Nicholas Burney                                                                                        Mini-CAT #2 –

Clinical Scenario: A 48 year old male with a PMH of DMII and obesity comes in for a yearly physical. His HgbA1c is 7.5 despite compliance with medication. He wants to know if a low-carb diet would be effective in helping control his blood sugar.

Search Question:

Is a carbohydrate-restricted diet more effective than a high-carb diet in improving glycemic control in diabetic patients?

Question Type: What kind of question is this?

Treatment

Assuming that the highest level of evidence to answer your question, will be meta-analysis or systematic review, what other types of study might you include if these are not available (or if there is a much more current study of another type)? Please explain your choices.

As low carb diet studies are several decades old, more recent and well-designed RCTs would be helpful in determining if LCDs are clinically effective at reducing HgbA1c.

PICO search terms:

P	I	C	O
Diabetic	Carbohydrate restriction	Standard diet	Improved glycemic control
Type II Diabetes Mellitus	Low Carb	Ad libitum diet	Lower Hgb A1c
TIIDM	LC diet		Remission of diabetes

Search tools and strategy used:

Please indicate what data bases/tools you used, provide a list of the terms you searched together in each tool, and how many articles were returned using those terms and filters.
Explain how you narrow your choices to the few selected articles.

PubMed

Search: Carbohydrate restriction diabetes – 3315

Filters: 10 years, meta-analysis, Systematic Review – 715

Search: Low carb diet diabetes – 55

Filters: 10 years, meta-analysis, Systematic Review – 12

Cochrane

Search: Low carb diabetes – 58

Filters: 10 years –  56

Search: Carbohydrate restriction diabetes – 8

Filters: 10 years – 5

Google scholar:

Search: Low carbohydrate diet diabetes meta analysis – 169,000

Filters:  10 years: 22,500

I chose 5 meta-analyses for this mini-CAT, as they demonstrate the highest level of evidence. I also tried to choose articles that followed patients for at least a year or more, to determine if the diets had efficacy beyond short-term compliance. I wanted to see if strict adherence could result in remission of diabetes, which was an outcome measured in one of the articles used. I also tried to choose articles that had similar definitions of low carbohydrate diet, which was generally under 45% of total caloric intake. However, some of the meta-analyses may have pooled studies with differing cut-offs for their definition of “low-carbohydrate” which can also skew the results and is something to be addressed in future studies. 

Results found:

1. Goldenberg, Joshua Z et al. “Efficacy and safety of low and very low carbohydrate diets for type 2 diabetes remission: systematic review and meta-analysis of published and unpublished randomized trial data.” BMJ (Clinical research ed.) vol. 372 m4743. 13 Jan. 2021, doi:10.1136/bmj.m4743

Type of Article: Meta-analysis

Objective

To determine the efficacy and safety of low carbohydrate diets (LCDs) and very low carbohydrate diets (VLCDs) for people with type 2 diabetes.

Design

Systematic review and meta-analysis.

Data sources

Searches of CENTRAL, Medline, Embase, CINAHL, CAB, and grey literature sources from inception to 25 August 2020.

Study selection

Randomized clinical trials evaluating LCDs (<130 g/day or <26% of a 2000 kcal/day diet) and VLCDs (<10% calories from carbohydrates) for at least 12 weeks in adults with type 2 diabetes were eligible.

Data extraction

Primary outcomes were remission of diabetes (HbA1c <6.5% or fasting glucose <7.0 mmol/L, with or without the use of diabetes medication), weight loss, HbA1c, fasting glucose, and adverse events. Secondary outcomes included health related quality of life and biochemical laboratory data. All articles and outcomes were independently screened, extracted, and assessed for risk of bias and GRADE certainty of evidence at six and 12 month follow-up. Risk estimates and 95% confidence intervals were calculated using random effects meta-analysis. Outcomes were assessed according to a priori determined minimal important differences to determine clinical importance, and heterogeneity was investigated on the basis of risk of bias and seven a priori subgroups. Any subgroup effects with a statistically significant test of interaction were subjected to a five point credibility checklist.

Results

Searches identified 14 759 citations yielding 23 trials (1357 participants), and 40.6% of outcomes were judged to be at low risk of bias. At six months, compared with control diets, LCDs achieved higher rates of diabetes remission (defined as HbA1c <6.5%) (76/133 (57%) v 41/131 (31%); risk difference 0.32, 95% confidence interval 0.17 to 0.47; 8 studies, n=264, I2=58%). Conversely, smaller, non-significant effect sizes occurred when a remission definition of HbA1c <6.5% without medication was used. Subgroup assessments determined as meeting credibility criteria indicated that remission with LCDs markedly decreased in studies that included patients using insulin. At 12 months, data on remission were sparse, ranging from a small effect to a trivial increased risk of diabetes. Large clinically important improvements were seen in weight loss, triglycerides, and insulin sensitivity at six months, which diminished at 12 months. On the basis of subgroup assessments deemed credible, VLCDs were less effective than less restrictive LCDs for weight loss at six months. However, this effect was explained by diet adherence. That is, among highly adherent patients on VLCDs, a clinically important reduction in weight was seen compared with studies with less adherent patients on VLCDs. Participants experienced no significant difference in quality of life at six months but did experience clinically important, but not statistically significant, worsening of quality of life and low density lipoprotein cholesterol at 12 months. Otherwise, no significant or clinically important between group differences were found in terms of adverse events or blood lipids at six and 12 months.

Conclusions

On the basis of moderate to low certainty evidence, patients adhering to an LCD for six months may experience remission of diabetes without adverse consequences. Limitations include continued debate around what constitutes remission of diabetes, as well as the efficacy, safety, and dietary satisfaction of longer term LCDs.

•  McArdle, P. D., Greenfield, S. M., Rilstone, S. K., Narendran, P., Haque, M. S., & Gill, P. S. (2018). Carbohydrate restriction for glycaemic control in Type 2 diabetes: a systematic review and meta-analysis. Diabetic Medicine. doi:10.1111/dme.13862 

Type of Article: Meta-analysis

Abstract: 

Aim

 To conduct a systematic review and meta-analysis to evaluate the effect of carbohydrate restriction on glycaemic control in Type 2 diabetes.

Methods

We searched Medline, EMBASE and CINAHL for the period between 1976 and April 2018. We included randomized controlled trials comparing carbohydrate restriction with a control diet which aimed to maintain or increase carbohydrate intake, and that reported HbA1c as an outcome and reported the amount of carbohydrate consumed during or at the end of the study, with outcomes reported at ≥3 months.

Results

We identified 1402 randomized controlled trials, 25 of which met the inclusion criteria, incorporating 2132 participants for the main outcome. Definitions of low carbohydrate varied among the studies. The pooled effect estimate from meta-analysis was a weighted mean difference of –0.09% [95% CI –0.27, 0.08 (P = 0.30); I 2 72% (P A subgroup analysis of diets containing 50– 130 g carbohydrate resulted in a pooled effect estimate of –0.49% [95% CI –0.75, –0.23  suggesting a clinically and statistically significant effect on HbA1c in favour of low-carbohydrate diets in studies of ≤6 months’ duration.

 Conclusions

There was no overall pooled effect on HbA1c in favour of restricting carbohydrate; however, restriction of carbohydrate to 50–130 g per day had beneficial effects on HbA1c in trials up to 6 months. Future randomized controlled trials should be of >12 months’ duration, assess pre-study carbohydrate intake, use recognized definitions of low-carbohydrate diets and examine reasons for non-adherence to prescribed diets in greater detail.

3. Snorgaard, Ole et al. “Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes.” BMJ open diabetes research & care vol. 5,1 e000354. 23 Feb. 2017, doi:10.1136/bmjdrc-2016-000354

Type of Article: Meta-analysis

Objective

Nutrition therapy is an integral part of self-management education in patients with type 2 diabetes. Carbohydrates with a low glycemic index are recommended, but the ideal amount of carbohydrate in the diet is unclear. We performed a meta-analysis comparing diets containing low to moderate amounts of carbohydrate (LCD) (energy percentage below 45%) to diets containing high amounts of carbohydrate (HCD) in subjects with type 2 diabetes.

Research design and methods

We systematically reviewed Cochrane library databases, EMBASE, and MEDLINE in the period 2004–2014 for guidelines, meta-analyses, and randomized trials assessing the outcomes HbA1c, BMI, weight, LDL cholesterol, quality of life (QoL), and attrition.

Results

We identified 10 randomized trials comprising 1376 participants in total. In the first year of intervention, LCD was followed by a 0.34% lower HbA1c (3.7 mmol/mol) compared with HCD (95% CI 0.06 (0.7 mmol/mol), 0.63 (6.9 mmol/mol)). The greater the carbohydrate restriction, the greater the glucose-lowering effect (R=−0.85, p<0.01). At 1 year or later, however, HbA1c was similar in the 2 diet groups. The effect of the 2 types of diet on BMI/body weight, LDL cholesterol, QoL, and attrition rate was similar throughout interventions.

Limitations

Glucose-lowering medication, the nutrition therapy, the amount of carbohydrate in the diet, glycemic index, fat and protein intake, baseline HbA1c, and adherence to the prescribed diets could all have affected the outcomes.

Conclusions

Low to moderate carbohydrate diets have greater effect on glycemic control in type 2 diabetes compared with high-carbohydrate diets in the first year of intervention. The greater the carbohydrate restriction, the greater glucose lowering, a relationship that has not been demonstrated earlier. Apart from this lowering of HbA1c over the short term, there is no superiority of low-carbohydrate diets in terms of glycemic control, weight, or LDL cholesterol.

4. Korsmo-Haugen, H.-K., Brurberg, K. G., Mann, J., & Aas, A.-M. (2018). Carbohydrate quantity in the dietary management of type 2 diabetes – a systematic review and meta-analysis. Diabetes, Obesity and Metabolism. doi:10.1111/dom.13499 

Type of Article: Meta-analysis

Aims: This systematic review and meta-analysis compares the effects of low carbohydrate diets (LCDs) on body weight, glycaemic control, lipid profile and blood pressure with those observed on higher carbohydrate diets (HCDs) in adults with type 2 diabetes.

Methods: MEDLINE, EMBASE, CENTRAL, CINAHL, Food Science Source and SweMed+ databases were systematically searched to identify randomised controlled trials (duration e 3 months) investigating the effects of a LCD compared to a HCD in the management of type 2 diabetes. Data were extracted and pooled using a random effects model and expressed as mean differences and risk ratio. Subgroup analyses were undertaken to examine the effects of duration of intervention, extent of carbohydrate restriction and risk of bias. The certainty of evidence was assessed using GRADE.

Results: Of the 1589 studies identified, 23, including 2178 participants, met inclusion criteria. Reductions were slightly greater on LCDs than HCDs for HbA1c (-1.0 mmol/mol, CI -1.9, – 0.1 [-0.09%, CI -0.17, -0.01]) and triglycerides (-0.13 mmol/l, CI -0.24, -0.02). Changes in weight, HDL- and LDL-cholesterol, total cholesterol and blood pressure did not differ significantly between groups. Subgroup analyses suggested that the difference in HbA1c was only evident in studies with duration of d6 months and with high risk of bias.

Conclusions: The proportion of daily energy provided by carbohydrate intake is not an important determinant of response to dietary management, especially when considering longer term trials. A range of dietary patterns including those traditionally consumed in Mediterranean countries seems suitable for translating nutritional recommendations for people with diabetes into practical advice.

5.  Silverii GA, Botarelli L, Dicembrini I, Girolamo V, Santagiuliana F, Monami M, Mannucci E. Low-carbohydrate diets and type 2 diabetes treatment: a meta-analysis of randomized controlled trials. Acta Diabetol. 2020 Nov;57(11):1375-1382. doi: 10.1007/s00592-020-01568-8. Epub 2020 Jul 8. PMID: 32638087.

Type of Article: Meta-Analysis

Aim: To assess whether LC diets are associated with long-term improvement in glycemic control and weight loss in people with T2DM, and their cardiovascular and renal safety.

Methods: Meta-analysis of randomized controlled trials lasting more than 3 months, retrieved through extensive search on PubMed, Embase, ClinicalTrial.gov, Cochrane databases up to March 1st, comparing LC diets and balanced carbohydrate diets in people with T2DM.

Results: We retrieved 37 trials, including 3301 patients. Average carbohydrate intake in LC diets was 36% of total energy. LC diets were associated with significant reduction of HbA1c at 3 months (MD – 0.17%, 95% CI – 0.27, – 0.07), no difference at 6 and 12 months, and significant increase at 24 months (MD 0.23%, 95% CI MD 0.02, 0.44). VLC diets were associated with significant HbA1c reduction at 3 and 6 months (MD – 0.43% – 0.60, – 0.26%, and MD – 0.40% 95% CI – 0.59, – 0.22, respectively), but not at 12 and 24 months. LC diets were associated with significant BMI reduction at 6 months (- 1.35 kg/m2 95% CI, – 2.18, – 0.52), but not at other time points. Only a minority of trials reported data on renal function, so renal safety could not be assessed. No significant differences in body weight, lipid profile, or blood pressure were found in the long term.

Conclusion: LC diets may produce small short-term improvements in HbA1c and weight, which are not maintained in the long term. Data on their renal safety are insufficient.

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting	Outcome(s) Studied	Key Findings	Limitations And Biases
Goldenberg (2021)	Meta-analysis	Searches identified 14 759 citations yielding 23 trials (1357 participants), and 40.6% of outcomes were judged to be at low risk of bias.	Primary outcomes were remission of diabetes (HbA1c <6.5% or fasting glucose <7.0 mmol/L, with or without the use of diabetes medication), weight loss, HbA1c, fasting glucose, and adverse events.	Pooled analysis showed that when remission was defined by an HbA1c level below 6.5% independent of medication use, LCDs increased remissions by an additional 32 per 100 patients followed (risk difference 0.32, 95% confidence interval 0.17 to 0.47; 8 studies, n=264   Seventeen studies reported on HbA1c levels at six months. LCDs achieved greater reductions in HbA1c than did control diets (mean difference –0.47%, –0.60 to –0.34; n=747; GRADE=high) At 12 months, eight studies reported on HbA1c levels, showing that the effect size had decreased by around half (mean difference –0.23%, –0.46% to 0.00%; n=489;	Remission of diabetes is a debatable definition with different thresholds of HgbA1c/fasting glucose.   Potential for numerous confounding factors such as unintentional caloric restriction.
McArdle (2018)	Meta-analysis	We identified 1402 randomized controlled trials, 25 of which met the inclusion criteria, incorporating 2132 participants for the main outcome.	Means and standard deviations (or standard error) were used to conduct meta-analyses for the primary outcomes HbA1c and body weight using a random-effects model, and to compare interventions using weighted mean difference (WMD) and 95% CIs	In conclusion, the present review provides evidence of short-term improvements in glycaemic control achieved by restriction of carbohydrate intake to 50–130 g per day; however, it suggests there is little evidence to support recommending a general restriction of carbohydrate intake for all people with Type 2 diabetes.   A small and clinically significant reduction of 5 mmol/mol (0.49%) in HbA1c was seen in the subgroup of studies using 50–130 g carbohydrate per day. These studies were ≤6 months in duration, or only reported outcomes at 6 months, an important limitation to the clinical application of this finding. Earlier reviews found that reductions in HbA1c or weight at 3 or 6 months were not maintained beyond 12 months	Differences in baseline glycemic control of participants of some studies, lack of adherence to the study diet, differences in protocols for adjustment of diabetic medications.
Snorgaard (2017)	Meta-analysis	We systematically reviewed Cochrane library databases, EMBASE, and MEDLINE in the period 2004–2014 for guidelines, meta-analyses, and randomized trials assessing the outcomes HbA1c, BMI, weight, LDL cholesterol, quality of life (QoL), and attrition.   We identified 10 randomized trials comprising 1376 participants in total.	BMI, HbA1c, LDL cholesterol, and weight	The magnitude of this greater glucose-lowering effect of low to moderate carbohydrate diets in the first year of intervention was related to the reported intake of carbohydrates measured as energy% (eight trials, R −0.85, p<0.01). The effect on glycemic control increased with the reported degree of carbohydrate restriction.    This meta-analysis conducted according to the GRADE criteria shows that nutrition therapy with a low to moderate E% carbohydrate diet induces a greater decline in HbA1c in subjects with type 2 diabetes compared with a standard HCD. Considering baseline HbA1c in the included studies, and that it was necessary to reduce glucose-lowering medication during LCD in many trials, the 0.34%-points (3.7 mmol/mol) improvement in glycemic control is of clinical significance.	Differences in adherence to diet, total daily caloric intake, glycemic index of the carbohydrates consumed by participants all can cause differences in estimation of the effect of the diet on the parameters measured.
Korsmo-Haugen (2018)	Meta-analysis	Of the 1589 studies identified, 23, including 2178 participants, met inclusion criteria.   We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, Food Science Source and SweMed+ for RCTs published between 1983 to January 2016. Our search terms were: (diet OR carbohydrate-restricted OR low carbohydrate diet OR dietary carbohydrates OR ketogenic diet OR Atkins diet OR diabetic diet) AND (type 2 diabetes OR diabetes mellitus OR type 2 OR diabetes OR non-insulin dependent diabetes mellitus), using MeSH terms when available	Weight, HbA1c, lipids, blood pressure and compliance to dietary intervention.	Short term benefits of low and very low carbohydrate diets in terms of weight loss and improvements in blood pressure and blood lipid profile have also been shown in normoglycaemic individuals 18,19. It has not been possible to disentangle whether the short term improvement in glycaemic control and a range of cardiovascular risk factors is a consequence of the weight loss or a direct result of carbohydrate restriction and/or the consequential redistribution of the proportion of energy provided by other macronutrients.   No differences in weight, blood pressure or total, LDL and HDL cholesterol were apparent in either the relatively short or longer term trials.	Patient compliance to recommended diet, changes in medication over time, trials may have high risk of bias
Silverii (2020)	Meta-analysis	We retrieved 37 trials, including 3301 patients.   Meta-analysis of randomized controlled trials lasting more than 3 months, retrieved through extensive search on PubMed, Embase, ClinicalTrial.gov, Cochrane databases up to March 1st, comparing LC diets and balanced carbohydrate diets in people with T2DM.	Mean HbA1c, weight, BMI, SBP, DBP, total HDL and LDL Cholesterol, Triglycerides, creatinine, eGFR, diet quality of life	Low-carbohydrate diets, in comparison with balanced diets, determine a small, although statistically signifcant, reduction of HbA1c. This beneft seems to be greater for diets with VLC content. This small advantage disappears in the longer term, and at 24 months balanced diets resulted to be superior to LC diets.	Small trials limit precision of treatment effect measurements, most studies have short follow up periods, possibility of overestimation of effects.

Conclusions:

Goldenberg (2021) concluded that patients on LCDs achieved higher rates of diabetes remission, decrease in use of diabetic medication, and lowering of HgbA1c at 6 months.  

McArdle (2018) concluded that a small but clinically significant reduction in HgbA1c was seen on LCD at 6 months, but with no significant changes in bodyweight.

Snorgaard (2017) concluded that a LCD (under 45% of calories) had a greater effect on glycemic control in DMII than a HCD in the short term.  

Korsmo-Haugen (2018) concluded that lower levels of HgbA1c were achieved with LCD compared to HCD in the short term. Small differences in triglyceride levels were also found but weight, blood pressure, and cholesterol levels were not affected.

Silverii (2020) concluded that LCDs, and especially VLCDs, are effective in reducing HgbA1c, but at 24 months, balanced diets appear to be better for glycemic control.

Overall: All 5 of these meta-analyses demonstrate that LCDs can be effective in helping diabetic patients control their HgbA1c levels with short term compliance, generally from 3 months to 12 months. After that, their effects may be diminished or disappear entirely.

Clinical Bottom Line

Articles Ranked:

Goldenberg (2021) – I weighted this strongest, as it represents the most current data available, and the authors also evaluated remission of diabetes as an outcome of interest.  

Silverii (2020)– I weighted this article second because it is also represents more recent data, and the authors focused on potential negative long term effects by evaluating RCTs that contained renal function data.

McArdle (2018)– I weighted this third, because the authors utilized a population pool of over 2000 participants and they identified a specific carbohydrate target zone that had the greatest effect on HgbA1c.

Snorgaard (2017)– I weighted this the fourth strongest, as they utilized less trials, but used data from after 2004, whereas some of the other meta-analyses included older trials. The authors also determined that the greater the carbohydrate restriction, the greater the effect on glycemic control in the short term.

Korsmo-Haugen (2018) -I rated this the weakest, as it was the older than most of the other articles, and the authors found selective-reporting issues in several of the trials they analyzed.

Magnitude of Effects

Across nearly all studies evaluated in the meta-analyses, carbohydrate-restricted diets resulted in greater glycemic control than did more balanced diets when evaluated at 6 months, but the effects mostly disappeared at 12 months.

Goldenberg (2021)- Among 23 studies comparing LCDs with mostly low fat control diets in patients with type 2 diabetes, on the basis of moderate to low certainty evidence, patients on LCDs achieved higher diabetes remission rates at six months (HbA1c <6.5%: NNT=3; HbA1c <6.5% and no diabetes medication: NNT=20).

Silverii (2020)- LC diets were associated with a significant reduction of HbA1c at 3 months (MD − 0.17%, 95% CI − 0.27, − 0.07) I 2 35%, no difference at 6 months (MD − 0.19%, 95% CI MD − 0.40, 0.01), I 2 58% and 12 months (MD − 0.02%, 95% CI MD − 0.12, 0.07), I 2 56%, and a significant increase at 24 months (MD 0.23%, 95% CI MD 0.02, 0.44), I 2 0%

McArdle (2018)– – Analysis of the subgroup of five low-carbohydrate diet studies (50–130 g per day) showed a statistically and clinically significant result in favour of the intervention diet [WMD –0.49% (95% CI – 0.75, –0.23; P < 0.001); I 2 0% (P = 0.56)]

Snorgaard (2017)– In the first year of intervention (3 or 6 months), LCD was followed by a 0.34%-point (3.7 mmol/mol) lower (95% CI 0.06 (0.7) to 0.63 (6.9)) HbA1c compared with HCD

Korsmo-Haugen (2018) – LCD was associated with a greater overall reduction in HbA1c (MD -1.0 mmol/mol, 95% CI – 1.9, -0.1 [-0.09 %, 95% CI -0.17, -0.01]) in the 16 studies included in this analysis.

 Clinical Significance:

The clinical bottom line is that carbohydrate-restricted diets may have some effects on glycemic control and HgbA1c in the short term, but the benefits are not very sustainable after 12 months. There is not much clinically significant data to assert that LCDs are more effective than isocaloric HCDs, but may be a useful alternative for short term HgbA1c if the patient is compliant with following it. There were also no clinically significant effects on body weight or cholesterol levels, which might be seen in other types of diets. There are numerous confounding factors in designing and assessing dietary studies, as they are typically not in controlled environments and individual factors may play significant roles in determining the outcomes of the participants.  

Additional Considerations:

Authors of several studies recommend that more trials be conducted where the amount of and source of carbohydrates is clearly identified, as different foods have different glycemic indices which influence increases of blood sugar. More trials should also be conducted that evaluate the long-term effects of such diets after 12 months. Several studies also did not account for adjustments of diabetic medications during the trials which may have had an influence on the results. This should be accounted for in future trials.