Fernando Ovalle

Insulin resistance, polycystic ovary syndrome, and type 2 diabetes mellitus

OBJECTIVE To review the definition and prevalence of two insulin resistance (IR)-associated phenotypes, polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus, as well as the risk and nature of their simultaneous presentation. DESIGN Review of published literature. RESULT(S) Insulin resistance affects between 10% and 25% of the general population. Two common disorders frequently associated with IR are PCOS, affecting 4% to 6% of reproductive-aged women, and type 2 diabetes mellitus, which is observed in about 2% to 6% of similarly aged women. Overall, about 50% to 70% of women with PCOS and 80% to 100% of patients with type 2 diabetes mellitus have variable degrees of IR. Insulin resistance and its secondary hyperinsulinemia appear to underlie many of the endocrine features of PCOS in a large proportion of such patients. The risk of type 2 diabetes mellitus among PCOS patients is 5- to 10-fold higher than normal. In turn, the risk of PCOS among reproductive-aged type 2 diabetes mellitus patients appears to be similarly increased. CONCLUSION(S) It remains to be determined whether PCOS and type 2 diabetes mellitus represent no more than different clinical manifestations of the same IR syndrome, with their phenotypic differences due to the presence or absence of a coincidental genetic defect at the level of the ovary or pancreas, respectively, or representing the result of etiologically different subtypes of IR syndromes.

Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study

BACKGROUND As new members of a drug class are developed, head-to-head trials are an important strategy to guide personalised treatment decisions. We assessed two glucagon-like peptide-1 receptor agonists, once-weekly albiglutide and once-daily liraglutide, in patients with type 2 diabetes inadequately controlled on oral antidiabetic drugs. METHODS We undertook this 32-week, open-label, phase 3 non-inferiority study at 162 sites in eight countries: USA (121 sites), Australia (9 sites), Peru (7 sites), Philippines (7 sites), South Korea (5 sites), UK (5 sites), Israel (4 sites), and Spain (4 sites). 841 adult participants (aged ≥18 years) with inadequately controlled type 2 diabetes and a BMI between 20 and 45 kg/m(2) were enrolled and randomised in a 1:1 ratio to receive albiglutide 30 mg once weekly titrated to 50 mg at week 6, or liraglutide 0·6 mg once daily titrated to 1·2 mg at week 1 and 1·8 mg at week 2. The randomisation schedule was generated by an independent randomisation team by the permuted block method with a fixed block size of 16. Participants and investigators were unmasked to treatment. The primary endpoint was change from baseline in HbA1c for albiglutide versus liraglutide, with a 95% CI non-inferiority upper margin of 0·3%. The primary analysis was by modified intention to treat. The study is registered with ClinicalTrials.gov, number NCT01128894. FINDINGS 422 patients were randomly allocated to the albigultide group and 419 to the liraglutide group; 404 patients in the abliglutide group and 408 in the liraglutide group received the study drugs. The primary endpoint analysis was done on the modified intention-to-treat population, which included 402 participants in the albiglutide group and 403 in the liraglutide group. Model-adjusted change in HbA1c from baseline to week 32 was -0·78% (95% CI -0·87 to -0·69) in the albigludite group and -0·99% (-1·08 to -0·90) in the liraglutide group; treatment difference was 0·21% (0·08-0·34; non-inferiority p value=0·0846). Injection-site reactions occurred in more patients given albiglutide than in those given liraglutide (12·9% vs 5·4%; treatment difference 7·5% [95% CI 3·6-11·4]; p=0·0002), whereas the opposite was the case for gastrointestinal events, which occurred in 49·0% of patients in the liraglutide group versus 35·9% in the albiglutide group (treatment difference -13·1% [95% CI -19·9 to -6·4]; p=0·00013). INTERPRETATION Patients who received once-daily liraglutide had greater reductions in HbA1c than did those who received once-weekly albiglutide. Participants in the albiglutide group had more injection-site reactions and fewer gastrointestinal events than did those in the liraglutide group. FUNDING GlaxoSmithKline.

Reasons for Not Intensifying Medications: Differentiating “Clinical Inertia” from Appropriate Care

Background“Clinical inertia” has been defined as inaction by physicians caring for patients with uncontrolled risk factors such as blood pressure. Some have proposed that it accounts for up to 80% of cardiovascular events, potentially an important quality problem. However, reasons for so-called clinical inertia are poorly understood.ObjectiveTo derive an empiric conceptual model of clinical inertia as a subset of all clinical inactions from the physician perspective.MethodsWe used Nominal Group panels of practicing physicians to identify reasons why they do not intensify medications when seeing an established patient with uncontrolled blood pressure.Measurements and Main ResultsWe stopped at 2 groups (N = 6 and 7, respectively) because of the high degree of agreement on reasons for not intensifying, indicating saturation. A third group of clinicians (N = 9) independently sorted the reasons generated by the Nominal Groups. Using multidimensional scaling and hierarchical cluster analysis, we translated the sorting results into a cognitive map that represents an empirically derived model of clinical inaction from the physician’s perspective. The model shows that much inaction may in fact be clinically appropriate care.Conclusions/RecommendationsMany reasons offered by physicians for not intensifying medications suggest that low rates of intensification do not necessarily reflect poor quality of care. The empirically derived model of clinical inaction can be used as a guide to construct performance measures for monitoring clinical inertia that better focus on true quality problems.

LONG-TERM EFFICACY OF TRIPLE ORAL THERAPY FOR TYPE 2 DIABETES MELLITUS

OBJECTIVE To report the status of 35 patients with type 2 diabetes mellitus approximately 3 years after the initiation of triple oral antidiabetic therapy--with a sulfonylurea, metformin, and a thiazolidinedione. METHODS Study patients were assessed for the need for the addition of insulin, and follow-up clinical and laboratory findings were analyzed. RESULTS At a mean follow-up of 37 months (range, 18 to 45), 26 (74%) of 35 patients (group A) had well-controlled blood glucose levels on triple oral therapy, with a mean glycated hemoglobin (HbA1c) value of 6.9 +/- 0.3% (upper limit of normal, 6.5%). In the nine other patients (group B), triple oral therapy failed and the use of insulin was necessary after a mean duration of 30 months (range, 18 to 42); the mean HbA1c in these patients was 8.8 +/- 0.5%. Both group A and B gained similar amounts of weight during the study period (14.2 +/- 2.1 lb versus 11.6 +/- 3.8 lb, respectively; P = 0.54). A search for potential predictors of success or failure revealed that both groups had similar baseline characteristics, including age, duration of diabetes, weight, body mass index, HbA1c, and baseline stimulated C-peptide levels, and none of these factors demonstrated a significant correlation with the response to therapy. The only difference found between the two groups was a significant increase in the stimulated C-peptide levels (from 3.6 +/- 0.9 ng/mL to 5.2 +/- 1.1 ng/mL; P = 0.002) during follow-up in the group that had good glycemic control with triple oral therapy, in comparison with a nonsignificant increase (from 3.7 +/- 0.8 ng/mL to 4.2 +/- 0.4 ng/mL; P = 0.46) in the group that failed to maintain glycemic control on triple oral therapy. CONCLUSION Triple oral antidiabetic therapy is an effective long-term treatment for a substantial proportion of patients with type 2 diabetes who initially achieve glycemic control with triple oral therapy, particularly those in whom production of endogenous insulin is increased when a thiazolidinedione is added.

Absence of obesity paradox in patients with chronic heart failure and diabetes mellitus: a propensity-matched study

Obesity is paradoxically associated with survival benefit in patients with chronic heart failure (HF). However, obesity complicates the management of diabetes mellitus (DM), which is common in HF. Yet, little is known about the impact of obesity in HF patients with DM. Therefore, we examined the association between obesity and outcomes in propensity‐matched cohorts of HF patient with and without DM.

A propensity-matched study of the effect of diabetes on the natural history of heart failure: variations by sex and age

Background: Poor prognosis in heart failure (HF) patients with diabetes is often attributed to increased co-morbidity and advanced disease. Further, this effect may be worse in women. Objective: To determine whether the effect of diabetes on outcomes and the sex-related variation persisted in a propensity score-matched HF population, and whether the sex-related variation was a function of age. Methods: Of the 7788 HF patients in the Digitalis Investigation Group trial, 2218 had a history of diabetes. Propensity score for diabetes was calculated for each patient using a non-parsimonious logistic regression model incorporating all measured baseline covariates, and was used to match 2056 (93%) diabetic patients with 2056 non-diabetic patients. Results: All-cause mortality occurred in 135 (25%) and 216 (39%) women without and with diabetes (adjusted HR = 1.67; 95% CI = 1.34 to 2.08; p<0.001). Among men, 535 (36%) and 609 (41%) patients without and with diabetes died from all causes (adjusted HR = 1.21; 95% CI = 1.07 to 1.36; p = 0.002). Sex–diabetes interaction (overall adjusted p<0.001) was only significant in patients ⩾65 years (15% absolute risk increase in women; multivariable p for interaction = 0.005), but not in younger patients (2% increase in women; p for interaction = 0.173). Risk-adjusted HR (95% CI) for all-cause hospitalisation for women and men were 1.49 (1.28 to 1.72) and 1.21 (1.11 to 1.32), respectively, also with significant sex–diabetes interaction (p = 0.011). Conclusions: Diabetes-associated increases in morbidity and mortality in chronic HF were more pronounced in women, and theses sex-related differences in outcomes were primarily observed in elderly patients.

TRIPLE ORAL ANTIDIABETIC THERAPY IN TYPE 2 DIABETES MELLITUS

To determine the effectiveness of triple oral antidiabetic therapy with a sulfonylurea, a biguanide, and a thiazolidinedione, we analyzed the results in 35 patients who had previously had inadequate glycemic control with a combination of glimepiride and metformin. The study cohort consisted of 27 men and 8 women (mean age, 55.8 years) who had had type 2 diabetes mellitus for a mean duration of 8.7 years. The addition of troglitazone (600 mg/day administered with the largest meal) to the glimepiride and metformin therapy yielded normal or near-normal glycemia in all 35 patients. Glycemic control was initially associated with mean weight gain; subsequently, however, mean weight was reduced to below the baseline level--perhaps attributable to the anorectic effect of metformin. Thus, for the first time, triple oral antidiabetic therapy with glimepiride, metformin, and troglitazone has been shown to be an efficacious therapeutic option for type 2 diabetes.

ARTIFACTUALLY LOW HEMOGLOBIN A1c CAUSED BY USE OF DAPSONE

OBJECTIVE To describe a case of artifactually decreased hemoglobin Alc (HbAlc) attributable to use of dapsone. METHODS We present a detailed case report and results of a related literature search. In addition, potential causes of artifactually lowered HbAlc values are discussed. RESULTS A 35-year-old patient with type I diabetes had high home-monitored blood glucose values, high clinic plasma glucose determinations, increased fructosamine levels, and low HbAlc values. The lowering of the HbAlc level was associated with use of dapsone, and the decrease in HbAlc value was proportional to the dose of dapsone. A literature search revealed one previous report of artifactual lowering of the HbAlc value, in which high methemoglobin levels were found and thought to be the cause of the artifactually decreased HbA1c. CONCLUSION By increasing methemoglobin levels and decreasing erythrocyte survival, dapsone can artifactually lower HbA1c. Clinicians should be aware of this potential side effect of dapsone.

Elements of the metabolic syndrome: association with insulin sensitivity and effects of ethnicity.

BACKGROUND The objectives of the present study were, within a group of 322 healthy European American (EA) and African American (AA) women, to, (1) determine the extent to which insulin sensitivity (Si) was correlated with the elements of the metabolic syndrome using the third Adult Treatment Panel (ATP III) criteria; (2) determine if ethnicity affected the relationships between Si and the elements of the metabolic syndrome; and (3) determine the amount of variance in elements of the metabolic syndrome independently explained by fasting insulin, the acute insulin response to glucose (AIRg), and Si. METHODS Si and AIRg were assessed with a frequently-sampled intravenous glucose tolerance test and minimal modeling; total body fat with dual-energy x-ray absorptiometry; and intra-abdominal adipose tissue (IAAT) with computed tomography scanning. RESULTS Among all women combined, Si was associated with fasting glucose (r = -0.18, p < 0.01), waist circumference (r = -0.36, p < 0.001), and high-density lipoprotein cholesteraol (HDL-C; r = 0.18, p < 0.01). However, the association of Si with elements of the metabolic syndrome other than fasting glucose and waist circumference differed with ethnicity; among EA, Si was correlated with triglycerides (r = -0.28, p < 0.01) and HDL-C (r = 0.29, p < 0.001), whereas among AA, Si tended to be correlated with systolic blood pressure (r = -0.17, p = 0.059). In multiple regression modeling, fasting insulin was independently related to more elements of the metabolic syndrome (fasting glucose, waist circumference, triglycerides, systolic and diastolic blood pressure) than were Si or AIRg (both related only to fasting glucose), after adjusting for ethnicity, age, and total fat or IAAT. CONCLUSIONS Correlation of Si with elements of the metabolic syndrome differed with ethnic group. Fasting insulin, rather than Si, best predicted most elements of the metabolic syndrome.

Cardiovascular implications of antihyperglycemic therapies for type 2 diabetes.

BACKGROUND Several risk factors for cardiovascular disease (CVD), including insulin resistance/hyperinsulinemia, hyperglycemia, overweight/obesity, dyslipidemia, and hypertension, are often present in varying combinations in patients with type 2 diabetes mellitus (DM). Patients with a clustering of these risk factors, termed the metabolic syndrome, are at greater risk for CVD than are patients with only a single risk factor. Although glycemic control is the central feature of type 2 DM management, patients require an individualized approach to therapy that takes their other CVD risk factors into account. OBJECTIVE This review examined the effects of antidiabetes therapy on glycemic control, as well as its potential to affect body weight, serum lipids, and blood pressure (BP), and thus CVD risk. METHODS Information was obtained by searching the MEDLINE and EMBASE databases from 1995 through March 2010. The search terms included type 2 DM, metabolic syndrome, CV complications of type 2 DM, and therapy for type 2 DM. Articles that described relevant details of the metabolic syndrome, CV complications of type 2 DM, and effects of antidiabetes therapy on glycosylated hemoglobin, body weight, serum lipids, and BP were selected for in-depth review. Only English language publications were reviewed. Clinical trials, meta-analyses, and review articles on the key words were preferentially selected for review and analysis. Non-English language publications, case reports, letters to the editor, and similar types of publications were excluded. RESULTS Although all approved antidiabetes agents lowered glucose, their effect on other CV risk factors, such as BP, lipids, and weight, differed significantly. Therapy with insulin, the sulfonylureas, and the thiazolidinediones was associated with weight gain. Metformin and the dipeptidyl-peptidase-4 inhibitors were generally considered weight neutral, whereas the glucagon-like peptide-1 receptor agonists and amylin agonists were associated with weight loss. Metformin, sulfonylureas, thiazolidinedioness, and dipeptidyl-peptidase-4 inhibitors had modest effects on serum lipid levels and BP. The glucagon-like peptide-1 receptor agonists generally had beneficial effects on serum lipid levels and systolic and diastolic BP. CONCLUSION A wide variety of agents were available to aid glycemic control in patients with type 2 DM. These agents had variable effects on known CV risk factors that might be present in this patient population, including excess body weight, elevated BP, and increased serum lipids. Some of the newer agents improved glycemic control while also having potentially favorable effects on these CV risk factors. The impact of various agents on known CV risk factors should be considered when selecting a therapeutic regimen.