Cardiovascular health and diabetes

My name is Fernando Florido and I am a GP in the United Kingdom. In this podcast I I give my summary of the online course by the EASD learning website “Cardiovascular health and diabetes”.

This podcast will be saved on a website. 

There is also a YouTube video on this subject and other NICE guidance. You can access the channel here:

https://www.youtube.com/channel/UClrwFDI15W5uH3uRGuzoovw 

The online course can be found on the EASD learning website:

https://easd-elearning.org/courses/cardiovascular-health-and-diabetes/

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Transcript

Hello everyone and welcome to the channel. My name is Fernando Florido and I am a GP in the United Kingdom. Today we are going to talk about the link between cardiovascular health and diabetes. The information that I am going to give is based on an online course that is available on the EASD learning website. I highly recommend it and I will put the link to access this course in the episode description. It has seven modules and it is likely to take you between 5 and 7 hours to complete it, depending on how quickly you can process the information. Today’s episode is a summary of the course, which I hope that you will find useful.

 As ever, remember that there is a YouTube version of this episode and the link to the YouTube channel is also in the episode description.

People with type 2 diabetes have twice as many coronary heart disease and strokes as those without it. At first glance, you could think it was too much, but in reality, this is a significant improvement. Previous data indicated that the risk of cardiovascular disease increased by around four to six times. Thus, doubling the risk indicates a significant improvement. Blood pressure control and strict cholesterol treatment are now standard management. And as a result, there are far fewer atherosclerotic events that affect persons with type 2 diabetes. However, as a result, heart failure is now becoming more common.

According to research, people with type 1 diabetes have steadily experienced a decline in CVD, CV mortality, and CV hospitalisation. However, there is still a significant gap between those who have type 1 diabetes and those who do not.

The same research, however, revealed that those with type 2 diabetes had experienced a far bigger improvement, resulting in, at worst, a doubling of the risk of cardiovascular disease (CVD), hospitalisation for CVD, and cardiovascular mortality. And once more, this has been associated with intensive blood pressure and cholesterol management; perhaps this is something that might be applied to patients with type 1 diabetes, where the focus is still often on glycaemia-related issues.

According to other studies, people with type 2 diabetes have an increased chance of developing heart failure. This increased risk is most noticeable in the middle-aged group, perhaps those up to the age of 55, and it appears to be less of an issue as people get older. Therefore, heart failure is now one of the most significant CVD symptoms in persons with type 2 diabetes.

Atherosclerotic disease, coronary heart disease, or strokes are still the earliest signs of vascular illness in the non-diabetic population. However, peripheral vascular disease or heart failure are the most typical early presentations of vascular disease in persons with type 2 diabetes.

Heart failure in diabetics is caused by a number of different ways. First, excess atherosclerotic disease. Also, the heart's ability to operate can then be impacted by hypertension itself. Additionally, a lot of our patients are now recovering from myocardial infarctions, and as time passes, the ventricle develops scarring that exacerbates heart failure. Furthermore, apart from atherosclerosis and hypertension, there is a heart condition known as "diabetic cardiomyopathy" that damages the myocardium. The ventricle becomes extremely stiff due to a combination of metabolic and pathological causes, making it difficult for the ventricle to relax and fill. And finally, diabetic autonomic neuropathy also plays a role in the development of heart disease in patients with diabetes.

Variations in glycaemic control and chronic hyperglycaemia are recognised epidemiologically as risk factors for cardiovascular disease in people with diabetes.

There are now numerous things we can do for our patients with diabetes to lower cardiovascular risk, just as there are numerous risk factors for heart disease in those with diabetes. One factor we take into account is lifestyle, but studies have shown that this is a pretty unsatisfactory intervention when we focus on heart disease, frequently failing to show any benefit on lowering cardiovascular disease rates. However, we continue to believe that lifestyle intervention is crucial for some people.

After bariatric surgery, cardiovascular morbidity and death have been demonstrated to decrease in people with type 2 diabetes.

Controlling glycaemia, blood pressure, and cholesterol are crucial for patients with diabetes.

Numerous trials have examined glycaemic control in persons with type 1 and type 2 diabetes. The effects of intensive glycaemic control on microvascular and macrovascular complications were investigated in these trials.

In the DCCT study which looked at type 1 diabetes patients, strict glycaemic management resulted in a highly significant decrease in retinopathy and nephropathy. Although the initial decline in cardiovascular events was modest, subsequent studies revealed that, up to 30 years after the initial intense management, the persons who received intensive management saw a decline in cardiovascular disease, as well as total mortality. As a result, a relatively short time of intense control has long-lasting repercussions on the cardiovascular system. This phenomenon is known as the "legacy effect" or "metabolic memory."

The UKPDS trial showed that strict glycaemic control in the first 10 years from diagnosis resulted in significant decreases in retinopathy, nephropathy, and neuropathy in individuals with newly diagnosed type 2 diabetes. There was, however, a rise in serious hypoglycaemia as well. Following UKPDS for a further 10 years, that is, for a total of 20 years of follow-up, there was a highly significant reduction in myocardial infarctions and mortality even if the initial reduction in myocardial infarction was not statistically significant. Again, the initial 10-year period of strict management following diagnosis has been shown to have long-lasting effects in lowering cardiovascular disease.

In contrast, other studies that examined the intensive management of glycaemia in individuals with type 2 diabetes who had this condition for a while revealed either no benefit in terms of cardiovascular disease or an increase in mortality in the intensive treatment group as a result of individuals receiving large amounts of insulin, massive weight gain, and very frequent hypoglycaemia.

A meta-analysis of all type 2 diabetes research findings revealed a decline in coronary heart disease but no impact on overall mortality. In light of this, we can say that glycaemic control does not have a very potent effect when compared, for instance, to blood pressure or cholesterol.

In conclusion, it is best if rigorous glycaemic intervention occurs as soon as possible following diagnosis if we are to receive cardiovascular benefits from it. And once someone has had diabetes for ten years or longer, it is doubtful that treating their glycemia will result in any significant cardiovascular benefits. At least this is supported by the evidence from older anti-diabetic medications. Research results may vary with newer medications because more advanced diabetic treatments now show improved cardiovascular risk in addition to lowering blood pressure and producing weight loss.

We will now look at individual treatments and their effect on cardiovascular disease.

The data for metformin comes from the UKPDS, where a very small subset experienced further benefits in terms of lower rates of myocardial infarction, cardiovascular disease, and overall mortality.

Secondary outcome data for pioglitazone showed significant decreases in cardiovascular death, myocardial infarction, and stroke. However, there were also adverse effects such weight gain, fluid retention, and a rise in fractures. As a result, pioglitazone is not that frequently used.

DPP4Inhibitors have been the subject of numerous studies. Major adverse cardiovascular events, or MACE, which were the focus of all these investigations, were unaffected. These medications have a modest glycaemic impact and are not extremely powerful. Therefore, it is not that surprising that MACE have not been affected.

A surprise side effect of saxagliptin and a subgroup of individuals using alogliptin was a large rise in heart failure hospitalizations. In conclusion, we can state that DPP-4 inhibitors do not affect MACE and that some of them have increased hospitalisation for heart failure, even if this has not always been confirmed in the other trials.

SGLT-2 inhibitors have been investigated in numerous cardiovascular outcome trials.

Empagliflozin, canagliflozin, and dapagliflozin have all demonstrated a highly significant decrease in heart failure hospitalisation and a significant decrease in severe adverse cardiovascular events (MACE).

A meta-analysis of SGLT2 inhibitor studies was able to show that the SGLT-2 inhibitors significantly decreased subsequent MACE events for patients with atherosclerotic disease. A very substantial decrease in heart failure hospitalisation followed for patients with heart failure or had a high cardiovascular risk.

Although it has been noted that SGLT-2 inhibitors have a fairly early onset of benefit, the mechanism of benefit is yet unknown.

A number of cardiovascular outcome trials using GLP 1 agonists have demonstrated significant decreases in major adverse cardiovascular events, cardiovascular mortality, and overall mortality. However, there was no impact on heart failure hospitalisation.

 The GLP-1 receptor agonists' mechanism of action is equally unknown. However, it has been noted that the improvement appears to be gradual rather than abrupt, as was the case with SGLT-2 inhibitors. And it has been widely assumed that the advantages relate to a slowing down of atherosclerosis progression. Theoretically, combining SGLT-2 inhibitors with GLP-1 receptor agonists may result in additional cardiovascular benefits and this is also a new area of research.

 Several recommendations and consensus statements have recently taken into account the findings of the cardiovascular outcome trials using SGLT-2 inhibitors and GLP-1 receptor agonists. The joint ADA/EASD consensus statement is a good illustration of this. It advises that, after metformin, you thoroughly assess the patient's cardiovascular status and that, if the patient has heart failure, you should consider SGLT-2 inhibitors as the next therapy. Consider using either SGLT-2 inhibitors or a GLP-1 receptor agonist if the patient has atherosclerotic disease or is at high risk of it.

One of the most researched strategies to try and lower cardiovascular risk in patients with diabetes is lipid lowering, notably using statins. We can now confirm, thanks to a meta-analysis, that coronary disease, stroke, and coronary revascularization can all be reduced by up to 25% for every 1 mmol decrease in LDL cholesterol. The meta-analysis included participants with existing cardiovascular disease (or "secondary prevention") as well as those without known cardiovascular disease (or "primary prevention"). And both groups experienced a similar reduction of about 25%.

A second meta-analysis revealed that those with diabetes who took high-dose statins benefited even more.

Renal outcomes were the subject of a third meta-analysis. It was confirmed in this meta-analysis that patients with diabetes and chronic kidney disease, or CKD, also benefited from decreases in atherosclerotic events. Therefore, it appears that statins are a treatment that can lower cardiovascular events in diabetes at all stages, including CKD as well as primary and secondary prevention.

Other methods of lowering cholesterol have been less promising.

Only minimal improvements for patients with diabetes were seen in trials with ezetemibe and fibrates.

Trials using PCSK9-inhibitors, a different innovative family of lipid-lowering medications, have been more encouraging, showing a significant decrease in adverse cardiovascular events.

All of the individuals who participated in these lipid-lowering investigations were older than 40. Therefore, the data suggests that statins are beneficial for diabetic patients over the age of 40, regardless of the baseline risk. Therefore, recommendations state that, in diabetes, statins should be started as soon as you reach the age of 40, regardless of your baseline risk or cholesterol level. The extent to which this benefit is reduced for those who are younger remains unknown, and different guidelines take different approaches to this. In general, the guidelines try to identify younger subjects who have other cardiovascular risk markers, such as microalbuminuria, or perhaps other microvascular complications, such as retinopathy. According to some recommendations, statins should be started in the younger age group for those who have these comorbidities.

Patients with diabetes have been included in many blood pressure-lowering trials over the years because high pressure is a clear risk factor for the development of cardiovascular disease. The advantages of decreasing blood pressure in persons with diabetes have been highlighted by combining all of these research studies into one very thorough meta-analysis.

Lowering of blood pressure led to a decrease in total mortality, cardiovascular disease, coronary heart disease, and strokes. Lowering blood pressure also slowed the onset of heart failure. The meta-analysis also took a look at microvascular events and found that reducing blood pressure has definite advantages in the development of renal failure, retinopathy, and albuminuria. Therefore, there is no question that decreasing blood pressure is advantageous in diabetes in both large and small vessel disease.

Other meta-analyses have demonstrated that lowering blood pressure is more important than the antihypertensive medication used. Since ACE inhibitors and angiotensin receptor blockers appear to have a minor advantage over other blood pressure-lowering medications, most guidelines recommend using them as a first line of treatment in diabetes.

Although studies in the non-diabetic population have recommended lower BP targets, such as a systolic BP of 120 mmHg, different guidelines now come out with somewhat different targets due to a variation in the outcomes of the diabetic and non-diabetic research. The majority of guidelines advise starting blood pressure medication for those with diabetes if their readings are over 140/90, but after that, the objectives can range from 140/80 to 130/80 mmHg, with the lower target being set for those with higher cardiovascular risk.

Aspirin medication has been the subject of many meta-analyses looking at primary prevention in diabetes. There hasn't been any evidence of a clear benefit, and risks have been identified, including a rise in gastrointestinal bleeding and the risk of developing haemorrhagic stroke.

Again, trials and their subgroups have been interpreted slightly differently. And some guidelines now advise against using aspirin for primary prevention in anyone who has diabetes. However, other guidelines would suggest trying to identify group of subjects at a greater risk, maybe due to comorbidities like CKD, and use aspirin in those people. However, it should be highlighted that in those people, the risk of bleeding also tends to be higher.

Research studies on multiple risk factor interventions have also been conducted, examining the combined effects of lipid-lowering therapy, blood pressure-lowering therapy, and better glycaemic management.

Unsurprisingly, after four years of intervention, there was a 50% reduction in the risk for diabetic nephropathy, retinopathy, and neuropathy development. After eight years, there was a 50% relative risk decrease for coronary bypass procedures, myocardial infarction, strokes, amputations, and CVD death.

After a 13-year follow-up, there was a 50% relative risk decrease in the rate of mortality. And finally, a 21-year follow-up revealed that this early, multiple risk factor intervention in our patients increased their life expectancy by over eight years. As a result, we can conclude that using all of these treatments together has an even bigger impact.

The fact that all SGLT2 inhibitors regularly reduced the number of heart failure hospitalizations led researchers to wonder if they would also be able to treat heart failure in persons without diabetes. As a result, more studies investigating SGLT2 inhibitors in heart failure populations without diabetes were carried out.

The outcomes are remarkably reliable. There were significant decreases in total mortality as well as a decline in cardiovascular death and heart failure hospitalizations. So, it was shown that, whether you had diabetes or not, the benefit was proportionately the same.

Dapagliflozin currently has a licence in Europe for the treatment of heart failure in both diabetic and non-diabetic patients. As a result, we'll start to notice regular use of these medications in non-diabetic patients.

It's critical that the patient's primary care physician is aware of the rationale behind prescribing the SGLT2 inhibitor, including whether it is given for diabetes control, for the improvement of heart failure prognosis or, of course, the third indication, which is now giving it to patients with chronic kidney disease (CKD) to enhance their renal prognosis.

If we're going to begin treating people with heart failure with dapagliflozin, or any other SGLT2 inhibitor, it's crucial that we first fully characterise the patient. We must determine whether a patient has diabetes or not and, if so, what medications are being used to manage it. If a patient has low HbA1c levels, taking, for example, a sulphonylurea or insulin, and is then given an SGLT-2 inhibitor for heart failure prognosis, there is a risk that this will result in hypoglycaemia. In these patients, it would be necessary to lower the insulin dosage or perhaps even discontinue some forms of treatment. On the other end of the spectrum, introducing an SGLT-2 inhibitor to a patient with a very high HbA1c without lowering the HbA1c first, would potentially increase the risk of ketoacidosis. Therefore, communication between cardiologists and diabetologists will be crucial in this regard.

We have come to the end of this episode. I hope that you have enjoyed it and found it useful and I hope that you will join me in the next one. Thank you for listening and goodbye.