Ketogenic Diets, Ketoacidosis and SGLT-2 Inhibitors - Part 2
Written by: Richard Feinman
In part 1, I described the mode of action of the SGLT-2 inhibitor class of drugs. This class of drugs blocks glucose uptake from the renal tubule thereby allowing some of the very high glucose in diabetes to be excreted in the urine [5-7]. For unknown reasons, the drugs have the serous side effect of risk of ketoacidosis which can be life-threatening. I described how ketoacidosis is prevented in normal people by a feedback system whereby the ketone bodies stimulate insulin release and inhibit lipolysis. This leads to reduced production of free fatty acids and repression of continued ketogenesis. The question is what happens in SGLT-2 inhibition and can you get benefit with a nutritional approach, namely ketogenic diets, in its place? The promised punch-line was that ketogenic diets can prevent ketoacidosis by being a safer alternative.
What Goes Wrong in SGLT-2 Inhibitors?
SGLT-2 inhibitors cause a rapid drop in blood glucose. This likely leads to a sudden fall in insulin and, in combination with possible insulin resistance, production of ketone bodies may be poorly regulated. In general, there is the sense that there will be the same kind of disjoint regulation seen in the type 1 response to external as opposed to endogenous insulin [10], and it may be impossible to obtain re-equilibration of the control system described in Figure 4 (see part 1). Also, some animal studies suggest that the SGLT-2 inhibitors may affect glucagon secretion from the alpha cells of the pancreas thereby increasing fatty acid release and ketogenesis. Finally, there is evidence that at least some SGLT-2 inhibitors my block excretion of acetoacetate (one of the ketone bodies) further increasing ketone levels.
Carbohydrate Restriction and SGLT-2 Inhibitors.
The 12 points of evidence summarized in our 2015 review [8] listed reduction or elimination of medication as one of the major arguments for carbohydrate restriction as the first approach to treating diabetes. Hallberg and coworkers [1-4] recently showed just how significant this phenomenon can be (Figure 5). Of the 23 participants in the ketogenic group (CCI; Continuous Care Intervention) who had been taking SGLT-2 inhibitors, 21 eliminated the drug during the first year and 18 had eliminated or reduced dosage during the second year. Overall, at two years, slightly more than half of the participants in this group (53.5%), had met the criteria for normalization of metabolic markers that could be designated as reversal of diabetes (only metformin use). An additional 17.6% of patients were considered to be in remission, defined as glycemic control without any medication use. While the control group (UC; Usual Care) reduced drug usage as well, the effect was not as striking.
The obvious question: if SGLT-2 are as effective as stated, if, in fact they are worth the serious risk, what would one say about a therapy that removed the need for SGLT-2 inhibitors?
Guidance From the ADA and the Medical Establishment.
While the American Diabetes Association (ADA) has recently gained some approbation for acknowledgement that LCHF/keto diets constitute one of the choices for people with diabetes [11, 12], their publications cannot be considered highly supportive. The recommendations do not confront the evidence that we presented [8] showing that carbohydrate restriction represents the first line of attack, the “default” approach, the one to try first. The overall effect of ADA publications, like those of other agencies, persists in misrepresentation of approaches based on carbohydrate restriction. The 2019 Consensus Statement, for example: “research studies on some low-carbohydrate eating plans generally indicate challenges with longterm sustainability, it is important to reassess and individualize meal plan guidance regularly for those interested in this approach,” the implication being that there exists a dietary approach where some plans do not challenge longterm sustainability but the existence of such a diet is not unknown. Sustainability of various diets has long been studied and LCHF does as well as any [8]. Also, unstated is the fact that sustaining a diet with mediocre results is a mediocre accomplishment. The ADA, moreover, includes diets with 45 % carbohydrate in the low-carbohydrate category, notwithstanding that at least two of the committee members have carried out the original work on genuine low-carbohydrate diets and know that that 45 % will not provide the benefits of more thorough-going carbohydrate reduction.
Most questionable in the context of this post is the ADA’s advice: “This meal plan …should be used with caution in patients taking sodium–glucose co-transporter-2 (SGLT2) inhibitors due to the potential risk of ketoacidosis.” The drug puts the patient at risk — the meal plan reduces the risk. This caution is not applied to any other diet choices. Also absent from the ADA’s comments are the observations that low-carbohydrate/ketogenic diets obviate the need for SGLT-2 inhibitors (Table 1 below).
While the medical profession maintains nearly obsessive caution about potential and largely imaginary risks of LCHF/keto diets, they remain somewhat sanguine about side effects of drugs. A summary from 2015 felt that ketoacidosis
“related to the use of SGLT2 inhibitors will probably turn out to be very low, with an ‘acceptable’ frequency. Still, physicians and patients need to be made aware that such risk may be increased in long-standing T2D patients with marked β-cell insufficiency or in latent autoimmune diabetes in adults with rapid evolution toward T1D and during prolonged starvation, after surgery, or during intercurrent illness.”
It’s not clear for whom the frequency is “acceptable” and what the quotation marks mean. To put things in perspective, Table 1 shows a warning from the label of FARXIGA (dapagliflozin) [3]. One has to wonder what health agencies would say if these precautions accompanied recommendations for LCHF/ketogenic diets.
Finally, recent observations suggest that SGLT-2 inhibitors may be protective of cardiovascular disease (CVD), important in that people with diabetes have increased risk [13]. The data, however, seem underwhelming although providing a good example of the difference in impact of relative risk reduction and absolute risk reduction (Figure 6). (The evolving idea that error is reduced if it is admitted, does not have universal acceptance). In addition, it seems reasonable to consider that the best way to reduce the risk of CVD associated with diabetes, is to put the diabetes into remission. The case has been made that a ketogenic diet along the lines carried out by Hallberg, et al. [1-4, 8] should be the “default” treatment for diabetes, that is, the one to try first. If it is not successful, SGLT-2 inhibitors are another choice.
Summary.
Paradoxically — seemingly perversely — while most drugs are designed to reduce blood sugar, dietary interventions, when they are recommended by health agencies, most often target weight loss, notwithstanding continued demonstration that weight loss is not required. Diabetes, both type 1and type 2, are diseases of carbohydrate intolerance. when recommending a nutritional approach, traditional medicine, the ADA, NIH and other private and government agencies, tend to recommend weight loss, even virtual starvation, rather than emphasizing blood glucose. The medical establishment remains, at best, lukewarm on carbohydrate restriction, notwithstanding the universally accepted idea that it represents the most direct approach to reducing hyperglycemia and, again, in spite of the recent successes of such dietary approaches in treating diabetes.
The SGLT-2 inhibitors provide a good example of the ambiguity and misleading behavior of health agencies: However effective the treatment for type 2 and likely benefit to type 1, ketoacidosis remains a serious risk with these drugs. At the same time LCHF/ketogenic diets present little or no risk of ketoacidosis and eliminate the need for SGLT-2 inhibitors. The ADA warning about SGLT-2 inhibitors in the context of such diets represents a clear example of bias that appears to be pervasive.
While lip service is paid to the role of nutrition in diabetes, the persistence of an epidemic of obesity and diabetes, continued concern about the cost of drugs and the demonstrated serious side-effects point to the need to face the challenge of dietary carbohydrate restriction.
References
1. Hallberg, S.J., McKenzie, A.L., Williams, P.T. et al. Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study. Diabetes Ther 9, 583–612 (2018) doi:10.1007/s13300-018-0373-9
2. Athinarayanan SJ, Adams RN, Hallberg SJ, et al. (2019) Long-Term Effects of a Novel Continuous Remote Care Intervention Including Nutritional Ketosis for the Management of Type 2 Diabetes: A 2-Year Non-randomized Clinical Trial. Front. Endocrinol. 10:348. doi: 10.3389/fendo.2019.00348
3. Hallberg SJ, Dockter NE, Kushner JA, Athinarayanan SJ. Improving the scientific rigour of nutritional recommendations for adults with type 2 diabetes: A comprehensive review of the American Diabetes Association guideline-recommended eating patterns. Diabetes Obes Metab. 2019;21:1769–1779. https://doi.org/10.1111/ dom.13736
4. Lennerz,BS, Barton A, Bernstein RK, et al. Management of Type 1 Diabetes With a Very Low–Carbohydrate Diet. Pediatrics. 2018;141(6):e20173349,
5. Joffe, D. (2018 ) SGLT2 Inhibitors: A New Class of Diabetes Medications. Diabetes In Control, Sep.19, 2018 http://www.diabetesincontrol.com/sglt2-inhibitors-a-new-class-of-diabetes-medications/
6. Rosenstock, Ferrannini, E. (2015) Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors. Diabetes Care; 38:1638–1642 |. DOI: 10.2337/dc15-1380
7. Food and Drug Administration. (2015) FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm. Accessed May 25, 2015.
8. Feinman RD, Pogozelski WK, Astrup A, et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition 2015;31:1–13
9. FARXIGA (datagliflozin) website https://www.farxiga-hcp.com/t2d-hospitalization-heartfailure.html last accessed February 4, 2020.
10. Derr, et al. (2003 ) Is HbA1c Affected by Glycemic Instability? Diabetes Care 26(10): 2728-2733. https://doi.org/10.2337/diacare.26.10.2728
11. American Diabetes Association. Chapter 4. Lifestyle management: Standards of Medical Care in Diabetes 2018. Diabetes Care 2018;41(Suppl. 1):S38–S50