>40 kg/m2). Extreme or morbid obesity is rapidly increasing in the U.S. and may have the potential of decreasing life expectancy. From 1986 to 2000, the prevalence of BMI >30 kg/m2 doubled, whereas that of BMI ≥40 kg/m2 quadrupled, and even extreme obesity of BMI ≥50 kg/m2 increased fivefold (2). Of particular concern is the alarming increasing prevalence of obesity among children (1), suggesting that the epidemic will worsen before it improves. Epidemiologic studies have demonstrated that increasing BMI is a causative factor in many life-threatening comorbidities, including type 2 diabetes, cardiovascular disease, and cancer. BMI has been established as an independent risk factor for premature mortality (4). Obesity is a major independent risk factor for the development of type 2 diabetes and is associated with the rapid increase in the prevalence of type 2 diabetes (3). In the U.S., the majority diagnosed with type 2 diabetes are overweight, with 50% obese (i.e., BMI >30 kg/m2) and 9% morbidly obese (BMI >40 kg/m2) (5). This twin epidemic of obesity and diabetes carries severe consequence for premature mortality (6). Lifestyle intervention programs with diet therapy, behavior modification, exercise programs, and pharmacotherapy are widely used in various combinations. Unfortunately, with extremely rare exceptions (7), clinically significant weight loss is generally very modest and transient, particularly in patients with severe obesity. In a recently published study (8), 80 adults with mild to moderate obesity (BMI 30–35 kg/m2) were randomized to nonsurgical intervention (very-low-calorie diet, orlistat, and lifestyle change) or to surgical intervention …

OBJECTIVE—The goal was to assess the 1-year efficacy and safety of the addition of pioglitazone or metformin to existing sulfonylurea (SU) therapy in patients with inadequately controlled type 2 diabetes.RESEARCH DESIGN AND METHODS—In this multicenter, double-blind study, patients were randomized to receive either pioglitazone 15 mg (n = 319) or metformin 850 mg (n = 320) and up to 45 mg/day and 2,550 mg/day, respectively. The primary efficacy endpoint was HbA1c at week 52. Fasting plasma glucose, insulin, and lipid profiles were also measured.RESULTS—HbA1c was reduced by 1.20% in the SU plus pioglitazone group and 1.36% in the SU plus metformin group, and fasting plasma glucose was reduced by 2.2 and 2.3 mmol/l in the respective groups. Fasting insulin levels were also reduced (pioglitazone arm −1.3 μIU/ml; metformin arm −0.8 μIU/ml). There were no significant between-treatment differences in these three parameters. Pioglitazone addition to SU significantly reduced triglycerides (−16 vs. −9%; P = 0.008) and increased HDL cholesterol (14 vs. 8%; P < 0.001) compared with metformin addition. LDL cholesterol was increased 2% by the addition of pioglitazone and decreased 5% by the addition of metformin to SU (P < 0.001). Urinary albumin-to-creatinine ratio was reduced by 15% in the SU plus pioglitazone group and increased 2% in the SU plus metformin group (P = 0.017). Both combinations were well tolerated with no evidence of hepatic or cardiac toxicity in either group.CONCLUSIONS—Clinically equivalent improvements in glycemic control were observed for both combinations. Compared with metformin plus SU, addition of pioglitazone to SU resulted in a reduction of the urinary albumin-to-creatinine ratio, a small but significant rise in LDL cholesterol, and significantly greater improvements in triglyceride levels and HDL cholesterol levels. Metformin plus SU was associated with a significant reduction in LDL cholesterol. SU plus pioglitazone is an effective and well-tolerated combination regimen that may provide additional beneficial effects for patients with type 2 diabetes.

We thank Dr. Conget and colleagues (1) for their comments on our article (2) and congratulate them on their article (3) on insulin pump use in type 2 diabetes, …

OBJECTIVE This 12-week study assessed the efficacy and tolerability of imeglimin as add-on therapy to the dipeptidyl peptidase-4 inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled with sitagliptin monotherapy. RESEARCH DESIGN AND METHODS In a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, imeglimin (1,500 mg b.i.d.) or placebo was added to sitagliptin (100 mg q.d.) over 12 weeks in 170 patients with type 2 diabetes (mean age 56.8 years; BMI 32.2 kg/m2) that was inadequately controlled with sitagliptin alone (A1C ≥7.5%) during a 12-week run-in period. The primary efficacy end point was the change in A1C from baseline versus placebo; secondary end points included corresponding changes in fasting plasma glucose (FPG) levels, stratification by baseline A1C, and percentage of A1C responders. RESULTS Imeglimin reduced A1C levels (least-squares mean difference) from baseline (8.5%) by 0.60% compared with an increase of 0.12% with placebo (between-group difference 0.72%, P < 0.001). The corresponding changes in FPG were −0.93 mmol/L with imeglimin vs. −0.11 mmol/L with placebo (P = 0.014). With imeglimin, the A1C level decreased by ≥0.5% in 54.3% of subjects vs. 21.6% with placebo (P < 0.001), and 19.8% of subjects receiving imeglimin achieved a decrease in A1C level of ≤7% compared with subjects receiving placebo (1.1%) (P = 0.004). Imeglimin was generally well tolerated, with a safety profile comparable to placebo and no related treatment-emergent adverse events. CONCLUSIONS Imeglimin demonstrated incremental efficacy benefits as add-on therapy to sitagliptin, with comparable tolerability to placebo, highlighting the potential for imeglimin to complement other oral antihyperglycemic therapies.

OBJECTIVE For intensified insulin therapy of type 1 diabetes, bolus injection of regular human insulin 30–15 min before a meal is currently recommended. This randomized study is aimed to determine whether insulin lispro (LIS), a new insulin analog with a rapid onset of action, can provide comparable blood glucose (BG) control by injection after the meal. RESEARCH DESIGN AND METHODS Eighteen type 1 diabetic subjects injected regular insulin (REG) at 40, 20, or 0 min before or LIS at 20 or 0 min before or 15 min after the start of a standardized test meal. BG excursions and area under the curve of BG excursions (AUC) at the six visits were compared by analysis of variance. Hypoglycemic events (BG ≤2.78 mmol/1) were evaluated in relation to the achieved postprandial BG control. RESULTS Mean AUC values were 2.00, 2.55, and 3.33 mmol · h · 1−1 for REG given 40, 20, and 0 min before the test meal, respectively, and −2.19, −2.15, and 1.98 mmol · h · 1−1 for LIS given 20 and 0 min before and 15 min after the start of the test meal, respectively. LIS injected 20 min (−20) or immediately (0) before the meal was significantly more effective in controlling postprandial BG excursion (P < 0.001) than any REG treatment. Postprandial injection of LIS (15) did not compromise postprandial BG control and resulted in less hypoglycemia. REG −40 and LIS −20 were associated with early hypoglycemia, but other hypoglycemic events were equally distributed among groups. CONCLUSIONS The optimal time for bolus insulin injection was 20 min before the meal for REG and immediately before the meal for LIS. LIS injected immediately after a standard meal provided postprandial BG control at least as good as REG injected from 40 to 0 min before the meal. Postprandial injection of LIS is an attractive new therapeutic option.

OBJECTIVE To investigate whether autonomic neuropathy or hyperglycemia plays a crucial etiological role in gastric retention of ingesta frequently found in type I diabetic patients. RESEARCH DESIGN AND METHODS We investigated the gastric emptying of a radiolabeled semisolid 1,168 kJ meal in 38 female and 45 male patients (age 18–75 years; illness duration 3–46 years). None took drugs affecting gastrointestinal motility. Fasted patients underwent tests of cardiovascular autonomic and peripheral nerve function. Blood glucose levels were determined before and after the scintigraphic recording of gastric emptying. RESULTS The percentage of meal remaining in the stomach at the end of the 50-min recording time was related significantly to the patients' degree of cardiovascular autonomic neuropathy [r (81) = 0.235, P < 0.028] but not to their degree of peripheral neuropathy, preprandial blood glucose level, HbA1c indicative of glycemic control, diabetes duration, and age. The patients' mean residual percentage of meal was significantly > that of 48 healthy subjects, that is, 71.1 ± 15.1 vs. 53.5 ± 13.1% [means ± SD; t (129) = 6.48, P < 0.0001]. The healthy individuals' mean residual percentage + 2 SD was exceeded in 22 patients. CONCLUSIONS Slow gastric emptying in patients with type I diabetes seems related to the degree of autonomic neuropathy but not to peripheral neuropathy, actual blood glucose, and glycemic control.

OBJECTIVE To investigate the effects of long-term high-dose oral magnesium (Mg) therapy (30 mmol/day) in patients with type II diabetes. Low plasma magnesium levels have been reported in type II diabetes and are associated with insulin resistance and diabetic late complications. RESEARCH DESIGN AND METHODS Forty patients with type II diabetes and hypomagnesemia were observed in a randomized double-blind placebo-controlled trial for 3 months (body mass index: 28 ± 4 kg/m2; HbA1c: 7.4 ± 0.8%). Plasma and urine magnesium and metabolic control parameters were determined, and side effects were considered, especially with regard to patients' compliance. RESULTS A significant increase in plasma magnesium levels was observed after 3 months of treatment (Mg: 0.73 ± 0.8 vs. 0.81 ±0.1 mmol/1), reaching magnesium levels of the control group (0.88 ± 0.8 mmol/1; NS); metabolic control, however, was not altered (HbA1c: 7.2 ± 0.7 vs. 7.4 ± 0.9%). Six months after the end of the trial, plasma magnesium declined to pretreatment levels (Mg: 0.73 ± 0.07 mmol/1). The prevalence of side effects was high at the beginning and was reduced significantly during treatment. CONCLUSIONS We conclude that oral magnesium replacement therapy corrects hypomagnesemia after a minimum treatment period of 3 months. These observations might be important for the prevention of diabetic late complications.

OBJECTIVE—Latent autoimmune diabetes in adults is type 1 diabetes presenting as non–insulin dependent diabetes. One feature of the selection criteria is time independent of insulin treatment. We examine the validity of this criterion. RESEARCH DESIGN AND METHODS—Patients were recruited in nine European centers, and clinicians reported on criteria for initiating insulin. All patients were tested for GAD antibodies (GADAs) in a central laboratory. We examined time to insulin treatment for GADA-positive patients in six participating centers. RESULTS—There was intercenter variation in the criteria used to initiate insulin. Median time to insulin was 16.15 months (interqartile range 6.7–25.5) in centers with GADA testing compared with 45.6 months (29.5–61.8) in centers without routine GADA testing (P < 0.002). CONCLUSION—Time to insulin should not be used to define patients with LADA because it is dependent on local clinical judgment and the use of laboratory tests for GADA.

OBJECTIVE— Circulating concentrations of an endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), are elevated in patients with increased cardiovascular risk. We hypothesized that ADMA predicts cardiovascular events and enhances risk prediction independent of established risk markers in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS— This prospective cohort study included 125 patients with type 2 diabetes. ADMA, l-arginine, high-sensitivity C-reactive protein (CRP), and routine clinical parameters were determined at baseline. First occurrence of cardiovascular events (myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, stroke, carotid revascularization, or all-cause mortality) was defined as a composite end point. RESULTS— During a median follow-up of 21 (interquartile range 11–27) months, 84 events occurred in 48 patients. According to multivariate Cox regression analysis, patients with baseline ADMA or CRP in the highest tertile had a significantly increased hazard ratio for incident cardiovascular events compared with those with ADMA or CRP in tertile 1 (2.37 [95% CI 1.05–5.35], P = 0.038, and 3.63 [1.59–8.28], P = 0.002). Assessing the joint effect of ADMA and CRP revealed that patients with either ADMA or CRP or both in the highest tertile had increased hazard ratios for cardiovascular events compared with patients with neither ADMA nor CRP in the highest tertile before and after adjustment for possible confounders (hazard ratio 4.59 [95% CI 2.07–10.15], P < 0.001). CONCLUSIONS— ADMA predicted cardiovascular events and enhanced the predictive role of CRP in patients with type 2 diabetes. ADMA therefore could improve cardiovascular risk assessment in patients with type 2 diabetes.

On behalf of the authors identified below, the corresponding author has formally requested to retract the above-cited article. An accompanying article (1) has also been retracted. The article reports on the DIA-AID 1 trial, which examined the safety and efficacy of DiaPep277 to treat type 1 diabetes. The DIA-AID 1 trial, as noted in the Duality of Interest section, was funded by Andromeda Biotech, Ltd. On 8 September 2014, Hyperion Therapeutics, Inc., which acquired Andromeda Biotech in June 2014, announced that it had chosen to terminate the DiaPep277 program. As stated in the press release …

In the print version of the article cited above, the affiliation for Didac Mauricio and Alberto De …

Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, Kawaguchi M, Canovatchel W, Meininger G. Canagliflozin compared with sitagliptin for patients with type …

Immunological complications of insulin therapy have been evident since animal insulins became available for the treatment of diabetes mellitus in 1922. Insulin allergy has been particularly common, with local symptoms still occurring in ∼ 5% of all patients. Insulin antibodies of high titers were observed in many patients treated with early insulin preparations containing proinsulin, C-peptide, and other peptide contaminants. Immunoglobulin G-insulin antibodies of very high levels can lead to immune-mediated insulin resistance, which is now extremely rare because of the widespread use of highly purified porcine insulin and human insulin preparations. Lipoatrophy, which was reported in 10–55% of patients treated with nonpurified bovine/porcine insulin preparations, has almost disappeared in patients since the advent of exclusive human insulin treatment. In view of the wide spectrum of immune-mediated complications of insulin therapy, much attention has been directed to the reduced immunogenicity and allergenicity of highly purified porcine insulins and the more recently available recombinant and semisynthetic human insulin preparations. Insulin antibodies of the immunoglobulin G and immunoglobulin E type can develop, however, in very low titers in patients treated exclusively with human insulin. Frequency and levels of immunoglobulin G insulin antibodies are identical in patients treated either with biosynthetic or semisynthetic human insulin preparations. Allergic symptoms to human insulin are now found in < 1% of de novo-treated patients, but still may occur when human insulin is used in the insulin-allergic patient. In summary, immunological complications of insulin therapy have decreased significantly during the last two decades and are now predominantly observed in patients with interrupted insulin therapy.

Miglitol (BAYm 1099), an α-glucosidase inhibitor, reduces the postprandial increase of blood glucose and serum insulin levels in type II (non-insulin-dependent) diabetes mellitus, as shown in short-term studies. In this study, the effects of long-term miglitol treatment on metabolic control, C-peptide secretion, hepatic glucose output, and peripheral insulin sensitivity (euglycemic clamp) were tested in 15 type II diabetic patients (8 receiving insulin, 7 receiving oral hypoglycemic agents). For 8 wk they received either miglitol (300 mg/day) or placebo with a double-blind crossover design that had a 4-wk washout period between treatments. Miglitol therapy induced a reduction of postprandial blood glucose levels (miglitol compared with placebo; areas under the curve; P > .002), whereas fasting blood glucose levels were not influenced. Miglitol caused a slight reduction of glycosylated hemoglobin levels (mean ± SE miglitol and placebo 9.50 ± 0.3 and 10.0 ± 0.4%, respectively; P > .05), which was more pronounced in insulin-treated patients. Miglitol caused a reduction of postprandial C-peptide increase (P > .03). Hepatic glucose output (both in the basal state and during euglycemic clamp conditions) and peripheral insulin sensitivity were not influenced by miglitol therapy. Specific side effects were observed in 11 patients; in 6 patients only to a moderate degree.- Long-term miglitol treatment induces a persistent reduction of postprandial blood glucose increase. This effect is more pronounced in type II diabetic patients on insulin therapy, which can cause a moderate improvement of overall metabolic control.

The binding properties of human insulin (recombinant DNA) and human proinsulin were compared in seven healthy volunteers. Specific cell binding of human proinsulin was significantly lower compared with the human insulin receptor binding with an approximately 100-fold lower average affinity (3.71 mol−1 × 108 for human insulin versus 0.042 mol−1 × 108 for human proinsulin). Native human proinsulin at low concentrations had no significant effect on specific human insulin receptor binding. Only at high hormone concentrations human proinsulin could displace human insulin from the insulin receptor. We conclude that in vivo proinsulin-insulin interactions at the receptor do not possess major clinical relevance.

The affinity of human (recombinant DNA) insulin and porcine insulin to preformed IgG-insulin antibodies of insulin-treated diabetic individuals was studied in 29 insulin-treated diabetic patients. The binding of 125I-human insulin and 125I-porcine insulin with antibodies was similar in the group of patients without insulin resistance (N = 25). The sera of insulin-resistant diabetic patients (N = 4), containing very high IgG-insulin immunoglobulins, showed a significantly lower affinity for human insulin compared with porcine insulin (P < 0.01). All four patients with insulin-antibody-mediated insulin resistance were positive for HLA-DR4, but negative for -DR3, supporting the concept of an immunogenetically transferred anti-insulin immune response in insulin-treated diabetic individuals. Based on the reduced binding of human insulin to IgG-antibodies of very high titers in patients with insulin resistance, a potential therapeutic advantage of human insulin therapy can be expected in such infrequent cases of immunologic insulin resistance.

The risk of severe hypoglycemia associated with the particular therapeutic approach of two University hospitals was assessed in 96% of all patients with insulin-dependent diabetes mellitus (IDDM) who had been admitted during a period of almost 3 yr to the diabetic wards of two hospitals and who participated in a structured teaching and treatment program. During a mean follow-up period of 18 mo, 10% of the conventionally treated patients (N = 384; age 30 ± 13 yr; duration of diabetes 12 ± 9 yr) and 9% of the CSII-treated patients (N = 50, age 28 ± 7 yr, duration of diabetes 13 ± 7 yr, total follow-up period 1093 patient-mo) experienced at least one severe hypoglycemic episode per year, and a total of 123 severe hypoglycemic episodes occurred. In a subgroup of 169 conventionally treated patients, mean glycosylated hemoglobin values decreased from 10.5 ± 1.9% before participation in the program to 9.2 ± 2.0% (P < 0.001) 18 ± 4 mo thereafter. For the CSII-treated patients, glycosylated hemoglobin values were 9.7 ± 1.9% before initiation of pump therapy and remained at the upper normal range from 3 mo thereafter throughout the study. There was no relationship between glycosylated hemoglobin levels and the occurrence of severe hypoglycemic episodes. Fifty-three severe hypoglycemic episodes were treated with glucagon injections by the patients' relatives (all but one effectively), 30 were managed by assisting physicians, and 44 led to hospitalization. Thus, successful attempts to improve glycosylated hemoglobin values in an unselected group of patients with IDDM were not associated with an unduly high risk of severe hypoglycemia when compared with the scarce data from the literature.