Managing Cardiovascular Complications in Diabetes (1)
I finished the book today. I wrote a brief review of the book on goodreads and gave it three stars. Many things covered in this book I’ve read about in detail elsewhere, e.g. in Sperling et al., Edwards et al., or, say, Eckel et al, but there was some new stuff in here as well. I really liked the first chapter, about ‘The Vascular Endothelium in Diabetes’; it covered some stuff which I’d never really gotten to the bottom of before (but due to the technical nature of that chapter I decided against covering it here). There are still a lot of details which I will not claim to fully understand, but I understand some of the main principles/mechanisms much better than I did. The book was occasionally difficult for me to read because it required knowledge about areas about which I didn’t know a great deal (e.g. haematology), and you should certainly not read this book if you don’t read more or less fluent medical textbook (“The focus of this book is to assist the physician or surgeon in preventing and managing CVD and CVD risk in diabetic patients”). As I pointed out in my goodreads review, the book was difficult for me to read for another reason as well. Authors of academic books should not use acronyms which they do not explain to the reader. Authors of such books should not explain unexplained acronyms five pages after they have used them for the first time. If they do, people might get angry at them.
I’m sure some people don’t care about such things, but this is the sort of stuff that can really piss me off, and it’s part of the reason why this book got three stars. Combining behaviour like that with some formatting errors and a few sentences which don’t make any sense because nobody seems to have proofread the damn thing, and you can end up with an academic publication which looks amateurish, even if it’s most certainly nothing of the sort. In terms of the formatting errors I will note that this is not the first Wiley-Blackwell publication like this I’ve seen – as I point out in my review of that book, the Edwards et al publication to which I link above had similar problems. It’s much rarer, I think, to see stuff like that in Springer publications.
I have added some observations from the book below. I plan to write another post about the book later on as I don’t think it’s fair to only give this book one post, considering how much stuff is in there. When I started out writing this post I was thinking that I’d make the quotes easier to read by adding relevant links where they might help. I realized quite fast that adding enough links to actually make a huge difference would most certainly not be worth it, though I have added a link here and there anyway in order to make the post more readable. I have also added a few bold sections below – I don’t like writing long posts and then have people not reading them because they’re long, so if you don’t particularly care about the topic covered below you might want to read the bolded parts in order to at least learn something from the post. There’s a lot more stuff about type 2 diabetes than about type 1 in this book, so when reading ‘diabetes’ below you should probably just think ‘type 2’.
I remember recently reading an article somewhere stating that there are many errors in medicine-related wikipedia articles and how that’s a problem, and I actually encountered an example of this while reading the book, though I can’t now remember which article it was. You should take it for granted that wiki articles to which I link in posts like these may have errors and inaccuracies (they may actually contain statements which are contradicted by the material covered in the book…), and I usually only link to them in posts like these to ‘translate’ the terms used without having to add a lot of additional text to the post in question. I’ll often not have read the articles to which I link when I link to as many as I do in this post, and a link to an article does not mean that I think all the stuff included in the article is correct. Okay, on to the book coverage:
“There is no doubt that diabetes is a significant contributor to the global burden of chronic non-communicable disease which accounts for over 36 million (63%) of deaths worldwide. Importantly, 80% of these deaths occur in low and middle income countries. [here’s a link to the source, the data above is from page 16. Note that “17.3 million (30%) [of all 57 million deaths worldwide] were due to CVDs.”] […] In an important contribution from the Global Burden of Metabolic Risk Factor of Chronic Disease Collaborating Group  national, regional and global trends in fasting plasma glucose and diabetes prevalence since 1980 were studied in a systematic analysis of health examination surveys involving over two and a half million participants and 370 country-years observations. They estimated that the number of people with diabetes increased from 153 (95% uncertainty interval 127–182) million in 1980 to 347 (314382) million in 2008 . [I included the quote partly because those numbers are interesting, partly because this quote from the introduction contains a good example of the kind of sloppiness I mention in the goodreads review; that last parenthesis was surely meant to say 314-382. But it doesn’t. And those kinds of small errors are all over the place.] […] In addition to increased risk of CVD patients with diabetes and established vascular disease have a poorer outcome than those without diabetes [7, 8]. Peripheral arterial disease is increased 2-4 fold in the diabetic population and lower limb amputations are at least 10 fold more common such that half of non-traumatic amputations are performed in diabetic patients [3, 7, 8].”
“a mean duration of diabetes of about a decade appears to confer an equivalent risk of CVD to a prior history of MI. In addition, recent work has shown that a history of DM results in six years of life years lost, mostly from CVD . […] 20% of all vascular events occur in patients without any traditional risk factors, necessitating the need for more precise clinical tools that aid clinicians in identifying those at highest risk . To help achieve this goal, there is growing interest in the development and exploitation of new biomarkers. […] A biomarker was defined by a National Institutes of Health (NIH) working group as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” . […] A biomarker should meet several criteria to be deemed clinically useful. This is structured around three fundamental questions : 1 Is the biomarker measurable? 2 Does the biomarker add new information? 3 Will the biomarker help the clinician to manage patients? Additional criteria include cost-effectiveness, safety, and replication of the biomarker in clinical scenarios. […] [Reclassification] is a relatively new concept, but potentially the most clinically relevant [of four criteria covered] as it assesses the ability of a test to reclassify individuals correctly into a different risk category; for example, an intermediate-risk subject into a high-risk subject, or a low-risk subject into an intermediate-risk subject […] The ability of the new test to achieve reclassification can be statistically examined by net reclassification improvement (NRI) or integrated discrimination improvement (IDI). The NRI method, which is determined by the proportion of individuals whose risk is correctly escalated or de-escalated, is more useful in primary prevention, where well-accepted categories of risk exist. The IDI estimates the change in predicted probability of an outcome between those with and without the outcome after the biomarker is added to the prediction model. The larger the value of the NRI or the IDI, the better the biomarker.”
Quite a few biomarkers are covered in the chapter, but I’d rather not talk too much about that stuff. There are various types of circulating biomarkers, imaging biomarkers and genetic biomarkers. A few have been included in national guidelines and the only class which does not seem to be useful in this context is the genetic one [“The AHA has given genomic testing in risk assessment in asymptomatic adults a Class III recommendation (no benefit)”]. Naturally reasons besides those related to assessing cardiovascular risk exist for doing genetic testing on diabetics, but if such tests are not useful in that respect then of course that limits their potential somewhat. Incidentally many biomarkers they talk about seem to measure similar things, meaning that adding them together don’t add a lot of information:
“It is logical to assume that if one biomarker measure gives a small incremental gain in risk prediction, multiple biomarkers would result in a larger one. However, trials of multiple biomarkers have disappointingly only shown at best a moderate improvement in usefulness when compared to standard risk factors .”
The biomarkers are assumed to hold most promise in the context of primary prevention, but “there is scant data on cost-effectiveness or differential benefit from specific treatments”. Okay, on to other stuff:
“Diabetic kidney disease […] is a clinical diagnosis and is defined by the presence of albuminuria, often with associated abnormal kidney function (an increase in creatinine or a decrease in creatinine clearance or estimated glomerular filtration rate [eGFR]) […] Diabetic nephropathy is a histological diagnosis, characterized by typical histopathological features including mesangial expansion, glomerular basement membrane thickening, and glomerulosclerosis with Kimmelstiel–Wilson lesions. Diabetic kidney disease is most commonly caused by diabetic nephropathy, but other kidney pathologies may be present […] Diabetic kidney disease is a chronic complication of diabetes and affects approximately one third of all diabetic patients [1, 2]. It is the most common cause of kidney failure requiring renal replacement therapy in Western countries  and can occur in both type 1 and type 2 diabetes with equivalent risks . The natural history and prognosis of diabetic kidney disease differ somewhat based on the type of diabetes and whether microalbuminuria is present […] In people with type 1 diabetes who have microalbuminuria, if left untreated, approximately 80% will develop macroalbuminuria (also called overt nephropathy) within 6–14 years [6, 7]. Subsequently, half of these will develop end-stage kidney disease (ESKD) over 10 years if there is still a lack of specific intervention. In contrast, approximately 20–40% of people with type 2 diabetes and microalbuminuria develop macroalbuminuria without intervention, and ESKD has been reported to develop in 20% of patients with overt nephropathy within 20 years . Some of these differences may relate to the older age and greater burden of comorbidity experienced by people with type 2 diabetes for a given duration of diabetes, meaning that more of them will die of cardiovascular and other complications before developing kidney disease.”
“Diabetic kidney disease has a heterogeneous presentation. Early stages are often asymptomatic and only detected by abnormal laboratory tests (albuminuria and changes in GFR). Albuminuria is one of the earliest detectable features of diabetic kidney disease […] As diabetes manifests as a systemic disease, patients with type 1 DM almost always have other signs of diabetic microvascular complications, such as retinopathy and neuropathy. Diabetic retinopathy usually precedes the onset of overt nephropathy, while the relationship between diabetic kidney disease and retinopathy is less predictable in type 2 diabetes. […] For people with type 1 diabetes, approximately 20–30% will have microalbuminuria after a mean duration of diabetes of 15 years [37, 38]. Similarly, 25% of individuals with type 2 diabetes have microalbuminuria after 10 years […] Proteinuria and abnormal kidney function are independent risk factors for renal outcomes in diabetes . […] As with treatment strategies for end-stage kidney disease secondary to other causes, dialysis and renal transplantation are both options for treatment for ESKD caused by diabetes. Lower survival rates have been observed for people with ESKD caused by diabetic kidney disease, with five years’ survival of 30%, according to USRDS data.”
“Cardiovascular disease (CVD) including coronary heart disease (CHD) is the major cause of mortality in patients with diabetes […] no more than 25% of the excess CHD risk in diabetes can be accounted for by established risk factors […] Hyperglycemia as a risk factor for CVD has been established for many years. Mortality from CVD accounts for more than 60% of deaths in patients with type 2 diabetes mellitus and clearly accounts for this ultimate complication of diabetes [3, 8]. The association between differing degrees of hyperglycemia and CVD risk has been an area of debate. The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that the incidence of myocardial infarction rose by 14% per 1% rise in HBA1c . This is in line with other studies showing that glucose is a continuous risk factor in people with both type 1 and type 2 diabetes. […] There is also evidence that glucose fluctuations (the highs and lows) are associated with increased oxidative stress […] Increased oxidative stress results from an imbalance between oxidant production and antioxidant defenses […] Diabetes mellitus, obesity, micro- and macrovascular complications have been consistently associated with increased oxidative stress [37, 38, 39] and several studies have demonstrated that hyperglycemia per se is associated with increased oxidative stress [39, 40]. […] Hypoglycemia is also associated with increased cardiovascular mortality [58, 59], although the mechanisms behind this remain unclear. […] As well as being associated with increased oxidative stress , hypoglycemia also has pro-inflammatory effects on the vasculature. […] These changes contribute to a hypercoagulable state associated with increased platelet aggregation and plasma concentrations of coagulation factors […] Acute hypoglycemia has also been associated with long QT syndrome, which is associated with an increased risk of sudden cardiac death .”
“The majority of people with type 2 DM [diabetes mellitus] are hypertensives […] There is no question about the need to treat hypertension in either the primary prevention or secondary prevention settings for cerebrovascular disease, irrespective of the presence of diabetes. A systematic review of the effects of different BP-lowering drug regimens in people with hypertension, diabetes, or vascular disease found that the relative risks of stroke and other major vascular outcomes were proportional to the BP reduction achieved . […] there is a general consensus that ACE inhibitors or ARB are the first-line drugs of choice in both diabetes and metabolic syndrome. In primary prevention, the only question is the level of BP above which treatment is indicated. […] The recommended threshold for treatment in primary prevention is currently under discussion in both diabetics and nondiabetics. […] there is increasing uncertainty about the use of absolute thresholds of BP to determine the need for treatment […] Although “lower should be better,” the results of recent clinical trials examining the benefits of normalizing risk-factor levels have been counter-intuitive and, sometimes, disconcerting, and have called into question this belief […] Many hypertensive patients in clinical practice receive more than one antihypertensive drug, and the use of combination therapy is widely recommended in hypertension guidelines. Combinations may be especially important for patients with diabetes, for whom recommended BP targets are challenging.”
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