Download and cardiovascular mortality in type 2 diabetes.

What are the risk factors for increased cardiovascular mortality in
Type 2 Diabetes? Is there a greater risk for type 2 Diabetics than
non-diabetics? If yes by how much is this risk greater and what
evidence is there to support?
Diabetes Mellitus is a well-established risk factor for cardiovascular
disease. Compared with non-diabetic subjects people with type 2
diabetes mellitus (T2DM) have a higher cardiovascular morbidity and
mortality, and are disproportionately affected by cardiovascular
disease.
TRADITIONAL RISK FACTORS:
Ø Dyslipidaemia
Ø Blood pressure
Ø Obesity
Ø Physical exercise
Ø Smoking
NON-TRADITIONAL RISK FACTORS:
Ø Insulin resistance and hyperinsulinemia
Ø Postprandial hyperglycaemia and glucose variability
Ø Microalbuminuria
Ø Haematological and thrombogenic factors
Ø Inflammation: C-reactive protein
Ø Homocysteine and vitamins
Ø Erectile dysfunction
Ø Genetics and epigenetics
Cardiovascular risk and Type 2 Diabetes
Patients with Diabetes Mellitus, particularly Type 2, have a
considerably increased risk for cardiovascular morbidity and mortality.
This excess risk is augmented by the high prevalence of traditional
risk factors such as hypertension, dyslipidemia, obesity, abdominal
obesity and cigarette smoking in patients with Type 2 diabetes
mellitus (T2DM), according to Martin-Timón et al (2014).
T2DM is associated with a 2-4 fold increase in occurrence of
coronary artery disease and stroke and a 2-8 fold increase in heart
failure, Martin-Timón et al (2014). The increased CVD risk in T2DM is
attributed to the interaction between traditional and non traditional risk
factors for CVD as listed by Anil and not hyperglycaemia alone. In a
review by Laakso, 2010 he points out to evidence that insulin
resistance and compensatory hyperinsulinaemia is strongly linked to
increased risk of CVD in T2DM and the fact that
hyperinsulinaemia in non diabetic patients increases their CVD risk.
Studies for prevention and management of these risk factors in
patients with T2DM have shown a risk reduction in cardiovascular
disease. The association of hyperglycaemia with increased CVD risk
was shown by the United Kingdom prospective diabetes study
(UKPDS). The results showed that a reduction of Hba1c by
1% reduced fatal and non fatal myocardial infarction(MI) by 18%
(American Diabetes Association, ADA, 2002). In a 10 year follow up
of the UKPDS, intensive glycaemic therapy showed a risk reduction
of 15% of MI, P=0.01.
The STENO-2 , 13 year follow up showed that early and intensive
multifactorial therapy was associated with 56% lower risk of al-cause
mortality, P=0.02 and 57% lower risk of death from CVD, P=0.04,
Dailey (2011)
Incidence of Coronary Artery Disease [CAD] and cardiovascular
mortality in type 2 diabetes.
As early as 1993 Stamler et al identified diabetes as being an
independent risk factor for cardiovascular mortality. The MRFIT trail
found that after adjusting for other risk factors such as hypertension,
age, race, cigarette smoking and elevated cholesterol, diabetic
patients had a 3 times greater mortality rate then non-diabetic
subjects.
A Finnish Study by Haffner et al (1998) showed that individuals
between 45 and 64 years of age with diabetes, who had no previous
MI, had the same mortality rate as those non diabetics who had had a
previous MI. This led them to conclude diabetes was an independent
risk factor for cardiovascular mortality.
The Framingham Study (Kannel et al 1979) showed a 2 -3 fold
increase in cardiovascular disease [CVD] in those with type 2
diabetes. Cardiovascular disease is known to be the lead cause of
death in developing countries. They found that elevations in HbA1c
were related to increased incidence of CVD in woman but not in men.
The incidence of CVD increased 1, 4 fold for each 1% increase in
HbA1c
Glycaemic control and cardiovascular mortality
In the San Antonio Heart study (Wei et al 1998) it was found that
cardiovascular mortality increased with an increase in fasting blood
sugar. Subjects with a FBG of > 11, 5 mlmol/L had a 4 times greater
cardiovascular mortality then those with fasting blood sugars <
8mlmol/L.
This finding confirmed the findings of the Rancho Bernardo Study by
Barrett- Connor et al (2013), which showed a linear progression in the
association of ischemic heart disease mortality rates with increases in
fasting blood glucose among men. Woman showed a threshold for
increased mortality at a fasting glucose level of 6.1 mlmol/L.
The UKPDS study showed a non-significant 16% reduction of
combined non-fatal and fatal myocardial Infarction with tighter
glycaemic control. The most significant finding was that Metformin
treatment in over weight patients was associated with a 39% risk
reduction of fatal and non-fatal Myocardial Infarction. (UKPDS Study
group 1998)
Survival rates in acute coronary syndromes
Diabetes has also shown to lead to worse survival out comes in MI
patients receiving thrombolytic therapy. This was demonstrated in the
GUSTO-1 trail (Mak et al 1997) and GISSI-2 trail. Insulin treated
patients had the worst outcomes in both trails and woman were at
highest risk in the GISSI-2 trail (Zuanetti et al 1993)
Timmer et al (2007) showed that diabetic patients undergoing
percutaneous coronary intervention (PCI) had a greater mortality rate
than non-diabetic patients.
Type 2 diabetes is also associated with increased mortality due to
heart failure (Poulsen et al 2010) and atrial fibrillation (Huxly et al
2011)
Framingham Heart Study as the results of this study have had a
significant contribution into understanding of CVD and Diabetes.
A connection between CVD and diabetes was suspected at the first
time in the mid of 19th century. But attention to this problem was very
little until the discovery of new drugs for treatment in mid 20th century
that prolonged life of patients with diabetes long enough to develop
CVD ( Kengne et al 2010). Since that CVD in patients with diabetes
has been evaluated and characterized in many studies.
Framingham Heart Study is a population-based prospective family
study that started in 1948 till now involving 3 generations of the
families collecting data on CVD and its risk factors. Diabetes was
recognized as a risk factor for CVD very early in the study being
associated with 2-4 fold increased risk for congestive heart failure,
myocardial infarction, stroke, peripheral artery disease and increased
mortality (Fox et al 2010). Study has shown that diabetes as a risk
factor was much stronger associated in women in comparison to men
(Kannel 1979).
Attributable risk – evaluates the impact of the risk factor on the
disease outcome has also been studied in Framingham study. It was
reported that the attributable risk of CVD because of diabetes
increased from 5.4% between the years 1952-1974 and 8.7%
between 1975-1998 years. The attributable risk ratio was calculated
as 1.62 (Fox 2007). In comparison the percentage of other CVD risk
factors as hypertension either decreased or remained stable.
All cause mortality and cardiovascular mortality was twice higher in
patients with diabetes as compared to patients without diabetes
(Preis et al 2009).
Framingham study has also compared CVD risk factors in patients
with diabetes and without. They found out that individuals with
diabetes had greater increase in BMI, greater decrease in LDL and
systolic blood pressure as compared to patients without diabetes.
These findings show that patients with diabetes did not achieve the
necessary decline in CVD risk factors in order to overcome the
increased risk for CVD which means that these factors should be
targeted more aggressively in patients with diabetes (Preis et al
2009).
Pathogenesis of macrovascular disease in diabetes.
Macrovascular
complications
are
mainly represented
by
atherosclerotic disease and its sequelae (Paneni et al., 2013) of
which persistent hyperglycaemia and insulin resistance are eminent
factors in its development together with other risk factors such as
arterial hypertension, dyslipidemia as well as genetic susceptibility.
Atherosclerosis is a chronic, systemic, and diffuse disease with focal
complications in different vascular beds (Lerman and Zeiher, 2005).
Elevated plasma insulin concentrations enhance very-low-density
lipoprotein
(VLDL)
synthesis,
leading
to
hypertriglyceridemia and
progressive elimination of lipid and
apolipoproteins from the VLDL particle leads to an increased
formation of intermediate-density and low-density lipoproteins, both of
which are atherogenic (DeFronzo and Ferrannini, 1991).
Endothelial and smooth muscle cell dysfunction cause alterations in
vascular homeostasis which are the main features of diabetic
vasculopathy that promote pro-inflammatory/thrombotic state that will
eventually lead to atherosclerosis.
According to DeFronzo and Ferrannini, insulin is known to be
atherogenic in the following ways:
◦ It enhances cholesterol transport into arteriolar smooth muscle
cells;
◦ It increases endogenous lipid synthesis by the arteriolar smooth
muscle cells;
◦ It stimulates proliferation of arteriolar smooth muscle cells and
augments collagen synthesis in vascular wall;
◦ It increases the formation of and decreases the regression of lipid
plaques;
◦ It stimulates the formation of various growth factors.
In type 2 diabetes, there is elevated insulin level due to insulin
resistance which partly explains why macrovascular disease is far
more common in people with diabetes.
High glucose concentrations alter vascular function which triggers the
imbalance between nitric oxide (NO) bioavailability which represents
a key marker in vascular health, and accumulation of reactive oxygen
species (ROS) leading to endothelial dysfunction (Creager and
Luscher, 2003). Experimental evidence supports the notion that
hyperglycaemia decreases endothelium-derived NO.
Studies have shown that reduced NO bioavailability is a strong
predictor of cardiovascular outcomes (Lerman and Zeiher).
Pathogenesis of cardiovascular disease
Atherosclerosis plays a key role in cardiovascular diseases (CVD)
involving large and medium sized arteries. Oxidative stress due to
metabolic abnormalities in Type 2 diabetes mellitus (T2DM) is
implicated as major role player in the pathogenesis of both micro and
macrovascular complications, Folli et al (2011). The metabolic
abnormalities in T2DM include:
◦ Hyperglycaemia
◦ Insulin resistance
◦ Hyperinsulinaemia
◦ Dyslipidaemia
According to Zafar (2015), the above mentioned abnormalities trigger
the events that lead to increased oxidative stress, which include:
◦ Activation of the polyol pathway
◦ Formation of Advanced glycation end (AGES) products
◦ Release of pro inflammatory hormones
◦ Production prothrombotic factors and abnormal platelet formation.
Folli et al (2011), states that the inactivation of two antiAtherosclerotic enzymes, namely endothelial nitric oxide synthase
and prostacyclin synthase, in T2DM further compounds the effects of
oxidative stress on vascular tissue.
Similarly oxidative stress plays a role in pathogenesis of CVD in non
diabetic population. Zafar (2015), hypothesizes that psychosocial
stress, triggers systemic inflammation which results in the stimulation
of a cascade of events , such as:
◦
◦
◦
◦
◦
Release of neuro endocrine transmitters
Endothelial dysfunction
Increased permeability of the microvascular circulation
Increased delivery of free fatty acids
Increased production of low density lipoproteins (LDL), with excess
LDLs being oxidised, forming antigenic oxLDL molecules.
The resultant inflammatory response causes formation of reactive
oxygen species (ROS) resulting in increased oxidative stress.
The activation of the innate immune system is thought to be the
common antecendent in the development of T2DM and
atherosclerosis, with the conclusion that Diabetes and CVD might be
from "common soil" and probably develop in parallel, Zafar (2015).
The increasing prevalence of coronary artery disease (CAD) along
the spectrum of glucose tolerance shows that T2DM is an
independent risk factor for CAD. As shown by the Chennai Urban
Population Study (CUPS) in India, CAD prevalence was 11% in the
total population, but increasing CAD prevalence was 9.1%, 14% and
21.4% in normal glucose tolerance, impaired glucose tolerance and
diabetes respectively, Mohan, Venatraman and Pradepa (2010).
Is there a correlation between glucose lowering and a reduction in
Cardiovascular risk in T2DM? Look at land mark studies such as the
ACCORD,ADVANCE and VADT trials amongst others.
Is there
any any significant difference in cardiovascular outcomes when
looking at these trails?
If yes what is the reason for this variability among CV outcomes in
different trials.
Diabetes has been identified as an independent risk factor for
cardiovascular risk as discussed in the previous thread. Looking at a
few of the landmark trials, lowering blood glucose does not
necessarily decrease cardiovascular risk.
The ADVANCE (Action in Diabetes and Vascular Disease: Preterax
and
Diamicron
Modified
Release
Controlled
Evaluation)
demonstrated that intense glucose control (HbA1c <6.5%) did not
have any significant effect on macrovascular events (p=0.32), death
from cardiovascular causes (p=0.12) or death from any other cause
(p=0.28) after 5 years (Patel et al., 2008).
The Veterans Affairs Diabetes Trial (VADT) found no significant
differences in the time to death or the rate of deaths from
cardiovascular causes (p=0.26) between intensive and standard
intervention groups. There were more amounts of sudden deaths in
the intensive-therapy group (p=0.08) (Duckworth et al., 2009).
The ACCORD (Action to Control Cardiovascular Risk in Diabetes)
trial compared intensive therapy (HbA1C < 6%) and standard therapy
(HbA1C between 7 and 7.9%). After 3.5 years, the intensive group
presented with increased deaths from cardiovascular causes
(p=0.02) and all cause mortalities (p=0.04) and the intensive arm of
the trial was thus terminated prematurely. It has to be mentioned that
around one third of the participants did suffer from a previous
cardiovascular event and about 90% of the patients were treated with
rosiglitazone. Significant weight gain and increased risk of severe
hypoglycaemia in the intensive group might possibly have contributed
to the outcomes. (ACCORD, 2008)(Rosenstock et al., 2013)
The United Kingdom Prospective Diabetes Study (UKPDS) recruited
newly diagnosed type 2 diabetes patients. After 10 years follow up,
intensive glucose control reduced the relative risk for myocardial
infarctions by 15% (p=0.01) and for death from any cause by 13%
(p=0.007). No significant risk reductions were observed for stroke or
peripheral vascular disease during or after the trial (Holman et al.,
2008).
From the long term UKPDS study results it looks like glucose control
might have a legacy effect and holds long-term benefits. The lack of
cardiovascular risk reduction observed with glucose control as seen
with the ADVANCE, ACCORD and VADT trials might suggest that
glucose should not be the only aspect to be targeted, but all
cardiovascular risk factors including hypertension, hyperlipidaemia
and hypercoagulability (Dluhy & McMahon, 2008).
In conclusion, try and treat all the risk factors to target (as that in itself
is not easy to achieve) and avoid going below an HbA1C of 6.5% in
patients at high risk of cardiovascular disease.
There is no study mentioning the intensive glucose lowering has
significant effect in reduction cardiovascular risk in type 2 DM.
According to ACCORD study
Intensive glycaemic control leads to increased mortality without
reducing major cardiovascular events when compared to standard
treatment. Moreover, intensive blood pressure control did not reduce
major cardiovascular events but did reduce strokes.
In addition, Intensive lipid control does not reduce composite
outcomes of fatal cardiovascular events, non-fatal myocardial
infarction or non-fatal stroke.
In Advance trial,
An intensive strategy with conventional agents can achieve mean
A1C levels of 6.5% safely with no increase in mortality and no
significant effect in reducing macrovascular disease.
But diabetic nephropathy was reduced by ∼20%.
From VADT study,
The results did not indicate a strong correlation between intensive
glucose control in this population and decreased rate of
cardiovascular events. At present, dyslipidaemia, and other
cardiovascular risk factors appears to be most effective approach to
reducing cardiovascular morbidity and mortality.
Glucose control and CVD risk
The interventional studies like ACCORD, VADT and ADVANCE have
not found the benefit of intensive glucose control in reducing the risk
of CVD, as already mentioned by Ilse and Aye in the previous post.
Some studies, such as the ACCORD, have actually found an
increased risk of CVD mortality with intensive glucose lowering and
the reason for this is not completely understood and hypoglycaemia
has been implicated to be a contributing factor.
The results from a UK General Practice Research Database , have
suggested a U- shaped relationship between Hba1c levels and CV
events , with the lowest hazard ratio at Hba1c of 7,5%, Maclsaac and
Jerums (2011).
Fang et al (2016), in a meta-analysis of 13 randomized controlled
trials with 58 160 type 2 diabetes patients, found that intensive
therapy reduces major cardiovascular events (MACE)and myocardial
infarction(MI) but had no effect on risk of total mortality, cardiac death
,stroke and congestive heart failure (CHF). The following results were
observed:
◦ MACE:
Relative risk , RR: 0.92, P=0.042
◦ MI:
RR:0.90, P=0.020
◦ Total Mortality:
RR:0.98, P=0.693
◦ Cardiac Death:
RR:1.0 , P0.999
◦ Stroke:
RR:0.94. P=0.333
◦ CHF :
RR:1,19, P= 0.108
Based on the trial results, my conclusion is that glucose lowering
has beneficial effects on reducing cardiovascular risk but other
factors, such as adverse drug effects might contribute to the
increased cardiovascular risk during intensive therapy.