Efficacy and Safety of Switching From the DPP-4 Inhibitor Sitagliptin to the Human GLP-1 Analog Liraglutide After 52 Weeks in Metformin-Treated Patients With Type 2 Diabetes: A randomized, open-label trial

OBJECTIVE To assess the efficacy and safety of switching from sitagliptin to liraglutide in metformin-treated adults with type 2 diabetes. RESEARCH DESIGN AND METHODS In an open-label trial, participants randomized to receive either liraglutide (1.2 or 1.8 mg/day) or sitagliptin (100 mg/day), each added to metformin, continued treatment for 52 weeks. In a 26-week extension, sitagliptin-treated participants were randomly allocated to receive instead liraglutide at either 1.2 or 1.8 mg/day, while participants originally randomized to receive liraglutide continued unchanged. RESULTS Although 52 weeks of sitagliptin changed glycosylated hemoglobin (HbA(1c)) by -0.9% from baseline, additional decreases occurred after switching to liraglutide (1.2 mg/day, -0.2%, P = 0.006; 1.8 mg/day, -0.5%, P = 0.0001). Conversion to liraglutide was associated with reductions in fasting plasma glucose (FPG) (1.2 mg/day, -0.8 mmol/L, P = 0.0004; 1.8 mg/day, -1.4 mmol/L, P < 0.0001) and body weight (1.2 mg/day, -1.6 kg; 1.8 mg/day, -2.5 kg; both P < 0.0001) and with an increased proportion of patients reaching HbA(1c) <7% (from ～30% to ～50%). Overall treatment satisfaction, assessed by the Diabetes Treatment Satisfaction Questionnaire, improved after switching to liraglutide (pooled 1.2 and 1.8 mg/day, 1.3; P = 0.0189). After switching, mostly transient nausea occurred in 21% of participants, and minor hypoglycemia remained low (3-4% of participants). Continuing liraglutide treatment at 1.2 mg/day and 1.8 mg/day for 78 weeks reduced HbA(1c) (baseline 8.3 and 8.4%, respectively) by -0.9 and -1.3%, respectively; FPG by -1.3 and -1.7 mmol/L, respectively; and weight by -2.6 and -3.1 kg, respectively, with 9-10% of participants reporting minor hypoglycemia. CONCLUSIONS Glycemic control, weight, and treatment satisfaction improved after switching from sitagliptin to liraglutide, albeit with a transient increase in gastrointestinal reactions.     

The Efficacy and Safety of Imeglimin as Add-on Therapy in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy

OBJECTIVE

A 12-week study assessed the efficacy and safety of a new oral antidiabetic agent, imeglimin, as add-on therapy in type 2 diabetes patients inadequately controlled with metformin alone.

RESEARCH DESIGN AND METHODS

A total of 156 patients were randomized 1:1 to receive imeglimin (1,500 mg twice a day) or placebo added to a stable dose of metformin (1,500–2,000 mg/day). Change in A1C from baseline was the primary efficacy outcome; secondary outcomes included fasting plasma glucose (FPG) and proinsulin/insulin ratio.

RESULTS

After 12 weeks, the placebo-subtracted decrease in A1C with metformin-imeglimin was −0.44% (P < 0.001). Metformin-imeglimin also significantly improved FPG and the proinsulin/insulin ratio from baseline (−0.91 mg/dL and −7.5, respectively) compared with metformin-placebo (0.36 mg/dL and 11.81). Metformin-imeglimin therapy was generally well-tolerated with a comparable safety profile to metformin-placebo.

CONCLUSIONS

Addition of imeglimin to metformin improved glycemic control and offers potential as a new treatment for type 2 diabetes.Imeglimin is the first in a new tetrahydrotriazine-containing class of oral antidiabetic agents, the glimins. Imeglimin decreases hepatic glucose production, increases muscle glucose uptake, and improves pancreatic glucose-dependent insulin secretion (1).Previous studies have demonstrated imeglimin to be as effective as metformin in improving glycemia (2). Since metformin is the preferred first-line therapy for type 2 diabetes, the current study examined the efficacy, safety, and tolerability of imeglimin in combination with metformin in patients with type 2 diabetes inadequately controlled with metformin alone.     

Canagliflozin Compared With Sitagliptin for Patients With Type 2 Diabetes Who Do Not Have Adequate Glycemic Control With Metformin Plus Sulfonylurea: A 52-week randomized trial

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.Patients with type 2 diabetes often require combinations of antihyperglycemic agents (AHAs) to maintain glycemic control because of the progressive nature of the disease (1,2). Metformin is the recommended first-line pharmacologic therapy for type 2 diabetes (1,2). For patients who do not achieve or sustain sufficient glycemic control with metformin, a second AHA is often added (2). With further decline in glycemic control (3,4), the addition of a third oral agent is increasingly common. Currently available classes of AHAs, such as dipeptidyl peptidase-4 inhibitors, peroxisome proliferator–activated receptor (PPAR)γ agonists, and sulfonylureas, have distinct risk/benefit profiles (2,5). A recent position statement by the American Diabetes Association and the European Association for the Study of Diabetes recommends individualization of treatment for patients and suggests the use of pharmacologic agents with complementary mechanisms of action in triple therapy combinations if A1C targets are not attained with dual combination therapy (2).Canagliflozin is an inhibitor of the sodium glucose cotransporter 2 (SGLT2) in development for the treatment of patients with type 2 diabetes (6–10). SGLT2 is responsible for the majority of glucose reabsorption in the kidney (11). Almost all glucose is reabsorbed from the tubules until renal tubular resorptive capacity is exceeded and urinary glucose excretion (UGE) ensues; the glucose concentration at which this occurs is referred to as the renal threshold for glucose. Canagliflozin lowers the renal threshold for glucose, markedly increasing UGE and thereby reducing blood glucose concentrations in patients with hyperglycemia. The increase in UGE results in a mild osmotic diuresis and also provides a net caloric loss (with most patients with type 2 diabetes losing an average of 80–120 g/day) (12). This mechanism of action, distinct from the mechanisms of glucose-lowering of current AHA classes and independent of insulin, should provide additive glycemic control across stages of type 2 diabetes and range of classes, including add-on to the combination of metformin and a sulfonylurea agent. This 52-week Canagliflozin Treatment and Trial Analysis–dipeptidyl peptidase-4 inhibitor (CANTATA-D2; second comparator trial) study evaluated the efficacy and safety of canagliflozin 300 mg compared with sitagliptin 100 mg as add-on therapy in subjects with type 2 diabetes inadequately controlled with metformin plus a sulfonylurea agent.     

The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone

OBJECTIVE

This 24-week trial assessed the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes with inadequate glycemic control with metformin alone.

RESEARCH DESIGN AND METHODS

This was a randomized, double-blind, placebo-controlled study of saxagliptin (2.5, 5, or 10 mg once daily) or placebo plus a stable dose of metformin (1,500–2,500 mg) in 743 patients (A1C ≥7.0 and ≤10.0%). Efficacy analyses were performed using an ANCOVA model using last observation carried forward methodology on primary (A1C) and secondary (fasting plasma glucose [FPG] and postprandial glucose [PPG] area under the curve [AUC]) end points.

RESULTS

Saxagliptin (2.5, 5, and 10 mg) plus metformin demonstrated statistically significant adjusted mean decreases from baseline to week 24 versus placebo in A1C (−0.59, −0.69, and −0.58 vs. +0.13%; all P < 0.0001), FPG (−14.31, −22.03, and −20.50 vs. +1.24 mg/dl; all P < 0.0001), and PPG AUC (−8,891, −9,586, and −8,137 vs. −3,291 mg · min/dl; all P < 0.0001). More than twice as many patients achieved A1C <7.0% with 2.5, 5, and 10 mg saxagliptin versus placebo (37, 44, and 44 vs. 17%; all P < 0.0001). β-Cell function and postprandial C-peptide, insulin, and glucagon AUCs improved in all saxagliptin treatment groups at week 24. Incidence of hypoglycemic adverse events and weight reductions were similar to those with placebo.

CONCLUSIONS

Saxagliptin once daily added to metformin therapy was generally well tolerated and led to statistically significant improvements in glycemic indexes versus placebo added to metformin in patients with type 2 diabetes inadequately controlled with metformin alone.Saxagliptin is a potent, selective dipeptidyl peptidase-4 (DPP-4) inhibitor, specifically designed for extended inhibition of the DPP-4 enzyme (1,2). DPP-4 rapidly cleaves and inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (1). GLP-1 and GIP regulate blood glucose homeostasis by stimulation of glucose-dependent insulin secretion (3). GLP-1 also delays gastric emptying and inhibits glucagon secretion (3,4). In rodents, GLP-1 has been shown to stimulate β-cell growth and differentiation and inhibit β-cell apoptosis (5). Such an approach is needed because the majority of patients with type 2 diabetes fail to achieve recommended glycemic targets with existing therapies, owing to safety and tolerability issues and loss of efficacy over time (6).Metformin is the most widely prescribed first-line agent for the management of type 2 diabetes and is standard first-line pharmacotherapy, along with diet and exercise (7). Mechanistically, metformin reduces hepatic glucose production and improves insulin sensitivity (8); however, metformin alone is frequently insufficient to maintain glycemic goals in the face of progressive β-cell failure and increasing insulin resistance (9). Consequently, many patients require multiple oral antihyperglycemic agents (9,10). Metformin works through pathways complementary to saxagliptin, and the combination of saxagliptin with metformin may improve glycemic control (11,12). Studies of other DPP-4 inhibitors in combination with metformin over 24 weeks have demonstrated increased efficacy versus placebo (13–15). The safety and efficacy of saxagliptin monotherapy in treatment-naive patients were established previously in a 12-week study across a dose range of 2.5 to 40 mg/day. Significant A1C reductions were demonstrated in all active treatment groups with maximal A1C efficacy observed with 5 mg saxagliptin. A test for log-linear trend across the treatment groups did not demonstrate a statistically significant dose response after 12 weeks of treatment. The overall frequency of adverse events was comparable across all treatment groups and placebo and did not appear to be dose related (16). The current trial (CV181-014) examined the efficacy and safety of saxagliptin in combination with metformin administered for up to 24 weeks in patients with type 2 diabetes inadequately controlled with metformin alone.     

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.     

Primary Care Management of Patients With Type 2 Diabetes: Overcoming Inertia and Advancing Therapy With the Use of Injectables

Type 2 diabetes (T2D) is a progressive disease caused by insulin resistance and associated progressive β-cell functional decline, as well as multiple other related metabolic and pathophysiologic changes. Left unchecked, T2D increases the risk of long-term microvascular and cardiovascular complications and is associated with excess morbidity and mortality. Despite multiple effective options for reducing hyperglycemia, patients are not optimally managed, largely due to delays in appropriate and timely advancement of therapy. Glucagon-like peptide-1 receptor agonists and basal insulin are recommended by treatment guidelines as effective options for advancing therapy to achieve glycemic control. However, injected therapies often face resistance from patients and clinicians. Glucagon-like peptide-1 receptor agonists are associated with weight loss, low risk of hypoglycemia, and potential beneficial cardiovascular effects. The class is recommended for patients across the spectrum of disease severity and represents an attractive option to add to basal insulin therapy when additional control is needed. Newer second-generation basal insulin analogues offer advantages over first-generation basal insulins in terms of lower hypoglycemia rates and greater flexibility in dosing. Incorporating injectable therapy into patient care in a timely manner has the potential to improve outcomes and must not be overlooked. Primary care clinicians play a significant role in managing patients with T2D, and they must be able to address and overcome patient resistance and their own barriers to advancing therapy if optimal treatment outcomes are to be achieved. The purpose of this expert opinion article was to provide a commentary on the key principle of advancing therapy with injectables to control hyperglycemia.     

外科减重手术与传统方法比较治疗肥胖患者2型糖尿病的Meta分析

目的系统评价外科减重手术与传统方法比较治疗肥胖患者2型糖尿病的疗效。方法计算机检索TheCochraneLibrary（2012年第12期）、PubMed、CNKI、CBM、VIP和WanFangData,查找外科减重手术与传统方法比较治疗肥胖患者2型糖尿病的随机对照试验,检索时限均为建库至2012年5月。由2名研究员根据纳入与排除标准独立筛选文献、提取资料和评价质量后,采用RevMan5．1．2软件进行Meta分析。结果最终纳入3个RCT。共340例患者。Meta分析结果显示：与传统方法相比,外科减重手术能提高肥胖患者2型糖尿病的缓解率,降低糖化血红蛋白水平,减轻肥胖患者体重,且术后并发症较轻。结论当前常用的外科减重手术治疗肥胖患者2型糖尿病的疗效优于传统方法,并发症较轻,值得临床借鉴。受纳入研究质量和数量限制,上述结论尚待进一步研究加以验证。     

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.     

西格列汀与沙格列汀治疗2型糖尿病的疗效对比研究

目的:比较西格列汀与沙格列汀治疗2型糖尿病的疗效。方法:将50例门诊初次确诊为2型糖尿病的患者随机分为西格列汀组和沙格列汀组各25例,分别用西格列汀或沙格列汀治疗12周,观察患者BMI、FPG、2 hPG、HbA1c等指标变化及低血糖发生情况。结果:治疗后两组FPG、2 hPG、HbA1c较治疗前均有明显下降,有统计学意义(P<0.01),BMI较治疗前均有轻度下降,但无统计学意义(P>0.05);两组间BMI、HbA1c、FPG、2 hPG、低血糖发生率等指标相比较无统计学意义(P>0.05)。结论:西格列汀及沙格列汀均能有效地控制2型糖尿病患者的血糖,轻度减轻体重,且低血糖发生率较低,但两者的疗效无明显差别。     

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.     

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.     

Predicting the Glycemic Response to Gastric Bypass Surgery in Patients With Type 2 Diabetes

OBJECTIVE

To find clinically meaningful preoperative predictors of diabetes remission and conversely inadequate glycemic control after gastric bypass surgery. Predicting the improvement in glycemic control in those with type 2 diabetes after bariatric surgery may help in patient selection.

RESEARCH DESIGN AND METHODS

Preoperative details of 154 ethnic Chinese subjects with type 2 diabetes were examined for their influence on glycemic outcomes at 1 year after gastric bypass. Remission was defined as HbA_1c ≤6%. Analysis involved binary logistic regression to identify predictors and provide regression equations and receiver operating characteristic curves to determine clinically useful cutoff values.

RESULTS

Remission was achieved in 107 subjects (69.5%) at 12 months. Diabetes duration <4 years, body mass >35 kg/m², and fasting C-peptide concentration >2.9 ng/mL provided three independent preoperative predictors and three clinically useful cutoffs. The regression equation classification plot derived from continuous data correctly assigned 84% of participants. A combination of two or three of these predictors allows a sensitivity of 82% and specificity of 87% for remission. Duration of diabetes (with different cutoff points) and C-peptide also predicted those cases in which HbA_1c ≤7% was not attained. Percentage weight loss after surgery was also predictive of remission and of less satisfactory outcomes.

CONCLUSIONS

The glycemic response to gastric bypass is related to BMI, duration of diabetes, fasting C-peptide (influenced by insulin resistance and residual β-cell function), and weight loss. These data support and refine previous findings in non-Asian populations. Specific ethnic and procedural regression equations and cutoff points may vary.Surgery is the most effective treatment for clinically severe obesity. Although most patients display a dramatic improvement in type 2 diabetes, not every patient has remission of diabetes after surgery, with some not seeing substantial improvement and many having recurrence at a later date, sometimes in association with weight regain (1–5). Bariatric surgery, now often referred to as “metabolic surgery,” has been recommended as an effective treatment option for type 2 diabetes for those obese patients who do not have satisfactory control with lifestyle change (1). Optimal outcomes of surgical treatment of diabetes will be obtained if the patients best suited to the surgery are selected, but a clinically relevant grading system to categorize and predict outcomes of metabolic surgery is lacking (1). To develop such a grading system, the responses of patients to metabolic surgery need to be carefully observed, and the characteristics of responders that may have predicted their successful outcomes must be identified. Perhaps even more important is the identification of a group that does not respond well to metabolic surgery, so that such patients are not exposed to the unnecessary risk of surgery without expectation of clear benefit.Many preoperative patient factors have been associated with outcomes, including age, diabetes duration, glycemic control (HbA_1c), fasting C-peptide concentration, BMI, ethnicity, and medications used to manage blood glucose, including oral hypoglycemic agents and insulin (6–10). There are a number of weaknesses in many of these studies, and these include insufficient numbers to identify all independent clinically relevant factors, dealing in a univariate manner with a number of factors that are clearly related to one another, use of varying criteria for remission, and failure to record potentially important clinical predictors.The primary aim of this study was to seek, in a clinically meaningful way, the preoperative predictors of diabetes remission (HbA_1c ≤6.0%) at 12 months after gastric bypass surgery in a cohort of ethnic Chinese patients with type 2 diabetes who reside in Taiwan. Secondary aims included the identification of preoperative predictors of HbA_1c ≤7.0% at 12 months, a comparison of the effectiveness of mini gastric bypass (MGB) and Roux-en-Y gastric bypass (RYGB) for weight loss and glycemic control, and examination of the relevance of weight loss after gastric bypass as a predictor of diabetes remission.     

Peripheral Neuropathy in Adolescents and Young Adults With Type 1 and Type 2 Diabetes From the SEARCH for Diabetes in Youth Follow-up Cohort: A pilot study

OBJECTIVE

To estimate the prevalence of and risk factors for diabetic peripheral neuropathy (DPN) in a pilot study among youth participating in the SEARCH for Diabetes in Youth study.

RESEARCH DESIGN AND METHODS

DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI) (examination for foot abnormalities, distal vibration perception, and ankle reflexes). An MNSI exam (MNSIE) score >2 is diagnostic for DPN.

RESULTS

The MNSIE was completed in 399 subjects, including 329 youth with type 1 diabetes (mean age 15.7 ± 4.3 years, duration 6.2 ± 0.9 years) and 70 with type 2 diabetes (mean age 21.6 ± 4.1 years, duration 7.6 ± 1.8 years). Glycated hemoglobin (A1C) was similar in both groups (8.8 ± 1.8% for type 1 vs. 8.5 ± 2.9% for type 2). The prevalence of DPN was significantly higher in youth with type 2 compared with those with type 1 diabetes (25.7 vs. 8.2%; P < 0.0001). In unadjusted analyses, diabetes type, older age, longer duration of diabetes, increased waist circumference, elevated blood pressure, lower HDL cholesterol, and presence of microalbuminuria (urinary albumin-to-creatinine ratio >30 mg/g) were associated with DPN. The association between diabetes type and DPN remained significant after adjustment for age and sex (odds ratio 2.29 [95% CI 1.05–5.02], P = 0.03).

CONCLUSIONS

DPN prevalence among youth with type 2 diabetes approached rates reported in adult populations with diabetes. Our findings suggest not only that youth with diabetes are at risk for DPN but also that many already show measurable signs of DPN.The incidence of both type 1 and type 2 diabetes in youth is increasing worldwide (1,2). Recent reports have projected that, if this trend continues, the prevalence of diabetes among the young in the U.S. could triple by the year 2050 (3). This could incur a significant burden on health care costs and on society, especially as these young people enter their peak working and earning capacity at the time when diabetes complications begin to occur. Diabetic peripheral neuropathy (DPN) is among the most distressing of all the chronic complications of diabetes and is a cause of significant disability and poor quality of life (4). Depending on the patient population and diagnostic criteria, the prevalence of DPN among adults with diabetes ranges from 30 to 70% (5–7). However, there are insufficient data on the prevalence and predictors of DPN among the pediatric population. Furthermore, early detection and good glycemic control have been proven to prevent or delay adverse outcomes associated with DPN (5,8,9). Near-normal control of blood glucose beginning as soon as possible after the onset of diabetes may delay the development of clinically significant nerve impairment (8,9). Therefore, children and adolescents with diabetes represent a critical target for primary prevention of this complication.The American Diabetes Association (ADA) recommends screening for DPN in children and adolescents with type 2 diabetes at diagnosis and 5 years after diagnosis for those with type 1 diabetes, followed by annual evaluations thereafter, using simple clinical tests (10). Since subclinical signs of DPN may precede development of frank neuropathic symptoms, systematic, preemptive screening is required in order to identify DPN in its earliest stages.There are various measures that can be used for the assessment of DPN. The Michigan Neuropathy Screening Instrument (MNSI) is a simple, sensitive, and specific tool for the screening of DPN (11). It was validated in large independent cohorts (12,13) and has been widely used in clinical trials and longitudinal cohort studies including the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) (13).The aim of this pilot study was to provide preliminary estimates of the prevalence of and factors associated with DPN among children and adolescents with type 1 and type 2 diabetes.     

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.     

Efficacy and Safety of PCSK9 Monoclonal Antibodies in Patients With Diabetes

PurposeProprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that have proven efficacy in improving cardiovascular outcomes. Roles for the PCSK9 molecule in metabolic pathways beyond LDL receptor processing and cholesterol homeostasis are well established. PCSK9 genetic variants associated with lower LDL-C levels correlate with a higher incidence of type 2 diabetes (T2DM), calling into question the appropriateness of these drugs in patients with T2DM and those at high risk of developing diabetes, and whether cardiovascular benefit seen with PCSK9 inhibitors might be offset by resultant dysglycemia. The purpose of this review was to examine the role of PCSK9 protein in glucose homeostasis, the impact of PCSK9 inhibition in relation to glucose homeostasis, and whether some of the cardiovascular benefit seen with PCSK9 inhibitors and statins might be offset by resultant dysglycemia.MethodsComprehensive literature searches of electronic databases of PubMed, EMBASE, and OVID were conducted by using the search terms hyperlipidaemia, PCSK9, diabetes, and glucose as well as other relevant papers of interest collected by the authors. The retrieved papers were reviewed and shortlisted most relevant ones.FindingsGenetically determined lower circulating LDL-C and PCSK9 concentrations may have an incremental effect in increasing T2DM incidence, but any perceived harm is outweighed by the reduced risk of atherosclerotic cardiovascular disease achieved through lower lifetime exposure to LDL-C. PCSK9 monoclonal antibodies are effective and safe in patients with T2DM and those at high risk of developing it. The number-needed-to-treat to prevent one atherosclerotic cardiovascular disease event in the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) study in the subgroup with diabetes is significantly lower than for those without. Therefore, T2DM or being at high risk to develop it should not be a reason to avoid these agents. The safety of PCSK9 inhibition in relation to glucose homeostasis may depend on the method of inhibition and whether it occurs in circulation or the cells. Data from experimental studies and randomized controlled trials suggest no detrimental effect of PCSK9 monoclonal antibodies on glucose homeostasis. More data and large randomized controlled studies are needed to assess the impact of other methods of PCSK9 inhibition on glucose homeostasis.ImplicationsPCSK9monoclonal antibodies markedly reduce LDL-C and consistently reduce cardiovascular mortality in patients with and without diabetes. Current evidence does not suggest an adverse effect of PCSK9 monoclonal antibodies on glycemic parameters.