Diabetic Ketoacidosis in a Type 2 Diabetes Patient After Initiation of Over-the-Counter Weight Loss Medications: A Cautionary Tale

Case Presentation

A 50-year-old Caucasian man with a history of obesity and type 2 diabetes presented to the emergency room with a 2-day history of blurry vision and severe polyuria and polydipsia. He was found to have diabetic ketoacidosis (DKA) and was admitted to the hospital for further management; endocrinology service was subsequently consulted. Review of his chart showed that he had been diagnosed with type 2 diabetes about 2 years before this admission when at an annual screening his A1C was 6.6% (49 mmol/mol). Metformin monotherapy was then started; however, he quickly stopped the medication because of gastrointestinal upset. He further improved his diet and increased his physical activity and, about 6 months before his admission with DKA, his primary care provider had changed his follow-up visits to once per year because his A1C was 6.1% (43 mmol/mol), his blood pressure was 130/78 mmHg, random LDL cholesterol was 115 mg/dL, and triglycerides were 304 mg/dL. No medications were prescribed.

At the time of his admission with hyperglycemic emergency, the diagnosis of DKA was made based on a serum glucose level of 621 mg/dL, bicarbonate of 20 mEq/L (normal range 22–32), anion gap of 19, and presence of serum ketones. The DKA episode was resolved 10 hours after admission to the intensive care unit (ICU) for intravenous fluid resuscitation and insulin therapy.

During initial inpatient evaluation, we found no signs or symptoms supporting concurrent infection or pancreatitis; he was hemodynamically stable and had a BMI of 32 kg/m², with a weight of 85 kg. His A1C was 12.8% (116 mmol/mol), triglycerides were 7,783 mg/dL, and total cholesterol was 411 mg/dL; thyroid-stimulating hormone and liver function tests were within normal limits.

As he was transferred from ICU to the floor to receive basal-bolus insulin therapy, further history was obtained from the patient. His family history was negative for diabetes in first-degree relatives. Importantly, he reported that about 2 weeks before the admission, he self-prescribed complex over-the-counter (OTC) therapy consisting of three types of supplements that were obtained from an online retailer with the intention of losing weight with the help of biological actions targeting reduction in body fat content (so-called “fat burners”) and reduction in body fluid retention (a natural diuretic supplement). He noted that, as he initiated the OTC medications, he developed progressive polyuria, polydipsia, and nocturia, managed by continuously drinking fluids, and experienced a weight loss of ∼10 kg.

The remaining hospital course was uncomplicated and, at discharge, he was prescribed physiologic basal-bolus insulin therapy with titration instructions, started on atorvastatin, and advised to stop all weight loss OTC medications.

At the 1-month follow-up in the endocrinology clinic, we found evidence of preserved β-cell function based on a fasting C-peptide level of 4.55 ng/mL (normal range 0.80–3.85) and a lack of immunological features of autoimmune diabetes (GAD65 autoantibodies <5 IU/mL [normal <5] and negative islet cell autoantibody titer).

Because his glycemic control was improving on insulin therapy, over the 4 months after his discharge from the DKA episode, we were able to gradually replace insulin therapy with a regimen consisting of daily glimepiride 1 mg and pioglitazone 30 mg, resulting in an A1C of 7.0% (53 mmol/mol), and his weight returned to the level it was before his initiation of the OTC medications. In addition to continuation of atorvastatin, we initiated fenofibrate therapy to improve his lipid control because his post-discharge fasting triglycerides ranged from 600 to 700 mg/dL despite optimal glycemic control. Given clinical (obesity and type 2 diabetes) and biochemical (dyslipidemia) evidence suggesting an insulin-resistant state, we performed abdominal ultrasound that demonstrated the presence of hepatic steatosis.

Questions

1. What can trigger DKA in patients with type 2 diabetes?

2. What is known about how OTC weight loss medications can affect the course of type 2 diabetes or precipitate DKA in these patients?

3. Is there a pathophysiological rationale behind the development of hyperglycemic crisis in patients with diabetes who are taking OTC weight loss medications?

Commentary

For a long time, DKA was thought to be synonymous with management failure in type 1 diabetes; however, it is now recognized that people with type 2 diabetes can also develop DKA (1). Several risk factors that can predispose a person with type 2 diabetes to DKA are now well described (2). The use of prescription medications for treatment of comorbid conditions and diabetes therapy itself can cause DKA. Glucocorticosteroids, second-generation antipsychotic agents, sodium–glucose cotransporter 2 inhibitors, and anticancer immune checkpoint inhibitors are implicated in the development of DKA in people with type 2 diabetes. In some people, a new diagnosis of type 2 diabetes can debut as DKA; these patients are described as having ketosis-prone diabetes mellitus (KPDM) (2).

Regardless of whether the DKA episode is caused by medications or is an initial presentation of diabetes, laboratory evaluation for markers suggestive of autoimmune β-cell destruction can help determine whether lifelong insulin therapy is indicated. More specifically, patients with latent autoimmune diabetes in adults (LADA) are characterized by immune-mediated slow deterioration of β-cell function necessitating insulin therapy in their diabetes course and may initially present as having non–insulin-dependent diabetes; LADA accounts for up to 10% of adult cases of presumed type 2 diabetes (3). Because there are no systematic studies assessing the prevalence of LADA in the patients previously diagnosed with type 2 diabetes who would develop DKA regardless of associated factors, it might be prudent to conduct biochemical screening of these patients for underlying β-cell autoimmunity.

To our knowledge, this a first case report of DKA developed in a person with known type 2 diabetes after recent initiation of OTC weight loss medications. This patient had no history of administering medications that can precipitate DKA in type 2 diabetes, as discussed above. Given our patient’s known history of diabetes, the KPDM scenario was unlikely. We evaluated whether he was at risk for LADA; however, two autoimmune markers associated with β-cell deterioration in LADA (anti-GAD65 and ICA) were negative.

Based on the patient’s A1C of 12.8%, we speculate that severe hyperglycemia was slowly evolving over the previous 1–2 months, resulting in a toxic metabolic environment with diminishing insulin production. Nevertheless, as discussed above, patients with type 2 diabetes and severe nonketotic hyperglycemia should have some clinical or biochemical triggers that would result in metabolism alteration predisposing to ketoacidosis. We believe that the OTC weight loss medications were directly implicated in DKA development in this patient.

One in seven adults in the United States have used OTC weight loss medications in their lifetime (4). There are two major concerns related to these nonprescription approaches to losing weight. First, these supplements are not regulated by the U.S. Food and Drug Administration, and second, there is very little scientific or clinical evidence regarding the mechanisms of action, therapeutic efficacy, and potential side effects of these OTC medications in humans (4). Furthermore, there have been no mechanistic or safety trials conducted with the OTC weight loss preparations in patients with diabetes. In the current marketing environment, the descriptions customers are given by the manufacturers of these OTC medications do not consider how associated comorbid conditions could affect a person’s overall health beyond weight loss.

Over the course of 2 weeks, our patient self-administered OTC weight loss medications advertised as “stimulant-free fat burner,” “thermogenic-free fat burner,” and “water weight loss agent.” In reviewing the supplement labels, we found that our patient had received daily 35 mg vitamin B6, ∼400 mg green tea leaf extract, 700 mg acetylated L-carnitine, 200 mg amino acid L-theanine, and ∼1,000 mg herb and root extracts with diuretic action from these products. Overall, proposed biological actions for how these supplements may lead to weight loss are accelerated fatty acid (FA) oxidation and excessive diuresis. To our knowledge, it is not well understood how these “natural” substances would affect cellular physiology to result in weight loss in humans. For example, total daily intake of vitamin B6 in our patient via the OTC supplements exceeded 20 times the normal daily requirements of the vitamin. In a series of in vitro and clinical studies, administration of nutrient supplements containing 30 mg vitamin B6 have resulted in significant weight loss in obese otherwise healthy subjects caused by reduction in fat content via mechanisms that may have involved increase in FA oxidation (5,6). There are, on the other hand, some data indicating that some of these “natural” substances that are intended to promote weight loss may adversely affect glucose metabolism. The dandelion root extract present in one of our patient’s supplements promotes diuresis and has been shown in vitro to induce apoptosis in pancreatic cells (7). There is also clinical and experimental evidence demonstrating that elevated levels of acetylated carnitines can impair insulin secretion through mechanisms involving reduction of β-cell mitochondrial respiratory capacity (8,9). Treatment of type 2 diabetes patients with green and black tea extracts had a neutral effect on glucose metabolism (10). Although these potential negative effects of the “natural” supplements on glucose metabolism may remain unnoticed in obese individuals without diabetes, these findings do raise concerns that these OTC weight loss medications may affect glycemic control in obese people with diabetes.

We suggest the following scenario of DKA development in our patient with type 2 diabetes after recent initiation of OTC medications for weight loss.

The pathophysiologic rationale behind the weight loss effect of the OTC medications is to reduce the amount of fat via acceleration of lipolysis and fat oxidation and to promote diuresis. In the presence of normal insulin action, FA production is regulated via inactivation of hormone-sensitive lipase, activation of acetyl CoA carboxylase (ACC) enzymes 1 and 2, prevention of lipolysis, and suppression of ketogenesis (11). The importance of ACC enzymes in FA metabolism was recently shown in rodents with fatty liver disease. Pharmacological inhibition of ACC enzymes in rats significantly reduced diet-induced hepatic steatosis but was associated with significant hypertriglyceridemia and accumulation of ketone bodies (12).

We believe that, at the time our patient started taking the OTC supplements, he was likely insulinopenic in the setting of progressive hyperglycemia and a glucotoxic environment promoting β-cell dysfunction. However, available insulin secretion was sufficient to inhibit ketogenesis. It might be that with the surge of FA oxidation promoted by the “natural” supplements, coupled with declining insulin production caused by either glucose toxicity, β-cell–toxic effects of L-carnitine and dandelion root extract, or both, not all FAs were able to undergo β-oxidation, resulting in excessive formation and accumulation of ketone bodies. The presence of distorted processes of FA metabolism in this patient was supported by marked hypertriglyceridemia, suggesting that available insulin was insufficient to control hormone-sensitive lipase activity in the setting of advanced lipolysis induced by the weight loss therapy. Finally, excessive diuresis caused by the OTC weight loss therapy resulting in relative dehydration could have been another trigger of the development of DKA (2).

Clinical Pearls

• People with type 2 diabetes can develop DKA. In this situation, it is reasonable to screen all such patients for underlying β-cell autoimmunity. History of concurrent medication use is important because several prescription medications can precipitate DKA in type 2 diabetes.

• The risk-benefit profile of OTC medications used for weight loss is unknown in people with type 2 diabetes. Here, we described a case of DKA in a patient with type 2 diabetes who self-prescribed OTC weight loss treatments.

• People with diabetes should be encouraged to discuss initiation of OTC medications with their providers and report at any time or at least during regular clinic visits, if they have started any OTC medications since the last clinical encounter.