A low-carbohydrate, ketogenic diet to treat type 2 diabetes

Prior to the advent of exogenous insulin for the treatment of diabetes mellitus in the 1920's, the mainstay of therapy was dietary modification. Diet recommendations in that era were aimed at controlling glycemia (actually, glycosuria) and were dramatically different from current low-fat, high-carbohydrate dietary recommendations for patients with diabetes [1, 2]. For example, the Dr. Elliot Joslin Diabetic Diet in 1923 consisted of "meats, poultry, game, fish, clear soups, gelatin, eggs, butter, olive oil, coffee, tea" and contained approximately 5% of energy from carbohydrates, 20% from protein, and 75% from fat [3]. A similar diet was advocated by Dr. Frederick Allen of the same era [4].

Recently, four studies have re-examined the effect of carbohydrate restriction on type 2 diabetes. One outpatient study enrolled 54 participants with type 2 diabetes (out of 132 total participants) and found that hemoglobin A_1c improved to a greater degree over one year with a low-carbohydrate diet compared with a low-fat, calorie-restricted diet [5, 6]. Another study enrolled 8 men with type 2 diabetes in a 5-week crossover outpatient feeding study that tested similar diets [7]. The participants had greater improvement in glycohemoglobin while on the low-carbohydrate diet than when on a eucaloric low-fat diet. The third study was an inpatient feeding study in 10 participants with type 2 diabetes [8]. After only 14 days, hemoglobin A_1c improved from 7.3% to 6.8%. In the fourth study, 16 participants with type 2 diabetes who followed a 20% carbohydrate diet had improvement of hemoglobin A_1c from 8.0% to 6.6% over 24 weeks [9]. Only these latter three studies targeted glycemic control as a goal, and two of these were intensely-monitored efficacy studies in which all food was provided to participants for the duration of the study [7, 8]. Three of the studies [6, 8, 9] mentioned that diabetic medications were adjusted but only one of them provided detailed information regarding these adjustments [9]. This information is critical for patients on medication for diabetes who initiate a low-carbohydrate diet because of the potential for adverse effects resulting from hypoglycemia.

The purpose of this study was to evaluate the effects of a low-carbohydrate, ketogenic diet (LCKD) in overweight and obese patients with type 2 diabetes over 16 weeks. Specifically, we wanted to learn the diet's effects on glycemia and diabetes medication use in outpatients who prepared (or bought) their own meals. In a previous article, we reported the results observed in 7 individuals [10]; this report includes data from those 7 individuals along with data from additional participants enrolled subsequently.

Of the 28 participants enrolled in the study, 21 completed the 16 weeks of follow-up. Reasons for discontinuing the study included unable to adhere to study meetings and unable to adhere to the diet; no participant reported discontinuing as a result of adverse effects associated with the intervention. All but one of the 21 participants were men; 62% (n = 13) were Caucasian, 38% (n = 8) were African-American (Table 1). The mean age was 56.0 ± 7.9 years.

Adequate food records were available for analysis in a proportion of participants at each of the 4 timepoints (Table 2). Participants completed food records at a mean of 2.5 and a median of 3 timepoints. In general, comparing baseline to subsequent timepoints, mean carbohydrate intake decreased substantially and energy intake decreased moderately while protein and fat intake remained fairly constant.

From baseline to week 16, the mean body weight decreased significantly from 131.4 ± 18.3 kg to 122.7 ± 18.9 kg, BMI decreased from 42.2 ± 5.8 kg/m² to 39.4 ± 6.0 kg/m², and waist circumference from 130.0 ± 10.5 cm to 123.3 ± 11.3 cm (Table 3). The percent change in body weight was -6.6%. The mean percent body fat decreased from 40.4 ± 5.8% to 37.0 ± 6.0%. Systolic and diastolic blood pressures did not change significantly over the 16 weeks. The mean heart rate decreased from 81.2 ± 12.9 beats per minute to 74.6 ± 14.0 beats per minute (p = 0.01).

Urine ketone data were missing in a median of 4 participants (range 0–8) at any given visit. The proportion of participants with a urine ketone reading greater than trace was 1 of 17 participants at baseline, 5 of 17 participants at week 2, and similar frequencies at subsequent visits until week 14 when 2 of 18 participants had readings greater than trace and week 16 when 2 of 21 participants had readings greater than trace. During the study, only 27 of 151 urine ketone measurements were greater than trace, with one participant accounting for all 7 occurrences of the highest urine ketone reading (large160).

In regard to serum measurements, the mean fasting glucose decreased by 17% from 9.08 ± 4.09 mmol/L at baseline to 7.57 ± 2.63 mmol/L at week 16 (p = 0.04) (Table 4). Serum sodium and chloride levels increased significantly, but only by 1% and 3%, respectively. Uric acid level decreased by 10% (p = 0.01). Serum triglyceride decreased 42% from 2.69 ± 2.87 mmol/L to 1.57 ± 1.38 mmol/L (p = 0.001). Increases occurred in both high-density lipoprotein (HDL) cholesterol (8%) and low-density lipoprotein (LDL) cholesterol (10%) but these changes were of borderline statistical significance (p = 0.08 and p = 0.1, respectively). The following blood tests did not change significantly: total cholesterol, potassium, bicarbonate, urea nitrogen, creatinine, calcium, thyroid-stimulating hormone, and hemoglobin.

The primary outcome, hemoglobin A_1c, decreased from 7.5 ± 1.4% at baseline to 6.3 ± 1.0% at week 16 (p < 0.001), a 1.2% absolute decrease and a 16% relative decrease (Table 4). All but two participants (n = 19 or 90%) had a decrease in hemoglobin A_1c (Figure 1). The absolute decrease in hemoglobin A_1c was at least 1.0% in 11 (52%) participants. The relative decrease in hemoglobin A_1c from baseline was greater than 10% in 14 (67%) participants, and greater than 20% in 6 (29%) participants. In regression analyses, the change in hemoglobin A_1c was not predicted by the change in body weight, waist circumference, or percent body fat at 16 weeks (all p > 0.05).

The improvement in glycemic control occurred while medications for diabetes were discontinued or reduced in most participants (Table 5). During the study, hypertension and hyperlipidemia medication doses were not increased from baseline nor were new agents added, except in 3 individuals. No serious adverse effects related to the diet occurred. One participant had a hypoglycemic episode requiring assistance from emergency services after he skipped a meal but the episode was aborted without need for transportation to the emergency room or hospitalization.

In this single-arm, 4-month diet intervention, an LCKD resulted in significant improvement of glycemia, as measured by fasting glucose and hemoglobin A_1c, in patients with type 2 diabetes. More importantly, this improvement was observed while diabetes medications were reduced or discontinued in 17 of the 21 participants, and were not changed in the remaining 4 participants. Participants also experienced reductions in body weight, waist circumference, and percent body fat but these improvements were moderate and did not predict the change in hemoglobin A_1c in regression analyses.

Several recent studies indicate that a low-carbohydrate diet is effective at improving glycemia. A few studies have shown that in non-diabetic individuals, low-carbohydrate diets were more effective than higher carbohydrate diets at improving fasting serum glucose [13, 14] and insulin [6, 14‐16], and at improving insulin sensitivity as measured by the homeostasis model [6]. One of these studies also included diabetic patients and noted a comparative improvement in hemoglobin A_1c after 6 months (low fat diet: 0.0 ± 1.0%; low carbohydrate diet: -0.6 ± 1.2%, p = 0.06) [6] and 12 months (low fat diet: -0.1 ± 1.6%; low carbohydrate diet: -0.7 ± 1.0%, p = 0.019) duration [5]. In a 5-week crossover feeding study, 8 men with type 2 diabetes had greater improvement in fasting glucose, 24-hour glucose area-under-the-curve (AUC), 24-hour insulin AUC, and glycohemoglobin while on the low-carbohydrate diet than when on a eucaloric low-fat diet [7]. In a 14-day inpatient feeding study, 10 participants with type 2 diabetes experienced improvements in hemoglobin A_1c and insulin sensitivity as measured by the euglycemic hyperinsulinemic clamp method [8]. Hemoglobin A_1c also improved in an outpatient study of 16 participants who followed a 20% carbohydrate diet for 24 weeks [9].

Similar to our results, three studies noted that diabetes medications were reduced in some participants[6, 8, 9], although details were provided in only one study. We also discontinued diuretic medications during diet initiation because of concern for additional diuresis incurred by the diet. This concern was based on the theoretical effects of the diet [17], observed effects of the diet on body water by bioelectric impedance [18], and practical experience with the diet [19]. Until we learn more about using low carbohydrate diets, medical monitoring for hypoglycemia, dehydration, and electrolyte abnormalities is imperative in patients taking diabetes or diuretic medications.

While body weight decreased significantly (-8.5 kg) in these 21 diabetic participants, the mean weight loss was less compared with what we observed in the LCKD participants of an earlier trial (-12.0 kg) [18]. Given that the diabetic participants had a higher baseline mean weight than the LCKD participants of our previous trial (131 kg vs. 97 kg), this translates into an even more dramatic disparity in percent change in body weight (-6.6% vs. -12.9%). This lesser weight loss might result from several factors. First, in the current study, most of the participants were taking insulin and/or oral hypoglycemic agents that are known to induce weight gain[20, 21] Second, these same agents, particularly insulin, inhibit ketosis, which is strived for in the earliest phases of the LCKD; while it remains unclear whether ketones actually play a role in weight loss on the LCKD, previous research in non-diabetic patients has shown a positive correlation between level of ketonuria and weight loss success [22]. Lastly, compared with our previous study the participants in the current study had more comorbid illness, lower socioeconomic status, and a shorter duration of follow-up (16 weeks versus 24 weeks), all of which are associated with reduced success on any weight loss program [23].

The main limitations of our study are its small sample size, short duration, and lack of control group. That the main outcome, hemoglobin A_1c, improved significantly despite the small sample size and short duration of follow-up speaks to the dramatic and consistent effect of the LCKD on glycemia. For other effects, however, such as the rises in serum LDL and HDL cholesterol, the small sample size might be the reason statistical significance was not reached. Future studies of larger samples and containing a control group are needed to better address questions about the effect of the LCKD on serum lipids in patients with type 2 diabetes.

In summary, the LCKD had positive effects on body weight, waist measurement, serum triglycerides, and glycemic control in a cohort of 21 participants with type 2 diabetes. Most impressive is that improvement in hemoglobin A_1c was observed despite a small sample size and short duration of follow-up, and this improvement in glycemic control occurred while diabetes medications were reduced substantially in many participants. Future research must further examine the optimal medication adjustments, particularly for diabetes and diuretic agents, in order to avoid possible complications of hypoglycemia and dehydration. Because the LCKD can be very effective at lowering blood glucose, patients on diabetes medication who use this diet should be under close medical supervision or capable of adjusting their medication.