Epidemiologic studies consistently indicate that consumption of nuts at least 5 times per week will reduce CAD and diabetes risks by 20% to 50%. Tree nuts are comprised predominantly of monounsaturated fats and are a rich source of antioxidants, fiber, phytosterols, magnesium, and folic acid, which might beneficially influence CV risk. Replacing refined carbohydrates with monounsaturated fats (using nuts and/or olive oil) will reduce post-prandial hyperglycemia and hypertriglyceridemia, increase high-density lipoprotein, and decrease oxidative stress . One practical way to accomplish this is to substitute nuts (all of which have very low glycemic indexes) for the sugary and starchy snack foods that are staples in the American diet.
The GLP-1 receptor agonists and DPP-4 inhibitors lower blood pressure and improve the lipid profile, which, although not appropriate as primary therapy, makes them especially valuable treatment options for patients with T2DM. These improvements may help to reduce the risk of cardiovascular events. Various approaches can be taken to initiate and modify GLP-1 receptor agonist and DPP-4 inhibitor therapy to improve efficacy and tolerability based on patient characteristics and concomitant therapies.
With the popularity of ACE inhibitors in mind, investigators conducted a systematic review of published studies to determine how effective the drugs actually are in reducing blood pressure. They also examined dose effectiveness, adverse effects, and the role of co-occurring conditions.
Researchers looked for double-blind studies comparing ACE inhibitors and placebo. All included studies were at least 3 weeks in duration and measured blood pressure as an endpoint at 3-12 weeks. Studies that featured a response-dependent titration of medications were included in the review. Only research that focused on patients with a blood pressure above 140/90 mm Hg was reviewed.
The review included 92 trials with a total of 12,954 participants (mean age, 54 years). Mean baseline blood pressure was 157/101 mm Hg and mean pulse pressure was 56 mm Hg. The majority (75%) of included studies was industry-sponsored, and 82% of the trials examined fixed-dose ACE inhibitors. The duration of trials was generally short, which limited data with regard to adverse events and study withdrawals.
The main potential source of bias in the research was a lack of information with regard to how the studies were blinded. In addition, the reviewers suggested that the researchers could have preferentially selected patients more likely to respond to ACE inhibitors. This selection bias could make ACE inhibitors appear more effective than they truly are.
The studies covered 14 ACE inhibitors. The degree of homogeneity with regard to their efficacy in reducing blood pressure was remarkable. No one medication appeared superior to others.
Overall, ACE inhibitors had a modest collective effect in reducing blood pressure. The mean reduction in systolic blood pressure ranged between 6 mm Hg and 9 mm Hg, and the mean reduction in diastolic blood pressure was 4-5 mm Hg. Less data were available with regard to the blood pressure effects of ACE inhibitors at 1-12 hours after dosing, but the average decrease in blood pressure with ACE inhibitors around their peak concentration was greater than their average efficacy (11.4/6.4 mm Hg).
The study provided some important information about the relationship between the dose of ACE inhibitors and their effect on blood pressure. Doses lower than the manufacturers' maximum recommended dosage had the same blood pressure-lowering effect as the maximum dose. For example, doses of one eighth to one quarter of the maximum achieved the blood pressure-lowering effect of the maximum dose in 60% to 70% of cases. Half of the maximum dose achieved it 90% of the time. There was no blood pressure-lowering effect at or below one sixteenth of the maximum suggested dose. These data suggest that use of the maximum dosage of ACE inhibitors to achieve greater blood pressure control is usually unnecessary.
The research also identified dosing information for individual ACE inhibitors and suggested that the manufacturers' recommended starting doses of benazepril, moexipril, and ramipril are higher than the minimum dose needed to reduce blood pressure. Conversely, captopril did not appear effective in reducing blood pressure at the manufacturers' recommended starting dose. Most of the maximum blood pressure-lowering effect of lisinopril was achieved at only one eighth of the recommended maximum dose.
ACE inhibitor dosing was also one of the biggest deficits in the current review. It was clear to the review authors that not all data in regard to the efficacy of different doses of ACE inhibitors were published. Instead, the data were supplied to regulators privately to determine the appropriate dosing range of ACE inhibitors.
Only half of trials provided data in regard to the rate of withdrawal due to adverse events. Collectively, there was no difference between ACE inhibitors and placebo in this critical outcome. ACE inhibitors did not significantly affect patients' heart rate.
Physicians might choose ACE inhibitors to treat hypertension for other possible health benefits associated with these medications, especially the potential to prevent type 2 diabetes. ACE inhibitors can have a positive effect on glucose metabolism through multiple mechanisms, and previous research suggested that they could prevent incident diabetes compared with other antihypertensive medications. Specifically, the Captopril Prevention Project demonstrated a 14% relative reduction in this outcome among participants receiving captopril vs a diuretic or beta-blocker. This benefit, associated with captopril, was evident regardless of the baseline risk for diabetes, although the incidence of diabetes was not a primary outcome of the study.
The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial directly examined the effect of ramipril vs placebo on the incidence of diabetes. This study examined patients with impaired fasting glucose levels or reduced insulin sensitivity but no history of cardiovascular disease. After a median of 3 years of treatment, ramipril was not associated with a significantly lower incidence of diabetes compared with placebo. Median fasting plasma glucose levels were also similar at the end of the trial. However, ramipril was associated with a higher rate of return to normoglycemia.
Physicians might also consider using ACE inhibitors for hypertension in order to prevent incident heart failure. However, although ACE inhibitors are associated with numerous positive outcomes, including reduced mortality, among patients with known heart failure, little evidence exists that they provide special protection against new heart failure. In a study of quinapril and placebo initiated shortly after myocardial infarction, there was no difference between treatment groups in a composite outcome of cardiovascular death and significant cardiovascular events. Specifically, no difference was found in the risk for heart failure among those patients at high cardiovascular risk. Similarly, in the Antihypertensive and Lipid-Lowering Treatment to Prevent Hearth Attack Trial (ALLHAT), the incidence of heart failure was similar among patients receiving lisinopril and chlorthalidone.
Although ACE inhibitors may not provide special protection against diabetes or heart failure among patients with hypertension, physicians should still consider these medications when managing hypertension. In fact, the nature of hypertension management dictates that they have to because most patients require more than 1 medication initially. In a recent study of men receiving care at a Veteran Affairs hospital, 60.4% of subjects with hypertension and significant cardiovascular risk were receiving multiple antihypertensive medications. Nevertheless, only 28% of these same patients had reached their goal blood pressure levels, indicating that they needed titration of their medications, if not the addition of other antihypertensive drugs.
The main results of the ACCOMPLISH trial, which demonstrated the superiority of a combination of initiating antihypertensive therapy with an ACE inhibitor plus a calcium channel blocker (CCB) over initiating with a thiazide-type diuretic, have been published in The New England Journal of Medicine, approximately 9 months after preliminary findings were presented at the annual Scientific Sessions of the American College of Cardiology. These results challenge current US hypertension guidelines, which recommend inclusion of a diuretic in first-line combination therapy.
Between 2003 and 2005, the international ACCOMPLISH trial randomized 11,506 patients with hypertension (mean age 68.4 years) who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide (HCTZ) as single capsule formulations. The only other antihypertensive medications permitted were beta-blockers, alpha-blockers, clonidine, and spironolactone. The trial was terminated early, after a mean follow-up of 36 months, when an interim analysis showed overwhelming efficacy in favor of the benazepril-amlodipine combination. Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-HCTZ group. Rates of blood pressure control (<>
The primary endpoint was the composite of death from cardiovascular causes, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization. There were 552 primary-outcome events in the benazepril-amlodipine group (9.6%) compared with 679 in the benazepril-HCTZ (11.8%), representing an absolute risk reduction with benazepril-amlodipine therapy of 2.2% and a relative risk reduction of 19.6%. For the secondary endpoint of death from cardiovascular causes, nonfatal MI, and nonfatal stroke, the hazard ratio was 0.79. Rates of adverse events were similar in the 2 treatment groups and consistent with those observed from clinical experience with the drugs.
In a press release issued by the University of Michigan Health System, Ann Arbor, lead investigator Kenneth Jamerson, MD, said, "This robust study showed us that switching patients to a single-pill combination meant that twice as many patients got to their blood pressure goal, regardless of previous therapy. The significant reduction in cardiovascular events we observed in patients will, I hope, show physicians that earlier use of a combination medication, especially with amlodipine, may be in the best interest of patients."
The updated recommendation is based on the results of the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), an international study supported by Boehringer Ingelheim, the Heart and Stroke Foundation of Ontario, and the Canadian Institutes of Health Research. The main results of ONTARGET, published in 2008,[9] showed that in 25,620 patients with vascular disease or type 2 diabetes, the combination therapy had a greater blood pressure-lowering effect than either telmisartan or ramipril alone, but it did not produce any additional benefit in terms of patient outcomes, and it was associated with more side effects, such as hyperkalemia, hypotension, and renal impairment. The guidelines also note that in patients with stage 3 chronic kidney disease (glomerular filtration rate > 30 mL/min) the ACE inhibitor plus ARB combination reduced urine protein but did not reduce cardiovascular outcomes, and it worsened renal outcomes, including the need for acute dialysis compared with the ACE inhibitor alone.
The only data to support improved patient outcomes with the combination of an ACE inhibitor plus an ARB are in people with heart failure, where, the guidelines note, the combination reduces recurrent hospitalization. Hence, the guidelines advise that the use of combination of ACE inhibitor with an ARB therapy should only be considered in selected and closely monitored people with advanced heart failure or proteinuric nephropathy. They advise that for people already on the combination and stable, physicians should consider that prescribing 1 of the 2 drug classes alone will reduce cardiovascular events to the same extent and that other therapeutic regimens have the potential to reduce cardiovascular events and blood pressure to a greater degree. Trials are ongoing of a combination of an ACE inhibitor with an ARB in people with chronic kidney disease and diabetes.
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