Managing Cardiovascular Complications in Diabetes (2)

My first post about the book, which includes a few general remarks and observations, can be read here. In this post I’ll cover some stuff from the last 150 pages. I’ve bolded relevant key points here the same way I did in the first post about the book.

“Atherosclerosis-related disease, coronary heart disease (CHD), peripheral vascular disease (PVD), and thrombotic stroke are major complications in people with type 2 diabetes mellitus [1]. A recent meta-analysis of 102 prospective studies demonstrated a hazard ratio of 2 for coronary death and non-fatal myocardial infarction (MI) and 2.5 for ischemic stroke [2]. In the United Kingdom Prospective Diabetes Study (UKPDS), for each 1% increase in HbA1c there was a 28% increase in PVD [3]. […] In the National Health and Nutrition Examination (NHANES III) performed in the USA, the prevalence of metabolic syndrome in diabetes was 86%. The prevalence of CHD in this group was 19.2%. In those with diabetes and no evidence of metabolic syndrome, CHD prevalence was 7.5%, which is comparable to those without diabetes or metabolic syndrome [10]. Many studies in different populations have confirmed that dyslipidemia is a common finding in type 2 diabetes. […] A basic abnormality is the overproduction of large VLDL from the liver […] LDL-cholesterol concentrations are generally similar to those of the background population. However, LDL-cholesterol remains a major risk factor […] Qualitative changes in LDL particles increase their atherogenicity. The particles are smaller and denser with less lipid core. […] Statins are first-line pharmacotherapy for diabetic dyslipidemia. Their use is based on a wealth of data from robust, randomized trials for both primary and secondary prevention of CVD events. […] A large number of diabetic patients (n=2,912) was included in HPS. Simvastatin, which reduced LDL-cholesterol by 0.9 mmol/l, was associated with a 33% relative risk reduction in major CVD events (p = 0.0003). This benefit was independent of baseline lipids, diabetes duration, glycemic control, and age. The authors [of the HPS] calculated that simvastatin therapy over five years should prevent a first major cardiovascular event in about 45 people per 1,000 treated […] It is clear that patients with diabetes and CHD respond in a similar way to the nondiabetic population. However, a substantial residual vascular risk persists […] A contributory factor to the failure to achieve therapeutic goals is statin intolerance […] in practice there is a significant minority of patients who cannot tolerate statins at all, or can only tolerate a small dose, insufficient to achieve the LDL goal.”

Subjects with both type 1 and type 2 diabetes are at increased risk of developing cardiovascular disease, with approximately three-quarters of patients with diabetes ultimately dying from vascular causes.” [In the first post I included this quote from a previous chapter: “Mortality from CVD accounts for more than 60% of deaths in patients with type 2 diabetes mellitus”. Estimates vary (and these estimates need technically not be in conflict with each other as 75% is more than 60%…), but regardless of the differences this is ‘the big one’.]

“Overall, the available data indicate that diabetes is associated with a range of metabolic abnormalities that adversely influence platelet function [I should note that they go into a lot of detail about these ‘metabolic abnormalities’, and this is stuff I deliberately excluded from the coverage because it’s very technical stuff]. Management of the platelet aspect of this prothrombotic state should involve normalization of the metabolic changes seen in diabetes and the appropriate use of antiplatelet therapy […] aspirin is used for secondary cardiovascular protection in diabetes [38, 39], a practice supported by two large meta-analyses [40, 41]. […] data indicate that aspirin may be less effective in secondary cardiovascular protection in diabetes […] there is no convincing evidence for the use of aspirin monotherapy for primary cardiovascular protection in diabetes, although some guidelines recommend its use in high-risk subjects. […] There is evidence to suggest that the type of hypoglycemic agent used may modulate predisposition to future ischemic events. Metformin is normally used as first-line therapy in subjects with type 2 diabetes. The UK Prospective Diabetes Study (UKPDS) has demonstrated reduced ischemic heart disease (IHD) risk in overweight patients using metformin compared with subjects not on this therapy […] Insulin is mainly used in type 2 diabetes after the failure of other hypoglycemic agents. Insulin-treated type 2 diabetes subjects are at a greater risk of cardiovascular events compared with noninsulin-treated subjects, which may simply be a reflection of longer disease duration, with a consequent increase in the risk of complications [91]. In healthy individuals, insulin has antithrombotic effects, but it has the opposite effects in the presence of insulin resistance […] There are no clear guidelines for the treatment of diabetes with ACS and there is a great variability between countries and even centers in the same country, which is largely dependent on local resources and data interpretation of different trials. […] Antithrombotic therapy following ACS has been through major changes over the past decade. […] Despite major advances in therapy, atherothrombotic complications remain the main cause of morbidity and mortality in individuals with diabetes. […] Considered together, current evidence indicates that diabetes subjects have a differential response to antiplatelet and anticoagulant drug therapy compared to subjects with normal glucose metabolism. Further studies are still needed to clarify the optimal antithrombotic strategy in this high-risk population.”

“It is difficult, if not impossible, to assess directly the efficacy of individual dietary components on CVD risk because of the challenges, both practical and financial, in modifying the diets of a large group of people for long periods of time, as well as the difficulty that arises in studying individual dietary components within the context of habitual dietary patterns. Therefore, most dietary factors with the intent of reducing CVD risk are evaluated on the basis of short-term interventions (weeks or months) using biomarkers […] rather than hard endpoints. By combining data from different types of studies, dietary patterns have emerged that are associated with a lower risk of CVD […] Moderate fat intake (25% to 35% of energy) is associated with lower triglyceride concentrations than a low-fat diet. […] Current recommendations are to consume a diet containing 25%E [read: 25 percent of daily energy intake] to 35%E as total fat [3, 4]. For individuals with diabetes, the recommendation is to consume diets toward the higher end of this range [5, 6]. […] Low-fat diets are associated with elevated triglyceride concentrations and depressed high-density lipoprotein (HDL)-cholesterol concentrations resulting from what is commonly referred to as carbohydrate-induced hypertriglyceridemia […] Carbohydrate-induced hypertriglyceridemia, resulting in elevated triglyceride concentrations, is caused by an enhanced rate of hepatic fatty acid synthesis and is precipitated by an excess flow of glucose from the gut to the liver [14, 15] and subsequent production of hepatic triglyceride-rich particles, termed very low-density lipoprotein (VLDL) […]. In some cases delayed triglyceride clearance associated with low-fat diets has also been observed, contributing to the elevated triglyceride concentrations […] Within the context of a stable body weight, replacement of dietary fat with carbohydrate results in higher triglyceride and VLDL-cholesterol concentrations, lower HDL-cholesterol concentrations, and a higher (less favorable) total cholesterol to HDL-cholesterol ratio [20, 21, 22, 23, 24, 25].” [Eckel et al. pointed this out as well and I included coverage of this in my post about that book as well; but this is an important piece of information that I do not mind repeating here. Note that not all carbohydrates are the same, and that dietary fiber seems to have a protective effect. The chapter from which the above quote, and the paragraph below, was taken covered many of the same things covered in Barasi].

“a series of randomized controlled intervention trials […] have failed to demonstrate a benefit of supplemental vitamin E, beta-carotene, vitamin C, or folate on CVD risk reduction [156, 157]. Recently, interest has been focused on the potential effect of supplemental vitamin D in CVD risk reduction. In contrast to the prior vitamins, the relationship between vitamin D and CVD risk is focused on nutrient insufficiency rather than supplemental amounts [156, 158]. Until the results of randomized controlled trials with vitamin D become available, it is premature to make any recommendations.”

“Diabetics are more likely than nondiabetics to experience ACS, and diabetes is an independent predictor for mortality in ACS. Diabetics are also more likely to develop complications of ACS and its management such as heart failure and bleeding. With a few exceptions, the management of ACS is similar in patients with and without diabetes. In patients with diabetes, management does not differ between patients who are insulin dependent and patients who do not require insulin. […] The management of ACS begins with determining the appropriate timing for coronary artery reperfusion. Patients with STEMI [ST-elevation myocardial infarction – see this] or an equivalent should receive emergent reperfusion, preferably with PCI. Patients with UA/NSTEMI [see the link in the brackets above] can be risk stratified to determine the appropriate timing for coronary angiography. In these patients angiography is used to decide if medical therapy, PCI, or CABG [Coronary Artery Bypass Grafting] is the preferred treatment strategy. All patients with ACS should be treated with antiplatelet and antithrombin therapy, as well as adjuvant therapy with a statin, ACEI, and beta-blocker.” [there’s an entire chapter about these things where they go into quite a bit of detail, but I decided against covering this stuff here as most of it is once again highly technical stuff which is not easy to blog].

Amputation of the lower limb is one of the most feared adverse health outcomes among patients with diabetes. […] PAD [Peripheral Artery Disease], referring to atherosclerotic occlusive disease of the lower limb arteries is a common, debilitating complication that correlates with cardiovascular disease mortality [2]. Diabetes is a significant independent risk factor for PAD (odds ratio of 2–3) [3], together with hypertension, cardiovascular disease, hyperlipidemia, smoking, and obesity [3, 4]. The prevalence of PAD in patients with type 2 diabetes has been estimated at 23.5% in a UK population [5], and is strongly dependent on the duration of diabetes [6, 7]. Compared with men without diabetes, the adjusted relative risk of PAD among men with diabetes increased from 1.39 with diabetes duration of 1–5 years’ to 4.53 for diabetes of >25 years’ duration [7]. […] a very high prevalence (71%) of PAD was recently reported in 1,462 elderly patients with diabetes (>70 years) in Spain as evaluated by a pathological ABI (ankle-brachial index) [8]. […] A recent meta-analysis [7] including 94,640 participants and 1,227 LEA [Lower-Extremity Amputation] cases reported in 14 studies demonstrated a substantial increase in the risk of LEA associated with glycemia in individuals with diabetes. The overall risk reduction (RR) for LEA was 1.26 (95% CI 1.16–1.36) for each percentage point increase in HbA1c.”

“A Scottish study showed that after LEA diabetic subjects had a 55% greater risk of death than those without diabetes [10]. […] Median time to death […] was 27.2 months with diabetes versus 46.7 months without diabetes (p<0.01) and survival rate 10 years after amputation was 22.9% in nondiabetic patients but only 8.4% in diabetic patients (p=0.0007). [I’ve read about these things before, and I should note that I do not believe these estimates are unique or aberrant. It’s not just that losing a leg sucks – when you’re so far along in the disease process that they have to start cutting off parts of you to keep you alive, you’re really quite likely not to live for a very long time. The prognosis of a diabetic who just had a LEA is much worse than that of the average breast cancer patient.] […] The clinical stage of symptomatic PAD can be classified using the Fontaine staging system [21]. Fontaine stage I represents those who have PAD but are asymptomatic; stages IIa and IIb include patients with mild and moderate-to-severe intermittent claudication, respectively; those with ischemic rest pain are classified in Fontaine stage III; and patients with distal ulceration and gangrene represent Fontaine stage IV. Diagnosing PAD in patients with diabetes is of clinical importance for two reasons. The first is to identify a patient who has a high risk of subsequent MI or stroke regardless of whether symptoms of PAD are present. Indeed, patients with diabetes and PAD have a fivefold increased risk [of MI/stroke] compared to the presence of either disease alone [22, 23, 24, 25]. An observational study less then ten years ago demonstrated that patients with diabetes and PAD stage IV (=ulcer) have a 100% mortality within six years [26]. The second reason is to elicit and treat symptoms of PAD, which may be associated with functional disability and limb loss.”

“PAD is often more subtle in its presentation in patients with diabetes than in those without diabetes […] Importantly, PAD in individuals with diabetes is usually accompanied by peripheral neuropathy with impaired sensory feedback […] The majority of patients with early PAD are either asymptomatic or have atypical leg symptoms, with “classical” claudication in only 10–35%, therefore detection is elusive unless actively sought. Given shared risk factors, it is axiomatic that there exists a high coprevalence of atherosclerosis in other vascular beds, including the coronary arteries in PAD patients [74]. […] patients with PAD are at a high risk of cardiovascular events and therefore benefit from aggressive secondary prevention […] Many studies have documented that secondary prevention is underused in patients with PAD […] Antiplatelet drugs that have been shown to reduce the incidence of vascular death, nonfatal myocardial infarction, and nonfatal stroke in patients with PAD are aspirin, ticlopidine, and clopidogrel [101]. Aspirin plus dipyridamole has not been proven to be more efficacious than aspirin alone in the treatment of patients with PAD [101].”

“Compared to patients with intermittent claudication (IC; stage II of PAD), patients with critical limb ischemia (CLI; stages III and IV after Fontaine) are in a more difficult situation: while amputation is rather infrequently necessary in patients with IC [108], amputation rates of 23% at 12 months were reported in patients with CLI [109]. In patients with CLI, the incidence of diabetes mellitus and chronic renal insufficiency is 70.4% and 27.8%, respectively [109]. Thus, patients with CLI are in the majority among patients with diabetes […] The prevalence of gangrene is about 20 to 30 times higher in patients with diabetes mellitus [110].” [In terms of the treatment options, they put it frankly in their recommendations in that chapter: “Primary amputations only in a leg-for-life situation”].


June 30, 2014 - Posted by | Books, Cardiology, Diabetes, Epidemiology, Medicine, Neurology, Pharmacology

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