Milk Origin and Cardiometabolic Health: History
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Subjects: Nutrition & Dietetics
Contributor:
Jack Penhaligan

The whole milk product (and individual milk ingredients) from different species could impact cardiometabolic health.

  • milk
  • cardiometabolic health
  • metabolism
  • glycaemia
  • energy expenditure
  • appetite
  • obesity
  • type II diabetes

1. Introduction

The consumption of cow dairy products is a dominant feature in the diet of many cultures globally, particularly among Western communities. There is some evidence from epidemiological studies and systematic reviews alike that dairy intake is inversely linked with the risk of developing metabolic syndrome [1][2][3]. More pertinently, a body of data supports a negative association between milk intake and the risk of developing dysglycaemia, dyslipidaemia, and hypertension [1][4]. However, with gold-standard data from long-term randomised controlled trials (RCTs) featuring type II diabetes (T2D) and cardiovascular disease (CVD) incidence as primary endpoints not currently available, the causality of these findings remains to be confirmed [5]. Nonetheless, putative explanations for a possible metabolic syndrome risk reduction include a direct modulation of the glycaemic response [2][6], and an indirect modulation of body weight through upregulation of postprandial thermogenesis [6][7][8] and/or suppression of appetite [9][10][11]. Features of, or responses to, milk that might contribute to any cardiometabolic protection include the bioactive peptide content [12][13]; fatty acid (FA) content [14], e.g., conjugated linoleic acid (CLA) [15]; glycaemic index (GI) [16][17]; promotion of satiety [18]; mineral content, particularly calcium, magnesium, and potassium [19][20][21][22]; and folate bioavailability [23].

Although there is growing data on the acute and chronic health benefits of cow milk, albeit not yet conclusive, whether milk from alternative (non-bovine) sources could provide comparable or superior cardiometabolic protection has not yet been comprehensively reviewed.

2. Current Status of Cow Milk Alternatives

The worldwide commercial production of cow milk decisively eclipses the relatively minor contributions from alternative animal species (Table 1). Nonetheless, these milks remain valuable primary sources for many countries and communities globally.

Table 1. Mean contribution of individual species’ milks towards global production. [24]

Milk Origin Global Milk Production (%) Global Milk Production (kg)
Cow 81.3 714,400,000,000
Buffalo 14.8 130,300,000,000
Goat 2.2 18,900,000,000
Sheep 1.3 11,800,000,000
Camel 0.4 3,200,000,000

Values rounded to nearest 0.1 percent or 109 kg.

Owing to the specific make-up of proteins (e.g., β-lactoglobulin; β-lg) and sugars (e.g., lactose) within cow milk, the global prevalence of cow milk allergy and intolerance is notably high. Approximately 65% of adults worldwide have a suboptimal capacity to digest and absorb lactose [25]. In Asian and American Indian populations, the reported prevalence of lactose intolerance is closer to 100% [26][27]. However, with marked compositional differences (see Figure 1), hypoallergenicity and improved tolerability have been indicated following the ingestion of goat [28], sheep [29], camel [30], buffalo [31], and donkey [32] milk, as compared to cow milk. It should be noted that throughout this review buffalo milk refers to the produce of animals of the Bubalus genus.

Lastly, non-dairy substitutes for milk, including soy, oat, rice, and nut ‘milk beverages’ have received growing attention. These plant-based alternatives are formulated through the disintegration of plant material, extraction in water, and subsequent homogenisation, which produces a ‘milk’ reminiscent of the consistency and appearance of animal milk [33]. Despite a typically substandard macronutrient profile relative to mammalian milk, plant-based ‘milks’ possess distinct functional ingredients, lower allergenicity and greater affordability, which have impelled a noticeable surge in demand and production.

Figure 1. The composition of different species’ milk by fat, protein, and lactose content per 100 mL [22][29][34][35]. Equine milk values represent the mean nutrient content in mare and donkey milks.

3. Application to Cardiometabolic Health

3.1. Influence of Milk Origin on Energy Balance & Obesity

3.1.1. Appetite Regulation

More recently, acute clinical interventional studies have begun to assess the anorexigenic potential of cow milk alternatives. In an unblinded whole-milk product RCT, a direct comparison of how isovolumetric goat- and cow-milk-based breakfasts modulated subjective appetite, ghrelin release, and than the cow milk-based meal. Moreover, a significant inverse correlation was observed between cumulative glucagon-like peptide-1 (GLP-1) secretion was conducted [36]. Following consumption of the goat milk-based meals, participants reported a significantly decreased desire to eat and marked reduction in hunger, despite the energy content of the goat milk-based meal being 59 kJ lower than the cow milk-based meal. Moreover, a significant inverse correlation was observed between cumulative than the cow milk-based meal. Moreover, a significant inverse correlation was observed between cumulative GLP-1 release and the area under the curve for both hunger and desire to eat after the goat milk-based breakfast only, whilst no significant differences were observed in ghrelin or glucagon-like peptide-1 (GLP-1) levels at any single time point. However, it must critically be noted that the test meals  were composed of mixed dairy with both milk and cheese of either cow or goat origin being co-administered. Moreover, participants were not blinded in this open-label RCT. Contrastingly, a double-blind acute crossover study found no significant differences in GLP-1, cholecystokinin (CCK), ghrelin, or leptin secretion following the ingestion of either protein-fortified whole cow milk or protein-fortified whole goat milk [37]. Although it was found significant within-treatment suppression of prospective consumption at specific timepoints in both the goat and cow milk groups (relative to baseline), no significant difference in cumulative appetite response was detected between treatments. However, this current acute trial was not powered for the detection of differences in appetite measures with the primary outcome being postprandial plasma amino acid (AA) response (see ‘Aminoacidaemia’). Finally, the organoleptic aspects of (unfamiliar) milks must also be considered in clinical studies that aim to assess the impact of milk origin on appetite and subsequent energy intake. A downregulation of energy intake due to an aversion to a food’s pungent flavour or odour, as was speculatively observed following goat milk ingestion in a mouse study [38], should not inform the anorexigenic properties of a food.
Further consideration of how cow milk alternatives may influence appetite comes from lower-evidence-level research. For instance, an in vitro simulation study has investigated the satiety-inducing effects of whey samples from cow, goat, or sheep milk (or a 60:20:20 mixture of all three) as they are digested along the gastrointestinal tract [39]. Digested goat whey produced the highest secretion of GLP-1, whilst a fermented mixture of cow, goat, and sheep milk whey generated the greatest CCK response. Elsewhere, a hexapeptide has been located from β-lg that could potently inhibit dipeptidyl dipeptidase IV (DPP-IV) activity [40]. DPP-IV is an enzyme that catalyses the breakdown of incretin hormones, thus its inhibition results in a prolonged exposure of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), subsequently reducing glucagon release and increasing insulin secretion. Direct comparisons of the effectiveness of cow, goat, and sheep β-lg-derived peptides for the inhibition of DPP-IV have been conducted [41]. An in silico analysis indicated that sheep and goat whey could limit DPP-IV activity more efficiently than cow milk β-lg; however, this was not supported by a corresponding in vitro analysis. Sheep milk (6.5–8.5 g/L) contains a notably higher concentration of β-lg than buffalo (3.9 g/L), cow (3.2–3.3 g/L), and goat (1.5–5.0 g/L) milk [42].
Although the above studies provide some support to the acute anorexigenic utility of whey protein [43], it remains to be ascertained whether any clinically meaningful improvements in long-term appetite control can be gained from cow whey protein consumption, let alone from goat or sheep whey protein consumption. Moreover, it should also be remembered that the comparison of whey protein, which often only forms around 20% of the gross milk protein content, cannot solely determine the entire therapeutic potential of a given milk. A systematic review has summarised that there is some evidence that casein ingestion may actually induce a greater suppression of appetite in the long term [44].

3.1.2. Energy Expenditure

Preclinical trials and clinical single-component randomised crossover studies alike have acknowledged that medium-chain triglycerides (MCT) consumption can potently elevate diet-induced thermogenesis, resting metabolic rate, and total energy expenditure relative to LCT consumption, under isoenergetic conditions [45][46][47][48][49]. An example of higher-quality evidence from an RCT neatly demonstrated a dose-dependent upregulation of daily energy expenditure by replacing varying amounts of LCTs with MCTs in their acute dose-response trial [50]. The observed increase in energy expenditure corresponded to a clinically meaningful mean change of +500 kJ/day with just small adjustments to the MCT:LCT ratio (15–30 g). Moreover, a longer-term 7-day overfeeding trial showed that postprandial thermogenesis was significantly higher among individuals who received an MCT-based liquid formula diet compared to those who received the LCT counterpart [51]. In this double-blind randomised crossover study, the thermic effect of food was 8.0% and 5.8% of total ingested energy for the MCT- and LCT-meals on day one, respectively. By day six, these values rose to 12.0% and 6.6%, respectively, demonstrating a greater thermogenic compensation with overconsumption of MCTs [51]. MCT assimilation putatively incurs a greater energy cost than LCTs due to elevated fat oxidation, reduced fat storage and heightened sympathetic nervous system (SNS) stimulation [45][46][50][52]. Consequently, substituting a milk with a higher MCT:LCT ratio for a less MCT-rich milk (e.g., goat milk for cow milk, 0.89 vs. 0.61 g total MCT/100 g milk, respectively) could enhance energy expenditure and thus aid weight maintenance [53][54][55] (see ‘Body Weight and Composition’).
Another single-component double-blinded RCT found that postprandial thermogenesis was significantly greater following whey protein (14.4%) than casein (12.0%) or soy (11.6%) protein ingestion [56], advocating the consumption of whey-dominant milk types (e.g., mare milk). Protein synthesis rate was two-fold higher in individuals following the ingestion of whey protein compared to casein protein [57], generating a greater direct thermogenic cost. However, indirect consequences of protein choice could also influence energy expenditure. For example, milks high in anabolic AAs such as leucine (e.g., sheep milk) could help to preserve or enhance lean body mass (LBM). Accordingly, LBM is closely related to fat-free mass, which is the single most important determinant of 24-h energy expenditure [58]. Hence, metabolic rate may be increased as a result [59][60][61].

3.1.3 Nutrient Processing

A higher calcium intake has been linked with improved lipid metabolism in some preclinical [62] and clinical [63] RCTs. However, these early findings are contested by a more recent systematic review with a meta-analysis of RCTs which found that increased dairy-derived calcium intake does not influence body weight despite a possible facilitation of fat loss during shorter-term energy-restriction [64]. Thus, with the existing body of knowledge, it cannot currently be concluded whether an increased supply of calcium can optimise lipid mobilisation or minimise an individual’s risk of progressing towards a positive fat balance [61][64].
Lactose and galactose may also be linked with increased fat utilisation relative to other substrates. A 4-day single-component randomised crossover study conducted in a cohort of seven lactating and seven non-lactating women has indicated that the ingestion of a galactose beverage may stimulate the postprandial mobilisation and oxidation of endogenous fat whilst reducing protein oxidation, compared to an isoenergetic, isonitrogenous glucose beverage [65].

3.1.4. Body Weight and Composition

Although the effects of cow milk consumption on body weight have been widely investigated in the literature [66], there is not as yet consensus on a positive relationship. In turn, far fewer studies have assessed the effectiveness of non-bovine milks for weight management. Nonetheless, some researchers have tracked changes in body weight following the administration of different species’ milk. An early RCT found that five months of goat milk ingestion resulted in significantly more weight gain compared to cow milk [67]. Whereas, another clinical RCT in Madagascan individuals reported no significant differences in weight gain between individuals receiving either cow or goat milk for 10 consecutive days [68]. However, it must be noted that the above two clinical trials were conducted in a cohort of undernourished children for whom weight gain was desirable, contrasting the status quo of many increasingly obesogenic societies.
A single-component randomised parallel RCT in 113 overweight individuals has shown that weight regain and fat accumulation following energy restriction was significantly lower with milk protein (calcium caseinate) supplementation, compared to an untreated control group [69]. However, this added protein was administered during a free-living weight maintenance phase during which time macronutrient intake was not measured and thus the energy content of the diets could not be precisely determined or matched. Nonetheless, it was reported enhanced weight control in the milk protein supplementation group, despite no estimated differences in energy intake.
Energy density has been reported as lowest in mare milk (1842–2051 kJ/kg), rising sharply with goat (3018 kJ/kg), camel (3283 kJ/kg), buffalo (3450 kJ/kg), and cow (3169–3730 kJ/kg) milk, before peaking in sheep milk (5932 kJ/kg) [70][71][72][73][74][75][76]. Hence, for any final benefit to weight management with the consumption of different species’ milk, these discrepancies in energy density would need to be fully offset by either a greater suppression of appetite and energy intake, or enhancement of energy expenditure. Therefore, an interesting question develops whether the increased protein content of sheep milk, for example, could sufficiently counterpoise its elevated energy content. However, it should also be considered that these cross-sectionally reported values of energy content are largely determined by fat content, which in turn is likely to vary with season.
To delineate which species’ milks merit further examination within the realm of weight management, some value can be gained by considering the underlying qualities of individual milks. As discussed in the preceding sections, milk components that might imply benefits for body and fat mass regulation include whey protein, casein protein, and AA content; MCT content; and mineral bioavailability [77][44].
Milk protein intake, generally, may optimise muscle mass, performance, and recovery, although these benefits are likely also contingent upon physical activity status [78][79][80]. Pertinently, the substitution of sheep milk for cow milk could optimise the proportion of daily energy intake ascribed to protein, in line with a commonly advocated high-protein antiobesity strategy [81][82][83][84]. Moreover, with greater concentrations of key AAs (e.g., leucine), sheep, buffalo, yak, and mare milk consumption could reinforce positive changes to body composition by conserving LBM during weight loss [85][60][61]. However, this theory remains to be substantiated with any empirical evidence from clinical studies. The administration of plant-based milk protein (e.g., soy protein) is presently unable to achieve the protein synthetic rate achieved by animal-based milks [86][87]. However, novel techniques such as unique plant breeding and anabolic AA fortification may soon reduce this imparity [88][89].
Caproic (C6:0), caprylic (C8:0), and capric (C10:0) acid undergo expedited hydrolysis before being transported directly to the portal circulation, whereas dietary LCTs typically undergo prolonged lipoprotein uptake and transport. Therefore, it is hypothesised that milk fat with a higher proportion of these MCTs (i.e., sheep and goat milk) may be more readily destined for β-oxidation rather than storage in adipose compartments whilst favouring protein synthesis and LBM retention [90][46][91][92]. However, this possibility is speculated in response to review articles, which themselves are largely based upon animal study findings.
Finally, some, but not all, clinical studies have suggested that dairy-derived calcium may augment weight loss above that of supplemental calcium [61][93]. Insufficient calcium intake elicits a surge in plasma 1,25-dihydroxyvitamin D, which precedes an influx of calcium into adipocytes. This rise in intracellular calcium levels subsequently thwarts the breakdown of stored triglycerides by inhibiting the functioning of hormone-sensitive lipase [94]. However, as stated above in ‘Nutrient Processing’, a 2015 systematic review with meta-analysis has reported that an increased calcium intake, through either supplementation or a higher dairy intake, may not lead to a reduction in body weight in the longer term [64]. Nonetheless, with the knowledge that buffalo and sheep milk contain an especially high content of calcium (see ‘Nutrient Processing’), the roles of these milks could be an interesting area within future weight-management research.

3.2 Influence of Milk Origin on Insulinaemia, Glycaemia, and Type II Diabetes

3.2.1. Insulinaemia

It has long been suggested that acute diet-induced stimulation of insulin release may be beneficial for individuals unable to effectively maintain euglycaemia [95][96]. A randomised crossover study in nine healthy volunteers has assessed the insulinaemic response to whole cow-milk product [97]. It was showed that ingesting 510 g of cow milk produced an insulin response not dissimilar to that of white wheat bread.
Besides lactose, the protein composition of milk has also been cited as an important determinant of postprandial insulin response following ingestion [44][36]. In addition to certain AA combinations, namely of arginine, leucine, and phenylalanine [98][99], a randomised crossover study among healthy participants has noted the insulinogenic effect of cow whey relative to cow casein and soy protein [56]. This finding has been supported in a narrative review [100] and in multiple RCTs among individuals with T2D [101][102]. Correspondingly, sheep milk contains a large amount of whey protein (around 10.6 g/L) and an unparalleled arginine, leucine, and phenylalanine content [59]. In addition, it has been reviewed that some, but not all, RCTs have found that whey protein more potently stimulates the release of both GLP-1 and GIP (key secretagogues of post-meal insulin), compared to alternative protein sources [44].
Milk is composed of a complex matrix of food components including low-GI carbohydrates; trans-palmitoleic FAs; and minerals, such as calcium, magnesium, and potassium. Multiple review papers have linked food components such as those described above with an amelioration of the postprandial insulin response [103]. Hence, with knowledge that the contents of such molecules vary with milk origin, it is expected that these discrepancies would impact the insulinotropic effect of a given species’ milk. For instance, palmitoleic acid content is greatest in mare milk (4.5%), followed by sheep (2.1%), goat (1.2%), and cow (1.0%) milk, whilst goat milk is the best source of potassium [104]. However, the alleged associations reported in such reviews are largely based upon data from either mechanistic animal studies using isolated food components or cross-sectional studies from which causality cannot be established. Thus, RCTs are required to determine the relationship between the molecules that make up the food matrix of milk and aspects of glucose control.
Although the insulinotropic effects of individual milk components have been scrutinised, few studies have explored the impact of whole milk product on insulin secretion. One randomised crossover study conducted among healthy Chinese men showed that the co-ingestion of soy milk with bread resulted in a significantly higher insulin response than the co-ingestion of cow milk with bread [105]. However, in a follow-up study by the same research group, it was revealed that cow milk may be equally as effective as soy milk for the regulation of blood glucose without the exaggerated insulin response, potentially owing to a greater GLP-1 response [106].
In terms of the effects of whole milk product from different animal origin on insulinaemia, knowledge from clinical experimental studies is extremely limited. An epidemiological study has suggested that rates of elevated fasting blood glucose, impaired glucose tolerance and T2D are significantly lower among the camel-milk-consuming communities of Rajasthan than the non-camel-milk-consuming communities [107]. Moreover, anecdotal reports in the literature have echoed these findings, observing the use of camel milk as an antidiabetic aid across Africa, Asia, and the Middle East [108][109]. However, a high risk of confounding is associated with these low-level-evidence observational studies. Stronger support comes from the findings of a 2-year RCT among individuals with type I diabetes (T1D) [110]. Participants who received 500 mL of whole camel-milk product daily in addition to their usual care experienced significant reductions in their insulin dose requirements compared to those receiving the usual care only. However, this RCT only recruited 12 participants into each group and neither the participants nor the researchers were blinded, making it extremely vulnerable to demand characteristics. Thus, higher-quality evidence from large-scale RCTs must be attained before any robustness can be associated with these therapeutic claims for camel milk.
Overall, there is a considerable paucity of studies which have conducted intra-trial comparisons regarding the influence of whole milk product from different origins on insulinaemia. However, a single acute randomised crossover study among 33 healthy participants was conducted which found no differences in postprandial insulin response or GLP-1 release following the administration of either a cow dairy- or goat dairy-based breakfast [36]. Longitudinal RCTs are needed to delineate how milk origin chronically influences insulin levels.
The only within-trial assessment of how different species’ milk influences insulin levels alone comes from an animal study [111]. This refeeding study in energy-restricted mice showed that serum insulin levels were significantly increased following the administration of buffalo and sheep milk for one week, but not after one-week goat or cow milk administration. However, with this finding only being present in fasting insulin levels and knowledge of the notable physiological discrepancies between mice and humans, caution must be taken in the interpretation of these findings, as with any data cited from animal studies.

3.2.2 Glycaemia

As with postprandial insulinaemia (see ‘Insulinaemia’), the only clinical RCT to have conducted direct comparisons of postprandial glycaemia following the consumption of whole milk product derived from different origins is the same study [36]. This acute unblinded crossover study assessed blood glucose for 3 h following the consumption of a mixed-meal of bread with milk and cheese from either cow or goat origin, however no significant differences were reported [36].
Whereas whey protein possesses a superior insulinotropic capacity, findings from an acute randomised crossover study suggest that casein and soy protein can reduce postprandial blood glucose spikes without the exaggerated insulin response to whey [56]. This analogy promotes the consumption of ‘caseinic’ milks (i.e., ruminant milks) or even soy ‘milk’ for the regulation of postprandial hyperglycaemia. However, it should be noted that it was recruited healthy, lean individuals and thus it is not known whether this response would be replicated among individuals with prediabetes and T2D.
In terms of AAs, leucine has been pinpointed as a potent facilitator of glucose disposal [60]. Correspondingly, it has been reported that the leucine content in sheep, buffalo, yak and mare milk notably exceeds that of cattle, donkey, goat, and camel milk [85]. However, there are no clinical trials that have investigated the potential glycaemic consequences of this leucine variability using whole-milk product.
Some researchers have also speculated that CLA can stimulate the uptake and subsequent utilisation or storage of glucose, without inducing an excessive secretion of insulin [112]. However, these claims are not supported by the conclusions of recent systematic reviews that have collectively examined clinical RCT data [113][114]. Indeed, one double-blind RCT in men with obesity reported a pro-diabetic effect of the CLA isomer trans-10, cis-12 [115]. Yet, as noted previously, CLA found in milk is predominantly of the cis-9, trans-11 isoform and the utility of CLA for glycaemic regulation may be isomer-specific [116]. There are not currently any studies that have investigated any milk origin-specific effects of CLA, despite it being known that varying concentrations of CLA are present in goat, cow and sheep milk.
Finally, and critically when discussing the glycaemic repercussions of any given food, milk is generally noted for its low GI [117][118]. GI is the two-hour incremental area under the curve (iAUC) for blood glucose following the ingestion of a food, relative to a standardised glucose (or white bread) load [119]. This desirable aspect of milk is primarily derived from its predominant major and minor carbohydrate portions of lactose and oligosaccharides, respectively (see Figure 1). Alternatively, plant-based milk substitutes, particularly coconut and rice beverages, which commonly reconstitute the absence of lactose with additional sugars or sweeteners, often have a considerably higher GI [120] . For instance, in a recent systematic review of international tables of GI values [117], reduced-fat cow milk was reported to have a mean GI value of 27 whilst GI values for coconut and rice milk beverages were as high as 68 and 92, respectively.
As a notable source of functional AAs, CLA and essential minerals, individuals unable to effectively maintain normoglycaemia could speculatively benefit from substituting in sheep milk for cow milk. Although, the glycaemic impact of an equicarbohydrate glucose load is attenuated when partially substituted for galactose, which is contrastingly found in greater quantities in cow milk, compared to sheep (and goat) milk [121][122].

3.2.3. Type II Diabetes

Despite a plethora of different trial designs (e.g., RCTs, observational, in vitro, and animal studies) documenting links between individual milk components (or occasionally whole milk product) and biomarkers of T2D, there remains a lack of high-quality evidence for a causal link between milk consumption and incidence of T2D [113]. A population-based epidemiological study, the CARDIA study, reported a dose-dependent inverse relationship between the inclusion of dairy products in the diet and the risk of overweight individuals developing insulin resistance syndrome over a 10-year period [123]. Moreover, a meta-analysis of 7 observational cohort studies including a total of 167,982 participants found that individuals with a high milk intake had a 13% reduced risk of T2D, compared to those with a low milk intake [124]. However, when sub-types of milk were examined, it was reported that this benefit was specific to the fat content with the risk reduction being overturned with the consumption of full-fat milk [124]. This incongruity derived from the distinct compositions of different milk types highlights the critical importance of evaluating the effects of milk origin, and thus varying fat content (see Figure 1), on T2D risk. Accordingly, although the acute impact of milk origin on insulinaemic and glycaemic consequences has been somewhat explored (see ‘Insulinaemia’ and ‘Glycaemia’), to date, there are no prospectively-controlled longitudinal studies that have assessed the long-term antidiabetic utility of cow milk alternatives. Thus, in accordance with required future research into cow milk, it is reiterated that long-term human RCTs with T2D events as the primary endpoint are needed to determine whether milk consumption (of any origin) is causally related to T2D risk [113].

3.3. Influence of Milk Origin on Cardiovascular Health

Largely owing to the SFA content of dairy products, the relationship between milk intake and CVD has long sparked contention in the literature. Although early research suggested that undesirable long-term cardiovascular consequences may arise from continued milk-fat consumption, this relationship is far more complex than previously envisioned [125][126][127]. Eclipsing any LDL-elevating effect of SFAs, complex milk composition far exceeds the impact of a single nutrient and implications for CVD should be considered for milk as a whole [113][104]. Pertinently, the majority of observational studies now actually oppose prior suggestions that dairy intake is positively and adversely associated with CVD risk. Indeed, a recent review appraising the current body of epidemiological evidence concluded that whole-fat dairy does not increase risk of CVD [128]. Similarly, in another review with a greater focus on liquid milk, it was found that largely from observational studies, demonstrating a negative association between whole-milk product and CVD risk, especially for stroke and hypertension [66]. However, corresponding data from RCTs is far more limited and although some studies have reported no adverse effects of milk consumption on CVD risk, these findings are predominantly either from acute intervention studies or from studies employing surrogate markers of CVD [113]. Hence, there is a persisting need for gold-standard evidence in the form of long-term RCTs with cardiovascular events as the primary endpoint in order to confirm any causal relationships between milk intake and CVD incidence.
More pertinently, there are currently no longitudinal observational studies or RCTs that have compared the long-term cardiovascular consequences of consuming whole milk product from one origin versus another. Thus, no consensus can currently be realised to form the basis of nutritional recommendations regarding the intake of different species’ milks for better cardiovascular health. Nonetheless, the following section collates the existing key findings from studies of ranging evidence quality and discusses how the varying compositions of milk from different origins could theoretically influence an individual’s risk of developing CVD.
The differences that are evident in the composition of different species’ milks (see Figure 1) could prove invaluable for the amelioration of cardiovascular health. Some researchers have produced lipid quality indices to detail and compare the potential influence of milk origin on lipoprotein metabolism (see ‘Lipidaemia’). These have been used to estimate the atherosclerotic and thrombotic risk of consuming milks of different origin. Accordingly, utilising gas chromatography, a 2019 analytical study performed comparisons between cow-, sheep-, and goat-milk samples [129]. With a notable source of PUFAs and n-3 FAs, sheep milk had the lowest index of thrombogenicity, whilst, with a high short-chain fatty acid (SCFA) and minimal SFA content, goat milk produced the lowest index of atherogenicity. However, one year later, the above lipid quality indices were reported to be optimal in mare milk, bettering the alternative species’ milks in the contrasting descending order of cow, goat, and sheep milk [104]. With both of these studies being conducted in Poland, this discrepancy emphasises the variability in milk composition with seasonal variance, breed diversity, lactation phase and so on. With knowledge that goat and sheep milk desirably contain higher concentrations of MUFAs, PUFAs, and MCTs, the 2019 findings [129] may possess greater external validity; however, this remains to be tested. With a lipid profile rich in linoleic (C18:2, n-6) and α-linolenic (C18:3, n-3) acids and a minimal palmitic (C16:0) and stearic (C18:0) acid content [130][131], the utility of mare milk should also be assessed for individuals with an increased risk of CVD.
The adverse association between high blood pressure and poor cardiovascular health in humans has been well-recognised in longitudinal observational studies and RCTs alike [132]. Pertinently, there is also an accumulating body of evidence from moderate-term RCTs [133][134] and review articles [89][135] that cow-milk peptides could have the potential to improve blood pressure, possibly, although evidence is lacking in clinical trials, through the inhibition of angiotensin-converting enzyme I (ACE). However, the majority of this work has been conducted among overweight individuals and it is therefore currently difficult to untangle any direct antihypertensive effect of milk peptides from the possible indirect benefit gained from body weight/fat loss [113].
Although evidence from RCTs comparing the antihypertensive utility of cow-milk alternatives is absent, some data from compositional analyses have acknowledged sheep and goat milk as a potential source of ACE-inhibitory peptides [76][136]. Another compositional study directly comparing the ACE-inhibitory capacity of sheep and cow milk products revealed that sheep milk peptides inhibited ACE activity by 50% (IC50) at a lower concentration [137]. Although this heightened potency could not be explained, it was speculated to be associated with an elevated proteolysis of sheep milk peptides compared to cow milk peptides.
Also, β-lg-derived peptides have generated antihypertensive promise in animal and in vitro trials [138], theoretically supporting a role for sheep-milk consumption (see ‘Appetite Regulation’); however, robust clinical evidence is limited. Assay techniques have also revealed that ACE-inhibitory peptides are produced from the proteolysis of β-casein, which again is found in higher quantities in sheep, goat, and buffalo milk than cow milk [59][139][140][141].
Finally, incorporating potassium, magnesium, and calcium into the diet whilst restricting sodium intake has been reviewed to ameliorate blood pressure control in some, but not all, clinical studies [142][143]. However, RCTs are required to assess whether these compositional differences can translate to meaningful disparities in biomarkers and incidence of CVD following milk consumption of different origin.

4. Conclusions

The effect of milk origin on cardiometabolic health is an emerging area of research. There is some data, although primarily from compositional analyses [35][144], in vitro studies [145], animal studies [146], and acute clinical RCTs [147][148][149], that milk from non-bovine origin (notably sheep and goat milk) could prove to be a viable substitute to cow milk for the maintenance, or even enhancement, of cardiometabolic health. However, a collation of the compositional differences and postulated therapeutic utility, indicate that the level of evidence required to form nutritional recommendations surrounding milk origin is currently lacking. Nonetheless, there are some interesting results, albeit largely from preliminary studies, that have generated excitement around sheep milk consumption for the possible attenuation of cardiometabolic risk. This interest is largely based upon its favourable profile of lipids (for example, MCTs, CLA), protein (for example,, leucine), and minerals (for example, calcium). In theory, these compounds could provide protection from obesity, T2D, and CVD through the modulation of postprandial glycaemia, lipidaemia and aminoacidaemia; nutrient processing; postprandial thermogenesis; and/or appetite. Comparably, with desirable nutritional compositions and some promising early findings, goat and buffalo milk may also prove to be robust alternatives to cow milk. However, as with sheep milk, there is currently a stark absence of high-quality research in humans. Hence, as remains pertinent for cow milk, to substantiate any claims that the consumption of cow-milk alternatives can improve cardiometabolic health, causal data from long-term clinical RCTs, ideally with T2D and/or CVD events as the primary endpoint, are required. Evidence from large-scale studies that support the conjectures formed  could not only be of value to individuals allergic or intolerant to cow milk, but potentially also to those at an increased risk of cardiometabolic disease.

This entry is adapted from the peer-reviewed paper 10.3390/nu14020290

References

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