INTRODUCTION

According to data published in 2020 by the US National Institutes of Health, over 34 million people in the United States have diabetes, with type 2 diabetes (T2DM) accounting for 90–95% of cases [1,2]. An additional 88 million adults have prediabetes, for an approximate total of over 45% of the adult population afflicted [1]. Cardiovascular disease (CVD) is the leading cause of death in people with diabetes and those with diabetes are twice as likely to experience heart disease or stroke [3]. Therefore, improving associated risk factors in those with T2DM or putting the condition into remission should be a foundational goal of interventions intended to reduce CVD incidence and mortality among nearly half the US adult population.

Metabolic syndrome, a cluster of factors driven by chronic hyperinsulinemia and closely related to T2DM, is also a substantial risk factor for CVD. Findings from the Women's Health Study showed that, across all ages studied, diabetes conferred the highest risk for coronary heart disease, with risk increased tenfold in women younger than age 55 [4▪]. In the same age group, metabolic syndrome and lipoprotein insulin resistance (LPIR) both conferred over six times the risk and hypertension accounted for more than quadruple the risk, as did obesity. These levels of increased risk are substantially greater than those conferred by more traditional risk factors, such as total cholesterol and low-density lipoprotein cholesterol (LDL-C; hazard ratios 1.39 and 1.38, respectively). Physical inactivity conferred a hazard ratio of just 1.53 – a figure that may be considered unimpressive compared those conferred by the metabolic parameters related to insulin resistance and glycemic control.

Gerald Reaven, the physician-researcher who coined the term ‘syndrome X’ – now called metabolic syndrome – noted over 35 years ago that chronic hyperinsulinemia and its resulting pathologies were risk factors for CVD, going so far as to say that resistance to insulin-mediated glucose disposal was predictive of CVD [5–9]. More recent research corroborates Reaven's findings: rather than being merely associated with CVD, hyperinsulinemia may be a causal agent in the pathogenesis of atherosclerosis, hypertension and endothelial dysfunction and appears to be etiologic even in the absence of T2DM [7–9,10▪,11,12].

A consistent observation is that the addition of insulin or increase in insulin dosage in the treatment of those with T2DM is associated with higher rates of major adverse cardiovascular events and all-cause mortality in a dose-dependent fashion [11,13]. Hyperinsulinemia – whether of endogenous or of iatrogenic origin (particularly at the high doses routinely used in clinical practice) – predisposes to hypertension, dyslipidemia, atherosclerosis, arrhythmias, and heart failure with overall increased cardiovascular risk and worsened mortality [13–15]. It must be noted that while perhaps best known for its role in regulating blood glucose, insulin performs an array of other functions, including suppressing endothelial nitric oxide synthase (eNOS) and stimulating renal sodium absorption and calcium ion influx into smooth muscle cells – effects which likely contribute to hyperinsulinemia's pathological role in CVD [11]. Apart from hyperinsulinemia, hyperglycemia is a known contributor to micro- and macrovascular damage [14].

These findings suggest that for the millions of people living with T2DM and metabolic syndrome, it would be prudent to implement interventions that target hyperglycemia, hyperinsulinemia/insulin resistance, and their resultant adverse health effects first and foremost with only a secondary focus on risk factors with weaker associations such as LDL-C. Dietary carbohydrate restriction is one such approach. 

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DIETARY CARBOHYDRATE RESTRICTION

An impressive body of literature supports the use of dietary carbohydrate restriction (i.e., low-carbohydrate or ketogenic diets) for improving T2DM and metabolic syndrome, including putting them into remission altogether. A 2019 consensus report from the American Diabetes Association stated that for individuals with diabetes, ‘reducing overall carbohydrate intake has demonstrated the most evidence for improving glycemia’ and that among those who are not meeting glycemic targets or for whom reducing medications is a priority, ‘reducing overall carbohydrate intake with low- or very low-carbohydrate eating plans is a viable approach’ [16]. A recent scientific statement from the American Heart Association (AHA) notes that the combination of T2DM and metabolic syndrome increases CVD risk as much as 5-fold and includes very low-carbohydrate diets in its lifestyle management recommendations [17].

Numerous reviews of low-carbohydrate diets (LCDs) covering several clinical trials support the efficacy of carbohydrate restriction for improving or reversing T2DM and metabolic syndrome [18▪,19–24]. The consistent and substantial efficacy of this approach has led researchers to posit that the condition may be ‘defined by’ the response to carbohydrate restriction, and that carbohydrate restriction should be ‘the first approach’ in diabetes management and the ‘default treatment’ for T2DM and metabolic syndrome [19,23,24].

Although perhaps best known among the public for weight loss, LCDs improve metabolic syndrome and glycemic control even in the absence of clinically meaningful weight loss [25–27]. Clinicians who employ therapeutic carbohydrate restriction in patients with T2DM report occasionally needing to reduce or discontinue insulin as soon as the first day a patient adopts the diet, as glycemia may begin to improve this quickly, long before significant weight loss has occurred [28,29▪]. Antihypertensive medication also typically needs to be reduced or discontinued over time [29▪,30]. This is worth noting because a significant proportion of people with T2DM, metabolic syndrome, or hypertension have a normal body mass index and thus it would not be reasonable to target weight loss for the purpose of improving glycemic control and insulin sensitivity. A compilation of data on diabetes from the National Institute of Diabetes and Digestive and Kidney Diseases noted that hyperglycemia, insulin resistance, metabolic syndrome, hypertension, atherogenic dyslipidemia, and obesity are among the major risk factors for coronary heart disease among individuals with T2DM, but specified that ‘there is little evidence that measures of obesity are related to CVD independent of other risk factors or that weight reduction through change in lifestyle yields benefit for CVD prevention’ [31]. It is essential, then, to identify a method for improving these risk factors that does not require clinically significant weight loss. Dietary carbohydrate restriction is effective for this purpose.

A variety of dietary and lifestyle interventions may be effective for improving CVD risk but carbohydrate restriction may be uniquely beneficial owing to its salutary effects on T2DM and metabolic syndrome. Being that carbohydrate is the most potent dietary stimulator of endogenous insulin secretion and the biggest determinant of appropriate mealtime boluses, it is reasonable to suggest that limiting carbohydrate intake may be the most effective way to reduce exposure to endogenous and exogenous insulin. Improved glycemic control will result in reduced need for insulin, as demonstrated by clinical trials of low-carbohydrate or ketogenic diets in which use of insulin (as well as dipeptidyl peptidase 4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, sulfonylureas, and thiazolidinediones) was eliminated or reduced. In one such trial, insulin injections were eliminated in 40% of subjects following a ketogenic diet and in the remaining 60% the mean daily dose was decreased by nearly half [32]. Overall, 94% of subjects following the ketogenic diet had eliminated or reduced use of insulin and over half had reversed T2DM by the end of one year (reversal defined as hemoglobin A1c (HbA1c) <6.5% with no diabetes medication or metformin only).

An audit of a small practice in the United Kingdom (UK) found that 46% of patients with T2DM who self-selected a low-carbohydrate diet experienced drug-free remission within 12 months (remission defined as HbA1c <6.5% and no use of antidiabetic medication) [33]. The remission rate dropped to 36% at a 24-month follow-up – a figure that is still impressive when compared to the remission rate of just 2% among patients following usual care in the UK. Additionally, 93% of those with prediabetes who self-selected a low-carbohydrate diet achieved HbA1c below the diabetic range – a finding that has implications for preventing the progression of prediabetes to T2DM among the 88 million US adults living with prediabetes. It is especially noteworthy that across multiple studies, subjects experienced better glycemic control and often improved blood pressure and improvements in biomarkers of metabolic and cardiovascular health while having medications reduced or eliminated [26,32,33,34▪,35]. This has important implications for reducing healthcare costs for individuals as well as for national healthcare systems.

RELUCTANCE REGARDING WIDER ADOPTION OF CARBOHYDRATE RESTRICTION: THE ROLE OF LOW-DENSITY LIPOPROTEIN-CHOLESTEROL

A preponderance of evidence supports the use of LCDs for improving or reversing T2DM and metabolic syndrome – two major contributors to the pathogenesis of CVD. Despite this evidence, there is reluctance among clinicians and public health agencies to recommend this nutritional strategy more widely. A main point of contention appears to be trepidation regarding the possibility of increased serum LDL-C in individuals who adopt LCDs. However, this fear is unwarranted as most individuals treated with a low-carbohydrate diet will not experience a clinically significant increase in LDL-C. In cases where LDL-C does increase, this change can be approached in a rational manner so as not to forgo the cardiovascular risk reducing benefits of carbohydrate restriction.

Randomized trials of LCDs consistently show minimal change in LDL-C. For example, in the DIRECT study, which compared low-carbohydrate, low-fat, and Mediterranean dietary patterns, LDL-C in the low-carb arm did not change significantly and there was no significant difference compared with the other arms [36]. Yancy et al.[37] compared low-carbohydrate to a low-fat diet and found an average increase in LDL-C of just 1.6 mg/dL with a less than 10% increase in LDL-C in approximately 70% of participants in the low-carbohydrate group. Similarly, Tay et al.[38] found no significant increase in LDL-C in type 2 diabetics treated with a low-carb diet. Furthermore, in a nonrandomized trial of a ketogenic diet for treatment of T2DM, Bhanpuri et al.[30,39] demonstrated that while there was a small average increase in LDL-C, there was a clinically significant decrease in LDL-P and an increase in LDL particle size – both more robust markers for cardiovascular risk than serum LDL-C concentration.

In light of improvements in other risk markers attributable to a low-carbohydrate diet, it is important to consider the overall cardiovascular risk in an individual when LDL-C does increase. Unlike serum LDL-C, which is only weakly associated with CVD, coronary artery calcium (CAC) scanning can more directly assess the presence of atherosclerosis and is believed to be superior to any other measure of risk [40▪]. Research employing CAC scores indicates that as many as half the individuals with an indication for pharmaceutical intervention (i.e., elevated LDL-C) have zero CAC, thus, as noted by Raggi, ‘…they are at extremely low risk and do not need drugs’ [40▪]. More widespread use of CAC scanning has revealed a surprising number of individuals with ‘severely elevated’ LDL-C who show no evidence of atherosclerosis and thus are at low risk for cardiovascular events [41▪–43▪]. Findings from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort showed that among subjects with LDL-C ≥190 mg/dL, a zero CAC score was associated with a low risk of cardiovascular events [43▪]. For these patients, the well established risk factors of older age, male sex, T2DM, and smoking were the key predictors of presence and progression of atherosclerosis – not serum LDL-C. In contrast to these patients with high LDL-C and zero CAC who are at low risk, the MESA investigators have shown that patients with diabetes and hypertension and zero CAC remain at significantly elevated risk of cardiovascular disease [44]. It is these risk factors that are best addressed by a low-carbohydrate diet.

In the event that an individual following a low-carbohydrate diet does experience an increase in LDL-C and the patient and provider conclude that the elevation is clinically significant and necessitates treatment, the low-carbohydrate diet need not be abandoned, as such a diet does not preclude use of pharmacologic treatments for hyperlipidemia. The availability of well tolerated lipid-lowering agents provides an opportunity for patients to continue experiencing the marked benefits of carbohydrate restriction for addressing the consequences of T2DM, hyperinsulinemia, and metabolic syndrome while at the same time mitigating the potential increased risk due to increased LDL-C. On the other hand, in assessing overall cardiovascular risk, a patient may decide that the benefits of a low-carbohydrate diet outweigh the potential increased risk attributable to LDL-C and elect not to use lipid-lowering treatment. The key is to account for patient preferences and values using a shared decision-making approach guided by evidence-based guidelines [45].

ATHEROGENIC DYSLIPIDEMIA: A BETTER TARGET THAN LOW-DENSITY LIPOPROTEIN-CHOLESTEROL

The atherogenic dyslipidemia risk triad – consisting of elevated triglycerides, reduced high-density lipoprotein cholesterol (HDL-C), and a preponderance of small, dense LDL particles – is a typical feature of metabolic syndrome and insulin resistance and has emerged as a more powerful predictor of CVD risk than LDL-C [10▪,46]. It was shown nearly a quarter-century ago that total cholesterol and LDL-C showed no significant correlation with risk for myocardial infarction (MI), whereas elevated triglycerides and decreased HDL-C showed significant correlation and a preponderance of small, dense LDL particles was associated with triple the risk for MI [47]. Research conducted since then has found a significant relationship between extent of coronary disease and serum triglycerides, HDL-C, and triglyceride/HDL-C ratio, but not for total cholesterol or LDL-C. The triglyceride/HDL-C ratio – an indicator of insulin sensitivity – showed the strongest association and was an independent indicator of the presence as well as the extent of disease [48]. Interestingly, a recent finding utilizing coronary artery CT angiography indicate that severity of coronary artery stenosis is positively correlated with elevated fasting glucose, HbA1c, and triglycerides, but not with serum LDL-C [49].

The overwhelming associations – some would say causal relationships – between T2DM, metabolic syndrome and CVD suggest that reducing the burden of CVD will require a shift away from a focus on LDL-C and toward improving glycemic control and insulin sensitivity. By way of inducing these improvements, carbohydrate restriction is consistently shown to favorably impact atherogenic dyslipidemia. Individuals with T2DM following a low-carbohydrate diet typically experience significant decreases in triglycerides and increases in HDL-C (resulting in an improved ratio between the two) plus significant reductions in blood pressure [19,33]. Subjects following a ketogenic diet for one year showed significant improvements in a host of metabolic and cardiovascular parameters, including HbA1c, triglycerides, HDL-C, blood pressure, and LPIR, as well as a significant decrease in the concentration of small, dense LDL particles and a decrease in 10-year atherosclerotic CVD risk [30]. Subjects also had reductions in or elimination of antihypertensive medications. Assessment of this cohort at two years confirmed that adherence to the ketogenic diet continued to support decreased small, dense LDL particles and an increase in large particles with no significant change in total LDL particles or apoB-containing lipoproteins [39].

SATURATED FAT

Another point of concern that precludes wider recommendation of low-carbohydrate diets for improving cardiovascular risk is the amount of saturated fat such diets may contain. Carbohydrate restriction does not inherently imply an increase in saturated fat consumption, as the cornerstone of LCDs is a reduction in carbohydrate intake rather than an increase in fat intake. (Reduced carbohydrate intake may result in a larger percentage of daily calories coming from fat without an increase in absolute fat intake.) It is possible to construct a low-carbohydrate diet that emphasizes foods rich in mono- and polyunsaturated fatty acids for those who favor these based on taste preferences, food sensitivities, or cultural considerations, but there appears to be no rationale for limiting saturated fats from a cardiovascular health standpoint. Limiting saturated fat intake is not required to realize the metabolic and cardiovascular benefits of carbohydrate restriction [25,50,51▪].

Recommendations to limit intake of saturated fat in any dietary pattern, not just carbohydrate restriction, are based on the observation that increased saturated fat consumption may result in increased serum LDL-C, and the belief that this increase inherently and independently increases risk for CVD. However, as discussed earlier, this premise is controversial, but to the extent that it may be true in some individuals, this increased risk is dwarfed by that conferred by T2DM, metabolic syndrome, and insulin resistance. Decades of research have failed to identify a plausible mechanism by which saturated fatty acids are causal in heart disease [52]. Numerous reviews and meta-analyses (including one published in the Journal of the American College of Cardiology) have found no significant evidence of an association between dietary saturated fat and increased risk for CHD or CVD and evidence that reducing dietary saturated fat intake is beneficial for cardiovascular health is also lacking [52,53▪,54▪,55,56]. A 2020 Cochrane review determined there were ‘little or no effects of reducing saturated fat’ on all-cause or cardiovascular mortality, nor on nonfatal MI or CHD mortality [57].

Reducing dietary carbohydrate, on the other hand, has been shown to induce improvements in numerous markers of cardiovascular health, as discussed earlier, and these improvements occur even when the diet is rich in saturated fat. Hyde et al.[25] showed that consumption of a higher fat, very-low-carb diet (74% of daily calories from fat, 100 g of which was saturated fat) resulted in the greatest decrease in triglycerides and HOMA-IR, the largest increase in HDL-C, and the most subjects with reversal of metabolic syndrome compared to moderate- and high-carb diets lower in total and saturated fat.

Despite mounting evidence that there is no association between saturated fat intake and CVD, the most recent iteration of the Dietary Guidelines for Americans (2020–2025) continues to recommend that saturated fat account for less than 10% of daily calories starting at age 2 [58]. However, a recent review determined that this 10% cap on saturated fat is not evidence-based [54▪]. The AHA recommends an even lower limit: 5–6% of daily calories, based on their statements that saturated fat ‘Increases risk of cardiovascular disease’ and ‘Raises bad cholesterol levels’ [59,60]. Use of the term ‘bad cholesterol’ is misaligned with findings regarding the absence of coronary calcification in many individuals despite dramatically elevated serum LDL-C, as discussed above. Continued use of this outdated and seemingly erroneous terminology may be doing a disservice to the lay public as well as to healthcare professionals.

As early as 1986, Reaven [6] expressed concern that public health messaging centered on limiting dietary fat would inevitably result in increased consumption of carbohydrate, which in many people would induce hyperinsulinemia and elevate triglycerides, increasing risk of coronary artery disease. Noting that reducing carbohydrate intake can improve all features of atherogenic dyslipidemia, Siri-Tarino et al.[56] proposed that dietary efforts intended to improve CVD risk should ‘primarily emphasize the limitation of refined carbohydrate intakes and a reduction in excess adiposity’. The lack of association between saturated fat intake and CVD, coupled with the adverse effects of carbohydrate overconsumption (particularly among those with T2DM or metabolic syndrome) suggests that the potential increase in LDL-C induced by carbohydrate restriction is outweighed by the latter's efficacy in improving glycemia and insulin sensitivity. As stated by Lawrence, ‘The focus on dietary manipulation of serum cholesterol may be moot in view of numerous other factors that increase the risk of heart disease’ [52]. A recent review of LCDs classified this approach as an ‘alternative dietary pattern’ but the evidence for the efficacy of carbohydrate restriction to improve a host of metabolic risk factors and biomarkers of cardiovascular risk suggests it may be appropriate to consider low-carbohydrate diets not as an alternative approach, but as the default method recommended for the millions of people living with T2D or metabolic syndrome [18▪,24].

CONCLUSION

Considering the millions of people living with T2DM and prediabetes, and the evidence implicating poor glycemic control, insulin resistance, and metabolic syndrome in risk for CVD, it may be prudent to shift the targets of a ‘heart-healthy diet’ away from the traditional goals of lowering serum total cholesterol and LDL-C and toward a focus on reducing insulin levels and improving glycemic control and insulin sensitivity, including reversal/remission of prediabetes, T2DM and metabolic syndrome. Carbohydrate restricted diets are effective interventions for such a purpose, and being that the main requirement is the restriction of carbohydrate intake, this approach can be customized to suit individual food sensitivities and preferences, as well as cultural, religious, and socioeconomic considerations.

Acknowledgements

The authors thank Eric C. Westman, MD, for professional mentorship.

Financial support and sponsorship

None.

Conflicts of interest

Amy Berger receives royalties from books related to low-carbohydrate diets.

Eric Thorn reports no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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