Improved Glycemic Control With Intraperitoneal Versus Subcutaneous Insulin in Type 1 Diabetes: A randomized controlled trial

OBJECTIVE

Continuous intraperitoneal insulin infusion (CIPII) with an implantable pump has been available for the past 25 years. CIPII, with its specific pharmacodynamic properties, may be a viable treatment alternative to improve glycemic control in patients with type 1 diabetes for whom other therapies have failed. There have been few studies in which CIPII was compared with subcutaneous insulin treatment for patients with type 1 diabetes with poor glycemic control.

RESEARCH DESIGN AND METHODS

In an open-label, prospective, crossover, randomized, 16-month study, the effects of CIPII and subcutaneous insulin were compared in 24 patients. The primary outcome measure was the incidence of hypoglycemia. Secondary outcome measures were A1C, and glucose profile, including time in euglycemia, as measured by continuous glucose monitoring.

RESULTS

The incidence of grade 1 hypoglycemic events was 4.0 ± 2.6 per week with subcutaneous insulin compared with 3.5 ± 2.3 per week during CIPII (P = 0.13). The absolute mean difference in A1C with CIPII compared with subcutaneous treatment was −0.76% (95% CI −1.41 to −0.11) (P = 0.03). Baseline time spent in euglycemia was 45.2 ± 12.6% and increased 10.9% (4.6–17.3) with CIPII compared with subcutaneous treatment (absolute value; P = 0.003). There were no differences in the occurrence rate for severe hypoglycemic events, daily insulin use, or BMI. No pump or catheter malfunction was observed during the study.

CONCLUSIONS

Although we did not observe a significant reduction in hypoglycemic events, improved glycemic control was achieved with the use of CIPII. We saw a 0.8% decrease in A1C and an 11% increase in the time spent in euglycemia.Meta-analyses conclude that continuous subcutaneous insulin infusion (CSII) is somewhat better than multiple daily injections (MDIs) for obtaining glycemic control in patients with type 1 diabetes (1–4). These differences tend to be smaller when synthetic insulin analogs are used. The absorption of subcutaneous infused insulin is influenced by many factors, sometimes responsible for unexpected hypo- and hyperglycemic events (5,6). In some patients with type 1 diabetes, this form of therapy does not yield acceptable and stable long-term glycemic control (7).The intraperitoneal administration of insulin allows blood glucose values to normalize more rapidly after a meal with more predictable insulin profiles than with subcutaneous insulin (8–10). Much of the intraperitoneal insulin is absorbed through the portal system, which more closely mimics normal physiological action, resulting in improved hepatic uptake and lower peripheral plasma insulin levels (11). Intraperitoneal insulin may lead to improved glucagon secretion and hepatic glucose production in response to hypoglycemia (12).The effects of continuous intraperitoneal insulin infusion (CIPII) in type 1 diabetes have been investigated in few randomized controlled trials, and all were done before the era of rapidly acting insulin analogs. The objective of our study was to assess the safety and efficacy of CIPII compared with intensified subcutaneous insulin therapy in patients with inadequately controlled type 1 diabetes.     

Oral Insulin: A Comparison With Subcutaneous Regular Human Insulin in Patients With Type 2 Diabetes

OBJECTIVE

To determine the pharmacokinetic and pharmacodynamic properties of an oral insulin (OI) formulation compared with subcutaneously injected regular human insulin (RHI).

RESEARCH DESIGN AND METHODS

Ten male patients with type 2 diabetes (means ± SD; A1C 7.0 ± 1.1%; BMI 28.3 ± 2.7 kg/m²) received either 300 units of insulin combined with 400 mg of delivery agent orally or 15 units RHI subcutaneously under isoglycemic clamp conditions.

RESULTS

Maximum insulin concentration was greater and onset of action was faster with OI (C_max 93 ± 71 vs. 33 ± 11 μU/ml; AUC_GIR^(0−1h) 173 ± 86 vs. 27 ± 32 mg/kg; P < 0.05). Mean insulin concentration and glucose infusion rate returned to baseline within 3 h after OI administration. Relative bioavailability of OI was 7 ± 4% (1st 2 h).

CONCLUSIONS

This proof-of-concept study demonstrated that absorption of OI is feasible under fasting conditions. OI has a fast onset and a short duration of action but also shows a rather high between-subject variability in absorption.Oral administration of insulin has the potential advantage of a more physiological action by its direct effect on hepatic glucose production (1,2). Thus far various oral insulin approaches however have only partially produced satisfactory results (1,3,4). Gastrointestinal absorption of insulin is hampered by factors such as enzymatic degradation and lack of permeation through epithelial cells (5). Noncovalent interaction of the novel drug-carrier molecule monosodium N-(4-chlorosalicyloyl)-4-aminobutyrate (4-CNAB) with insulin might create more favorable physico-chemical properties for gastrointestinal insulin absorption (6,7). In this study, 4-CNAB has been combined with human insulin to facilitate gastrointestinal insulin absorption.     

Insulin Degludec Versus Insulin Glargine in Insulin-Naive Patients With Type 2 Diabetes: A 1-year,randomized, treat-to-target trial (BEGIN Once Long)

OBJECTIVE

To compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs).

RESEARCH DESIGN AND METHODS

In this 1-year, parallel-group, randomized, open-label, treat-to-target trial, adults with type 2 diabetes with A1C of 7−10% taking OADs were randomized 3:1 to receive once daily degludec or glargine, both with metformin. Insulin was titrated to achieve prebreakfast plasma glucose (PG) of 3.9−4.9 mmol/L. The primary end point was confirmation of noninferiority of degludec to glargine in A1C reduction after 52 weeks in an intent-to-treat analysis.

RESULTS

In all, 1,030 participants (mean age 59 years; baseline A1C 8.2%) were randomized (degludec 773, glargine 257). Reduction in A1C with degludec was similar (noninferior) to that with glargine (1.06 vs. 1.19%), with an estimated treatment difference of degludec to glargine of 0.09% (95% CI −0.04 to 0.22). Overall rates of confirmed hypoglycemia (PG <3.1 mmol/L or severe episodes requiring assistance) were similar, with degludec and glargine at 1.52 versus 1.85 episodes/patient-year of exposure (PYE). There were few episodes of nocturnal confirmed hypoglycemia in the overall population, and these occurred at a lower rate with degludec versus glargine (0.25 vs. 0.39 episodes/PYE; P = 0.038). Similar percentages of patients in both groups achieved A1C levels <7% without hypoglycemia. End-of-trial mean daily insulin doses were 0.59 and 0.60 units/kg for degludec and glargine, respectively. Adverse event rates were similar.

CONCLUSIONS

Insulins degludec and glargine administered once daily in combination with OADs provided similar long-term glycemic control in insulin-naive patients with type 2 diabetes, with lower rates of nocturnal hypoglycemia with degludec.The increasing prevalence of type 2 diabetes and its associated complications pose a significant global health care and economic burden (1). The landmark U.K. Prospective Diabetes Study demonstrated the benefits of improved glucose control and highlighted the progressive nature of type 2 diabetes as a result of β-cell failure. Approximately 50% of patients with type 2 diabetes may require insulin therapy in addition to oral antidiabetic drugs (OADs) within 6 years of diabetes diagnosis (2,3). Clinical guidelines by the American Diabetes Association and European Association for the Study of Diabetes currently recommend initiating basal insulin in patients with type 2 diabetes either directly after metformin or after maximizing a combination of OADs with or without glucagonlike peptide-1 receptor agonists and then titrating insulin to meet a glycosylated hemoglobin (A1C) target of 7% without significant hypoglycemia (4,5).Several barriers to introducing insulin have been identified that may result in delayed achievement of glycemic control and progression of diabetes complications (6,7). These barriers include patients’ fear of injections and misconceptions about insulin therapy, clinicians’ fear of perceived complexity of insulin regimens, and both parties’ fear that introducing insulin will negatively affect patient lifestyle and weight gain (8). Additionally, the risk, consequences, and fear of hypoglycemia remain a significant limiting factor in intensifying insulin therapy and optimizing glycemic control (9).Long-acting insulin analogs have been developed to produce a more physiological basal insulin action than seen with such human insulin preparations as neutral protamine Hagedorn (NPH) insulin, and they are associated with lower hypoglycemia rates (particularly nocturnal) while achieving similar glycemic control (10–12). These analogs have lowered the barrier for insulin introduction in patients with type 2 diabetes and are recommended when OADs alone cannot maintain glucose control (10,12,13). There is still a need, however, for the development of basal insulins with improved pharmacokinetics and pharmacodynamics, with the goal of achieving glycemic targets in more patients with even less hypoglycemic risk (14). Insulin degludec is a novel, ultra-long-acting basal insulin. On subcutaneous injection, degludec forms a depot of soluble multihexamers that dissociates slowly and consistently, resulting in a flat, stable profile and a duration of action longer than 42 h (15,16). A previous phase 2 clinical trial comparing once daily degludec with glargine in insulin-naive patients with type 2 diabetes (17) and two phase 3 studies comparing once daily degludec with glargine in basal-bolus therapy in patients with type 1 (18) and type 2 diabetes (19) demonstrated that degludec provides similar glycemic control with less hypoglycemia than glargine.BEGIN Once Long is the largest phase 3 study in the clinical development program of insulin degludec and was designed as a 52-week, treat-to-target trial to compare the efficacy and safety of insulin degludec with those of insulin glargine, both administered in a basal regimen in combination with metformin, in insulin-naive participants with type 2 diabetes inadequately controlled with OADs.     

Exercise Training and Quality of Life in Individuals With Type 2 Diabetes: A randomized controlled trial

OBJECTIVE

To establish whether exercise improves quality of life (QOL) in individuals with type 2 diabetes and which exercise modalities are involved.

RESEARCH DESIGN AND METHODS

Health Benefits of Aerobic and Resistance Training in individuals with type 2 Diabetes (HART-D; n = 262) was a 9-month exercise study comparing the effects of aerobic training, resistance training, or a combination of resistance and aerobic training versus a nonexercise control group on hemoglobin A_1c (HbA_1c) in sedentary individuals with type 2 diabetes. This study is an ancillary analysis that examined changes in QOL after exercise training using the Short Form-36 Health Survey questionnaire compared across treatment groups and with U.S. national norms.

RESULTS

The ancillary sample (n = 173) had high baseline QOL compared with U.S. national norms. The QOL physical component subscale (PCS) and the general health (GH) subscale were improved by all three exercise training conditions compared with the control group condition (resistance: PCS, P = 0.005; GH, P = 0.003; aerobic: PCS, P = 0.001; GH, P = 0.024; combined: PCS, P = 0.015; GH, P = 0.024). The resistance training group had the most beneficial changes in bodily pain (P = 0.026), whereas physical functioning was most improved in the aerobic and combined condition groups (P = 0.025 and P = 0.03, respectively). The changes in the mental component score did not differ between the control group and any of the exercise groups (all P > 0.05). The combined training condition group had greater gains than the aerobic training condition group in the mental component score (P = 0.004), vitality (P = 0.031), and mental health (P = 0.008) and greater gains in vitality compared with the control group (P = 0.021).

CONCLUSIONS

Exercise improves QOL in individuals with type 2 diabetes. Combined aerobic/resistance exercise produces greater benefit in some QOL domains.Quality of life (QOL) is a comprehensive construct that typically includes physical, emotional, and social aspects of well-being, such as physical functioning, role limitations attributable to physical or emotional problems, bodily pain, and energy level (1). Previous exercise studies in healthy subjects and individuals with cardiovascular disease risk or other medical conditions (i.e., hypertension, chronic obstructive pulmonary disease [COPD], cancer) have found significant improvements in QOL after exercise training (2–6). Although most of these previous studies were small and not randomized controlled trials, recent data have provided more convincing evidence of the beneficial effects of exercise on QOL. Specifically, Martin et al. (4) in a large randomized controlled trial (N = 430) found a significant increase in most QOL domains in response to three different amounts of aerobic exercise training in overweight and obese postmenopausal women with high blood pressure. In addition, QOL improved with greater amounts of exercise training in a dose-dependent manner (4).Adults with diabetes report a lower QOL than nondiabetic individuals (1,6), and exercise training may have promise for improving QOL in individuals with type 2 diabetes (4). Physical activity interventions have been shown to improve glycemic control (7,8). Given that poor glycemic control is a potential mediator between diabetes and QOL (9) changes in hemoglobin A_1c (HbA_1c) occurring as a result of an exercise intervention may lead to improvements in QOL. To date, limited data exist regarding the effects of exercise training on QOL in sedentary adults with type 2 diabetes. Although exercise training interventions generally have shown beneficial effects on QOL in diabetic populations, many of these studies used small sample sizes, short follow-up periods, and self-directed exercise interventions rather than well-verified, supervised exercise interventions (10–13). However, two recently published trials overcame many of these limitations (14,15). Reid et al. (14) performed an analysis of QOL data from the Diabetes Aerobic and Resistance Exercise (DARE) trial, in which 218 individuals were randomized to a 22-week intervention comprising aerobic exercise only, resistance training only, combined training (aerobic and resistance), or no-exercise control condition. The authors found that mental health QOL improvements were greater in the control group compared with the resistance and the combined training groups. In addition, physical QOL improved in the resistance training group compared with the control group. Nicolucci et al. (15) examined QOL from the Italian Diabetes and Exercise Study (IDES) in which 606 individuals received either 150 min/week of supervised, progressive, mixed (aerobic and resistance) training plus exercise counseling versus counseling alone. Their results demonstrated improved QOL with increasing exercise volume.Thus, past studies have provided evidence for a beneficial effect of exercise training interventions on QOL in nonmedically ill and in chronically ill populations; however, the largest trials to date conflict on whether exercise benefits mental health QOL in individuals with type 2 diabetes (14,15). The current study is an ancillary analysis from the Health Benefits of Aerobic and Resistance Training in individuals with type 2 diabetes (HART-D) trial (16). In this study, we attempted to further elucidate QOL outcomes by assessing changes in all QOL subscales measured on the Short-Form 36 Health Survey (SF-36) and compared SF-36 scores to U.S. national norms. Changes in QOL from preintervention to postintervention were compared across the four exercise conditions (aerobic only, resistance only, combined aerobic and resistance, and no-exercise control). We hypothesized that the resistance training group would demonstrate the greatest improvements in physical functioning QOL subscales, and that there would be no beneficial effects of exercise interventions on mental health QOL subscales.     

Web-Based Collaborative Care for Type 2 Diabetes: A pilot randomized trial

OBJECTIVE—To test Web-based care management of glycemic control using a shared electronic medical record with patients who have type 2 diabetes.RESEARCH DESIGN AND METHODS—We conducted a trial of 83 adults with type 2 diabetes randomized to receive usual care plus Web-based care management or usual care alone between August 2002 and May 2004. All patients had GHb ≥7.0%, had Web access from home, and could use a computer with English language–based programs. Intervention patients received 12 months of Web-based care management. The Web-based program included patient access to electronic medical records, secure e-mail with providers, feedback on blood glucose readings, an educational Web site, and an interactive online diary for entering information about exercise, diet, and medication. The primary outcome was change in GHb.RESULTS—GHb levels declined by 0.7% (95% CI 0.2−1.3) on average among intervention patients compared with usual-care patients. Systolic blood pressure, diastolic blood pressure, total cholesterol levels, and use of in-person health care services did not differ between the two groups.CONCLUSIONS—Care management delivered through secure patient Web communications improved glycemic control in type 2 diabetes.Health care limited to clinic visits does not meet the needs of many patients with diabetes. Care systems that use Web-based communication provide an opportunity to shift the focus in health care away from the office and toward patients’ daily lives at home. Patient interaction with online care plans and electronic medical records may further enhance the effectiveness of chronic care (1,2). Little is known, however, about the impact of using Web communications and shared electronic medical records in the primary care of patients with diabetes.We present the results of a randomized trial examining a Web-based diabetes support program that aimed to improve glycemic control for patients with type 2 diabetes. The program consisted of access from home to the electronic medical record, secure electronic communications between patients and providers, and interactive disease management tools. We hypothesized that glycemic control would improve in the group receiving the intervention.     

Glulisine Versus Human Regular Insulin in Combination With Glargine in Noncritically Ill Hospitalized Patients With Type 2 Diabetes: A randomized double-blind study

OBJECTIVE

To compare the efficacy and safety of the rapid-acting insulin analog glulisine and regular insulin in hyperglycemic hospitalized patients.

RESEARCH DESIGN AND METHODS

A total of 180 hospitalized patients with type 2 diabetes received either glulisine (n = 88) or regular insulin (n = 92) before each meal in combination with insulin glargine at bedtime in a randomized double-blind fashion. All previous diabetes medications were discontinued if applicable. Doses of insulin were adjusted to obtain target blood glucose concentrations of <130 mg/dl before meals and at bedtime while avoiding hypoglycemia.

RESULTS

Overall mean blood glucose concentrations were ∼8 mg/dl lower in the glulisine group than in the regular insulin group (152.6 ± 66.6 vs. 160.4 ± 70.8 mg/dl; P < 0.0002). This improvement was wholly due to ∼22 mg/dl lower levels after 4 days of therapy (140 ± 55 vs. 162 ± 71 mg/dl; P < 0.0007); after day 4, this difference progressively increased such that mean blood glucose concentrations from day 7 onward were ∼31 mg/dl lower in the glulisine group. The mean daily incidence of hypoglycemia was slightly but not significantly lower in the glulisine than the regular insulin group (0.10 ± 0.02 vs. 0.14 ± 0.03 episode/day; P > 0.35).

CONCLUSIONS

In hospitalized type 2 diabetic patients, glulisine may provide better glycemic control than regular insulin, especially in those who have a prolonged length of stay.Accumulating evidence suggests that hyperglycemia is associated with an increased risk of complications and mortality in hospitalized patients. In critically ill patients, improved glycemic control reduces short- and long-term mortality, rates of multiorgan failure, systemic infections, and length of hospitalization (1–3). Likewise, in patients admitted to general medical and surgical areas hyperglycemia is associated with a prolonged hospital stay, infection, disability, and death (4–6), suggesting that poor glycemic control is associated with poor clinical outcome.Insulin is the most effective and the most preferred agent for the treatment of hyperglycemia in hospitalized patients (7). However, inpatient insulin therapy is often complicated by variable meal delivery, unpredictable food consumption, and medical conditions, including liver and kidney disease, that predispose to hypoglycemia. Rapid-acting insulin analogs, which have been shown to reduce the risk of hypoglycemia in the outpatient setting (8), may hence be a better choice than regular insulin for the treatment of hyperglycemia in noncritically ill hospitalized patients. The present study was therefore undertaken to compare the efficacy and safety of the rapid-acting insulin analog glulisine and regular insulin in hyperglycemic hospitalized patients.     

Factors Associated With Psychological Insulin Resistance in Individuals With Type 2 Diabetes

OBJECTIVE

To describe the predictive relationships of selected sociodemographic, biomedical, and psychosocial variables to reluctance to use insulin among patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

A total of 178 patients with type 2 diabetes participated in this cross-sectional, observational study. Data were obtained by patient interview using validated measures of diabetes attitude, knowledge, self-efficacy, care communication, and perceived barriers to treatment, as well as sociodemographic and biomedical data.

RESULTS

Women and ethnic minorities with type 2 diabetes have more psychological barriers to insulin treatment (P < 0.05). The final regression model showed that individuals who believed in the value of tight glucose control, had strong self-efficacy, and had better interpersonal processes with their healthcare providers were less reluctant to use insulin treatment (R² = 0.403; P < 0.0001).

CONCLUSIONS

Diabetes self-efficacy and better interaction with clinicians were important in decreasing patients'' reluctance to use insulin, known as psychological insulin resistance.Despite the known benefits of insulin, many patients are reluctant to use insulin therapy (1–3). A patient''s reluctance to initiate insulin may be called “psychological insulin resistance” (PIR).Little is known about what factors influence PIR. We examined the relationships among PIR, sociodemographic, biomedical, and psychosocial factors identified in previous studies (4–7) and tested a predictive model of PIR.     

Effectiveness of nurse-led brief alcohol intervention: a cluster randomized controlled trial

AIM: This paper reports an evaluation of the effectiveness and cost-effectiveness of nurse-led screening and brief intervention in reducing excessive alcohol consumption among patients in primary health care. BACKGROUND: Excessive alcohol consumption is a major source of social, economic and health problems. However, such consumption is responsive to brief alcohol intervention. To date, brief intervention research in primary health care has focused on general practitioner-led interventions, and there is only circumstantial evidence of effectiveness in nurse-led interventions. However, nurses are increasingly taking a lead in health promotion work in primary care. METHODS: A pragmatic cluster-randomized controlled trial was carried out between August 2000 and June 2003 to evaluate the effects of a brief intervention compared with standard advice (control condition). A total of 40 general practice clusters (intervention = 21 and control = 19) recruited 127 patients (intervention = 67 and control = 60) to the trial. Excessive consumption was identified opportunistically via the Alcohol Use Disorders Identification Test. After baseline assessment, patients received either a 5-10 minutes brief intervention using the 'Drink-Less' protocol or standard advice (control condition). Follow-up occurred at 6 and 12 months postintervention. RESULTS: Analysis of variance weighted for cluster size revealed no statistically significant differences between intervention and control patients at follow up. A majority of patients in both conditions reduced their alcohol consumption between assessment and subsequent measurement. Economic analysis suggested that the brief intervention led to no statistically significant changes in subsequent health service resource use relative to standard treatment. CONCLUSION: The brief intervention evaluated in this trial had no effect over standard advice delivered by nurses in primary health care. However, there was a reduction in excessive drinking across both arms of the trial over time. Due to nurse drop-out, this trial was significantly underpowered. Future research should explore barriers to nurses' involvement in research trials, particularly with an alcohol focus. A larger trial is required to evaluate the effectiveness of nurse-led screening and brief alcohol intervention in primary care.     

Feasibility and Effectiveness in Clinical Practice of a Multifactorial Intervention for the Reduction of Cardiovascular Risk in Patients With Type 2 Diabetes: The 2-year interim analysis of the MIND.IT study: a cluster randomized trial

OBJECTIVE

To evaluate the feasibility and effectiveness of an intensive, multifactorial cardiovascular risk reduction intervention in a clinic-based setting.

RESEARCH DESIGN AND METHODS

The study was a pragmatic, cluster randomized trial, with the diabetes clinic as the unit of randomization. Clinics were randomly assigned to either continue their usual care (n = 5) or to apply an intensive intervention aimed at the optimal control of cardiovascular disease (CVD) risk factors and hyperglycemia (n = 4). To account for clustering, mixed model regression techniques were used to compare differences in CVD risk factors and HbA_1c. Analyses were performed both by intent to treat and as treated per protocol.

RESULTS

Nine clinics completed the study; 1,461 patients with type 2 diabetes and no previous cardiovascular events were enrolled. After 2 years, participants in the interventional group had significantly lower BMI, HbA_1c, LDL cholesterol, and triglyceride levels and significantly higher HDL cholesterol level than did the usual care group. The proportion of patients reaching the treatment goals was systematically higher in the interventional clinics (35% vs. 24% for LDL cholesterol, P = 0.1299; 93% vs. 82% for HDL cholesterol, P = 0.0005; 80% vs. 64% for triglycerides, P = 0.0002; 39% vs. 22% for HbA_1c, P = 0.0259; 13% vs. 5% for blood pressure, P = 0.1638). The analysis as treated per protocol confirmed these findings, showing larger and always significant differences between the study arms for all targets.

CONCLUSIONS

A multifactorial intensive intervention in type 2 diabetes is feasible and effective in clinical practice and it is associated with significant and durable improvement in HbA_1c and CVD risk profile.Cardiovascular disease (CVD) is the leading cause of death, hospital admission, and disability among people with type 2 diabetes, and the overall burden is expected to increase further as the result of a worldwide diabetes epidemic (1). The incidence of CVD in people with diabetes is more than twice that observed in nondiabetic people, and the case fatality rate after a first myocardial infarction in people with diabetes is much higher than that in nondiabetic people (2,3). This makes primary prevention of CVD particularly important in people with diabetes. Compelling evidence has accumulated on the effectiveness of optimal blood pressure (BP) management and cholesterol lowering in the reduction of CVD incidence in people with diabetes (4–8). A targeted multifactorial intervention involving glucose control and the correction of multiple CVD risk factors substantially reduces CVD and all-cause mortality in people with type 2 diabetes (9,10). On the basis of this evidence, the disease management approach currently endorsed by international guidelines recommends the correction of all major CVD risk factors to target levels that closely approach values of low-risk populations (11–13). Notwithstanding the efforts to develop and propagate CVD prevention guidelines, the recommended target values for BP and lipids are achieved only in a small proportion of diabetic patients in clinical practice (14–16); in addition glucose control is often less than optimal, and there is evidence that HbA_1c may increase with time irrespective of treatment (17,18). It remains debatable whether the evidence resulting from clinical trials can be translated into actual clinical practice, particularly when an intervention strategy targeting multiple risk factors is involved. Such intervention is, in fact, much more demanding for both the patient and the physician than treating a single factor, and it is therefore particularly difficult to implement. The most commonly mentioned factors in poor implementation of guidelines include organizational factors, inadequate perception of the patient’s global risk, a clinical inertia resulting in inadequate up titration of therapy when the target is not reached, and poor patient adherence to chronic treatments related to polypharmacy (19–21).The Multiple INtervention in type 2 Diabetes.ITaly (MIND.IT) study is a pragmatic, cluster randomized trial (clinicaltrials.gov identifier NCT01240070) that compares the usual clinical practice with a protocol-driven treatment strategy aimed at the optimal correction of hyperglycemia and major CVD risk factors in patients with type 2 diabetes and no previous cardiovascular events. The study aim is to evaluate in a clinical, practice-based setting the feasibility and the efficacy of a multifactorial intervention designed according to guidelines for primary CVD prevention in people with type 2 diabetes. In this article, we present data on the effects of a 2-years intervention on major CVD risk factors and HbA_1c.     

Cost-effectiveness of Insulin Degludec Versus Insulin Glargine in Insulin-naive Chinese Patients With Type 2 Diabetes

Purpose

The goal of this study was to investigate the long-term economic outcomes of insulin degludec versus insulin glargine use in Chinese patients with type 2 diabetes mellitus (T2DM) whose oral antidiabetic drugs did not provide sufficient glycemic control.

Benchmarking Is Associated With Improved Quality of Care in Type 2 Diabetes: The OPTIMISE randomized,controlled trial

OBJECTIVE

To assess prospectively the effect of benchmarking on quality of primary care for patients with type 2 diabetes by using three major modifiable cardiovascular risk factors as critical quality indicators.

RESEARCH DESIGN AND METHODS

Primary care physicians treating patients with type 2 diabetes in six European countries were randomized to give standard care (control group) or standard care with feedback benchmarked against other centers in each country (benchmarking group). In both groups, laboratory tests were performed every 4 months. The primary end point was the percentage of patients achieving preset targets of the critical quality indicators HbA_1c, LDL cholesterol, and systolic blood pressure (SBP) after 12 months of follow-up.

RESULTS

Of 4,027 patients enrolled, 3,996 patients were evaluable and 3,487 completed 12 months of follow-up. Primary end point of HbA_1c target was achieved in the benchmarking group by 58.9 vs. 62.1% in the control group (P = 0.398) after 12 months; 40.0 vs. 30.1% patients met the SBP target (P < 0.001); 54.3 vs. 49.7% met the LDL cholesterol target (P = 0.006). Percentages of patients meeting all three targets increased during the study in both groups, with a statistically significant increase observed in the benchmarking group. The percentage of patients achieving all three targets at month 12 was significantly larger in the benchmarking group than in the control group (12.5 vs. 8.1%; P < 0.001).

CONCLUSIONS

In this prospective, randomized, controlled study, benchmarking was shown to be an effective tool for increasing achievement of critical quality indicators and potentially reducing patient cardiovascular residual risk profile.The prevalence of type 2 diabetes is still rising; the fifth edition of the Diabetes Atlas estimates that there were 366 million people worldwide with diabetes in 2011 (1), an increase from the 285 million cited in the 2010 edition (2). Management of patients with type 2 diabetes is complex because of multiple priorities; its goal is to control not only glycemia but also the other modifiable risk factors for microvascular and macrovascular disease, as well as to prevent and manage the related complications. For effective intervention, treatment needs to be both multifactorial in approach and tailored to the individual patient. Studies have shown that cardiovascular disease risk in type 2 diabetes was reduced by control of key modifiable variables such as HbA_1c as a measure of chronic hyperglycemia (3), blood pressure (BP) (4,5), and LDL cholesterol (6–8). The picture is less clear-cut, however, with respect to the risk-benefit ratio of achieving a HbA_1c target level <7% (53.0 mmol/mol). Indeed, some studies have shown that prevention of macrovascular events did not significantly improve if more stringent HbA_1c targets <6.5% (47.5 mmol/mol) were met (9,10).Despite the availability of extensive guidelines for the treatment of type 2 diabetes, there are gaps in knowledge, attitude, and practice, for both patients and physicians that are proving difficult to close (11). New strategies that have been shown to help patients meet key target goals and improve clinical outcomes are currently being investigated. One of the approaches that may drive improvement in quality of care is benchmarking. Benchmarking in the clinical setting typically includes feedback on the performance of a patient or physician, which is ranked against that of a peer group. Very few randomized, controlled trials of benchmarking for type 2 diabetes in primary care have been reported, and the effectiveness of this approach is as yet undetermined (12–14).The OPTIMISE (OPtimal Type 2 dIabetes Management Including benchmarking and Standard trEatment) study was initiated (15) to assess prospectively in a randomized, controlled trial the effect of benchmarking on the quality of primary care for patients with type 2 diabetes and its impact on achieving preset targets. Baseline results from the OPTIMISE study demonstrated that target achievement for three critical quality indicators of vascular risk was suboptimal in a primary care setting (16). The results of the OPTIMISE study through 12 months of follow-up are presented here.     

Health-Related Quality of Life, Treatment Satisfaction, and Costs Associated With Intraperitoneal Versus Subcutaneous Insulin Administration in Type 1 Diabetes: A randomized controlled trial

OBJECTIVE

To investigate the effects of continuous intraperitoneal insulin infusion (CIPII) compared with subcutaneous insulin on health-related quality of life (HRQOL) and treatment satisfaction, and to perform a cost analysis in type 1 diabetes.

RESEARCH DESIGN AND METHODS

We used an open-label, prospective, crossover, randomized, 16-month study (N = 24). HRQOL and patient satisfaction were assessed with questionnaires (the 36-item short-form health survey [SF-36], the World Health Organization-Five Well-Being Index [WHO-5], and the Diabetes Treatment Satisfaction Questionnaire [DTSQ]). Direct costs of CIPII and continuous subcutaneous insulin infusion (CSII) were compared.

RESULTS

Questionnaire scores were higher with CIPII than with subcutaneous therapy. Yearly direct pump- and procedure-associated costs for CIPII were estimated at €10,910 compared with €4,810 for CSII.

CONCLUSIONS

Apart from improving glycemic control, CIPII improved HRQOL and treatment satisfaction compared with subcutaneous insulin. Direct pump- and procedure-associated costs are considerably higher for CIPII, however.We recently showed that treatment with continuous intraperitoneal insulin infusion (CIPII) compared with subcutaneous insulin results in better glycemic control, expressed as a 0.8%-point decrease in A1C (1). The aim of the current analysis was to assess the effects of CIPII on health-related quality of life (HRQOL) and treatment satisfaction compared with intensified subcutaneous insulin therapy, and to provide up-to-date cost calculations of direct pump- and procedure-associated costs.     

Effects of Combined Ezetimibe and Simvastatin Therapy as Compared With Simvastatin Alone in Patients With Type 2 Diabetes: A prospective randomized double-blind clinical trial

OBJECTIVE

To assess the effects of inhibited gastrointestinal cholesterol absorption in statin-treated dyslipidemic patients.

RESEARCH DESIGN AND METHODS

In a multicenter prospective randomized double-blind placebo-controlled trial, we primarily compared by ANCOVA the effect of 2-month ezetimibe (10 mg/day) or placebo therapy on LDL cholesterol serum levels in 108 type 2 diabetic patients with albuminuria <200 μg/min and total cholesterol concentrations >135 mg/dl despite simvastatin treatment (40 mg/day).

RESULTS

Unlike placebo, ezetimibe decreased LDL cholesterol from 99 ± 31 to 66 ± 22 mg/dl, total cholesterol from 162 ± 36 to 124 ± 30 mg/dl, and apolipoprotein B from 83 ± 22 to 64 ± 18 mg/dl (P < 0.0001 for all changes versus placebo). A total of 72 and 17% of patients on ezetimibe or placebo achieved LDL levels <70 mg/dl, respectively (P < 0.0001). Treatment was well tolerated.

CONCLUSIONS

Adding ezetimibe to simvastatin therapy helps to improve the pro-atherogenic lipoprotein profile in type 2 diabetic patients who fail to reach recommended lipid targets with statin therapy alone.Inhibited gastrointestinal cholesterol absorption by add-on ezetimibe therapy (1) reduced cholesterol levels in patients with persistent dyslipidemia despite statin therapy (1–6). Advantages of dual- versus single-drug lipid-lowering therapy, however, could not be definitely established, since the effects of ezetimibe combined with a given dosage of a statin were compared with those of monotherapy with another competitor statin (4,5) or even with the same statin but given at higher dosages (2). To address this issue, the Ezetimibe and Simvastatin in Dyslipidemia of Diabetes (ESD) study (ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00157482","term_id":"NCT00157482"}}NCT00157482) compared the lipid-lowering effects of ezetimibe or placebo added on the same background statin therapy in type 2 diabetic patients with persistent hypercholesterolemia despite HMG-CoA reductase inhibition.     

Active Care Management Supported by Home Telemonitoring in Veterans With Type 2 Diabetes: The DiaTel randomized controlled trial

OBJECTIVE

We compared the short-term efficacy of home telemonitoring coupled with active medication management by a nurse practitioner with a monthly care coordination telephone call on glycemic control in veterans with type 2 diabetes and entry A1C ≥7.5%.

RESEARCH DESIGN AND METHODS

Veterans who received primary care at the VA Pittsburgh Healthcare System from June 2004 to December 2005, who were taking oral hypoglycemic agents and/or insulin for ≥1 year, and who had A1C ≥7.5% at enrollment were randomly assigned to either active care management with home telemonitoring (ACM+HT group, n = 73) or a monthly care coordination telephone call (CC group, n = 77). Both groups received monthly calls for diabetes education and self-management review. ACM+HT group participants transmitted blood glucose, blood pressure, and weight to a nurse practitioner using the Viterion 100 TeleHealth Monitor; the nurse practitioner adjusted medications for glucose, blood pressure, and lipid control based on established American Diabetes Association targets. Measures were obtained at baseline, 3-month, and 6-month visits.

RESULTS

Baseline characteristics were similar in both groups, with mean A1C of 9.4% (CC group) and 9.6% (ACM+HT group). Compared with the CC group, the ACM+HT group demonstrated significantly larger decreases in A1C at 3 months (1.7 vs. 0.7%) and 6 months (1.7 vs. 0.8%; P < 0.001 for each), with most improvement occurring by 3 months.

CONCLUSIONS

Compared with the CC group, the ACM+HT group demonstrated significantly greater reductions in A1C by 3 and 6 months. However, both interventions improved glycemic control in primary care patients with previously inadequate control.Within the Veterans Health Administration, ∼500,000 veterans receive care for diabetes annually; diabetes is a leading cause of morbidity and mortality and a major contributor to health care cost (1,2). Sampling data from 2009 indicate that ∼28% of veterans nationally have suboptimal glycemic control with A1C ≥8% (3). Increases in A1C levels above the normal range in patients with diabetes are associated with progressive increases in morbidity and mortality due to micro- and macrovascular disease (4). Intensive glycemic control can reduce microvascular complications in both type 1 and type 2 diabetes (5,6). However, recent studies have not demonstrated that intensive glycemic control for 3–6 years with achieved A1C targets from 6.4 to 6.9% reduces macrovascular complications in patients with long-standing type 2 diabetes (7–9). In contrast, intensive glycemic control initiated early in the course of either type 1 or type 2 diabetes appears to reduce the risk of subsequent macrovascular complications significantly even when glycemic control later deteriorates (10,11).Home-based telemedicine has been examined as a tool for management of chronic diseases (12), including diabetes (13–19). This approach can obviate geographic barriers; provide automated education, feedback, and data transmission; and facilitate provider-to-patient communication (12). However, outcomes with home telemonitoring in diabetes and other chronic diseases have been variable (12). Of several randomized controlled trials (RCTs) using home telemonitoring in diabetes care (13–19), only two have reported significant improvement in A1C (17,18). Neither of these trials included active medication management by a provider in response to real-time transmission of self-monitored blood glucose (SMBG) data or have specifically targeted patients not meeting glycemic control goals in response to pharmacological therapy under conditions of usual care.The present study compared the efficacy of home telemonitoring coupled with active medication management by a nurse practitioner (ACM+HT intervention) with a lower-intensity care coordination intervention (CC intervention) consisting of monthly telephone contact with a diabetes nurse educator. Our study specifically targeted veterans with A1C levels ≥8% after ≥1 year receiving pharmacological therapy under conditions of usual care.     

Closed-Loop Basal Insulin Delivery Over 36 Hours in Adolescents With Type 1 Diabetes: Randomized clinical trial

OBJECTIVE

We evaluated the safety and efficacy of closed-loop basal insulin delivery during sleep and after regular meals and unannounced periods of exercise.

RESEARCH DESIGN AND METHODS

Twelve adolescents with type 1 diabetes (five males; mean age 15.0 [SD 1.4] years; HbA_1c 7.9 [0.7]%; BMI 21.4 [2.6] kg/m²) were studied at a clinical research facility on two occasions and received, in random order, either closed-loop basal insulin delivery or conventional pump therapy for 36 h. During closed-loop insulin delivery, pump basal rates were adjusted every 15 min according to a model predictive control algorithm informed by subcutaneous sensor glucose levels. During control visits, subjects’ standard infusion rates were applied. Prandial insulin boluses were given before main meals (50–80 g carbohydrates) but not before snacks (15–30 g carbohydrates). Subjects undertook moderate-intensity exercise, not announced to the algorithm, on a stationary bicycle at a 140 bpm heart rate in the morning (40 min) and afternoon (20 min). Primary outcome was time when plasma glucose was in the target range (71–180 mg/dL).

RESULTS

Closed-loop basal insulin delivery increased percentage time when glucose was in the target range (median 84% [interquartile range 78–88%] vs. 49% [26–79%], P = 0.02) and reduced mean plasma glucose levels (128 [19] vs. 165 [55] mg/dL, P = 0.02). Plasma glucose levels were in the target range 100% of the time on 17 of 24 nights during closed-loop insulin delivery. Hypoglycemia occurred on 10 occasions during control visits and 9 occasions during closed-loop delivery (5 episodes were exercise related, and 4 occurred within 2.5 h of prandial bolus).

CONCLUSIONS

Day-and-night closed-loop basal insulin delivery can improve glucose control in adolescents. However, unannounced moderate-intensity exercise and excessive prandial boluses pose challenges to hypoglycemia-free closed-loop basal insulin delivery.Closed-loop insulin delivery is an emerging technology that may transform management of type 1 diabetes (1). Coupling subcutaneous continuous glucose monitoring (2,3) and insulin pump delivery (4), the closed-loop technology delivers insulin in a continually glucose-responsive fashion to reduce the risk of hypoglycemia and to improve overall glucose control (5,6).This novel approach differs from conventional pump therapy through the use of a control algorithm that directs subcutaneous insulin delivery according to subcutaneous sensor glucose levels (7). Previous randomized studies with an adaptive algorithm controlling basal insulin demonstrated effectiveness of closed loop during sleep (8,9). Application after a standard evening meal and late-afternoon exercise resulted in a 20% improvement in the number of glucose levels overnight within the target range while reducing the risk of nocturnal hypoglycemia in children and adolescents (8). Similar improvements were observed in adults after a standard dinner and a large evening meal accompanied by alcohol (9). Feasibility of closed-loop control has also been explored in pregnancy (10,11). The future challenge is to determine whether closed-loop insulin delivery can maintain glycemic control after meals, physical exercise, and snacks, where to date, published studies have been encouraging but have lacked a conventional therapy comparator (12,13).Meals and physical activity cause rapid fluctuations in blood glucose levels, which challenge the closed-loop approach because of delays associated with the subcutaneous route of insulin delivery and glucose sensing errors. We addressed this question by evaluating closed-loop basal insulin delivery systems with proven efficacy overnight during a 36-h period that comprised waking hours and common daily activities, including a typical school day, and behaviors of adolescents.     

Postprandial Vascular Effects of VIAject Compared With Insulin Lispro and Regular Human Insulin in Patients With Type 2 Diabetes

OBJECTIVE

Recent studies suggested an impact of prandial insulin delivery on postprandial regulation of tissue blood flow. This study compared the effect of VIAject with human regular insulin and insulin lispro on postprandial oxidative stress and endothelial function in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Fourteen patients (seven men; aged 61.5 ± 1.8 years; duration of diabetes 6.6 ± 4.6 years; A1C 7.2 ± 0.5% [mean ± SEM]) received a prandial injection of VIAject, human regular insulin, and insulin lispro. At baseline and after a standardized liquid meal test (Ensure Plus), the postprandial increases in asymmetric dimethylarginine (ADMA) and nitrotyrosine levels were investigated. In addition, the postprandial effects on microvascular blood flow, skin oxygenation, and vascular elasticity were measured.

RESULTS

Treatment with VIAject resulted in a significant reduction in the peak postprandial generation of ADMA compared with human insulin and insulin lispro (VIAject −27.3 ± 22.6, human insulin 97.7 ± 24.4, and insulin lispro 66.9 ± 33.9 nmol/l; P < 0.05, respectively). The postprandial increases in nitrotyrosine levels were significantly less after VIAject than after human regular insulin (VIAject −0.22 ± 0.17 vs. human insulin 0.25 ± 0.15 μg/ml; P < 0.05), whereas nitrotyrosine after insulin lispro was in between (insulin lispro 0.09 ± 0.07 μg/ml; NS). In parallel, earlier and more pronounced increases in microvascular blood flow and skin oxygenation were obtained after VIAject compared with those after human insulin or insulin lispro (P < 0.05, respectively). All insulin formulations resulted in comparable improvements in central arterial elasticity.

CONCLUSIONS

Treatment with VIAject reduced postprandial oxidative stress and improved endothelial function compared with human regular insulin or insulin lispro.Type 2 diabetes is closely related to atherosclerosis and the development of cardiovascular complications such as myocardial infarction or stroke. Recent studies on cardiovascular end points in patients with type 2 diabetes call into question the value of A1C-focused treatments in reducing macrovascular complications of diabetes (1–3). Other markers such as glucose excursions, hypoglycemia, or postprandial generation of oxidative stress may add important information for the judgment of cardiovascular risk in patients with type 2 diabetes (1,2). Postprandial microvascular blood flow is under dynamic regulation and is diversely affected by changes in postprandial glucose and insulin levels (4). Increasing postprandial insulin levels stimulate microvascular blood flow by inducing the endothelial release of nitric oxide via the activation of the phosphatidylinositol 3-kinase system (5,6). In contrast, increasing blood glucose levels were shown to oppose the insulin effects on endothelial cells and to impair postprandial microvascular blood flow (7). A reduced first-phase insulin release with an augmented increase in postprandial glucose levels followed by an impairment in endothelial function and postprandial microvascular blood flow is an early feature of type 2 diabetes (4,8). These findings suggest that a physiological timing of prandial insulin release fulfills an important role not only in controlling postprandial blood glucose levels but also in maintaining normal tissue perfusion and nutrition. In addition, recent studies have shown that in insulin-treated patients with type 1 and type 2 diabetes, the pharmacokinetic profile of insulin formulations affects postprandial microvascular blood flow and that treatment with fast-acting insulin analogs reduces postprandial oxidative stress and restores endothelial function more effectively than treatment with human regular insulin (9–11).VIAject is a new, ultra–fast-acting insulin formulation shown to have more rapid insulin absorption than that for human regular insulin and insulin lispro. The aim of this study was to compare the effect of preprandial subcutaneous administration of insulin VIAject with preprandial application of human regular insulin and insulin lispro on several markers of endothelial and microvascular function after a standardized liquid meal test in patients with type 2 diabetes.     

Insulin Analogs Versus Human Insulin in the Treatment of Patients With Diabetic Ketoacidosis: A randomized controlled trial

OBJECTIVE

To compare the safety and efficacy of insulin analogs and human insulins both during acute intravenous treatment and during the transition to subcutaneous insulin in patients with diabetic ketoacidosis (DKA).

RESEARCH DESIGN AND METHODS

In a controlled multicenter and open-label trial, we randomly assigned patients with DKA to receive intravenous treatment with regular or glulisine insulin until resolution of DKA. After resolution of ketoacidosis, patients treated with intravenous regular insulin were transitioned to subcutaneous NPH and regular insulin twice daily (n = 34). Patients treated with intravenous glulisine insulin were transitioned to subcutaneous glargine once daily and glulisine before meals (n = 34).

RESULTS

There were no differences in the mean duration of treatment or in the amount of insulin infusion until resolution of DKA between intravenous treatment with regular and glulisine insulin. After transition to subcutaneous insulin, there were no differences in mean daily blood glucose levels, but patients treated with NPH and regular insulin had a higher rate of hypoglycemia (blood glucose <70 mg/dl). Fourteen patients (41%) treated with NPH and regular insulin had 26 episodes of hypoglycemia and 5 patients (15%) in the glargine and glulisine group had 8 episodes of hypoglycemia (P = 0.03).

CONCLUSIONS

Regular and glulisine insulin are equally effective during the acute treatment of DKA. A transition to subcutaneous glargine and glulisine after resolution of DKA resulted in similar glycemic control but in a lower rate of hypoglycemia than with NPH and regular insulin. Thus, a basal bolus regimen with glargine and glulisine is safer and should be preferred over NPH and regular insulin after the resolution of DKA.Diabetic ketoacidosis (DKA) is the most serious hyperglycemic emergency in patients with type 1 and type 2 diabetes. DKA is the most common cause of death in children and adolescents with type 1 diabetes and accounts for half of all deaths in diabetic patients aged <24 years (1). Recent series in adult patients with DKA have reported a mortality rate of <5% (2,3). DKA is responsible for >100,000 hospital admissions in the U.S. and substantial spending related to direct and indirect costs (2). It has been estimated that treatment of DKA episodes represent more than one of every four health care dollars spent on direct medical care for adult patients with type 1 diabetes (4).The mainstay in the treatment of DKA involves the administration of regular insulin via continuous intravenous infusion or by frequent subcutaneous or intramuscular injections of regular insulin or rapid-acting insulin analogs (5–7). Although several controlled studies have shown that low-dose insulin therapy is effective regardless of the route of administration, most patients are treated with intravenous regular insulin until resolution of DKA (8). When this occurs, subcutaneous insulin therapy can be started. The American Diabetes Association recommends the transition to NPH and regular insulin twice daily or to a multidose regimen of short- or rapid-acting and intermediate- or long-acting insulins (2,8). Several studies have reported hospital rates of hypoglycemic events up to 37% with the use of NPH and regular insulin after discontinuation of intravenous insulin (3,9). The inadequate duration of action of NPH insulin and an undesirable peak activity at 4–6 h after injection (10) as well as the high day-to-day variability in absorption (11) partially explains the high rate of hypoglycemic events. In recent years, the use of long-acting basal and rapid-acting insulin analogs has been recommended as a more physiological approach than NPH and regular insulin for glucose control in the hospital (12,13); however, no previous studies have evaluated the safety and efficacy of insulin analogs in the management of patients with hyperglycemic crises. Accordingly, the aim of this multicenter, randomized, open-label study was 1) to determine differences in treatment response between regular insulin and rapid-acting insulin analogs during the acute intravenous treatment of DKA and 2) to determine differences between treatment with glargine plus glulisine and a split-mixed regimen of NPH plus regular insulin after the transition to subcutaneous insulin following resolution of DKA.     

Better Glycemic Control and Weight Loss With the Novel Long-Acting Basal Insulin LY2605541 Compared With Insulin Glargine in Type 1 Diabetes: A randomized,crossover study

OBJECTIVE

To compare effects of LY2605541 versus insulin glargine on daily mean blood glucose as part of a basal-bolus regimen for type 1 diabetes.

RESEARCH DESIGN AND METHODS

In this randomized, Phase 2, open-label, 2 × 2 crossover study, 137 patients received once-daily basal insulin (LY2605541 or glargine) plus mealtime insulin for 8 weeks, followed by crossover treatment for 8 weeks. Daily mean blood glucose was obtained from 8-point self-monitored blood glucose profiles. The noninferiority margin was 10.8 mg/dL.

RESULTS

LY2605541 met noninferiority and superiority criteria compared with insulin glargine in daily mean blood glucose (144.2 vs. 151.7 mg/dL, least squares mean difference = −9.9 mg/dL [90% CI −14.6 to −5.2], P < 0.001). Fasting blood glucose variability and A1C were reduced with LY2605541 compared with insulin glargine (both P < 0.001). Mealtime insulin dose decreased with LY2605541 and increased with insulin glargine. Mean weight decreased 1.2 kg with LY2605541 and increased 0.7 kg with insulin glargine (P < 0.001). The total hypoglycemia rate was higher for LY2605541 (P = 0.04) and the nocturnal hypoglycemia rate was lower (P = 0.01), compared with insulin glargine. Adverse events (including severe hypoglycemia) were similar, although more gastrointestinal-related events occurred with LY2605541 (15% vs. 4%, P < 0.001). Mean changes (all within normal range) were higher for alanine aminotransferase, aspartate aminotransferase, triglycerides, and LDL-cholesterol and lower for HDL-cholesterol with LY2605541 compared with insulin glargine (all P < 0.02).

CONCLUSIONS

In type 1 diabetes, compared with insulin glargine, LY2605541, a novel, long-acting basal insulin, demonstrated greater improvements in glycemic control, increased total hypoglycemia, and reduced nocturnal hypoglycemia, as well as reduced weight and lowered mealtime insulin doses.The quest to prolong the action of insulin, which led to modern basal insulins, began in the 1930s with development of protamine zinc insulin (1,2). Basal insulins, such as protamine zinc, lente, isophane (NPH insulin), and ultralente insulins, were originally developed as suspensions to prolong action by delaying absorption (3,4). More recently, insulins glargine (GL) and detemir were developed to prolong subcutaneous absorption by altering amino acid structure (GL) or adding fatty acylated side chains (detemir) (4,5). Insulin degludec, a basal insulin in development, has the goal to achieve an effect longer than 24 h by prolonging subcutaneous absorption (6). Longer-acting insulins may be expected to reduce the need for twice-daily injections, variability, and the risk of hypoglycemia, as well as to provide minimal peak activity. Despite these refinements, current basal insulins cannot restore physiologic distribution of the twofold portal to systemic insulinemia because of subcutaneous systemic absorption, which results in similar portal and systemic levels. Thus, reduced hepatic insulin action must be balanced with excess peripheral insulin action to maintain glucose homeostasis.LY2605541 is a novel, long-acting basal insulin consisting of insulin lispro covalently modified with a 20-kDa polyethylene glycol moiety. It is a solution-based basal insulin with a time-action profile that is believed to be modulated indirectly through slowed depot absorption and reduced clearance due to increased molecular size. LY2605541 has a duration of action of more than 36 h with low variability, acting considerably longer than insulin glargine (7).This exploratory Phase 2 clinical trial was designed to determine if LY2605541 was noninferior to insulin GL for reduction of daily mean blood glucose (BG) in patients with type 1 diabetes on a basal-bolus regimen and to compare safety and efficacy of LY2605541 and insulin GL.     

A Study of Dapagliflozin in Patients With Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin Sensitizers: Applicability of a novel insulin-independent treatment

OBJECTIVE

To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs).

RESEARCH DESIGN AND METHODS

This was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort (n = 4), patients in the treatment cohort (n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]).

RESULTS

At week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated −0.70 and −0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C ≥0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and −9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were −1.9, −4.5, and −4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group.

CONCLUSIONS

In patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo.Treatment of hyperglycemia in patients with type 2 diabetes remains a challenge, particularly in those who require insulin as the disease progresses (1,2). Various combinations of insulin with oral antidiabetic agents (OADs) have been investigated (2–8). Often, these combination therapies become less effective in controlling hyperglycemia over time, particularly as a result of weight gain and worsening insulin resistance as well as progressive failure of insulin secretion.Hypoglycemia, weight gain, and subsequent increased insulin resistance are significant factors that limit optimal titration and effectiveness of insulin (2). Weight gain with insulin therapy, used alone or with OADs (7–9), is in part a consequence of reducing glucosuria (10,11). Among commonly used OADs, thiazolidinediones (TZDs) and sulfonylureas intrinsically contribute to weight gain, whereas metformin causes weight loss and dipeptidyl peptidase-4 inhibitors are weight neutral. Overall, there is a need for novel agents that can be safely administered to help achieve glycemic targets without increasing the risks of weight gain or hypoglycemia.A novel approach to treating hyperglycemia targets receptors for renal glucose reabsorption (12). Agents that selectively block sodium-glucose cotransporter 2 (SGLT2), located in the proximal tubule of the kidney, inhibit glucose reabsorption and induce its elimination through urinary excretion (13). Preclinical models have shown that SGLT2 inhibition lowers blood glucose independently of insulin (14–17). Dapagliflozin, a highly selective inhibitor of SGLT2, has demonstrated efficacy, alone or in combination with metformin, in reducing hyperglycemia in patients with type 2 diabetes (18,19) but has not been tested in patients requiring insulin. This study was designed to determine whether dapagliflozin is effective in lowering blood glucose in patients with type 2 diabetes who have not responded adequately to insulin combined with oral therapies that act through insulin-dependent mechanisms.