The importance of a comprehensive multifactorial treatment approach in type 2 diabetes





Naveed SATTAR, PhD,
FRCPath, FRCP

James M. MCLAREN, MBChB
MRCP(UK)
Institute of Cardiovascular and
Medical Sciences, BHF Glasgow
Cardiovascular Research Centre
University of Glasgow
UNITED KINGDOM

The importance of a
comprehensive multifactorial
treatment approach in
type 2 diabetes

 

by J. M. McLaren and
N. Sattar,
United Kingdom

Diabetes care historically has prioritized glycemic control over other metabolic and pathophysiological factors as the main method by which diabetes-related morbidity and mortality can be reduced. The hallmark of diabetes mellitus is an elevation of the blood glucose and it was presumed that if blood glucose was near normalized it would follow that associated comorbidities could be potentially avoided or markedly improved. The landmark trial in type 2 diabetes, UKPDS (United Kingdom Prospective Diabetes Study), did not, however, fully support this, and although it demonstrated significant benefits of glycemic control in reducing microvascular complications, the same magnitude of benefits was not initially seen in macrovascular disease and mortality. In the last decade further research has expanded our understanding of the complex interaction of hyperglycemia with outcomes in patients with diabetes. Evidence has, in fact, shown that controlling blood glucose levels too tightly is associated with a paradoxical increase in cardiovascular deaths (yet fewer nonfatal cardiovascular events), although the mechanisms behind this pattern are still not conclusively understood. Furthermore, other research demonstrating the greater cardiovascular benefits of focusing on blood pressure and lipid lowering to obtain improvements in mortality and macrovascular disease in diabetes has led to a paradigm shift in the management of macrovascular disease. Observational and randomized controlled trial evidence has also supported a multifaceted approach concentrating not only on glycemia, but also on other established cardiovascular risk factors. These developments have led to international guidelines outlining the importance of specifically tailoring glycemic control to the individual and giving more importance to the management of blood pressure, cholesterol, and smoking cessation. This article reviews these developments in the management of type 2 diabetes mellitus, briefly discusses new paradigms resulting from recent trials, and highlights questions that remain unanswered and avenues that require further research.

Medicographia. 2016;38:20-27 (see French abstract on page 27)

The prevalence of type 2 diabetes mellitus is increasing worldwide due to increasing levels of obesity, and by 2030 it is estimated that there will be 400 million patients with diabetes.1 There is an increased mortality rate associated with diabetes and a 50-year-old with diabetes but no previous macrovascular disease will die on average six years earlier than his/her counterpart without diabetes.2 There are several causes for this increased mortality rate, including infectious diseases and various cancers, but the predominant cause is premature vascular deaths.2 Around 10% of cardiovascular deaths in high-income countries are associated with diabetes.3

In the last 20 years, remarkable reductions in diabetes cardiovascular complications have been noted and this is largely attributed to improved management of modifiable risk factors such as hypertension, lipid control, and smoking cessation, although glucose reductions and earlier diagnosis have also likely contributed (Figure 1).4

Despite these improvements, rates of macrovascular disease in the diabetic population remain significantly higher than in the nondiabetic population. In the USA in 2010 the myocardial infarction rate in diabetics was 45.5 events per 10 000 population compared with 25.8 events per 10 000 population in nondiabetics.4 Similarly, in people with diabetes the stroke event rate was 52.9 per 10 000 population compared with 34.3 strokes per 10 000 population in people who did not have diabetes.4 The challenge remains not only to improve and lower this morbidity further without causing harm, but also to find a solution for the increasing prevalence of type 2 diabetes worldwide and prevent the rising levels of obesity. That noted, much of the rising prevalence of diabetes has been associated with improved survival so that more patients with diabetes are now living longer.5

The conundrum of glycemic control

In 1998, the seminal UKPDS trial (United Kingdom Prospective Diabetes Study) demonstrated the benefits of intensive glucose control in type 2 diabetes patients, particularly with regard to microvascular benefit. Over 10 years, 3867 patients with newly diagnosed type 2 diabetes were treated with a sulfonylurea, metformin, or insulin to either conventional control (HbA1c of 7.9% [6.9%-8.8%]) or intensive control (HbA1c of 7% [6.9%-8.8%]).6 At 10 years in the intensive arm of the study there was a significant 25% relative risk reduction in all microvascular disease and a nonsignificant trend of a 16% risk reduction for myocardial infarction.6 Micro- and macrovascular disease though appeared to have differing relationships with glycemia, in that microvascular disease increased exponentially with higher levels of HbA1c whereas macrovascular disease increased with any elevation of glycemia above the normal range.7 Rather unexpectedly, patients treated with metformin had a 30% risk reduction in myocardial infarction despite only showing a 0.6% reduction in HbA1c over the course of the study (which was less than the 0.9% reduction observed for the whole study).6 After completion of the original study, in the 10-year-follow up of UKPDS the benefits on microvascular disease remained and a significant 15% risk reduction in macrovascular disease became evident.8 This finding in the 10-year follow up suggests that whilst strong obvious initial benefits were gained in microvascular disease, metformin’s macrovascular benefits are likely sustained and become clearer over time. An important note about the UKPDS study is that was conducted in an era prior to the widespread use of statins and blood pressure–lowering agents. This did allow for easier assessment of the effect of glycemia on risk of comorbidities but care needs to be taken when comparing it with more recent trials where patients are often on statins and blood pressure–lowering medication.

Figure 1
Figure 1. Trends in age-standardized rates of diabetes-related
complications among US adults with diagnosed diabetes, 1990-
2010.

Diabetes-related cardiovascular complications have declined with improved
care, but substantial burden remains.
Modified from reference 4: Gregg et al. New Engl J Med. 2014;370(16):1514-
1523. © 2014, Massachusetts Medical Society.

UKPDS demonstrated a strong and direct relationship between glycemia and microvascular disease but since the correlation with macrovascular disease and mortality was less evident much research effort has gone into exploring this complex relationship in the last 10 to 15 years.

One of the most recent trials of glucose lowering in type 2 diabetes, the ACCORD trial (Action to Control CardiOvascular Risk in Diabetes), was actually terminated early after 3.5 years due to the higher cardiovascular mortality in the intensive treatment arm of the study.9 The HbA1c was 6.4% (46 mmol/mol) in the intensive arm of the study, compared with 7.5% (59 mmol/l) in the control group.9 There were higher rates of severe hypoglycemia in the intensive arm (10.5% vs. 3.5%), which may have affected cardiovascular outcomes and this is still broadly thought to be the most likely explanation.10 Other possible explanations are the higher levels of weight gain. A recent review by Rutter et al implies that the higher level of mortality could be linked to the already present advanced comorbidities (for example renal failure and cardiovascular disease) and this is supported somewhat by data from other studies reviewed by Rutter, which show that patients with no comorbidities and an HbA1c of <6.5% (48 mmol/mol) do not appear to have an elevated level of mortality.11

The complex relationship between glucose and cardiovascular risk has been difficult to extrapolate as initial presumptions were that elevated glycemia would have a direct causal relationship with cardiovascular risk. The Emerging Risk Factor Collaboration (ERFC) meta-analysis, which included 700 000 individuals, showed that fasting blood glucose was in fact nonlinearly and moderately associated with cardiovascular disease risk, whereas blood pressure and total cholesterol were more strongly and log-linearly associated with risk.2 Above a certain glycemic point, cardiovascular risk appears elevated but significant glycemia reductions below that threshold are unlikely to derive further significant benefits in cardiovascular risk.

Further studies support this and posttrial analyses of the ADVANCE study (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) suggested that above a certain baseline HbA1c of 7% (53 mmol/mol), macrovascular events were increased by 38% but below that level there was no significant linear risk reduction.12 The baseline threshold for microvascular events in ADVANCE appeared to be lower at an HbA1c of 6.5% (48 mmol/mol) above which point the risk of events increased by 40%.12 ADVANCE was published in 2008 (and included 11 140 participants) and by then a large number of participants were also on blood pressure– and lipid-lowering medications to control risk factors, unlike the UKPDS trial in the late 1990s. In total, these findings suggest that macrovascular risk due to dysglycemia in diabetes is clearer once HbA1c is beyond around 7.0%, whereas microvascular risk escalates sooner than this, at the point of diagnosis.

The ORIGIN study (Outcome Reduction with an Initial Glargine Intervention) adds further weight to the notion that lowering glycemia from a low baseline is not necessarily effective. Basal insulin glargine was added to normal diabetes care and by 7 years, at the end of the study, the intervention group had an HbA1c of 6.2% (44 mmol/mol) compared with 6.5% (48 mmol/mol) in the control group.13 Both groups therefore had tight (below threshold) control of glycemia and an improvement in the HbA1c by 0.3% but did not consequently reduce cardiovascular events.

Several meta-analyses have combined individual trial data and come to similar conclusions but added further insight into the glucose-risk relationship. A meta-analysis by Ray et al showed that for every 0.9% HbA1c reduction over 5 years there was a 15% nonfatal myocardial infarction reduction and a 17% coronary heart disease reduction, but no improvements in overall mortality or stroke disease.14 Turnbull et al conducted a meta-analysis of four major studies of glucose lowering including UKPDS, ADVANCE, ACCORD, and VADT (Veterans Affairs Diabetes Trial). This meta-analysis additionally shows that patients with no prior history of vascular disease appeared to gain the most cardiovascular risk reduction with more aggressive glucose control, and indicates that when vascular disease is already established marked reductions in glycemia are unlikely to significantly improve cardiovascular risk further.15

It is therefore reasonable to aim for tight control and an HbA1c of approximately 6.5% (48 mmol/mol) early in the course of type 2 diabetes; but as time progresses and in the elderly, or if comorbidities develop, it may be appropriate to relax this control to ~7% (53 mmol/mol) given the lack of any macrovascular benefit below this glycemic threshold and the possibility for increased harm. Glycemic control should therefore be individualized and several recent international diabetes guidelines including the Scottish Intercollegiate Guidelines Network (SIGN), National Institute for Health and Clinical Excellence (NICE), and American Diabetes Association (ADA) guidelines are in keeping with this.16-18

Of course, whether trying to achieve tight control using newer glucose-lowering therapies gives different results to those seen with more established diabetes therapies requires future investigation. Perhaps most notably, another new paradigm has been opened up with the recent finding in the EMPAREG outcome study which tested the cardiovascular benefits of empagliflozin—a sodium glucose-transporter 2 (SGLT2) inhibitor— in individuals with diabetes and existing cardiovascular disease. Very unexpectedly, there were striking reductions in cardiovascular and total mortality as well as in heart failure hospitalizations, whereas there were no significant benefits on nonfatal myocardial infarctions or stroke.19 In the study 7020 patients were treated over a median 3.1 years, and rates of death from cardiovascular cause were 3.7%, vs 5.9% in the placebo group (38% relative risk reduction), hospitalization for heart failure was 2.7% and 4.1%, respectively (35% relative risk reduction), and death from any cause 5.7% and 8.3%, respectively (32% relative risk reduction).19 The results could not be explained by a 0.3% difference in HbA1c, nor could they be explained by modest reductions in blood pressure and weight with active therapy. The pattern of effects and early separation in survival curves in Kaplan-Meier analyses also seem to suggest that the drug may be affecting hemodynamic processes early but not necessarily influencing atherothrombosis measurably, as least in this group of patients. Further work will urgently address the mechanisms and also address whether this is a class effect. In the meantime, it would appear that to lower cardiovascular disease in diabetes it may matter more how you lower glucose than necessarily how much you lower it by. This new paradigm should open up many new avenues for research. It also underlies the potential that many patients with diabetes and cardiovascular disease may have subclinical cardiac dysfunction and are therefore at higher risk of heart failure.

Lipid-lowering benefits

The benefits of lipid-lowering medications, particularly statins, have been shown to be as effective in both diabetic and nondiabetic groups of patients. There have been four major outcome trials involving diabetic patients or containing large numbers of diabetic patients that constitute this evidence base, including the HPS study (Heart Protection Study), ALLHATLLT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial-Lipid Lowering Trial), ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm), and CARDS (Collaborative Atorvastatin Diabetes Study). The CARDS study contained only diabetes patients but the other studies contained significant numbers of diabetes patients as subgroups for useful analysis.20 The CTT meta-analysis (Cholesterol Treatment Trialists) summarizes the main findings of these large studies and includes a total of 18 000 diabetic patients.21 For every 1 mmol/L decrease in low-density lipoprotein (LDL)-cholesterol there was a reduction in the combined endpoint of coronary heart disease–associated death and nonfatal myocardial infarction by 22%, hazard ratio 0.78 (99% CI [confidence interval], 0.69-0.87), cardiovascular disease events by 21%, hazard ratio 0.79 (99% CI, 0.72-0.86), vascular death by 13%, hazard ratio 0.87 (99% CI, 0.76-1.00), and all-cause death by 9%, hazard ratio 0.91 (99% CI, 0.82-1.01).21 What is notable is that statin benefits in relative terms were equal between groups with or without preexisting cardiovascular disease, but also in absolute terms the patients who gained most benefits were higher-risk patients on statins for secondary prevention. For instance, comparing the number of cardiovascular events per 1000 diabetes patients over 5 years if LDL-cholesterol was lowered using a statin by 1 mmol/ L, there would be a reduction in the number of events by 57 when used for secondary prevention compared with 36 fewer events when used for primary prevention.21

In line with the accumulating evidence of substantial cardiovascular benefits of statins in diabetes, cholesterol levels have been falling in keeping with rising prescription rates. In our review of many diabetes trials that roughly averaged around the 1990s, the average total cholesterol was approximately 5.4 mmol/L in patients with type 2 diabetes.22 By 2006, the average cholesterol levels had declined to 4.5 mmol/L, with a further fall to 4.2 mmol/L by 2008.22

Most national and international guidelines now recommend that modest doses of statins be prescribed to all patients with type 2 diabetes above the age of 40 years of age.17 More intensive statin doses can be targeted to those at highest risk of subsequent events. This includes those with diabetes and preexisting cardiovascular disease (a group we showed to be at markedly increased chances of premature mortality) or those with evidence of proteinuria or chronic kidney disease.23 Further guidance or research is needed to establish when to prescribe statins to younger individuals with type 2 diabetes.

The evidence for statins is therefore strong, but up until recently other lipid agents had failed to show any benefits in diabetes. The FIELD study (Fenofibrate Intervention and Event Lowering in Diabetes) assessed fenofibrate use in diabetes, and although there was a significant decrease in nonfatal myocardial infarction there was a paradoxical increase in all-cause mortality.24 In 2010, the ACCORD study added fenofibrate or placebo to simvastatin and did not show any significant gains in all-cause mortality or cardiovascular morbidity.25 That noted, in the recently published IMPROVE-IT trial (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial), which compared combination therapy of daily ezetimibe and simvastatin with simvastatin monotherapy in patients following a recent acute coronary syndrome, in the subgroup of diabetes patients (n=4933) ezetimibe therapy led to a further 0.4- mmol/L lowering of LDL-cholesterol and a 14% reduction in major cardiovascular events.26 These results establish ezetimibe as an evidence-based add-on to statins in patients with diabetes who fail to meet targets on statin therapy.

Blood pressure and the renin-angiotensinaldosterone system

Hypertension is strongly linearly related to increased risk of all diabetes-related comorbidities as clearly shown in the UKPDS 36 trial.27 For every 10-mm Hg decrease in mean systolic blood pressure there was an 11% risk reduction in myocardial infarction, a 13% reduction in microvascular events, a 15% decrease in diabetes-related deaths, and a 12% reduction for any complication relating to diabetes.27 In 2009, Ray et al showed in their meta-analysis the respective benefits that glycemic control, reduction in LDL-cholesterol, and blood pressure lowering each have in reducing cardiovascular events (Figure 2, page 24).14

It is clear that the impact of hypertension on diabetes-associated cardiovascular risk is strong, further emphasizing the need to prioritize blood pressure and lipid control with statins early in patients with type 2 diabetes. That is not to say that glycemic control is not important, but merely concentrating on good glycemic control alone will have less impact on cardiovascular events and mortality than blood pressure or lipid control. The evidence for hypertension association is therefore strong, but what has been more difficult to ascertain has been the optimal point at which to treat blood pressure and what blood pressure target to aim for. This has been disputed over the last 10 years, but recently the extensive meta-analysis by Emdin et al published in 2015 has helped support a cut-off point at which benefit of treating blood pressure in patients with type 2 diabetes should be gained.28 A total of 40 blood pressure trials including 100 354 diabetes patients were included in the meta-analysis, and in keeping with previous research, for every elevation in systolic blood pressure by 10 mm Hg there was a corresponding increase in complications. What this review added was a clear cut-off point which showed that treating a systolic blood pressure greater than 140 mm Hg improved all outcomes, as shown in Figure 3.28

Figure 2
Figure 2. Relative benefits of glucose lowering, blood pressure
lowering, and low-density lipoprotein–cholesterol lowering on cardiovascular
events per 200 diabetes patients treated for 5 years.

Abbreviations: HbA1C, glycated hemoglobin; LDL-C, low-density lipoprotein
cholesterol, SBP, systolic blood pressure.
After data from reference 14: Ray et al. Lancet. 2009;373(9677):1765-1772.

Figure 3
Figure 3. Standardized associations between 10–mm Hg lower systolic blood pressure and all-cause mortality, macrovascular outcomes,
and microvascular outcomes stratified by mean systolic blood pressure of trial participants at entry.

Macrovascular outcomes include cardiovascular events, coronary heart disease, stroke, and heart failure; and microvascular outcomes include renal failure, retinopathy, and albuminuria. Mean baseline blood pressure is weighted by number of participants. The area of each square is proportional to the inverse variance of the estimate. Horizontal lines indicate 95% CIs of the estimate.
Abbreviations: BP, blood pressure; CI, confidence interval; SBP, systolic blood pressure.
After reference 28: Emdin et al. JAMA. 2015;313(6):603-615. © 2015, American Medical Association.

In all diabetes-associated outcomes there was strong evidence supporting treating blood pressure above 140 mm Hg (systolic), but for some outcomes such as stroke, retinopathy, or albuminuria there was also benefit in treating hypertension when baseline systolic blood pressure was less than 140 mm Hg, so targets of near 130 mm Hg may be useful in selecting patients at elevated risks of these latter complications.28

A slightly different aspect of blood pressure– lowering agent use in diabetes relates to the inhibition of the renin-angiotensin-aldosterone system. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been shown in a large meta-analysis to significantly reduce the progression of diabetic kidney disease, irrespective of blood pressure. ACE inhibitors reduced the progression of micro-to macroalbuminuria by 45%, a relative risk reduction of 0.55 (95% CI, 0.26-0.71), and ARBs reduced the progression by 51%, a relative risk reduction of 0.49 (95% CI, 0.32- 1.05).29 They also reduced the progression to end-stage renal failure, which is obviously the most important potential consequence of diabetes-related microvascular kidney disease. Accordingly, ACE inhibitors and ARBs are prioritized early in hypertension algorithms for patients with diabetes, but it is important to note that all blood pressure–lowering medications work to lessen the risk and no classes should be avoided (unless there are specific contraindications) if blood pressure levels remain elevated. Interestingly, in the Emdin meta-analysis, it appeared that calcium channel blockers showed slightly more benefit in lowering the risk of stroke, whereas ACE inhitors/ARBs or diuretics did more to lower the risk of heart failure.28

Multi-intervention management for diabetes

We have so far focused mainly on isolated glycemic or risk factor control but it is clear that maximal impact will occur when these separate interventions are combined. In the last 5 years, observational evidence supports significant gains in cardiovascular disease reduction and mortality via this approach in diabetes. The National Health And Nutrition Examination Survey (NHANES) looked at data from 1999-2008 and included 1977 participants with diabetes aged 30-74.30 During this period the Framingham heart study predicted that the10-year risk would decrease significantly as can be seen in Figure 4.

The reasons for the significant decreases in the risk of developing heart disease can be attributed to several factors during this 8-year period. In the male participants the total cholesterol was reduced to 4.6 mmol/L from 5.3 mmol/L during this period, and rates of smoking declined to 15% from 20%. HbA1c improved to 7.3% from 7.7%, and the average systolic blood pressure went down to 128.7 mm Hg from 130.5 mm Hg in 1999-2000.30 These significant reductions and improvements were also noted in the female participants of the study. This observational evidence base showed the improvements that had been made in a large number of patients over a prolonged period of time.

Figure 4
Figure 4. Estimated 10-year risk (95% CI) of developing coronary heart disease
among NHANES participants with diagnosed diabetes aged 30-74 years, stratified
by race or ethnicity.

The estimated risk was calculated using risk equations generated from the Framingham Heart Study.
Abbreviations: CHD, coronary heart disease; CI, confidence interval; NHANES, National Health And
Nutrition Examination Survey.
Modified from reference 30: Ford. Diabetes Care. 2011;34(6):1337-1343. © 2011, American Diabetes
Association.

In 2008, the seminal STENO-2 study provided early randomized controlled data to support a multifactorial approach to diabetes, albeit in a modest number of patients. In the STENO-2 study, 160 participants were randomized to either standard care or intensive care which included the following targets: an HbA1c of 6.5% (48 mmol/mol), blood pressure of <130/80, total cholesterol 31

In the intervention group patients with microalbuminuria were also given blockers of the renin-angiotensin-aldosterone system, regardless of blood pressure, and low-dose primary prevention aspirin. The follow-up period for STENO-2 was 13.3 years and the absolute risk reduction for death in the intervention group was 20%, hazard ratio 0.54 (95% CI,0.32 to 0.89; P=0.02), and the absolute risk reduction for death due to cardiovascular causes was 13%, hazard ratio 0.43 (95% CI, 0.19 to 0.94; P=0.04).31 During the study there were no significant differences and changes in behavior between the groups with regard to smoking, exercise, diet, and weight, which suggests that the primary gains were made through medical management of cholesterol, blood pressure, and glycemia. Whether the addition of aspirin also added benefit is not clear, and the current evidence base would suggest that aspirin should be used only for secondary prevention in patients with or without diabetes.

Bringing it all together

In 2012, we produced a table (Table I, page 26) to conceptualize the relative impact of glucose, blood pressure, and lipid control on diabetes complications as well as the cost of use and complexity of the respective drug regimens.32 The table suggests that on the one hand cardiovascular risk reduction is more impacted by lipid and blood pressure lowering, whereas glucose reduction has a slow burn effect.32 By contrast, glucose and blood pressure lowering are more important in lowering microvascular risks. Of course, the recent EMPAREG outcomes trial adds a new twist to the story for patients with diabetes and cardiovascular disease, suggesting that SGLT2 inhibitors may be particularly apt at lowering cardiovascular death and heart failure risks in this group of patients.19

Table I
Table I. Relative benefits on diabetes-associated outcomes ( low/
modest, ↓↓↓ significant) and relative cost of use and complexity
(+ low, ++ moderate, +++ high) of glucose lowering, blood pressure
lowering, and statins.

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor
blocker; CHD, coronary heart disease.
After reference 32: Ferguson and Sattar. Diabetes Obes Metab. 2013;15(5):
387-391. © 2012, Blackwell Publishing Ltd.

 

Summary and going forward

The aforementioned trials have highlighted the benefits of a multifactorial approach to the management of diabetes, with particular emphasis on the importance of managing lipids and blood pressure to reduce cardiovascular disease. However, what remains less certain is the extent to which microvascular and macrovascular risk can be further improved and if there are other pathways or mechanisms (perhaps subclinical fluid overload in those with diabetes and cardiovascular disease, potentially revealed by EMPA-REG outcomes) to further improve morbidity and mortality.

A final point to note is that we are largely failing in tackling obesity through changes in lifestyle in patients with diabetes or at elevated risk for diabetes. Many countries are also facing rising obesity levels generally. Lifestyle management is an area in need of further research since tackling obesity not only improves risk factors but importantly improves patients’ quality of life. Furthermore, if we can even delay diabetes for a few years in those noted to be at elevated risk, the benefits to patients are enormous since mounting evidence indicates that the younger one develops diabetes, the higher the future risks are.33

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Keywords: blood pressure; cardiovascular disease; cholesterol; glycemia; risk factor modification; type 2 diabetes