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Is the diagnosis latent or patent?
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 Ronald Tamler |
A 54-year-old white man came to my office because he was unhappy with his glycemic control. He was diagnosed with type 2 diabetes last year. However, it appeared that he probably had diabetes in 2004 when he was hospitalized for hyperglycemia and discharged without a diagnosis or medication.
The patient came to see me after starting sitagliptin 100 mg six months earlier, in addition to glipizide 10 mg twice a day and metformin 500 mg daily. He was experiencing worsening polydipsia and polyuria. He stated that he had lost 40 lb unintentionally since his diagnosis.
While he had initially responded to oral treatment, HbA1c from three months ago was elevated at 8.9%. The patient was testing his blood glucose levels regularly several times per day, with levels consistently in the 200s and 300s. He never experienced hypoglycemic events. The patient denied diabetic retinopathy or neuropathy.
Medical history relevant for hypothyroidism was diagnosed four years ago. His medications, in addition to glipizide, metformin, and sitagliptin: aspirin 81 mg, several multivitamins, and levothyroxinine 125 mcg daily. He had a family history positive for diabetes in the maternal grandfather, but no other family members had diabetes or other endocrine disease.
Pertinent physical findings: Lean white male in no acute distress, 145 lb, heart rate 80, blood pressure 134 mm Hg/90 mm Hg, BMI 21. Dry skin; remainder of the exam was completely unremarkable. Chem 12 is normal, LDL cholesterol elevated at 121, urine microalbumin normal.
What is wrong with this patient? What is your first step?
- He has poorly controlled type 2 diabetes due to insulin resistance. Gradually increase his metformin dose to achieve target HbA1c for type 2 diabetes of less than 6.5%.
- He has poorly controlled type 2 diabetes due to dietary indiscretion. Provide him with dietary counseling and see the patient in follow-up after three months.
- He has uncontrolled hypertension. Start lisinopril 10 mg daily for his blood pressure.
- He is in an insulin-deficient state. Test for ketones, start the patient on glargine, 12 U daily in your office and obtain tests for antibodies to islet cells and GAD-65.
- The patient has dyslipidemia. Start simvastatin 40 mg daily to achieve a target LDL cholesterol of less than 100 mg/dL.
CASE DISCUSSION
The correct answer is D. This patient has very poorly controlled diabetes despite treatment with three oral agents, with high blood glucose levels, polydipsia and polyuria. In addition, his weight loss suggests an insulin-deficient state. His lean habitus and history of hypothyroidism (quite possibly as a result of Hashimoto’s thyroiditis) suggest an autoimmune component at the core of this insulin-deficient state.
In a situation like this one, the patient should be tested for ketosis (with a urine dipstick or a serum sample). Some physicians will also obtain a C-peptide to demonstrate decreased insulin production, but I felt that it would not yield additional information in this particular case.
Autoimmune diabetes is now seen as a spectrum reaching from type 1 diabetes, with its traditional definition of rapid insulin-dependence in predominantly young patients, to LADA, latent autoimmune diabetes of adults. It is estimated that about 5% to 10% of all newly diagnosed patients with noninsulin dependent diabetes (thus initially labeled type 2 diabetes, as is the case here) have in reality LADA.
It is defined by three features: Adult age at onset (typically older than 30); diabetes-associated auto-antibodies (particularly against glutamic acid decarboxylase, GAD); and a delay from the onset of diagnosis until insulin is required for treatment.
At present, it is not exactly known what genetic or environmental factors might trigger LADA, but a lot of efforts have focused on the HLA region on chromosome 6. What is known, however, is that up to 94% of patients with LADA will require insulin treatment within six years after initial diagnosis of diabetes, as opposed to a mere 14% of patients with type 2 diabetes and no auto-antibodies.
There are no guidelines on how to treat LADA, but sulfonylurea treatment does not appear conducive to islet cell preservation. Metformin and TZDs have been successfully used as adjuncts in LADA and, together with incretin mimetics, may have benefits on islet cell preservation. The European Union has funded an initiative called ACTION-LADA in order to investigate this entity further and look into treatment options such as immuno-modulation.
In the meantime, what to do with our patient?
He did not test positive for ketones, but I started him on glargine, 12 U daily, right then in my office (which approximately correlated to his weight in kg * 0.2). A GAD-antibody came back highly positive at 33 U/ml a few days later; at that time, the patient was asked to return to our practice.
Even within the few days since initiating insulin therapy, he had started feeling better. The patient was taken off his oral medication and started on prandial insulin in addition to the glargine. His HbA1c three months later was 6.8%.
It should be noted that the patient should have been diagnosed with diabetes during his hospitalization, in 2004. Sadly, 12% of hospitalized patients have hyperglycemia without a diagnosis of diabetes, and many never get appropriate follow-up.
What about the other answers?
Answer A is invalid, because the patient’s symptoms clearly indicate a state of insulin deficiency. While the metformin is under-dosed, this patient will never achieve target HbA1c with just a dose increase. That’s why it he had to be started on insulin therapy right then in the office, no matter what the GAD and islet cell antibody tests would show.
Answer B is even less expeditious in dealing with the patient’s hyperglycemia and therefore an inappropriate course of action. While this patient’s blood pressure is indeed not quite at goal, the focus in this practice session had to be glycemic control.
The same can be said for his lipid levels. Triglyceride levels play a key role in the calculation of LDL cholesterol levels; they are typically elevated in uncontrolled hyperglycemia. The right course of action is to obtain a repeat fasting lipid profile at a time of better glycemic control and then opt for the appropriate treatment.
Ronald Tamler, MD, PhD, MBA is an Instructor in the Division of Endocrinology at Mount Sinai School of Medicine.