Diabetes and the brain (IV)
Here’s one of my previous posts in the series about the book. In this post I’ll cover material dealing with two acute hyperglycemia-related diabetic complications (DKA and HHS – see below…) as well as multiple topics related to diabetes and stroke. I’ll start out with a few quotes from the book about DKA and HHS:
“DKA [diabetic ketoacidosis] is defined by a triad of hyperglycemia, ketosis, and acidemia and occurs in the absolute or near-absolute absence of insulin. […] DKA accounts for the bulk of morbidity and mortality in children with T1DM. National population-based studies estimate DKA mortality at 0.15% in the United States (4), 0.18–0.25% in Canada (4, 5), and 0.31% in the United Kingdom (6). […] Rates reach 25–67% in those who are newly diagnosed (4, 8, 9). The rates are higher in younger children […] The risk of DKA among patients with pre-existing diabetes is 1–10% annual per person […] DKA can present with mild-to-severe symptoms. […] polyuria and polydipsia […] patients may present with signs of dehydration, such as tachycardia and dry mucus membranes. […] Vomiting, abdominal pain, malaise, and weight loss are common presenting symptoms […] Signs related to the ketoacidotic state include hyperventilation with deep breathing (Kussmaul’s respiration) which is a compensatory respiratory response to an underlying metabolic acidosis. Acetonemia may cause a fruity odor to the breath. […] Elevated glucose levels are almost always present; however, euglycemic DKA has been described (19). Anion-gap metabolic acidosis is the hallmark of this condition and is caused by elevated ketone bodies.”
“Clinically significant cerebral edema occurs in approximately 1% of patients with diabetic ketoacidosis […] DKA-related cerebral edema may represent a continuum. Mild forms resulting in subtle edema may result in modest mental status abnormalities whereas the most severe manifestations result in overt cerebral injury. […] Cerebral edema typically presents 4–12 h after the treatment for DKA is started (28, 29), but can occur at any time. […] Increased intracranial pressure with cerebral edema has been recognized as the leading cause of morbidity and mortality in pediatric patients with DKA (59). Mortality from DKA-related cerebral edema in children is high, up to 90% […] and accounts for 60–90% of the mortality seen in DKA […] many patients are left with major neurological deficits (28, 31, 35).”
“The hyperosmolar hyperglycemic state (HHS) is also an acute complication that may occur in patients with diabetes mellitus. It is seen primarily in patients with T2DM and has previously been referred to as “hyperglycemic hyperosmolar non-ketotic coma” or “hyperglycemic hyperosmolar non-ketotic state” (13). HHS is marked by profound dehydration and hyperglycemia and often by some degree of neurological impairment. The term hyperglycemic hyperosmolar state is used because (1) ketosis may be present and (2) there may be varying degrees of altered sensorium besides coma (13). Like DKA, the basic underlying disorder is inadequate circulating insulin, but there is often enough insulin to inhibit free fatty acid mobilization and ketoacidosis. […] Up to 20% of patients diagnosed with HHS do not have a previous history of diabetes mellitus (14). […] Kitabchi et al. estimated the rate of hospital admissions due to HHS to be lower than DKA, accounting for less than 1% of all primary diabetic admissions (13). […] Glucose levels rise in the setting of relative insulin deficiency. The low levels of circulating insulin prevent lipolysis, ketogenesis, and ketoacidosis (62) but are unable to suppress hyperglycemia, glucosuria, and water losses. […] HHS typically presents with one or more precipitating factors, similar to DKA. […] Acute infections […] account for approximately 32–50% of precipitating causes (13). […] The mortality rates for HHS vary between 10 and 20% (14, 93).”
It should perhaps be noted explicitly that the mortality rates for these complications are particularly high in the settings of either very young individuals (DKA) or in elderly individuals (HHS) who might have multiple comorbidities. Relatedly HHS often develops acutely specifically in settings where the precipitating factor is something really unpleasant like pneumonia or a cardiovascular event, so a high-ish mortality rate is perhaps not that surprising. Nor is it surprising that very young brains are particularly vulnerable in the context of DKA (I already discussed some of the research on these matters in some detail in an earlier post about this book).
This post to some extent covered the topic of ‘stroke in general’, however I wanted to include here also some more data specifically on diabetes-related matters about this topic. Here’s a quote to start off with:
“DM [Diabetes Mellitus] has been consistently shown to represent a strong independent risk factor of ischemic stroke. […] The contribution of hyperglycemia to increased stroke risk is not proven. […] the relationship between hyperglycemia and stroke remains subject of debate. In this respect, the association between hyperglycemia and cerebrovascular disease is established less strongly than the association between hyperglycemia and coronary heart disease. […] The course of stroke in patients with DM is characterized by higher mortality, more severe disability, and higher recurrence rate […] It is now well accepted that the risk of stroke in individuals with DM is equal to that of individuals with a history of myocardial infarction or stroke, but no DM (24–26). This was confirmed in a recently published large retrospective study which enrolled all inhabitants of Denmark (more than 3 million people out of whom 71,802 patients with DM) and were followed-up for 5 years. In men without DM the incidence of stroke was 2.5 in those without and 7.8% in those with prior myocardial infarction, whereas in patients with DM it was 9.6 in those without and 27.4% in those with history of myocardial infarction. In women the numbers were 2.5, 9.0, 10.0, and 14.2%, respectively (22).”
That study incidentally is very nice for me in particular to know about, given that I am a Danish diabetic. I do not here face any of the usual tiresome questions about ‘external validity’ and issues pertaining to ‘extrapolating out of sample’ – not only is it quite likely I’ve actually looked at some of the data used in that analysis myself, I also know that I am almost certainly one of the people included in the analysis. Of course you need other data as well to assess risk (e.g. age, see the previously linked post), but this is pretty clean as far as it goes. Moving on…
“The number of deaths from stroke attributable to DM is highest in low-and-middle-income countries […] the relative risk conveyed by DM is greater in younger subjects […] It is not well known whether type 1 or type 2 DM affects stroke risk differently. […] In the large cohort of women enrolled in the Nurses’ Health Study (116,316 women followed for up to 26 years) it was shown that the incidence of total stroke was fourfold higher in women with type 1 DM and twofold higher among women with type 2 DM than for non-diabetic women (33). […] The impact of DM duration as a stroke risk factor has not been clearly defined. […] In this context it is important to note that the actual duration of type 2 DM is difficult to determine precisely […and more generally: “the date of onset of a certain chronic disease is a quantity which is not defined as precisely as mortality“, as Yashin et al. put it – I also talked about this topic in my previous post, but it’s important when you’re looking at these sorts of things and is worth reiterating – US]. […] Traditional risk factors for stroke such as arterial hypertension, dyslipidemia, atrial fibrillation, heart failure, and previous myocardial infarction are more common in people with DM […]. However, the impact of DM on stroke is not just due to the higher prevalence of these risk factors, as the risk of mortality and morbidity remains over twofold increased after correcting for these factors (4, 37). […] It is informative to distinguish between factors that are non-specific and specific to DM. DM-specific factors, including chronic hyperglycemia, DM duration, DM type and complications, and insulin resistance, may contribute to an elevated stroke risk either by amplification of the harmful effect of other “classical” non-specific risk factors, such as hypertension, or by acting independently.”
More than a few variables are known to impact stroke risk, but the fact that many of the risk factors are related to each other (‘fat people often also have high blood pressure’) makes it hard to figure out which variables are most important, how they interact with each other, etc., etc. One might in that context perhaps conceptualize the metabolic syndrome (-MS) as a sort of indicator variable indicating whether a relatively common set of such related potential risk factors of interest are present or not – it is worth noting in that context that the authors include in the text the observation that: “it is yet uncertain if the whole concept of the MS entails more than its individual components. The clustering of risk factors complicates the assessment of the contribution of individual components to the risk of vascular events, as well as assessment of synergistic or interacting effects.” MS confers a two-threefold increased stroke risk, depending on the definition and the population analyzed, so there’s definitely some relevant stuff included in that box, but in the context of developing new treatment options and better assess risk it might be helpful to – to put it simplistically – know if variable X is significantly more important than variable Y (and how the variables interact, etc., etc.). But this sort of information is hard to get.
There’s more than one type of stroke, and the way diabetes modifies the risk of various stroke types is not completely clear:
“Most studies have consistently shown that DM is an important risk factor for ischemic stroke, while the incidence of hemorrhagic stroke in subjects with DM does not seem to be increased. Consequently, the ratio of ischemic to hemorrhagic stroke is higher in patients with DM than in those stroke patients without DM [recall the base rates I’ve mentioned before in the coverage of this book: 80% of strokes are ischemic strokes in Western countries, and 15 % hemorrhagic] […] The data regarding an association between DM and the risk of hemorrhagic stroke are quite conflicting. In the most series no increased risk of cerebral hemorrhage was found (10, 101), and in the Copenhagen Stroke Registry, hemorrhagic stroke was even six times less frequent in diabetic patients than in non-diabetic subjects (102). […] However, in another prospective population-based study DM was associated with an increased risk of primary intracerebral hemorrhage (103). […] The significance of DM as a risk factor of hemorrhagic stroke could differ depending on ethnicity of subjects or type of DM. In the large Nurses’ Health Study type 1 DM increased the risk of hemorrhagic stroke by 3.8 times while type 2 DM did not increase such a risk (96). […] It is yet unclear if DM predominantly predisposes to either large or small vessel ischemic stroke. Nevertheless, lacunar stroke (small, less than 15mm in diameter infarction, cyst-like, frequently multiple) is considered to be the typical type of stroke in diabetic subjects (105–107), and DM may be present in up to 28–43% of patients with cerebral lacunar infarction (108–110).”
The Danish results mentioned above might not be as useful to me as they were before if the type is important, because the majority of those diabetics included were type 2 diabetics. I know from personal experience that it is difficult to type-identify diabetics using the Danish registry data available if you want to work with population-level data, and any type of scheme attempting this will be subject to potentially large misidentification problems. Some subgroups can be presumably correctly identified using diagnostic codes, but a very large number of individuals will be left out of the analyses if you only rely on identification strategies where you’re (at least reasonably?) certain about the type. I’ve worked on these identification problems during my graduate work so perhaps a few more things are worth mentioning here. In the context of diabetic subgroup analyses, misidentification is in general a much larger problem in the context of type 1 results than in the context of type 2 results; unless the study design takes the large prevalence difference of the two conditions into account, the type 1 sample will be much smaller than the type 2 sample in pretty much all analytical contexts, so a small number of misidentified type 2 individuals can have large impacts on the results of the type 1 sample. Type 1s misidentified as type 2 individuals is in general to be expected to be a much smaller problem in terms of the validity of the type 2 analysis; misidentification of that type will cause a loss of power in the context of the type 1 subgroup analysis, which is already low to start with (and it’ll also make the type 1 subgroup analysis even more vulnerable to misidentified type 2s), but it won’t much change the results of the type 2 subgroup analysis in any significant way. Relatedly, even if enough type 2 patients are misidentified to cause problems with the interpretation of the type 1 subgroup analysis, this would not on its own be a good reason to doubt the results of the type 2 subgroup analysis. Another thing to note in terms of these things is that given that misidentification will tend to lead to ‘mixing’, i.e. it’ll make the subgroup results look similar, when outcomes are not similar in the type 1 and the type 2 individuals then this might be taken to be an indicator that something potentially interesting might be going on, because most analyses will struggle with some level of misidentification which will tend to reduce the power of tests of group differences.
What about stroke outcomes? A few observations were included on that topic above, but the book has a lot more stuff on that – some observations on this topic:
“DM is an independent risk factor of death from stroke […]. Tuomilehto et al. (35) calculated that 16% of all stroke mortality in men and 33% in women could be directly attributed to DM. Patients with DM have higher hospital and long-term stroke mortality, more pronounced residual neurological deficits, and more severe disability after acute cerebrovascular accidents […]. The 1-year mortality rate, for example, was twofold higher in diabetic patients compared to non-diabetic subjects (50% vs. 25%) […]. Only 20% of people with DM survive over 5 years after the first stroke and half of these patients die within the first year (36, 128). […] The mechanisms underlying the worse outcome of stroke in diabetic subjects are not fully understood. […] Regarding prevention of stroke in patients with DM, it may be less relevant than in non-DM subjects to distinguish between primary and secondary prevention as all patients with DM are considered to be high-risk subjects regardless of the history of cerebrovascular accidents or the presence of clinical and subclinical vascular lesions. […] The influence of the mode of antihyperglycemic treatment on the risk of stroke is uncertain.”
Control of blood pressure is very important in the diabetic setting:
“There are no doubts that there is a linear relation between elevated systolic blood pressure and the risk of stroke, both in people with or without DM. […] Although DM and arterial hypertension represent significant independent risk factors for stroke if they co-occur in the same patient the risk increases dramatically. A prospective study of almost 50 thousand subjects in Finland followed up for 19 years revealed that the hazard ratio for stroke incidence was 1.4, 2.0, 2.5, 3.5, and 4.5 and for stroke mortality was 1.5, 2.6, 3.1, 5.6, and 9.3, respectively, in subjects with an isolated modestly elevated blood pressure (systolic 140–159/diastolic 90–94 mmHg), isolated more severe hypertension (systolic >159 mmHg, diastolic >94 mmHg, or use of antihypertensive drugs), with isolated DM only, with both DM and modestly elevated blood pressure, and with both DM and more severe hypertension, relative to subjects without either of the risk factors (168). […] it remains unclear whether some classes of antihypertensive agents provide a stronger protection against stroke in diabetic patients than others. […] effective antihypertensive treatment is highly beneficial for reduction of stroke risk in diabetic patients, but the advantages of any particular class of antihypertensive medications are not substantially proven.”
Treatment of dyslipidemia is also very important, but here it does seem to matter how you treat it:
“It seems that the beneficial effect of statins is dose-dependent. The lower the LDL level that is achieved the stronger the cardiovascular protection. […] Recently, the results of the meta-analysis of 14 randomized trials of statins in 18,686 patients with DM had been published. It was calculated that statins use in diabetic patients can result in a 21% reduction of the risk of any stroke per 1 mmol/l reduction of LDL achieved […] There is no evidence from trials that supports efficacy of fibrates for stroke prevention in diabetic patients. […] No reduction of stroke risk by fibrates was shown also in a meta-analysis of eight trials enrolled 12,249 patients with type 2 DM (204).”
“Significant reductions in stroke risk in diabetic patients receiving antiplatelet therapy were found in large-scale controlled trials (205). It appears that based on the high incidence of stroke and prevalence of stroke risk factors in the diabetic population the benefits of routine aspirin use for primary and secondary stroke prevention outweigh its potential risk of hemorrhagic stroke especially in patients older than 30 years having at least one additional risk factor (206). […] both guidelines issued by the AHA/ADA or the ESC/EASD on the prevention of cardiovascular disease in patients with DM support the use of aspirin in a dose of 50–325 mg daily for the primary prevention of stroke in subjects older than 40 years of age and additional risk factors, such as DM […] The newer antiplatelet agent, clopidogrel, was more efficacious in prevention of ischemic stroke than aspirin with greater risk reduction in the diabetic cohort especially in those treated with insulin compared to non-diabetics in CAPRIE trial (209). However, the combination of aspirin and clopidogrel does not appear to be more efficacious and safe compared to clopidogrel or aspirin alone”.
When you treat all risk factors aggressively, it turns out that the elevated stroke risk can be substantially reduced. Again the data on this stuff is from Denmark:
“Gaede et al. (216) have shown in the Steno 2 study that intensive multifactorial intervention aimed at correction of hyperglycemia, hypertension, dyslipidemia, and microalbuminuria along with aspirin use resulted in a reduction of cardiovascular morbidity including non-fatal stroke […] recently the results of the extended 13.3 years follow-up of this study were presented and the reduction of cardiovascular mortality by 57% and morbidity by 59% along with the reduction of the number of non-fatal stroke (6 vs. 30 events) in intensively treated group was convincingly demonstrated (217). Antihypertensive, hypolipidemic treatment, use of aspirin should thus be recommended as either primary or secondary prevention of stroke for patients with DM.”
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