Prediabetes and Cardiovascular Disease: Pathophysiology and Interventions for Prevention and Risk Reduction

Synopsis

Prediabetes is a state characterized by impaired fasting glucose or impaired glucose tolerance. This review discusses the pathophysiology and macrovascular complications of prediabetes. The pathophysiologic defects underlying prediabetes include insulin resistance, alpha- and beta-cell dysfunction, increased lipolysis, inflammation, and suboptimal incretin effect. Recent studies have revealed that the long-term complications of diabetes manifest in some people with prediabetes; these complications include microvascular and macrovascular disorders. Finally, we present an overview of randomized control trials aimed at preventing progression from prediabetes to type 2 diabetes and discuss their implications for macrovascular risk reduction.

Introduction

Type 2 diabetes mellitus (T2DM) is one of the major causes of premature morbidity and mortality worldwide with the World Health Organization (WHO) reporting that one in ten adults worldwide had T2DM in 2014.¹ In the United States, one out of every five health care dollars is spent on diabetes related healthcare.² Diabetes Mellitus also imposes a huge drain in developing countries on national health budgets comprising on average at least 5% of their total health expenditures on diabetes in 2010.³ Of these, macrovascular complications are the largest contributor to the direct and indirect costs of diabetes.⁴ The development of T2DM is punctuated by an interlude of prediabetes, itself a toxic state that is associated with the development of macrovascular complications.

Diagnosis and Burden of Prediabetes

The prelude to diabetes is prediabetes in what can be described as a continuum from normoglycemia through worsening dysglycemia. Prediabetes is defined specifically as impaired glucose tolerance and/or impaired fasting glucose.⁵ According to the American Diabetes Association (ADA) impaired glucose tolerance (IGT) is defined as a 2-hour plasma glucose value in the 75-gram oral glucose tolerance test (OGTT) of 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L).⁶ Impaired fasting glucose (IFG) is defined as a fasting plasma glucose of 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L).⁶ Finally prediabetes can also be defined as a hemoglobin A1c (HbA1c) of 5.7% –6.4% (39–46 mmol/mol).^6,7 It bears stressing that the ADA criteria stipulate normal glucose tolerance (NGT) as a fasting glucose level less of than 100mg/dl and a 2-hr post-load OGTT plasma glucose level of less than 140mg/dl. In regards to using HbA1c as a diagnosis of prediabetes, it must be stressed that there are many well characterized “pitfalls” such as anemia, chronic kidney disease, and other systemic illness and hematological disorders that disrupt the reliability of HbA1c as an integrated measure of mean plasma glucose.^8–12 In particular, racial and ethnic differences in the relationship between blood glucose values and HbA1c call for caution when utilizing HbA1c levels for the diagnosis of prediabetes. 8–14 It is always prudent to confirm diagnosis with actual blood glucose measurement before instituting therapeutic measures.⁸ Estimates by the Centers for Disease Control and Prevention (CDC) in the United States indicated that there were ~29 million adults with diabetes and 86 million with prediabetes in 2014.^15,16 Worldwide, there are more than 400 million people with prediabetes and projections indicate that more than 470 million people will have prediabetes by 2030.¹⁷ In addition, many studies from across the globe have pointed out that the risk of many co-morbidities are the same in diabetes and prediabetes and affect all age groups.^18–23

Pathophysiological Defects in Prediabetes

The known pathophysiological defects that underlie T2DM are being increasingly recognized in the prediabetic state.^24–28 The natural progression of dysglycemia involves increasing insulin resistance and loss of pancreatic β-cell function.²⁹ Significant defects in insulin action and secretion are consistently demonstrable in the prediabetic state of IGT.^30–32 Several cross-sectional studies and a few longitudinal studies have carefully documented the various defects leading to prediabetes and T2DM.^33–35

Findings from Longitudinal Assessment of Insulin Action and Secretion

A landmark longitudinal study that tracked high risk subjects from the stage of NGT to prediabetes reported that the transition to prediabetes was associated with an increase in body weight, increase in insulin resistance, and a decline in the endogenous insulin secretion (beta-cell dysfunction).²⁹ The study further demonstrated that progression from prediabetes to T2DM was accompanied by a worsening of weight gain, insulin resistance, and beta-cell dysfunction.²⁹ Thus the salient finding from the longitudinal observation was that insulin resistance and beta-cell failure co-evolve simultaneously rather than sequentially, as was previously believed. Individuals who maintained NGT status, despite weight gain and associated insulin resistance, were those who mounted a robust endogenous insulin secretory response.²⁹ Thus, if beta-cells cannot overcome insulin resistance, dysglycemia ensues. A supportive post-mortem study reported ~40% deficit in relative β-cell volume among individuals with prediabetes compared to those with normal fasting glucose concentrations.³⁵

Lipolysis, Incretin, Alpha Cell, and Inflammation in Prediabetes

Further defects in the prediabetic state include increased lipolysis, decreased endogenous levels of glucagon-like peptide 1 (GLP-1), and impaired postprandial suppression of glucagon secretion by the alpha-cells of the pancreas.^36–40 Additionally, as listed in Table 1, aberrant expression of proinflammatory cytokines adds to the toxic milieu of prediabetes. For instance, low adiponectin levels have been demonstrated to be predictive of progression from NGT to prediabetes, and from prediabetes to T2DM.^39,41 Elevated levels of molecular markers such as intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-α (TNF-α) have been reported.⁴² Figure 1 shows the recognized pathophysiological defects in T2DM, highlighting those that have also been described in prediabetes.^43–44

Table 1.

Pathophysiological Defects in Prediabetes

Defect	References
Loss of beta-cell volume	35
Defects in insulin action and secretion	24,26,29–31,33,51,52
Endothelial dysfunction	26,52
Arterial Stiffness	72–74
Increased lipolysis	25,36
Reduced incretin levels	36,38
Increased hepatic glucose production	26, 32,33
Impaired glucagon levels	33
Dysregulated cytokines	41,42,99

Figure 1.

Recognized pathophysiological defects in type 2 diabetes mellitus and prediabetes. From Dagogo-Jack, S. Diabetes risks from prescription and nonprescription drugs. ADA press, Alexandria VA, 2016, with permission.

Emerging insights regarding the gut microbiome and its association with cardiometabolic disorders, such as obesity, diabetes, dyslipidemia, etc., have relevance to prediabetes. Recently, a disturbed gut microbiota expressed as gut dysbiosis (an intestinal physical barrier abnormality) has been associated with the progression and maintenance of obesity, T2DM, cardiovascular disease (CVD) and the metabolic syndrome.^45–50 Future research into this area will help shed light onto the proximal chronology of the associated between gut dysbiosis and early dysglycemia/prediabetes.

Predictors of Glycemic Progression to Prediabetes/T2DM

Conversion from Prediabetes to T2DM

An analysis of six prospective studies on progression from prediabetes to T2DM revealed the following features: (1) baseline fasting plasma glucose (FPG) and the 2-h OGTT glucose values were positively associated with diabetes risk; (2) the rate of progression from prediabetes to T2DM was exponential among subjects in the top quartile of baseline FPG but increased linearly with increasing 2-h OGTT glucose levels; (3) incident diabetes occurred at higher rates in Hispanic, Mexican-Americans, Pima, and Nauruan populations than among other ethnicities such as Caucasians; (4) increased BMI predicted T2DM risk in low risk populations but not in populations with the highest incidence of T2DM.^51,52 Of note, weight gain significantly predicted the risk of incident T2DM in African-Americans in the Atherosclerosis Risk in Communities study.⁵³

Normoglycemia to Prediabetes Transition

Longitudinal studies in subjects from a high-risk population (PIMA Indians) with baseline NGT indicated that weight gain, insulin resistance, and progressive loss of insulin secretory response to glucose predicted transition from NGT to IGT (prediabetes).^29,53 The longitudinal mean weight change in NGT → NGT subjects (nonprogressors) vs. NGT → IGT progressors was 2.6 kg vs. 5.2 kg during a 6-year follow-up period.²⁴

In the Baltimore Longitudinal Study of Aging (BLSA), 62% of the initially NGT participants progressed to prediabetes during 10 years of follow-up, yielding an annualized rate of prediabetes 6.2% in the BLSA.⁵⁴

In the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study, initially normoglycemic African American and European American offspring of parents with T2DM were followed longitudinally for the primary outcome of incident prediabetes (IFG or IGT). During a mean 2.62 years of follow-up 101 of 343 POP-ABC participants developed incident prediabetes, yielding an annualized rate of ~11%.⁵⁵ Compared to nonprogressors, POP-ABC participants who developed incident prediabetes were older, more likely to be male, had higher baseline BMI and fat mass, lower levels of physical activity (adjusted for food habits), lower measures of insulin sensitivity, disposition index; serum adiponectin and HDL cholesterol levels, and higher triglyceride levels.^41,55–57

Macrovascular Complications of Prediabetes

The macrovascular disorders associated with prediabetes include CVD, stroke, and peripheral vascular disease. As figure 2 depicts, these disorders are established in patients with T2DM, but their initiation and progression are well recognized to occur during the prediabetes stage.^58–61 In fact, the traditional CVD risk factors (dyslipidemia, obesity, hypertension) are quite prevalent among individuals with prediabetes.^62–67

Figure 2.

Recognized macrovascular complications associated with prediabetes.

Data from references^57–74.

Cardiovascular Disease

A recent meta-analysis based on 35 studies reported data for the association between myocardial infarction and congestive heart failure as well as coronary artery disease and atherosclerosis have all been reported in individuals with prediabetes.^67–69 In the EPIC-Norfolk study, a 1% increase in 27 HbA1c within the normal range was associated with increased 10-year cardiovascular mortality. The EPIC-Norfolk findings are in accord with data from the Paris Prospective Study cohort which 70 showed a doubling of CVD mortality in IGT subjects compared with NGT subjects. The finding of increased mortality is underscored by the fact that most patients with prediabetes harbor features of insulin resistance (metabolic) syndrome, including upper-body obesity, hypertriglyceridemia, decreased HDL cholesterol levels and hypertension, among others. Components of the metabolic syndrome often can be identified in prediabetic subjects several years before the diagnosis of ^71,72 T2DM. These features translate into advanced atherosclerotic vascular changes which are often preceded by impairment of endothelium-dependent vasodilation, vascular smooth muscle dysfunction and increased arterial stiffness.⁷³

A recent cross-sectional study reported a positive association between prediabetes and the prevalence of arterial stiffness, suggesting that early intervention on prediabetes control might prevent arterial stiffness.⁷⁴ Remarkably, the prediabetes state is associated a nearly 3-fold higher prevalence of unrecognized myocardial infarction compared with NGT status, as was demonstrated in the Multi-Ethnic Study of Atherosclerosis (MESA) study.⁶²

More recently, a randomized controlled trial of 6522 patients with coronary artery disease and prediabetes found that while acarbose did not reduce the risk of major adverse cardiovascular events, it did reduce the incidence of diabetes.⁷⁵

Stroke

Compared to NGT subjects, individuals with prediabetes have an increased risk of cerebrovascular diseases, including transient ischemic attack, stroke, and recurrent stroke.^65,76–79 A recent study by Tanaka and colleagues demonstrated that both diabetes and prediabetes were associated with poor early prognosis 30 days after acute ischemic stroke.⁸⁰ A study by Qiao et al. indicates that the 2-hr postload OGTT glucose level is a strong predictor of stroke and future cardiovascular disease.⁸¹ In the recently published KORA-MRI study, among 400 subjects who underwent MRI, 103 subjects had prediabetes and 54 had established diabetes. Subjects with prediabetes had an increased risk for carotid plaque and adverse functional cardiac parameters.⁸² In the IRIS trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or transient ischemic attack, treatment with pioglitazone significantly decreased the risks of stroke, myocardial infarction or development of T2DM as compared with placebo treament.^83,84

Peripheral Vascular Disease

Prediabetes is common in patients with peripheral vascular disease; however, the exact mechanisms remain to be fully elucidated. The development of diabetes is independently associated with mortality in PVD patients in some but not all studies.^85,86

Interactions among Prediabetes and CVD Risk Factors

Epidemiologic studies have shown that prediabetes is a strong predictor of CVD.^84–89 The studies include DECODE and Funagata Diabetes Study, among others.^88–91 In the San Antonio Heart Study, there was evidence that the risk for CVD starts to increase long before the onset of clinical diabetes.^92–94 Obesity and overweight, known risk factors for T2DM and prediabetes, have also been associated with CVD risk.^95–98 Overweight and obesity have been frequently associated with low-grade, chronic, systemic inflammation characterized by increased levels of pro-inflammatory markers including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and C-reactive protein.⁹⁹ Also, overweight people with prediabetes often present with dyslipidemia (higher triglycerides and lower HDL cholesterol)^99–104 Hypertension is another CVD risk factor that has been examined in prediabetes.^105–109 The DREAM¹⁰⁵ and NAVIGATOR¹⁰⁶ studies assessed the effect of blood pressure control on the progression from prediabetes to T2DM. Similarly, the Diabetes Prevention Program investigators reported lower rates of incident hypertension among prediabetic individuals randomized to the intensive lifestyle arm as compared to the placebo arm.¹⁰⁷

Intervention Studies to Prevent Progression from Prediabetes to T2DM and Development of CVD

Prevention of T2DM

Table 2 lists lifestyle and pharmacological intervention studies to prevent T2DM among individuals enrolled with prediabetes. Lifestyle intervention has clearly been demonstrated to decrease progression to T2DM.^106–111 The results of the DPP, Finnish Diabetes Prevention Study (FDPS), and other pertinent studies showed approximately 60% risk reduction for incident T2DM in the lifestyle arm compared to placebo.^112–116 In both the DPP and FDPS, every 1 kg decrease in weight in the lifestyle arm was associated with 15%–16% in future T2DM risk.^{115,117–122}

Table 2.

Pertinent Prediabetes Intervention Studies

Study	Intervention	Number of subjects	Study population	Risk reduction	Years
Da Qing121	Diet and exercise	577	Chinese IGT adults, mean age 46, BMI 26	31–46% after 6 years	1986–1992
Finnish DPS119	Diet and exercise	522	IGT adults, mean age 55, BMI 31	58% after 3.2 years	1993–1998
STOP-NIDDM124	Acarbose	1428	IGT adults, mean age 55, BMI 31	25% after 3.3 years	1995–1998
DPP120	Diet and exercise	3234	IGT adults, mean age 54 years, BMI 34	Metformin 31%, lifestyle 58% after 2 years	1996–1999
Xendos125	Orlistat and diet and exercise	3305	Swedish, BMI >30, mean age 43, 21% with IGT	Entire group 37%, IGT 45% after 4 years	1997–2002
DREAM126	Rosiglitazone	5269	IGT and/or IGF subjects mean age 54.7 years, BMI 30.9	62% after approximately 3 years	2001–2003
IDDP-1129	Lifestyle modifications and metformin or lifestyle modifications	531	Indian, IGT mean age 46 years, BMI 25.8	Diet and exercise 28.5%, Metformin 26.4%, Diet and exercise and metformin 28.2% after 30 months	2001–2004
ACT-NOW132	Pioglitazone	602	IGT, mean age 53, BMI 33	72% with pioglitazone over 2.4 years	2004–2006
CANOE127	Combination rosiglitazone and metformin vs placebo	207	IGT, mean age 50, BMI 31.3	26% in the combination group after 3.9 years	2004–2006
IDDP-2130	Lifestyle modifications or pioglitazone and lifestyle modifications	407	Indian IGT, mean age 45.3, BMI 25.9	28% though pioglitazone not additive to lifestyle modification	2006–2009
Navigator128	Nataglinide and lifestyle modifications or Valsartan and lifestyle modifications	9306	IGT, mean age 63.7, BMI 30.5	Nataglinide none, Valsartan 14%	2005–2010

There are also studies showing potential benefits from a variety of different pharmacotherapies.¹²² Pioglitazone was found to decrease the risk of diabetes by ~70% in obese subjects with prediabetes in the ACT NOW study.¹²³ Table 2 lists pertinent randomized controlled trials from around the world that demonstrated significant decrease in progression of prediabetes to diabetes. These include the STOP-NIDDM (25% risk reduction), Xendos (45% risk reduction), DREAM (62% risk reduction), CANOE (26% risk reduction) and the Valsartan arm of the NAVIGATOR trial (14% risk reduction).^124–128 It must be noted, however, that in both the IDPP1 and the follow-up study IDPP2, pharmacologic intervention provided no additional benefit beyond lifestyle modification in subjects randomized to Lifestyle + Metformin or Lifestyle + Pioglitazone arms.^129,130 Furthermore, all the medications tested for diabetes prevention have had untoward adverse effects (sometimes severe), and attempts to withdraw the medications have resulted in glycemic rebound.^131–132 Given these limitations of pharmacotherapy, the current guidelines from the ADA recommend lifestyle modifications as first line approach for diabetes prevention.⁶ Indications for possible use of metformin include women with a history of gestational diabetes and high-risk individuals unresponsive to optimal lifestyle modification.⁶

Prevention of CVD in Prediabetes

Long term follow-up of the Da Qing study demonstrated that diabetes prevention through lifestyle modification was associated with decreased cardiovascular and all-cause mortality after 23 years.¹³³ In the DPP, intensive lifestyle intervention that significantly decreased the risk of T2DM also reduced the need for antihypertensive medications.¹⁰⁷ The prevalence of hypertension in the DPP cohort at baseline was approximately 30% in the three comparison groups (placebo, metformin, lifestyle).¹⁰⁷ After 3 years of follow-up, the prevalence of hypertension was observed to have increased to approximately 40% in the placebo and metformin arms.¹⁰⁷ Surprisingly, the hypertension prevalence remained at the baseline rate of 30% in the intensive lifestyle group 3 years later.¹⁰⁷ Thus, lifestyle intervention designed to prevent T2DM also seems to have prevented incident hypertension in this initially prediabetic cohort.¹⁰⁷ The DPP investigators also reported that subjects assigned to intensive lifestyle intervention showed decreased blood pressure, increased HDL cholesterol levels, and lower triglyceride levels and a reduction in the more atherogenic small, dense LDL particles during approximately 3 years of follow-up.¹⁰⁷ Consonant with these findings, there was a reduced need for lipid lowering medications in the DPP,^{107, 109,110} as has been observed by others.^{111–113,134,135}

The Mediterranean diet is appealing as a specific nutritional recommendation, based on convincing reports of its benefits on cardiometabolic endpoints. For example, results from the PREDIMED (PREvención con DIeta MEDiterránea) randomized nutrition intervention trial for the primary prevention of CVD showed a 40% reduction in the incidence of T2DM in participants assigned to a Mediterranean diet supplemented with extra-virgin olive oil compared with those assigned to a low-fat control diet.^136,137 Other reports on the Mediterranean diet showed concordant findings on cardiometabolic profile. Mediterranean-style diet has been shown to result in greater weight loss along with improvement in inflammatory markers compared with general lifestyle counseling (14kg vs. 3kg, P< 0.001).^138–141

Besides the impact of lifestyle intervention on CVD risk factors, there is considerable interest in knowing whether prevention of diabetes also prevents related CVD. This has been a question under investigation by the Diabetes Prevention Program Outcome Study (DPPOS) research group. Analysis of regression patterns in the DPPOS showed that individuals whose blood glucose returned to normal experienced a 56% long-term reduction in diabetes incidence compared to those who remained dysglycemic.¹⁰⁹ Although CVD outcomes data collection is still in progress, additional inference from the DPPOS study would suggest that regression from prediabetes to normal may also be associated with decreased risk for CVD.^111,142

Clinical Translation and Conclusion

Prediabetes is a toxic cardiometabolic state associated with increased risk for microvascular and macrovascular complications.¹⁴³ Physicians and healthcare providers should screen patients routinely for prediabetes and refer those with the condition for intensive lifestyle counseling. The goal is to achieve and maintain > 5% weight loss through caloric restriction and increased physical activity, similar to the DPP and kindred studies (Table 2).^6,34,63–64 Healthcare providers should endeavor to build strong ties within healthcare systems, communities, and payers, to increase the availability of evidence-based structured lifestyle programs.

In a recent survey 33.6% of outpatients (out of 1.16 million outpatient visits analyzed) had prediabetes, based on HbA1c results. Amazingly, < 1% of those patients whose HbA1c tests showed prediabetes were recognized and diagnosed as such by clinicians. Of the abysmally low numbers whose prediabetes status was properly captured in the clinical records, only 23% had documentation of treatment (lifestyle modification and/or metformin) in the medical record.¹⁴⁴ The prediabetes period presents an opportunity to intervene during the disease process. Primary care physicians, specialists, health systems and patients themselves all have an obligation to ensure that the opportunity for prevention is not missed.^145–149

While it has long been known that diabetes confers significant cardiovascular risks, it is now becoming established that CVD risks precede diabetes and are evident in people with prediabetes. Given the millions of people with prediabetes around the globe, the impact on cardiovascular health is staggering. However, identifying and intervening in the at-risk prediabetic populations requires education, increased awareness, care coordination, organization and novel reimbursement mechanisms at multiple levels (health systems, society and individual).

Key Points.

• Prediabetes carries an increased risk in cardiovascular disease

• Significant physiological, metabolic, and biochemical features are dysregulated in prediabetes

• Extensive Randomized Controlled Trials have demonstrated that lifestyle modification can decrease the rate of progression from prediabetes to diabetes.

• Early detection and intervention is vitally important for prevention of prediabetes progression to diabetes