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Scientific Highlights: 2016 Asia Pacific conference on cardiometabolic diseases management

Scientific Highlights: 2016 Asia Pacific conference on cardiometabolic diseases management
  • Cardiometabolic
  • Diabetes
    Hypertension

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Publication

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metformin
prediabetes
Hypertension

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Practical

Clinical management of insulin resistance, diabetes and cardiovascular disease was the focus of the 2016 Asia  Pacific  conference,  organized  by  EXCEMED.  Participants  learned  about  the  pathophysiology  of cardiometabolic medicine, together with evidence-based strategies that advocate the early diagnosis of diabetes  (or  pre-diabetes).  This  strategy  considerably  reduces  the  risk  of  cardiovascular  disease development in at risk people. Highlights of the congress presentations are summarized below:

  • Pre-diabetes: disease or opportunity?
  • Origin of vascular combinations in diabetes: fat versus or combined with glycaemia?
  • Insulin sensitizers and cardiovascular outcomes in diabetes
  • Optimizing metformin
  • The need for combination therapy
  • Kidney function and drug choice: old and new molecules
  • Hypertension in different populations
  • High heart rate and the CV risk in hypertension
  • Hypertension and coronary artery disease
  • Blood pressure targets in hypertension: evidence for and against SPRINT
  • Is heart rate a target in hypertensive treatment?
  • Combination treatment: RAS blockers are not the only possibility
  • The prevention of heart failure development in hypertension

Pre-diabetes: disease or opportunity?


By  identifying  the  common  signs  of  pre-diabetes  (i.e.  obesity,  impaired  glucose  tolerance  [IGT]  and impaired fasting glucose [IFG]), clinicians can treat patients at the earliest possible stage. Intervening with lifestyle measures and oral antidiabetic therapies may delay the development of type 2 diabetes mellitus (T2DM) and its complications. Patricia Gatbonton  (Philippines)  described obesity  as  an  insulin-resistant  state,  calling  it  the  single most important risk factor for progression from IGT to diabetes. Lifestyle interventions alone, such as increasing physical activity to achieve weight loss, can be successful at reducing IGT, particularly in people with very early signs of pre-diabetes, but antidiabetic therapy can have additive effects.

  • IFG is defined as a 2-h post-glucose lode of 100-125 mg/dl (5.6–-6.9 mmol/l)
  • IGT is defined as a 2-h post-glucose load of 140-199 mg/dl (7.8-11 mmol/l)
  • IGT is associated with metabolic syndrome and is a strong predictor of cardiovascular disease


Table 1 shows the guiding principles for pre-diabetes management, as presented by P.  Gatbonton.

As  pre-diabetes  progresses,  pharmacologic  therapy  may  prevent  hyperglycemia,  normalize  glucose tolerance, and minimize loss of beta-cell mass and microvascular complications.  In patients with IFG and IGT who also have at least one other common risk factor for diabetes, therapies such as metformin, DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 analogs, α-glucosidase inhibitors, basal insulin and thiazolidenediones may be beneficial, explained Gatbonton.
 

Origin of vascular combinations in diabetes: fat versus or combined with glycaemia?


Reducing excess fat and blood-vessel injury, early in the disease process, may be the best way to improve mortality and reduce the likelihood of cardiovascular events in people with diabetes. When the focus is on glycaemia management alone, metformin is the only pharmacological agent to show any improvement on other cardiometabolic parameters. John Kennedy Cruickshank (UK) said that reducing general or central obesity, or hepatic or perivascular fat – is clearly key to improving cardiometabolic health. Patients with T2DM (and type 2 diabetes) are at least twice as likely as nondiabetic people to develop cardiovascular diseases, therefore a focus on maintaining or improving arterial structure & function is appropriate.
 
He  challenged  the  traditional  ‘gluco-centric’  view  of  type  2  diabetes,  describing  the  limitations  of randomized clinical trials that focus on glycaemia management but fail to show improvements in mortality or cardiovascular events. Blood vessels are sites of target organ damage, and therefore should also be the focus of long-term treatment, he added.
 

Insulin sensitizers and cardiovascular outcomes in diabetes


Clinical  trials  including  the  UKPDS  and  PROactive  studies  show  that  therapy  with  insulin  sensitizers  – including  metformin  and  thiazolidienediones  –  significantly  reduces  the  risk  of  cardiovascular  disease  in patients with diabetes.  Rates  of  myocardial  infarction,  stroke  and  mortality  were  all  lower  in  patients  receiving  metformin compared with other diabetic therapies, explained Susan Yu Gan (Philippines).    Intensive  regimens  that  focus  on  glycemic  control  undoubtedly  have  some  benefits  for  people  with diabetes, but they do not improve cardiovascular outcomes or reduce mortality, she explained. Insulin  resistance  within  the  heart  increases  the  risk  of  cardiovascular  events.  The  heart  requires  more energy than any other organ (70% from free-fatty acids; up to 30% from glucose); in normal conditions, the heart  can  switch  between  both  energy  sources;  however,  people  with  insulin  resistance  and  type  2 diabetes exhibit metabolic inflexibility, which ultimately increases the risk of cardiovascular disease.  

Optimizing metformin


Metformin  is  the  oldest  and  most  frequently  prescribed  oral  glucose-lowering  agent  in  the  world.  The pharmacological  profile  of  metformin  continues  to  support  its  position  as  the  preferred  first-line  oral therapy for people with T2DM, and also for its use in combination regimens. Metformin confers benefits on glycaemic control and cardiovascular safety, but also has several anticancer properties. Thy Khue Nguyen (Vietnam) gave a comprehensive profile of metformin use, confirming that it remains the predominant choice of oral therapy due to its abilities to prevent or delay the development of T2DM and many of its complications.  
 
The risks and benefits of Metformin therapy were common themes across presentations at the conference (Figure 1).

Metformin is also efficacious treatment for polycystic ovarian disease and appears to protect people with T2DM from developing pancreatic or kidney cancer. In addition, metformin improves overall survival rates in people with head and neck squamous cell carcinoma.  Metformin  increases  insulin  sensitivity  and  decreases  hepatic  glucose  production.  Although  its  exact mechanism at a molecular level remains unknown, two general mechanisms illustrate the drug’s role (or action within a cell), explained Dr Nguyen:

  • Metformin activates AMP-activated protein kinase

                        This  decreases  glucose,  protein  and  lipid  synthesis  in  cells,  but  increases  fatty  acid oxidation and glucose uptake

  • Metformin increases the glucagon-like peptide (GLP)-1 plasma level

                       However, it has no direct inhibitory effect on DPP-IV activity (DPP-IV degrades GLP-1).


Metformin  use  is  contraindicated  in  people  with  severely  impaired  renal  or  impaired  hepatic  function, alcoholism, conditions promoting tissue hypoxia (including several cardiovascular diseases), major surgery, type 1 diabetes or ketoacidosis. Metformin should also be used with caution in patients on concomitant diuretic therapy, said Dr Nguyen.

The need for combination therapy


As  no  single  class  of  oral  antidiabetic  agent  addresses  the  all  of  the  key,  progressive  cardiometabolic pathologies associated with T2DM, dual-combination regimens (involving metformin and another first-line agent) are being advocated. Approximately 55% of newly diagnosed patients with T2DM have a baseline
glycosylated  haemoglobin  (HbA 1 C)  value  >7.6%  and  are  therefore  eligible  for  this  aggressive  treatment approach.   Combination therapy in T2DM has numerous potential benefits, said Susan Yu Gan (Philippines):

  • Early and robust lowering of HbA 1 C
  • Avoidance of clinical inertia associated with a stepwise approach to therapy
  • Potential for early combination therapy to improve beta-cell function
  • Initiation of therapeutic interventions that have with complementary mechanisms of action
  • Potential to use lower than maximal doses of individual agents (to minimize side effects).

Combinations should be based on pharmacotherapeutic firepower, added Dr Yu Gan (Table 2). Agents with complementary mechanisms of action that also offer ancillary benefits (such as reducing the risk of CVD), and  favourable  safety/tolerability  profiles,  should  be  selected.  Triple oral  therapy  regimens may  also  be
suitable for selected patient populations.

Table  2:  Combining  antihyperglycaemic  therapies  offers  additional  cardiometabolic  benefits  to  people with T2DM


Kidney function and drug choice: old and new molecules


Metformin can be used in patients with T2DM who have mild or moderate kidney disease (i.e., creatinine clearance 45-59 ml/min or estimated glomerular filtration rate [eGFR] 45 -59 mL/min/1.73m 2 ). The starting dose  should  be  500  mg  or  850  mg  hydrochloride,  once  daily,  rising  to  a  maximum  of  1000  mg  (in  two divided daily doses).   Made Ratna Saraswati (Indonesia) focused on the role of hyperglycaemia in diabethic nephropathy, and how to select therapy to intensify glycemic control in kidney dysfunction. Renal function should be monitored every 3 months and metformin must be discontinued immediately if the CrCl or eGFR fall to <45 ml/min or <45 ml/min/1.73m2 respectively. End-stage renal disease remains a major problem for people with T2DM: microalbuminuria and renal impairment are frequently observed in patients over time, and rates of renal disease are particularly higher in patients of Asian ethnicity. When renal damage is delayed in people with diabetes through intensive glycaemic control, blood pressure is optimized, said Dr Saraswati. 

Hypertension in different populations


Although hypertension is the most important cardiovascular risk factor and the most common cause of death worldwide, there are notable ethnic differences in its symptom prevalence and severity. There are also ethnic differences in the types of complication that hypertensive people experience. In addition, ethnic differences may also influence the choice of pharmacotherapy for individual patients.
 
Thananya Boonyasirinant (Thailand) explained that, compared with other ethnic groups, people of non-Hispanic black origin are more likely to develop hypertension (Figure 2). These people also develop hypertension earlier than other ethnic groups, have a higher average blood pressure,
have a higher overall prevalence of hypertension and a higher rate of complications, such as:

  • 4.2 times greater risk of end-stage renal disease
  • 1.8 times greater risk of fatal stroke
  • 1.5 times higher risk of cardiovascular death
  • 1.3 times higher risk of nonfatal stroke.

 
Non-Hispanic black people who develop hypertension also experience more severe target organ damage and low response to renin-angiotensin system blockers, compared with patients from other ethnic backgrounds. Antihypertensive trreatment selection should therefore follow the guidelines produced by JNC and NICE, which recommend that pharmacotherapeutic choices should take into account the patient’s ethnicity.
 
Many factors contribute to the ethnic differences in hypertension risk and severity, including genetics, diet (especially excessive salt and calorific intake), lifestyle choices (including physical exercise, tobacco and alcohol use), and presence of comorbid conditions.
 
Within the Asia Pacific region, although hypertension is less common than in the Western world, its prevalence is higher in the Philippines and Japan than in China or The Republic of Korea (Figure 2). Again, the reasons for this are multifactorial.  
 
Boonyasirinant explained that differences between typical Japanese and ‘Western’ diets might confer different risk factors. For example, diets that are relatively higher in sodium and alcohol but lower in calcium and animal protein are associated with a higher prevalence of hypertension and stroke. Conversely, diets that are relatively lower in saturated fats (e.g. meat) but higher in omega-3 polyunsaturated fats (e.g. fish), are associated with a lower prevalence of ischaemic heart disease.

 

High heart rate and the CV risk in hypertension

 
Heart rate reduction (towards the optimal limit) is of proven benefit for people with cardiovascular and cardiometabolic diseases. Reducing a high heart rate is therefore an important therapeutic goal in these patients; one that can be achieved by lifestyle factors or pharmacotherapeutic intervention, such as treatment with beta-blockers.
 
Khai Pham Gia (Vietnam) described how heart rate reduction may help to prevent cardiac ischaemia and improve overall cardiovascular prognosis.
 
The patient’s heart rate is a key factor for predicting risk. An increased resting heart rate is associated with more rapid and severe progression of cardiovascular disease (Figure 3) and related cardiometabolic conditions (including ischaemic heart disease, heart failure and diabetes mellitus), but also non-cardiac-related diseases. Consequently, treatment or intervention to reduce resting heart rate is mandatory.

Pham Gia recommended that heart rate should be measured at every medical check up, with electrocardiography being the most accurate form of monitoring. Heart rate should be measured for 30 s, twice; blood pressure should also be recorded twice during one clinical checkup. If therapy to reduce heart rate is required, the benefits of beta blockade are evident from research involving patients with heart failure, he added.
 
A large body of evidence demonstrates that increased heart rate is an independent cardiovascular risk factor in the general population. It is worth noting that the number of heart beats is inversely related to mortality. Indeed, heart rate is a predictor of long-term mortality in post-AMI patients and it is an important factor for risk prediction in patients with acute coronary syndromes in the GRACE score.  
 
In normal conditions, heart rate is around 50-80 bpm at rest and 170-200 bpm at maximum exercise, although both figures may naturally be slower in people over 60 years of age.  Hypertension and coronary artery disease Hypertension is one of the main promoters of atherosclerosis and there is a direct relationship between blood pressure values and coronary artery disease risk, said Ki-Hoon Han (Korea). This risk is particularly important when hypertension is poorly controlled, or when patients have cardiometabolic comorbidities such as hyperlipidaemia, metabolic syndrome or target-organ damage.
 
Activation of the renin-angiotensin system is one of the main mechanisms leading to coronary artery disease in hypertension. Another crucial risk factor is obesity, since adipose tissue is a vital organ producing several substances leading to functional and structural alterations of the vessel wall, explained Dr Han.   Treatment of coronary artery disease in patients who are hypertensive centres on the administration of beta-blockers and ACE-inhibitors; angiotensin receptor blockers are indicated for patients who experience cough with ACE-inhibitor therapy.  
 
Maintaining blood pressure levels at <130/80 mmHg may offer optimal prevention of CVD events without increasing the risk of adverse events, added Dr Han.
 

Blood pressure targets in hypertension: evidence for and against SPRINT  

 
In favour: Ki-Hoon Han; against: Kamal Kumar Sethi
Findings of the Systolic Blood Pressure Intervention Trial (SPRINT) 1  suggest that there are additional beneficial effects when the treatment target for systolic blood pressure values is 120 mmHg, compared with the standard treatment target of 130 mmHg.  
 
In favour of SPRINT
Han described some of the potentially beneficial points that emerged following publication of the SPRINT study:
 

  • A lower SBP goal (at least < 130 mmHg) may be appropriate for patients aged ≥50 years
  • The J-curve hypothesis may be of less concern in CAD patients than previously thought (this hypothesis describes a paradoxical increase in mortality/morbidity associated with excessive blood pressurereduction)
  • There may also be less concern regarding the risk of renal hypoperfusion in patients with chronic kidney disease
  • Screening for end-organ damage should be thorough: there were higher rates of some serious adverse events (hypotension, syncope, electrolyte abnormalities, acute kidney injury/failure) in the intensive-treatment group in SPRINT
  • Studies (and clinical practice) may become less reliant on nurse- or physician-monitored office blood pressure monitoring (in favour of fully automated monitoring)

 
It is unclear whether a more aggressive blood-pressure lowering approach such as the one advocated in SPRINT might be appropriate for patients with multiple comorbidities, including diabetes mellitus. Further data are needed to clarify this, emphasized Dr Han.
 
Against SPRINT
However, Sethi took a cautious approach as he disputed several of the SPRINT findings. He emphasized that these results cannot be applied to the general hypertensive population.  
 
First, any beneficial effect was mainly driven by the reduction of progression to heart failure; no effect was observed on stroke, which is the cardiovascular event usually most sensitive to blood pressure reduction.  
 
Second, in SPRINT, blood pressure measurement was performed by an automatic device with no health care professional assistance. Thus these values are not comparable with clinic blood pressure measurement protocols that have been followed in other robust clinical trials. Finally diabetic patients were not enrolled in the SPRINT Study.
 
Professor Sethi concluded that more data are required, involving non-selective hypertensive populations or people at low cardiovascular risk, before it is reasonable to consider redefining the optimal goal for systolic blood pressure.
 
1.  SPRINT Research Group, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure
Control. N Engl J Med. 2015 Nov 26;373(22):2103-16.  
  

Is heart rate a target in hypertensive treatment?


P Brian Tomlinson (Hong Kong, China) expanded on earlier presentations that discussed how an elevated heart rate (>80 beats per min) is an independent risk factor for cardiovascular mortality in hypertensive patients. He explained how reducing tachycardia is an important treatment target.
 
Professor Tomlinson believes that the utilization of drugs that lower heart rate, such as selective beta blockers, might offer an adjunctive beneficial effect beyond blood pressure reduction. Although heart rate reduction is associated with a decrease in cardiovascular events, hypertension guidelines do not consider it to be a target for pharmacological treatment.  
 
He dispelled many of the myths and misunderstandings surrounding tachycardia, which he considers to be overlooked in the pathophysiology of cardiovascular disease development and outcome. Tachycardia is being frequently observed in normo- and hypertensive people, but is neither transient nor a marker of BP lability. He also called tachycardia a predictor of both hypertension and increased cardiovascular mortaility.  
 
The mechanisms of tachycardia’s harmful effects are well understood and may result in atherosclerosis or plaque rupture as well as amplifying the tensile stress in arteries. Tachycardia is also a risk factor for cardiovascular events, independent of its association with hypertension (Figure 4), added Professor Tomlinson.

 

Combination treatment: RAS blockers are not the only possibility  


Combination therapy is the evidence-based cornerstone of antihypertensive treatment, said Stefano Taddei (Italy). This approach is associated with better blood pressure control and greater reduction in cardiovascular events, compared with monotherapy. In fact, blood pressure values will only normalise in up to 30% of patients on antihypertensive monotherapy.
 
Two-drug combination regimens should incorporate agents that have different, but complementary, mechanisms of action: this strategy enables the combination to have an additive effect on blood pressure reduction (Figure 5). 

 

Fixed-dose combinations are recommended by guidelines because the lower pill burden increasesthe likelihood of treatment adherence.   In addition to classical RAS-blocker based combinations, a new fixed-dose combination of bisoprolol plus amlodipine is available in clinical practice, explained Professor Taddei. This effective combination is particularly useful for treating patients with high heart rate, atrial fibrillation, aortic aneurysm and other conditions requiring beta-blocker based therapy.
 
Professor Taddei cautioned that few controlled clinical trials were designed to compare combination strategies. He described the lack of additive blood pressure-lowering effects in trials that combined calcium antagonists and diuretics, and cautioned against this common combination regimen.  
 
Other drug combinations to be avoided also include those that have a negative effect on blood pressure lowering include 1 -antagonist + clonidine. Professor Taddei added that combining a beta-blocker with clondine or with a non dihydropyridine Ca-antagonist has the potential to be dangerous.

The prevention of heart failure development in hypertension  

 
Preventing heart failure development in people with hypertension is becoming a key therapeutic goal. Effective reduction of 24-h blood pressure helps to prevent organ damage and heart failure; appropriate dipping at night may also help to prevent the development of vascular disease.
 
Brian Tomlinson (Hong Kong, China) made these comments in a presentation that  outlined the benefits of heart failure prevention. He illustrated how the prevalence of heart failure is increasing, adding that hypertension is a major underlying risk factor for this condition. Indeed, hypertension is present in 75% of patients who develop heart failure.
 
Undoubtedly, lifestyle changes are important for reducing blood pressure values (and thereby reducing the risk of heart failure development). However, such changes alone are insufficient in many cases, and pharmacotherapy is often required in order to achieve target blood pressure levels.  
 
Guidelines generally recommend renin-angiotensin system blockers and calcium antagonists for patients who exhibit hypertension-related organ damage (including left ventricular hypertrophy [LVH], which may predict the developing of heart failure).  
 
Increased heart rate is another predictor of heart failure (and cardiometabolic disease) that is observed in normo- and hypertensive people; it may result from increased underlying sympathetic activity, and may be controlled by pharmacotherapeutic measures described earlier in this newsletter.  
 
Once heart failure has developed, guidelines recommend thiazide diuretics, certain beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and mineralocorticoid receptor antagonists, in addition to other measures (Figure 6).
 
Treatments should be initiated at doses appropriate for the degree of heart failure, then increased gradually to achieve the target dose or the maximum tolerated dose, explained  
 
Hypertension causes heart failure to develop as a result of myocardial damage from coronary artery disease. Heart failure may involve reduced left ventricular ejection fraction (LVEF) or reduced ejection fraction (HFREF); alternatively, it may result directly from effects on the myocardium that cause LVH or damage that resuits in heart failure with preserved ejection fraction (HFpEF). HFREF and HFPEF have similar prevalence and prognosis, explained Professor Tomlinson. He added that echocardiography is necessary to distinguish between both conditions, as they present with the same clinical symptoms and signs.

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Regional conference
Ho Chi Minh City, Vietnam
Apr 23 - 24, 2016
Target audience
General practitioners, Cardiologists, endocrinologists and Internists managing diabetes and cardiometabolic diseases from the Asia-Pacific region.
by Excemed
Cardiometabolic, Endocrinology and metabolism