George Dailey

The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study

Objectives To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A1C) achieved during therapy. Design Post hoc epidemiological analysis of a double 2×2 factorial, randomised, controlled trial. Setting Diabetes clinics, research clinics, and primary care clinics. Participants 10 209 of the 10 251 participants enrolled in the ACCORD study with type 2 diabetes, a haemoglobin A1C concentration of 7.5% or more during screening, and aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or two or more additional risk factors for cardiovascular disease (dyslipidaemia, hypertension, current smoker, or obese). Interventions Intensive (haemoglobin A1C <6.0%) or standard (haemoglobin A1C 7.0-7.9%) glucose control. Main outcome measures Severe hypoglycaemia was defined as episodes of “low blood glucose” requiring the assistance of another person and documentation of either a plasma glucose less than 2.8 mmol/l (<50 mg/dl) or symptoms that promptly resolved with oral carbohydrate, intravenous glucose, or glucagon. Results The annual incidence of hypoglycaemia was 3.14% in the intensive treatment group and 1.03% in the standard glycaemia group. We found significantly increased risks for hypoglycaemia among women (P=0.0300), African-Americans (P<0.0001 compared with non-Hispanic whites), those with less than a high school education (P<0.0500 compared with college graduates), aged participants (P<0.0001 per 1 year increase), and those who used insulin at trial entry (P<0.0001). For every 1% unit decline in the haemoglobin A1C concentration from baseline to 4 month visit, there was a 28% (95% CI 19% to 37%) and 14% (4% to 23%) reduced risk of hypoglycaemia requiring medical assistance in the standard and intensive groups, respectively. In both treatment groups, the risk of hypoglycaemia requiring medical assistance increased with each 1% unit increment in the average updated haemoglobin A1C concentration (standard arm: hazard ratio 1.76, 95% CI 1.50 to 2.06; intensive arm: hazard ratio 1.15, 95% CI 1.02 to 1.21). Conclusions A greater drop in haemoglobin A1C concentration from baseline to the 4 month visit was not associated with an increased risk for hypoglycaemia. Patients with poorer glycaemic control had a greater risk of hypoglycaemia, irrespective of treatment group. Identification of baseline subgroups with increased risk for severe hypoglycaemia can provide guidance to clinicians attempting to modify patient therapy on the basis of individual risk. Trial registration ClinicalTrials.gov number NCT00000620.

Gastrointestinal tolerability of extended-release metformin tablets compared to immediate- release metformin tablets: results of a retrospective cohort study

SUMMARY Objective: Metformin, a biguanide antihyperglycemic medication, lowers blood glucose in patients with type 2 diabetes with minimal risk of hypoglycemia. Most common side effects include diarrhea, nausea and vomiting. Extended-release metformin (Glucophage XR)*, a once-daily tablet using the patented GelShield Diffusion System release mechanism, may be better tolerated than immediate-release metformin (Glucophage). This retrospective chart review examined the overall gastrointestinal (GI) tolerability of both formulations. Research design and methods: Patient charts were reviewed and data were collected from October 2001 to May 2002. Adult patients with type 2 diabetes started on extended-release metformin (metformin-XR) or switched from immediate-release metformin to metformin-XR within the previous 2 years were eligible for inclusion in the metformin-XR cohort. Patients started on immediate-release metformin within the previous 2 years were eligible for inclusion in the immediate-release metformin cohort. Previous experience of GI side effects while taking immediate-release metformin did not prevent inclusion in either cohort, though patients with significant underlying GI disease or moderate to severe hepatic or renal impairment were excluded. GI tolerability was assessed during the first year of treatment with immediate-release metformin or metformin-XR. Primary endpoints were overall GI tolerability and frequency of diarrhea during the first year of treatment. Results: A total of 471 patients’ charts were reviewed and data were collected from four diabetes clinics; 310 (metformin-XR) and 158 (immediate-release metformin) eligible patients were included. Patients were, on average, 56 years old, and overweight (mean body mass index 33 kg/m2). The majority of patients were Caucasian (50%), Hispanic (24%) or Black (19%). Mean daily doses were 1258 mg (range 500–2500 mg) for metformin-XR and 1282 mg (range 500–2550 mg) for immediate-release metformin. About 25% of the metformin-XR cohort had been switched from immediate-release metformin due to a history of GI adverse events (AE). Despite this, the frequency of any GI AE was similar between metformin-XR and immediate-release metformin (11.94 vs. 11.39%, p = 0.86). The incidence of individual GI AE also did not differ significantly between cohorts. In a cohort of 205 patients started on immediate-release metformin and switched to metformin-XR, the frequency of any GI AE was 26.34% (while taking immediate-release metformin; n = 205) vs. 11.71% (after switching to metformin-XR; n = 205) ( p = 0.0006) and the frequency of diarrhea was 18.05% (while taking immediate-release metformin) vs. 8.29% (after switching to metformin-XR) ( p = 0.0084). Conclusions: In this retrospective chart review, patients switched from immediate-release metformin to metformin-XR experienced fewer GI side effects on comparable doses of the extended-release metformin.

Repaglinide in Type 2 Diabetes: A 24-Week, Fixed-Dose Efficacy and Safety Study

In this 24‐week multicenter, double‐blind, randomized, fixed‐dose trial, 361 patients having type 2 diabetes recieved daily preprandial treatment with placebo (n = 75), repaglinide 1 mg (n = 140), or repaglinide 4 mg (n = 146). By a last‐observation carried‐forward calculation, repaglinide 1 mg or 4 mg treatment decreased mean fasting plasma glucose (FPG) values (by −47 mg/dL or −49 mg/dL) while the placebo group had increased FPG values (by 19 mg/dL). For the repaglinide treatment groups at the end of the study, changes in HbA1c from baseline values ranged from 1.8 to 1.9 percentage points lower than the placebo group. There were no events of severe hypoglycemia. Nearly all hypoglycemic symptom episodes had blood glucose levels above 45 mg/dL. Repaglinide was well tolerated in a preprandial fixed‐dose regimen of 1 mg or 4 mg, assigned without adjustment for clinical parameters.

Consensus Report: The Current Role of Self-Monitoring of Blood Glucose in Non-Insulin-Treated Type 2 Diabetes

The Coalition for Clinical Research—Self-Monitoring of Blood Glucose Scientific Board convened a meeting in San Francisco, CA, July 20–21, 2011, to discuss the current practice of self-monitoring of blood glucose (SMBG) in non-insulin-treated (NIT) type 2 diabetes mellitus (T2DM). Twelve physician panel members from academia, practice, and government attended this meeting. These experts came from the United States, Brazil, Canada, France, Germany, Italy, and the United Kingdom. In addition, three consultants from Australia, Germany, and the United States contributed to the groups final report. This coalition was organized by Diabetes Technology Society. Self-monitoring of blood glucose was studied from eight perspectives related to patients with NIT T2DM: (1) epidemiological studies; (2) randomized controlled trials (RCT)s and meta-analyses; (3) targets, timing, and frequency of SMBG use; (4) incidence and role of SMBG in preventing hypoglycemia with single-drug regimens and combination regimens consisting of antihyperglycemic agents other than secretagogues and insulin; (5) comparison of SMBG with continuous glucose monitoring; (6) technological capabilities and limitations of SMBG; (7) barriers to appropriate use of SMBG; and (8) methods and end points for appropriate future clinical trials. The panel emphasized recent studies, which reflect the current approach for applying this intervention. Among the participants there was consensus that: SMBG is an established practice for patients with NIT T2DM, and to be most effective, it should be performed in a structured format where information obtained from this measurement is used to guide treatment; New, high-quality efficacy data from RCTs have demonstrated efficacy of SMBG in NIT T2DM in trials reported since 2008; Both patients and health care professionals require education on how to respond to the data for SMBG to be effective; and Additional well-defined studies are needed to assess the benefits and costs of SMBG with end points not limited to hemoglobin A1c.

Early and Intensive Therapy for Management of Hyperglycemia and Cardiovascular Risk Factors in Patients With Type 2 Diabetes

BACKGROUND Type 2 diabetes mellitus (T2DM) results in significant morbidity and mortality. Results of recent randomized controlled trials demonstrated the ability of early and intensive therapy to reduce the risk of microvascular complications. However, controversy surrounds the ability of such therapy to reduce the risk for macrovascular complications. OBJECTIVES This article reviews results from recent clinical trials in patients with T2DM as well as extended follow-up of earlier trials to determine if early, intensive, and individualized therapy aimed at the underlying pathogenesis of the disease could decrease the risk for long-term complications, including cardiovascular disease (CVD). METHODS Information was obtained by a search of the PUBMED and EMBASE databases using the search terms type 2 diabetes mellitus, glycosylated hemoglobin, pathophysiology of type 2 diabetes, glycemic control, early intervention, multifactorial intervention, cardiovascular disease, β-cell function, and antidiabetes therapy for the period between 1995 and 2010. Articles dealing with outcomes trials, impact of therapy on microvascular and macrovascular complications, effects of therapeutic agents on the pathophysiology of T2DM, and the impact of agents on CV risk factors were then preferentially selected for in-depth review. RESULTS Large-scale clinical trials in patients with T2DM, although largely negative at 5 years for macrovascular end points, suggested benefit for patients with a shorter duration of T2DM (ie, <10 years) and still supported a treatment strategy of early, intensive, and individualized therapy to prevent long-term complications of the disease. In Steno-2, after 13 years of follow-up, early, intensive, multifactorial therapy was associated with a 56% lower risk of all-cause death (P = 0.02) and a 57% lower risk of death from CVD (P = 0.04). In the 10-year follow-up to the United Kingdom Prospective Diabetes Study, intensive therapy was associated with a significant 15% reduction in the risk of myocardial infarction (P = 0.01) and a significant 13% reduction in the risk of death from any cause (P = 0.007). Therapy should be aimed at correcting underlying pathophysiologic defects, including β-cell failure and insulin resistance, and should also correct underlying risk factors for CVD whenever possible. CONCLUSIONS Early and intensive antidiabetes treatment was recommended in patients with T2DM, particularly those with a shorter duration of disease and without a history of CVD. The goal was to safely lower glycosylated hemoglobin to <7%, therefore providing beneficial effects on the risk for complications. Hypoglycemia should be avoided. In addition, less aggressive treatment might be suitable for older patients with longstanding diabetes and a history of CVD events. Clinical trial results also provided support for a second important aspect of individualized treatment for patients with T2DM-multifactorial intervention aimed at controlling CVD risk factors.

The metabolic syndrome: a call to action.

Metabolic syndrome, a cluster of risk factors that enhances the risk for atherosclerotic cardiovascular disease, has received increasing attention in recent years, especially as the worldwide prevalence of obesity has become better defined. Recent controversy has questioned the scientific basis for metabolic syndrome, but does not negate its value as a description of a common phenotype of patients encountered in clinical practice. Revised and refined diagnostic criteria may be useful for physicians. While more research is needed to understand the pathology of the metabolic syndrome, there is no ambiguity that physicians should treat cardiovascular risk factors in individuals with metabolic syndrome.

Relationship of Insulin Dose, A1c Lowering, and Weight in Type 2 Diabetes: Comparing Insulin Glargine and Insulin Detemir

BACKGROUND A pooled analysis of randomized controlled trials of individuals with type 2 diabetes mellitus (T2DM) was conducted to compare dosing and impact of two basal insulin analogs, insulin glargine (glargine) and insulin detemir (detemir), on weight and hemoglobin A1c (A1c). METHODS Twenty-two studies of at least 20 weeks in duration in individuals with T2DM initiating glargine/detemir were included. Results were combined using a weighted-average method and a bivariate random effect model. Outcomes included changes in weight, A1c, and insulin dose from study start to end. RESULTS One study was head-to-head comparison of glargine and detemir. Detemir (four studies) was administered once or twice daily, with 50% starting on detemir once daily but needing therapy intensification. Glargine was used once daily in all 22 studies. The Egger test was borderline significant for change in weight over the course of the treatment for glargine (0.29; 90% confidence interval [CI] -0.01, 0.58), and heterogeneity was not observed for detemir (-0.18; 90% CI -0.59, 0.23). Heterogeneity was observed for change in A1c over the course of the treatment (glargine, -1.19, 90% CI -1.74, -0.63; detemir, -2.65, 90% CI -4.86, -0.45). Nonheterogeneity for change in A1c over the course of the treatment was achieved by excluding five studies for glargine and one study for detemir; however, all studies were included in subsequent analyses. In the unadjusted model, glargine and detemir showed similar results for mean A1c change (-1.4% vs. -1.4%), weight gain (2.5 vs. 1.7 kg), and weight/A1c (1.8 vs. 1.2 kg/%). A significantly higher detemir dose was needed to achieve the same A1c change (51.5 vs. 38.8 U/day). CONCLUSIONS Although absolute weight gain was higher with glargine versus detemir, weight gain per A1c change was similar. A higher detemir dose was required to achieve a similar A1c reduction.

New strategies for basal insulin treatment in type 2 diabetes mellitus

BACKGROUND The clinical progression of type 2 diabetes mellitus (DM) is well understood. Glycemic control gradually deteriorates, and progression of DM eventually leads to an increased risk for microvascular and macrovascular complications. Reassessment of current insulin treatment strategies leading to restoration of glycemic control is essential to prevent or stop the progression of type 2 DM and its complications. OBJECTIVE The purpose of this article was to review the importance of instituting a strategy of basal insulin therapy in patients with type 2 DM. METHODS Relevant articles were obtained through an online search of PubMed and MEDLINE for literature published from 1990 to 2003. The search terms used were insulin therapy, combination oral therapy, treatment failure, glycemic control, insulin analogues, insulin glargine, basal insulin, and microvascular complications. RESULTS Large-scale intervention trials, such as the United Kingdom Prospective Diabetes Study (UKPDS), have reported that patients with type 2 DM treated with oral combination therapy are unable to maintain glycemic control. These observations have led to a reassessment of the role of insulin therapy in type 2 DM. The importance of tight glycemic control through the aggressive use of insulin early in the course of the disease is apparent from the UKPDS, Diabetes Control and Complications Trial, and other, smaller studies. Considerable evidence indicates that initiating a basal insulin-replacement strategy with an existing oral regimen can result in regaining glycemic control. Evidence emerging from recent studies indicates that use of intensive insulin therapy early in the course of the disease may have a positive clinical impact on outcome and slow the progression of complications. The availability of basal insulin analogues has expanded treatment options and improved the efficacy of therapeutic regimens for type 2 DM. CONCLUSIONS The available data suggest using an earlier transition from monotherapy to combination therapy to minimize disease-associated morbidity. The availability of new insulin analogues has expanded therapeutic options and offers the potential to enhance the efficacy of therapeutic regimens for type 2 DM as well as improve the ease and safety of treatment when glycosylated hemoglobin cannot be maintained <7% on > or =1 oral antidiabetic agent.

Overall Mortality in Diabetes Mellitus: Where Do We Stand Today?

Life expectancy for a patient with type 2 diabetes remains substantially shorter than an equivalent individual without diabetes, largely because of a greater risk of cardiovascular disease. Diabetes is also associated with an increased incidence of many types of cancer, suggesting that malignancy may also contribute to higher rates of mortality. Hyperglycemia is one of the key risk factors for diabetes-associated macro- and microvascular disease, and as such, intensive glycemic control is associated with improved outcomes for patients, including a reduction in this risk of death from any cause, when initiated early in the disease course. Recent trials in patients with more advanced disease have failed to demonstrate a mortality benefit with intensive glycemic control, although this may reflect their short observation period. Intensive multifactorial therapy, including lifestyle intervention and control of hyperglycemia, hypertension, lipids, thrombosis, and microalbuminuria, is likely to be the best strategy against diabetes-associated macrovascular mortality. However, analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial indicates that there may be a subpopulation of patients who are unable to achieve glycemic targets with intensive therapy and that aggressive intensification of treatment in this group may increase mortality risk. It remains to be determined whether the relationship between diabetes and malignancy is causal or whether they share common risk factors. Current recommendations for a healthy lifestyle based on good diet, physical exercise, and weight management in order to control diabetes-related complications are likely to apply in reducing the risk of many forms of cancer and should be advocated for all patients.

Lipid effects of glyburide/metformin tablets in patients with type 2 diabetes mellitus with poor glycemic control and dyslipidemia in an open-label extension study

BACKGROUND Because both type 2 diabetes and elevated plasma lipid levels are important independent risk factors for cardiovascular disease and coronary heart disease, the choice of an antihyperglycemic agent for patients with type 2 diabetes--in whom abnormal plasma lipid levels are often seen-should take into account effects on lipids as well as on markers of glycemic control. OBJECTIVE This study assessed the effects on lipid levels of glyburide/metformin tablets in the treatment of type 2 diabetes, particularly in a group of patients who had poor glycemic control and dyslipidemia at baseline. METHODS This 52-week, open-label study was an extension of a 32-week, double-blind, placebo-controlled study. The patient population was drawn from 3 groups: those who completed the double-blind study, those who were discontinued from the double-blind study, and those who were ineligible for the double-blind study based on predefined measures of glycemic control (screening fasting plasma glucose > 240 mg/dL and glycosylated hemoglobin [HbA1c] < or = 12%, or HbA1c 11%-12%) and were directly enrolled in the open-label extension study. Patients with an HbA1c of < 9% received glyburide/ metformin tablets 1.25 mg/250 mg BID; those with an HbA1c > or = 9% received glyburide/ metformin tablets 2.5 mg/500 mg BID. Changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels were assessed for 52 weeks. RESULTS The study population included 828 patients: 515 who completed the double-blind study, 138 who were discontinued from the double-blind study, and 175 who were enrolled directly. Direct enrollees had poor glycemic control and dyslipidemia at baseline. Improvements in plasma lipid levels were seen as early as week 13. At week 52, the mean change in TC from baseline was -8.0 mg/dL for the total population (95% CI, -10.9 to -5.2; P < 0.05) and -23.2 mg/dL for direct enrollees (95% CI, -30.1 to -16.4; P < 0.05). The mean decrease in LDL-C from baseline for the total population was 2.86 mg/dL (95% CI, -5.3 to -0.4; P < 0.05), compared with a reduction of 13.3 mg/dL for direct enrollees (95% CI, -18.5 to -8.1; P < 0.05). Mean HDL-C levels were minimally affected. Mean TG levels decreased by 27.8 mg/dL for the entire population (95% CI, -42.9 to -12.8; P < 0.05) and by 99.7 mg/dL for direct enrollees (95% CI, -152.5 to -46.8; P < 0.05). CONCLUSION In this open-label extension study, treatment with glyburide/ metformin tablets for type 2 diabetes had a durable, favorable effect on lipid levels, particularly in those with poor glycemic control and dyslipidemia at baseline.