Importance of Postprandial Glucose in Relation to A1C and Cardiovascular Disease.

IN BRIEF This article reviews the evidence regarding the impact of postprandial glucose (PPG) on overall A1C and its relation to cardiovascular disease (CVD). To date, four randomized, controlled trials have evaluated the impact of PPG reduction on CVD; however, only one of these successfully demonstrated a positive effect. Despite this, epidemiological evidence does indicate a cardiovascular benefit of PPG reduction, and agents that can be used to manage PPG in people with type 2 diabetes are also discussed.

Options for empagliflozin in combination therapy in type 2 diabetes mellitus.

OBJECTIVE: To update clinicians with an overview of empagliflozin for the treatment of type 2 diabetes mellitus (T2DM), with focus on use in combination regimens. METHODS: Keyword searches were conducted in the Medline database to identify literature reporting clinical trials of at least 12 weeks' duration using empagliflozin treatment in patients with T2DM. RESULTS: When given as monotherapy or in combination therapy (as add-on or single-pill therapy) with metformin, pioglitazone, sulfonylurea, linagliptin, and insulin, empagliflozin produced clinically meaningful reductions in glycated hemoglobin levels, plasma glucose concentrations, bodyweight, and blood pressure. These changes were sustained during long-term treatment. In a dedicated cardiovascular event trial, empagliflozin on top of standard of care demonstrated a significant reduction in the risk of cardiovascular mortality and all-cause mortality. Across the clinical trials, empagliflozin combination therapies were well tolerated, and empagliflozin used alone was not associated with increased risk of hypoglycemia versus placebo. Indeed, the combination of empagliflozin and metformin had a significantly reduced rate of hypoglycemia compared with the combination of metformin and a sulfonylurea. On the other hand, empagliflozin treatment did have increased risk of genital infections compared with placebo. In clinical trials to date, diabetic ketoacidosis was not seen more frequently with empagliflozin than with placebo, but physicians should be alert to the possibility of this rare event. CONCLUSION: Empagliflozin has the potential to make an important contribution to the treatment of patients with T2DM. In some patients, empagliflozin may be used as monotherapy, but it is most likely to be used in combination with other therapies. Given the reduced risk of mortality seen when empagliflozin was added to standard care in patients at high cardiovascular risk, as well as the lack of alternative options for patients at lower cardiovascular risk, empagliflozin may be added to ongoing regimens for a significant proportion of patients.

Mechanistic and clinical aspects of renin-angiotensin-aldosterone system blockade in the prevention of diabetes mellitus and cardiovascular disease.

OBJECTIVE: To review the rationale for the use of renin-angiotensin-aldosterone system (RAAS) inhibition to prevent type 2 diabetes mellitus and cardiovascular events and to discuss clinical data evaluating the relationship between RAAS blockade and diabetes prevention. METHODS: PubMed was searched to identify preclinical and clinical data addressing this aim. RESULTS: Potential mechanisms of angiotensin II-mediated insulin resistance and type 2 diabetes may include impaired blood flow and sympathetic activity, increased oxidative stress, alterations in insulin signaling, and effects on adipose tissue. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have demonstrated reduced incidences of new-onset diabetes in patients with prediabetes or hypertension and in other cardiovascular populations; however, insight into the corresponding impact on cardiovascular-related morbidity and mortality has been lacking. A recent trial (NAVIGATOR) was designed to evaluate incident diabetes and cardiovascular outcomes as part of its primary endpoint. In this trial, valsartan-based therapy reduced the incidence of new-onset diabetes by 14% relative to placebo over the 5-year follow-up period (P<.001). Cardiovascular outcomes, however, were not significantly affected by active treatment, which may be attributed to a number of potential confounding factors including the low rate of cardiovascular disease at baseline, concurrent implementation of lifestyle modification in all patients, and the substantial use of other risk-reducing agents. CONCLUSIONS: Angiotensin II has been implicated in a number of pathophysiologic processes with the potential to indirectly or directly influence the pathogenesis of insulin resistance and type 2 diabetes. Most clinical trials show a reduced risk of new-onset diabetes with RAAS blockade; however, recent results of the NAVIGATOR trial show that the addition of valsartan to lifestyle modification reduces the risk of diabetes, but does not improve cardiovascular outcomes.

Efficacy and safety of inhaled insulin (exubera) compared with subcutaneous insulin therapy in patients with type 2 diabetes: results of a 6-month, randomized, comparative trial.

OBJECTIVE: Glycemic control using inhaled, dry-powder insulin plus a single injection of long-acting insulin was compared with a conventional regimen in patients with type 2 diabetes, which was previously managed with at least two daily insulin injections. RESEARCH DESIGN AND METHODS: Patients were randomized to 6 months' treatment with either premeal inhaled insulin plus a bedtime dose of Ultralente (n = 149) or at least two daily injections of subcutaneous insulin (mixed regular/NPH insulin; n = 150). The primary efficacy end point was the change in HbA1c from baseline to the end of study. RESULTS: HbA1c decreased similarly in the inhaled (-0.7%) and subcutaneous (-0.6%) insulin groups (adjusted treatment group difference: -0.07%, 95% CI -0.32 to 0.17). HbA1c < 7.0% was achieved in more patients receiving inhaled (46.9%) than subcutaneous (31.7%) insulin (odds ratio 2.27, 95% CI 1.24-4.14). Overall hypoglycemia (events per subject-month) was slightly lower in the inhaled (1.4 events) than in the subcutaneous (1.6 events) insulin group (risk ratio 0.89, 95% CI 0.82-0.97), with no difference in severe events. Other adverse events, with the exception of increased cough in the inhaled insulin group, were similar. No difference in pulmonary function testing was seen. Further studies are underway to assess tolerability in the longer term. Insulin antibody binding increased more in the inhaled insulin group. Treatment satisfaction was greater in the inhaled insulin group. CONCLUSIONS: Inhaled insulin appears to be effective, well tolerated, and well accepted in patients with type 2 diabetes and provides glycemic control comparable to a conventional subcutaneous regimen.

Once-daily insulin glargine compared with twice-daily NPH insulin in patients with type 1 diabetes.

OBJECTIVE: To present the findings in a randomized, parallel-group study, comparing once-daily insulin glargine with twice-daily NPH insulin in patients with type 1 diabetes previously treated with multiple daily injections of basal and regular insulin. METHODS: Of 394 patients with type 1 diabetes treated for up to 28 weeks, 195 received insulin glargine and 199 received NPH insulin, in addition to preprandial regular insulin. Glycemic control and hypoglycemic episodes were assessed. RESULTS: A greater mean decrease in fasting blood glucose (FBG) was achieved at endpoint with insulin glargine than with NPH insulin (-21 mg/dL versus -10 mg/dL [-1.17 mmol/L versus -0.56 mmol/L]; P = 0.015), and a greater percentage of patients treated with insulin glargine reached the target FBG (32.6% versus 21.3%; P = 0.015). Similar percentages of patients in both treatment groups achieved glycosylated hemoglobin values of 7.0% or less at endpoint (insulin glargine, 35.8%; NPH insulin, 35.4%). After the 1-month titration phase, the percentage of patients who reported at least one symptomatic hypoglycemic event confirmed by a blood glucose value of less than 50 mg/dL (2.8 mmol/L) was significantly lower with insulin glargine than with NPH insulin (73.3% versus 81.7%; P = 0.021). Furthermore, the percentage of patients who reported at least one symptomatic hypoglycemic event confirmed by a blood glucose value of less than 36 mg/dL (2.0 mmol/L) was significantly lower with insulin glargine than with NPH insulin (36.6% versus 46.2%; P = 0.033). CONCLUSION: Once-daily insulin glargine was at least as effective as twice-daily NPH insulin in improving fasting glycemic control and resulted in fewer reported symptomatic hypoglycemic events.