Synopsis of the 2017 U.S. Department of Veterans Affairs/U.S. Department of Defense Clinical Practice Guideline: Management of Type 2 Diabetes Mellitus

DESCRIPTION: In April 2017, the U.S. Department of Veterans Affairs (VA) and the U.S. Department of Defense (DoD) approved a joint clinical practice guideline for the management of type 2 diabetes mellitus. METHODS: The VA/DoD Evidence-Based Practice Work Group convened a joint VA/DoD guideline development effort that included a multidisciplinary panel of practicing clinician stakeholders and conformed to the Institute of Medicine's tenets for trustworthy clinical practice guidelines. The guideline panel developed key questions in collaboration with the ECRI Institute, which systematically searched and evaluated the literature through June 2016, developed an algorithm, and rated recommendations by using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. RECOMMENDATIONS: This synopsis summarizes key features of the guideline in 7 areas: patient-centered care and shared decision making, glycemic biomarkers, hemoglobin A1c target ranges, individualized treatment plans, outpatient pharmacologic treatment, glucose targets for critically ill patients, and treatment of hospitalized patients.(AU)

Identifying the independent effect of HbA1c variability on adverse health outcomes in patients with Type 2 diabetes.

AIMS: To characterize the relationship between HbA1c variability and adverse health outcomes among US military veterans with Type 2 diabetes. METHODS: This retrospective cohort study used Veterans Affairs and Medicare claims for veterans with Type 2 diabetes taking metformin who initiated a second diabetes medication (n = 50 861). The main exposure of interest was HbA1c variability during a 3-year baseline period. HbA1c variability, categorized into quartiles, was defined as standard deviation, coefficient of variation and adjusted standard deviation, which accounted for the number and mean number of days between HbA1c tests. Cox proportional hazard models predicted mortality, hospitalization for ambulatory care-sensitive conditions, and myocardial infarction or stroke and were controlled for mean HbA1c levels and the direction of change in HbA1c levels during the baseline period. RESULTS: Over a mean 3.3 years of follow-up, all HbA1c variability measures significantly predicted each outcome. Using the adjusted standard deviation measure for HbA1c variability, the hazard ratios for the third and fourth quartile predicting mortality were 1.14 (95% CI 1.04, 1.25) and 1.42 (95% CI 1.28, 1.58), for myocardial infarction and stroke they were 1.25 (95% CI 1.10, 1.41) and 1.23 (95% CI 1.07, 1.42) and for ambulatory-care sensitive condition hospitalization they were 1.10 (95% CI 1.03, 1.18) and 1.11 (95% CI 1.03, 1.20). Higher baseline HbA1c levels independently predicted the likelihood of each outcome. CONCLUSIONS: In veterans with Type 2 diabetes, greater HbA1c variability was associated with an increased risk of adverse long-term outcomes, independently of HbA1c levels and direction of change. Limiting HbA1c fluctuations over time may reduce complications.

A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance.

AIMS/HYPOTHESIS: Chronic sub-acute inflammation contributes to the pathogenesis of type 2 diabetes mellitus and cardiovascular disease. High doses of salicylate reduce inflammation, glucose and triacylglycerols, and may improve insulin sensitivity, suggesting therapeutic potential in impaired fasting glucose and/or impaired glucose tolerance. This trial aimed to evaluate the effect of salsalate vs placebo on insulin resistance and glycaemia in impaired fasting glucose and/or impaired glucose tolerance. METHODS: We conducted a 12 week, two-centre, randomised, placebo-controlled study to evaluate the effect of salsalate (up to 4 g/day) vs placebo on systemic glucose disposal. Secondary objectives included treatment effects on glycaemia, inflammation and cardiovascular risk factors. Seventy-eight participants with impaired fasting glucose and/or impaired glucose tolerance from two VA healthcare systems were enrolled. Randomisation assignment was provided by the coordinating center directly to site pharmacists, and participants and research staff were blinded to treatment assignment. RESULTS: Seventy-one individuals were randomised to placebo (n = 36) or salsalate (n = 35). Glucose disposal did not change in either group (salsalate 1% [95% CI -39%, 56%]; placebo 6% [95% CI -20%, 61%], p = 0.3 for placebo vs salsalate). Fasting glucose was reduced by 6% during the study by salsalate (p = 0.006) but did not change with placebo. Declines in glucose were accompanied by declines in fasting C-peptide with salsalate. Insulin clearance was reduced with salsalate. In the salsalate group, triacylglycerol levels were lower by 25% (p = 0.01) and adiponectin increased by 53% (p = 0.02) at the end of the study. Blood pressure, endothelial function and other inflammation markers did not differ between groups. Adipose tissue nuclear factor κB (NF-κB) activity declined in the salsalate group compared with placebo (-16% vs 42%, p = 0.005), but was not correlated with metabolic improvements. The frequency of tinnitus was low but tended to be higher with salsalate therapy (n = 4 vs n = 2). CONCLUSIONS/INTERPRETATION: In summary, salsalate therapy was well tolerated, lowered fasting glucose, increased adiponectin and reduced adipose tissue NF-κB activity. These changes were not related to changes in peripheral insulin sensitivity, suggesting additional mechanisms for metabolic improvement. TRIAL REGISTRATION: ClinicalTrials.gov NCT00330733. FUNDING: Office of Research and Development, Medical Research Service, Department of Veterans Affairs and NIH K24 DK63214.

Prevalence of primary hyperaldosteronism in mild to moderate hypertension without hypokalaemia.

Screening for primary hyperaldosteronism (PHA) is often indicated in individuals with resistant hypertension or hypokalaemia. However, in the far larger subset of the hypertensive population who do not fit into these criteria, the evidence for screening is conflicting and dependent on the disease prevalence. The purpose of this study was to examine the prevalence of PHA in a large population with mild to moderate hypertension and without hypokalaemia using a carefully controlled study protocol including a normotensive control population. Hypertensive subjects underwent medication washout and both hypertensive and normotensive subjects placed on a high-sodium diet prior to biochemical and haemodynamic testing. Study specific cutoff values were based on results from the normotensive population studied under identical conditions. A screening test (serum aldosterone/PRA ratio [ARR]>25 with a serum aldosterone level >8 ng/dl) was followed by a confirmatory test (urine aldosterone excretion rate [AER] >17 microg/24 h) to demonstrate evidence of PHA. An elevated ARR with a concomitant elevated serum aldosterone was present in 26 (7.5%) individuals. Of these, 11 (3.2%) had an elevated AER, consistent with evidence of PHA. Individuals with PHA had higher blood pressure and lower serum potassium levels while on a high-sodium diet. Sodium restriction neutralized these differences between PHA and essential hypertensives. The prevalence of PHA in this mild to moderate hypertensive population without hypokalaemia is at most 3.2%, a rate that might lead to excessive false positives with random screening in comparable populations. Hyperaldosteronism, when present, is responsive to sodium restriction.

Redefining efficacy of antihypertensive therapies beyond blood pressure reduction--the role of angiotensin II antagonists.

Antihypertensive efficacy must be redefined beyond blood pressure (BP) lowering per se to include reducing the cardiovascular complications of hypertension. Treatment decisions should be based on results from large clinical trials with relevant clinical outcomes. Several recent morbidity and mortality trials with angiotensin II receptor antagonists (AIIAs) provide an evidence-based rationale for the use of AIIAs in patients with hypertension. Studies with AIIAs in comparison to conventional antihypertensive agents showed improved morbidity and mortality outcomes in patients with hypertension and left ventricular hypertrophy (losartan) and diabetes mellitus (losartan and irbesartan). Trials with some members of the AIIA class (candesartan and valsartan) have not demonstrated such benefits in comparison to conventional agents, possibly due to differences in BP control during the trials. The results of these AIIA outcome trials have impacted on recently issued clinical guidelines for management of hypertension.

Comparing office-based and ambulatory blood pressure monitoring in clinical trials.

Ambulatory blood pressure monitoring (ABPM) is commonly used in clinical trials. Yet, its ability to detect blood pressure (BP) change in comparison to multiple office-based measurements has received limited attention. We recorded ambulatory and five daily pairs of random zero (RZ) BPs pre- and post-intervention on 321 adult participants in the multicentre Dietary Approaches to Stop Hypertension trial. Treatment effect estimates measured by ambulatory monitoring were similar to those measured by RZ and did not differ significantly for waking vs 24-h ambulatory measurements. For systolic BP, the standard deviations of change in mean 24-h ambulatory BP (8.0 mmHg among hypertensives and 6.0 mmHg among nonhypertensives) were comparable to or lower than the corresponding standard deviations of change in RZ-BP based on five daily readings (8.9 and 5.9 mmHg). The standard deviations of change for mean waking ambulatory BP (8.7 and 6.7 mmHg) were comparable to those obtained using three to four daily RZ readings. Results for diastolic BP were qualitatively similar. Ambulatory monitoring was more efficient (ie, a smaller sample size could detect a given BP change) than three to four sets of daily RZ readings and required fewer clinic visits. The average of 33 ambulatory BP readings during the waking hours had an efficiency comparable to that from the mean of four daily pairs of RZ-BPs. Participants readily accepted the ABPM devices, and their use requires less staff training. ABPM provides a useful alternative to RZ-BP measurements in clinical trials.

Influence of dietary sodium on the renin-angiotensin-aldosterone system and prevalence of left ventricular hypertrophy by EKG criteria.

We investigated the interplay of dietary sodium and renin-angiotensin-aldosterone system (RAAS) activity with the prevalence of left ventricular hypertrophy (LVH) in essential hypertension. Electrocardiograms (EKG) were reviewed for the presence of LVH in 160 hypertensive patients. We then compared the rate of LVH to levels of plasma renin activity (PRA) and serum aldosterone under high and low sodium diet conditions. On high sodium diet, serum aldosterone was significantly higher (7.7+/-0.93 vs 5.7+/-0.35 ng/dl, P=0.02) in participants with LVH. With low sodium diet and upright posture, PRA was significantly lower in subjects with LVH vs those without (5.6+/-1.1 vs 7.6+/-0.56 ng/ml/h, P=0.026). Aldosterone levels on low sodium diet were not different between those with and those without LVH. PRA was then dichotomized at the lowest quartile under low sodium/upright posture conditions to define a 'low renin' group. In a multivariate logistic regression containing renin status (low renin vs normal/high renin), aldosterone on a high sodium diet, age, body mass index, gender, race, duration of hypertension, systolic and diastolic blood pressure and salt-sensitivity only low-renin status on a low sodium diet (P=0.019) and serum aldosterone on a high sodium diet (P=0.04) were significant predictors of LVH. Thus, reduced modulation of renin activity in response to sodium restriction and an increased aldosterone on a high sodium diet appear to identify characteristics of hypertensive patients predisposed to abnormal cardiac remodelling.

Increased red cell sodium-lithium countertransport and lymphocyte cytosolic calcium are separate phenotypes in patients with essential hypertension.

Increased red blood cell sodium-lithium countertransport (SLC) activity and elevated intracellular calcium have been observed in hypertensive patients. The association of these ion transport abnormalities with each other and with another phenotype, insulin resistance, has been suggested. We investigated whether elevated SLC activity and increased lymphocyte cytosolic calcium (Ca(cyt)) occur in the same individuals and whether either is associated with hyperinsulinaemia. We measured SLC activity, lymphocyte Ca(cyt)and fasting insulin levels in hypertensive patients and normal subjects. Consistent with prior studies, SLC activity was significantly and positively correlated with fasting insulin levels (r = 0.45, P < 0.01). However, SLC activity and lymphocyte Ca(cyt) were significantly but inversely correlated (r = -0.42, P < 0.01) and lymphocyte Ca(cyt) was also inversely correlated with fasting insulin (r = -0.55, P < 0.001). When the study participants were instead separated into two groups based on fasting insulin levels, those above the median (15 microU/ml) had significantly higher SLC activity and significantly lower Ca(cyt). When separated by lymphocyte Ca(cyt) levels (above or below 120 nM) those patients with low lymphocyte Ca(cyt) had significantly higher SLC activity and significantly higher insulin levels. Multiple linear regression showed that fasting insulin was significantly predictive of SLC activity (P = 0.05) and Ca(cyt) (P < 0.01). Thus, elevated SLC activity and increased lymphocyte Ca(cyt) are separate and distinct ion transport phenotypes in hypertensive patients, linked through a relationship to hyperinsulinaemia that is direct with SLC activity and inverse with lymphocyte Ca(cyt).

The impact of angiotensin II receptor blockade and the DASH diet on markers of endogenous fibrinolysis.

Hypertension is associated with impaired fibrinolysis. Both angiotensin receptor blockers (ARB) and the DASH (Dietary Approaches to Stop Hypertension) diet effectively lower blood pressure in hypertensive patients. Some evidence suggests that treatment with ARBs could increase fibrinolysis, however, data is conflicting. The impact of the DASH diet on fibrinolytic parameters is not known. Fifty-five hypertensive participants (35 African-American, 20 white) were randomly assigned to receive 8 weeks of either a control diet or the DASH diet. The diets did not differ in sodium content (approximately 3 g/day). Within each diet, individuals were randomly assigned to receive losartan or placebo for 4 weeks in double-blind, cross-over fashion. Tissue plasminogen activator (t-PA) antigen, t-PA activity, plasminogen activator inhibitor-1 (PAI-1) activity and plasma renin activity (PRA) were measured at the end of a 2-week run-in period on the control diet and after each treatment period. The DASH diet did not affect markers of fibrinolysis. Losartan significantly lowered t-PA antigen levels (-1.8 ng/mL, P = 0.045), but had no effect on t-PA or PAI-1 activities. This effect was more pronounced in whites (-4.1 ng/mL (P = 0.003)) compared with African-Americans (-0.3 ng/mL (P = 0.7), P-interaction = 0.03). Results were not materially affected by adjustment for basline values or changes in blood pressure. This study demonstrates that losartan reduces t-PA antigen levels in white, but not African-American hypertensive individuals. In contrast, the DASH diet had no significant effect on markers of fibrinolysis in whites or African-Americans.

Effects of diet and sodium intake on blood pressure: subgroup analysis of the DASH-sodium trial.

BACKGROUND: Initial findings from the Dietary Approaches to Stop Hypertension (DASH)-Sodium Trial demonstrated that reduction of sodium intake in two different diets decreased blood pressure in participants with and without hypertension. OBJECTIVE: To determine effects on blood pressure of reduced sodium intake and the DASH diet in additional subgroups. DESIGN: Randomized feeding study. SETTING: Four clinical centers and a coordinating center. PARTICIPANTS: 412 adults with untreated systolic blood pressure of 120 to 160 mm Hg and diastolic blood pressure of 80 to 95 mm Hg. INTERVENTION: Participants followed the DASH diet or a control (typical U.S.) diet for three consecutive 30-day feeding periods, during which sodium intake (50, 100, and 150 mmol/d at 2100 kcal) varied according to a randomly assigned sequence. Body weight was maintained. MEASUREMENTS: Systolic and diastolic blood pressure. RESULTS: In all subgroups, the DASH diet and reduced sodium intake were each associated with significant decreases in blood pressure; these two factors combined produced the greatest reductions. Among nonhypertensive participants who received the control diet, lower (vs. higher) sodium intake decreased blood pressure by 7.0/3.8 mm Hg in those older than 45 years of age (P < 0.001) and by 3.7/1.5 mm Hg in those 45 years of age or younger (P < 0.05). CONCLUSION: The DASH diet plus reduced sodium intake is recommended to control blood pressure in diverse subgroups.