Very Low Carbohydrate Ketogenic Diets and Diabetes

NARRATIVE REVIEW ❙

Very low carbohydrate ketogenic diets and diabetes

Pamela Dyson Abstract PhD, RD, OCDEM, Oxford University NHS Very low carbohydrate ketogenic diets (VLCKD) have been widely promoted for the Foundation Trust, Oxford, UK; and NIHR Biomedical Research Centre, Oxford, UK management of diabetes. There is confusion among people with diabetes and health professionals about the efficacy and safety of these diets and this review aimed to explore the role of VLCKD for people with diabetes. Correspondence to: An electronic search of English language articles was performed using MEDLINE (1980 Pamela Dyson, PhD, RD, OCDEM, Churchill to January 2020), EMBASE (1980 to January 2020) and the Cochrane Central Register of Hospital, Oxford OX3 7EJ, UK; email: pamela. Controlled Trials (1980 to January 2020). Randomised controlled trials (RCTs) >12 weeks [email protected] duration comparing VLCKD, defined as <50g carbohydrate/day, with higher carbohydrate intakes in people at risk of or with diagnosed diabetes were included. Primary outcomes included HbA1c and weight and secondary outcomes were lipid concentrations. There were no RCTs examining the role of VLCKD for diabetes prevention. Two RCTs in diagnosed type 2 diabetes reported significant weight loss, but outcomes for glycaemic control and lipid concentrations were inconsistent. There were no RCTs in people with type 1 diabetes, although observational trials reported lower HbA1c, with a high prevalence of dyslipidaemia and hypoglycaemia. A lack of high-quality evidence limits the use of VLCKD in people with diabetes. Copyright © 2020 John Wiley & Sons. Practical Diabetes 2020; 37(4): 121–126 Key words very low carbohydrate ketogenic diet; diabetes

Introduction diets (VLCKD) providing <50g car- The search for the optimal diet for bohydrate/day are more effective the treatment of diabetes has caused than standard low carbohydrate much controversy and debate, diets (50–130g carbohydrate/day). resulting in confusion and uncer- This supposition is supported by tainty for both people with diabetes two recent meta-analyses of low and health professionals alike. carbohydrate diets reporting that Recent dietary guidelines have con- those studies with the lowest daily centrated on evidence-based recom- carbohydrate intake found the mendations and concluded that largest reduction in HbA1c.5,6 In individualisation is key, and that addition, some recent reviews have there are a variety of dietary strate- made the case for VLCKD in the gies that are suitable for people with prevention and treatment of both diabetes including low-fat healthy type 1 and type 2 diabetes, although eating, Mediterranean-style diets, most authors recognise that there is low energy diets, carbohydrate man- heterogeneity in studies investigat- agement and, for those with type 2 ing diabetes.7–10 diabetes, low carbohydrate diets.1,2 This review aims to investigate There have been calls for low carbo- the role of VLCKD in the preven- hydrate diets to be used as the tion and treatment of diabetes. default strategy in people with type 2 diabetes,3 although current availa- Definition of VLCKD ble evidence indicates that despite There is no formal definition of significant improvements in both VLCKDs,11 but they are character- glycaemic control and body weight, ised by a severe reduction in carbo- there is no evidence of superiority hydrate intake, leading to the pres- of low carbohydrate diets over other ence of circulating ketone bodies, dietary strategies over the longer primarily β-hydroxybutyrate, which term.4 It may be that this lack of are produced by fat oxidation for superiority is related to the degree energy production in the absence of of carbohydrate restriction, and that available glucose. In addition, there very low carbohydrate ketogenic is no consensus at present on the

level of ketone concentrations that indicate dietary ketosis, or accept- able levels of ketosis in those with Records identified through Additional records identified type 1 diabetes.7 Physiological stud- database searching (n=113) through other sources (n=10) ies have demonstrated that diets providing <50g carbohydrate/day will induce ketosis, although this is highly variable and some individuals Records after duplicates removed (n=120) require as little as <20g/day before ketosis occurs.12,13 In order to achieve ketosis, most VLCKDs rec- Records screened (n=120) Records excluded (n=106) ommend complete avoidance of all starchy and sugary carbohydrates, limited amounts of low carbohydrate fruit and vegetables and Full-text articles assessed for Full-text articles excluded (n=12): unlimited amounts of protein eligibility (n=14) • Duration <12 weeks (n=1) (meat, fish, eggs and cheese) and • Reported carbohydrate intake fats. Dairy products containing car- >50g/day (n=11) bohydrate (milk, yogurt, ice cream) are usually avoided, although cheese Studies included in qualitative and butter are included as they synthesis (n=2) contain little or no carbohydrate. In common with other analyses,3,4 this review considers that VLCKDs Figure 1. Flow chart of search strategy and study selection are defined as those providing <50g carbohydrate/day. reporting actual intakes of <50g/ retrieved for eligibility testing. Only day were included. Primary out- two studies met the inclusion crite- Methods comes included weight and HbA1c ria and both were conducted in Data sources and search strategy and secondary outcomes included people with type 2 diabetes.16,17 This review was conducted with ref- lipid concentrations, adverse events Characteristics of these two studies erence to the Cochrane Handbook for and medication changes. are shown in Table 1, and the pri- Systematic Review of Interventions14 mary outcomes in Table 2a. Both and reported according to PRISMA Data extraction studies reported significantly greater guidelines,15 although only a single Data extraction was carried out by the reductions in body weight in the investigator screened the literature author and reported on a specially intervention group compared to and selected the studies for inclu- designed spreadsheet. Extracted control (9.6kg and 4.2kg), but only sion. An electronic search of English information included: study details one study demonstrated signifi- language articles published since (duration); characteristics of the cantly greater reduction in HbA1c 1980 (as HbA1c was not commonly study participants (demographic, (-5mmol/mol).16 Table 2b summa- reported before this time) was per- anthropometric and biochemical); rises changes in lipid concentrations formed using MEDLINE (1980 to descriptions of the intervention and and shows that there are small January 2020), EMBASE (1980 to comparator diets (amount of carbo- changes from baseline to follow-up. January 2020) and the Cochrane hydrate and other macronutrients); One study reported significantly Central Register of Controlled Trials outcomes (HbA1c, weight, lipid con- greater reductions in triglyceride (1980 to January 2020). In addition, centrations, rates of attrition, dietary concentrations (-0.6mmol/L),16 recently published meta-analyses of adherence); changes in medication and the other greater increases in low carbohydrate diets were hand- and adverse events. As only two HDL concentrations,17 although searched to identify any additional studies met the inclusion criteria as the reported difference between VLCKD interventions included in and they were heterogeneous in the two groups was just 0.1mmol/L, the analyses. terms of mode of delivery of the the clinical relevance of this is intervention, pharmacological treat- questionable. Eligibility criteria ment, the diets used for comparison In common with most dietary The selection criteria included ran- and length of follow-up, risk of bias intervention studies, attrition rates domised controlled trials (RCTs) was not assessed and a meta-analysis were relatively high, with one study >12 weeks comparing interventions was not performed. reporting that 46% of the control evaluating VLCKD (<50g carbo group dropped out of the study, hydrate/day) with higher carbo Results compared with 8% of the interven- hydrate intakes in people at risk The flow diagram illustrating the tion group.16 The second study had of type 2 diabetes or with diag- search and selection of studies is higher rates of attrition at 53% and nosed type 1 or type 2 diabetes. As shown in Figure 1. The initial data- 41% respectively.17 ketosis occurs at levels <50g carbo- base search returned 123 results One study reported greater hydrate/day, only those studies and 14 full-text articles were reductions in medication in the

First Duration Numbers Dietary intervention author, (weeks) year Comparator Intervention Comparator Intervention

Saslow, 32 13 12 On-line ‘Create your Plate’ plan from On-line ad libitum very low 201716 the American Diabetes Association. A carbohydrate ketogenic diet providing low fat diet high in green vegetables, 20–50g carbohydrate per day lean protein and limited starchy and together with behavioural adherence sugary foods strategies

Westman, 24 46 38 Low glycaemic index, reduced energy Ad libitum very low carbohydrate 200817 diet providing 55% of energy as ketogenic diet providing <20g carbohydrate carbohydrate/day

Table 1. Descriptive summary of studies of very low carbohydrate ketogenic diets in people with type 2 diabetes

First Body weight change (kg) Changes in HbA1c (mmol/mol) author, year Comparator Intervention Difference P-value Comparator Intervention Difference P-value (C) (I) (I-C) (C) (I) (I-C)

Saslow, -3.0 (-7.3, 1.3) -12.7 (-16.1, -9.2) -9.6 (-14.0, -5.3) <0.001 -3 (-6, 0.0) -8 (-11, -6) -5 (-8, -2) 0.02 201716*

Westman, -6.9 -11.1 -4.2 0.01† -5 -15 -10 0.06† 200817**

*Data are estimated marginal means (EMM) and 95% confidence limits by linear mixed-effects model analysis. **Data are presented as mean changes. †Adjusted for baseline values.

Table 2a. Summary of results of very low carbohydrate ketogenic diets trials in people with type 2 diabetes (body weight and glycaemic control)

First Total cholesterol (mmol/L) HDL (mmol/L) LDL (mmol/L) Triglycerides (mmol/L) author, year I-C P-value I-C P-value I-C P-value I-C P-value

Saslow, NR NR 0.1 (-0.03, 0.2) 0.13 0.1 (-0.2, 0.5) 0.4 -0.6 (-1.1, -0.2) 0.01 201716*

Westman, 0.03 NS 0.1 <0.05 0.1 NS -0.5 NS 200817**

NR: not reported. NS: not significant. *Data are estimated marginal means (EMM) and 95% confidence limits by linear mixed-effects model analysis. **Data are presented as estimates from reported within-group mean changes.

Table 2b. Summary of results of very low carbohydrate ketogenic diets trials in people with type 2 diabetes (lipids concentrations) intervention group compared to prevention in 22 subjects reported inconsistent in terms of glycaemic the control group,17 and the other mean weight losses of 5.2% at 12 control and changes to medica- included only those taking met- months follow-up, and these data tion, although both studies formin and reported no differ- will be used to plan a full RCT.18 reported significantly greater ence in medication changes There is no evidence of VLCKD on weight loss in the intervention between groups.16 remission of type 2 diabetes, but a group. Observational trials, case pilot study investigating a low reports and audits in people with Discussion energy, low carbohydrate diet (<26% type 2 diabetes have reported pos- Prevention, remission treatment of energy) reported remission in four itive significant effects of VLCKD type 2 diabetes out of 21 participants (19%).19 for both glycaemic control (-9 to There is a lack of evidence for the In terms of treatment, two -33mmol/mol) and for weight loss role of VLCKD in the prevention studies met the inclusion criteria (7.5 to 14kg),20–24 although con- and remission of type 2 diabetes. and the results are presented clusions are limited by the lack of One small pilot study investigating above. In summary, outcomes were a comparator group. In addition,

in many of these reports, the intervention was self-selected by the 192.8 participants and this may explain 200 Prescribed carbohydrate intake the positive outcomes. It is intui- tive that a diet that is self-selected 100 Reported carbohydrate intake at follow-up will be better tolerated and lead to 90 25 greater adherence. It has been 80 argued that data from observa- 70 tional studies such as these are of more use than evidence from 60 RCTs, which is not applicable to 50 dietary interventions as it does not 40 allow for the many critical influ- 30

26 (g/day) Carbohydrate intake ences on personal choice; despite 20 this, RCT evidence is still consid- 10 ered of the highest grade and remains crucial for establishing 0 efficacy, safety and superiority. Westman17 Iqbal32 Goldstein31 Mayer33 Saslow34,35* Saslow16 Tay36–38** One of the greatest challenges for those adopting VLCKD is that of *Saslow34,35 results at 3 and 12 months follow-up, respectively. **Tay36–38 results at 6, 12 and 24 long-term adherence, and over time months follow-up, respectively. many participants appear to shift Figure 2. Prescribed and reported daily intake of amount of carbohydrate (g/day) in to higher carbohydrate intakes randomised controlled trials of VLCKD in people with type 2 diabetes (130–160g/day).27 Of the 14 studies eligible for inclusion in this review, diabetes differs fundamentally from reported that current HbA1c con- 11 were excluded as reported those with type 2 diabetes as energy centrations were 39±6mmol/mol.43 intakes were >50g/day at fol- restriction for weight loss is not Conclusions from both these low-up.28–38 Of these, four studies commonly a feature, meaning that studies are limited by the lack of a prescribed very low carbohydrate those with type 1 diabetes are con- comparator group and data about intakes (<20g/day) for an initial suming greater amounts of fat baseline HbA1c values before the period of two to 24 weeks, followed (commonly 60–70% of energy as VLCKD was instigated. In the major- by gradual reintroduction of carbo- fat) in order to achieve energy bal- ity of studies reporting positive gly- hydrate.28–30,33 Nine studies pre- ance. In addition, the challenges of caemic outcomes in type 1 diabetes, scribed maintenance of carbohy- matching insulin therapy to very the participants tend to be highly drate restriction of <50g/day for the low carbohydrate intakes may motivated, have self-selected a duration of the study,16,17,31,32,34–38 increase the risk of both diabetic VLCKD, and are willing to adopt although only two studies reported ketoacidosis and hypoglycaemia.40 tight glycaemic targets and to mon- adequate adherence.16,17 In the Recent reviews of the role of low itor blood glucose concentrations majority of studies, mean intakes of carbohydrate diets in people with frequently. Consequently, it is not carbohydrate exceeded the pre- type 1 diabetes have included clear how this can be translated to scribed amounts (see Figure 2). only studies that were cross-sec- general populations of people with This increasing intake in the tional, or case series reports or type 1 diabetes.40 amount of carbohydrate over time observational studies lacking a com- is neatly demonstrated in the two parator group.40,41 The majority of Medication changes studies reporting intakes at differ- these studies have recommended The majority of observational ent time-points over longer-term carbohydrate intakes of >50g/day, studies of VLCKD in people with follow-up.34–38 meaning that they do not qualify as type 2 diabetes that described VLCKD, although the lack of die- changes in medication reported Type 1 diabetes tary intake data limits identification reductions in both glucose-lower- There is no evidence for the role of of actual carbohydrate intake. A ing and antihypertensive medica- VLCKD in the prevention of type 1 recent observational study in 11 tion,8 and in those with type 1 diabetes, and although a case report adults with type 1 diabetes who diabetes, insulin requirements were in three individuals has suggested adopted a ketogenic diet (defined significantly reduced.41 that it does have a role in remission, as <55g carbohydrate/day, although this requires further research.39 positive ketone concentrations were Adverse events VLCKDs have been promoted for reported) for mean ± SD of 2.6±3.3 Concern has been expressed about the management of type 1 diabetes years reported HbA1c concentra- the long-term health effects of low in both adults and children, tions of 31±4mmol/mol.42 In chil- carbohydrate diets generally44 and although there is a lack of high- dren, a recent online survey of VLCKD specifically.45,46 The most quality evidence as no long-term 131 who self-selected a VLCKD commonly reported side effects are RCTs have been conducted. The (reported intake 36g carbohydrate/ gastrointestinal and include consti- use of VLCKD in those with type 1 day) for mean ± SD of 1.4±1.2 years pation and diarrhoea.47 Short-term

VLCKD should be avoided in those KEY POINTS treated with SGLT2 inhibitor.55 In two observational studies in ● The role of very low carbohydrate ketogenic diets (VLCKD) for people with diabetes those with type 1 diabetes who is unclear self-selected a VLCKD, one recorded ● There is little high-quality evidence for VLCKD; two randomised controlled trials (RCTs) in low annual rates of hospitalisation people with type 2 diabetes reported significantly greater weight loss, but inconsistent for either hypoglycaemia (1%) or effects on glycaemic control and medication diabetic ketoacidosis (1%), although ● Observational trials and case reports suggest that VLCKD improved glycaemic control in 69% reported at least one episode type 1 diabetes, but conclusions are limited by the absence of RCTs of symptomatic hypoglycaemia per 43 ● Reported adverse events included dyslipidaemia and hypolgycaemia in type 1 diabetes month. In the second study, partic- ● There is insufficient high-quality evidence to support the use of VLCKD ipants were fitted with continuous glucose monitors for seven days and higher rates of hypoglycaemia adverse events include headaches, of VLCKD often make the case that (<3.0mmol/L) were observed with muscle cramps and weakness,46 the increases in LDL, which are participants experiencing a median often called ‘keto flu’, but these associated with low triglyceride con- (range) of 0.9 (0.0–2.0) episodes symptoms usually resolve after a few centrations, may reflect the pres- per day.42 It is important to remem- days. The main longer-term health ence of large, buoyant lipoprotein ber that the participants in these issues are related to increased risk particles, and that this is a low-risk studies all self-selected a VLCKD, of cardiovascular disease (CVD) sub-type.43 However, in those using and were likely to be highly moti- associated with high saturated fat VLCKD, the long-term cardiovascu- vated and display other attributes intakes,46,48 insufficient intake of lar outcomes of this high LDL/low related to glycaemic control such as micronutrients,49 and specifically triglyceride lipid profile is unknown. frequent blood glucose monitoring for those with diabetes, increased Micronutrient deficiencies that and insulin adjustment,56 and under risk of diabetic ketoacidosis and may be associated with VLCKD con- the circumstances it is of interest hypoglycaemia.40 In terms of CVD sist of those nutrients found in that rates of hypoglycaemia are as risk, a recent review claims that unprocessed carbohydrate food high as reported. although nutritional ketosis is widely (whole grains, milk, fruit and starchy regarded as a normal metabolic vegetables), including various vita- Conclusions state, in fact ketone bodies are more mins, minerals, dietary fibre and Low carbohydrate diets providing harmful than glucose for activating phytochemicals with antioxidant <130g carbohydrate/day are now inflammatory processes and con- properties.52 Few studies have generally accepted as a viable strat- tributing to CVD risk.50 Lipid con- reported micronutrient intake or egy for the management of type 2 centrations are established CVD risk nutrient deficiency, although a sys- diabetes, but evidence for more factors, and although many studies tematic review concluded that the stringent carbohydrate restriction reported significant reductions in dietary interventions used in many is lacking. The majority of studies triglyceride concentrations, this low carbohydrate studies had a in those with type 2 diabetes was accompanied by increased potential risk of micronutrient inad- reported that the participants were LDL concentrations and often by equacy and that supplementation unable to adhere to the severe car- increased total cholesterol.46 In should be considered.49 bohydrate restriction, thus limiting the majority of studies in people In the absence of medication conclusions, although significant with type 2 diabetes, where energy adjustment, a VLCKD increases the weight loss is reported. High qual- restriction led to significant weight risk of hypoglycaemia in the case of ity evidence is lacking in people loss, only small and insignificant those with type 1 and type 2 diabe- with type 1 diabetes, and although changes in lipid concentrations tes, and may increase the risk of observational trials reported low were reported. Weight reduction euglycaemic diabetic ketoacidosis HbA1c concentrations, this is offset improves CVD risk factors and in in those with type 2 diabetes and by increased dyslipidaemia and the presence of significant weight diabetic ketoacidosis in type 1 dia- hypoglycaemia. Studies of people loss there is no difference between betes. Hypoglycaemia was rarely with type 1 diabetes have relied on different high or low carbohydrate recorded in studies of participants those who had already self-selected diets for primary prevention of with type 2 diabetes, and this was a VLCKD, and this lack of data CVD.51 Conversely, in studies of partly due to both proactive and from high quality trials prevents VLCKD in those with type 1 dia reactive reduction in hypoglycae- the translation of these results to betes, higher fat intakes were rec- mia medication (usually insulin wider populations of people with ommended for energy balance and sulphonylurea). There have type 1 diabetes. Although it may and weight maintenance and this been case reports of euglycaemic be true that VLCKDs are useful in appeared to result in significant dys- diabetic ketoacidosis in those with people with diabetes, more rigor- lipidaemia. Two observational stud- type 2 diabetes using sodium- ous well-designed studies are ies reported dyslipidaemia in >80% glucose cotransporter 2 (SGLT2) essential to establish the evidence and >62% of those with measured therapy who adopted a VLCKD,53,54 base before these diets can be lipid concentrations.42,43 Supporters and the general consensus is that generally recommended.

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