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I recently was asked to see a 46-year-old woman who was diagnosed with diabetes 11 years ago. When I walked into the room, I saw this nonobese Caucasian woman and her husband, who both greeted me with a handshake. She was concerned about her poor diabetes control: Her glycated hemoglobin (A1C) level had risen from 6.2% to 8.4% in just one year, which is why she was there. Her story fascinated me.
She was diagnosed with type 1 diabetes in 1996. Her overall glucose control during the past decade was for the most part good, with most of her A1C levels in the 6.5–7.4% range.
In 2006, her physician placed her on the angiotensin-converting enzyme (ACE) inhibitor enalapril (Vasotec, Merck) for "renal protection." She had no retinopathy. At the time, her A1C was 6.2% and she had no albuminuria, although from the records brought to me she had not been tested for microalbuminuria since 2004. It should be noted that her insulin dose had been decreased by 50%, she had lost 6.8 kg (15 lb) during the 6 months prior to starting the enalapril, and her blood pressure on the day the drug was prescribed was 100/64.
One week after starting the low-dose enalapril, our patient was brought to the local emergency room by her husband. Her blood pressure was 60 systolic, and her mental status, according to the progress note from the emergency room, was "stuporous." Intravenous saline and dextrose were started. Her initial capillary blood glucose measured at the bedside was 58 mg/dl. Her initial laboratory results revealed a serum sodium of 124 mEq/L (normal 136–145 mEq/L), and her potassium was 6.9 mEq/L (normal 3.7–5.2 mEq/L). Her electrocardiogram had changes consistent with hyperkalemia. The emergency room physician noted her entire body was hyperpigmented. He subsequently drew a serum cortisol (which later came back at 2.0 mg/dl; with this stress it should have been well over 20 mg/dl) and gave her 100 mg of intravenous hydrocortisone. Within a few hours her blood pressure, mental status, and blood glucose normalized. Within 24 hours her electrolytes were near normal.
This patient was successfully treated for Addisonian crisis by the very alert emergency room physician, but her presentation was exacerbated by the initiation of the ACE inhibitor. She survived, but during her recent visit I saw that she was being treated with large doses of prednisone and fludrocortisone (Florinef, Bristol-Myers Squibb). The high doses of the glucocorticoid were at least partially responsible for her poor control when I saw her.
Why did this happen? As the patient's husband noted to me, she was lucky to survive.
This episode is unusual, yet it is all related to the wealth of literature about the benefit of inhibiting the renin-angiotensin system in patients with diabetes.1 Clearly the use of both ACE inhibitors and angiotensin receptor-blockers (ARBs) are effective initial therapy for patients with hypertension, early diabetic nephropathy, or both.1
Yet, what data are available that indicate we should be putting alll patients with diabetes on one of these drugs?
Our patient was clearly unusual: She had early and undiagnosed Addison's disease, a fatal disease without appropriate therapy. In the past 17 years I have seen three deaths from undiagnosed Addison's disease in people with other autoimmune endocrinopathies (type 1 diabetes, Hashimoto's thyroiditis, and Grave's disease) in addition to celiac disease and vitiligo.
Most people put on prophylactic ACE inhibitors for renal protection do
fine. Indeed, the MICRO-HOPE trial published in 2000 showed that in diabetic
patients 
55 years old, use of the ACE inhibitor ramipril (Altace, King)
significantly reduced the combined outcome of myocardial infarction, stroke,
or cardiovascular death by
25%.2 But does that
study of individuals with mostly type 2 diabetes relate to our younger patient
with type 1 diabetes where the drug was started for "renal
protection"?
To me, the issue is that each patient needs to be evaluated individually. ACE inhibitors (and ARBs) have enjoyed well-deserved popularity, as their use has revolutionized the treatment of both hypertension and diabetic renal disease. But that doesn't mean all patients should be placed on them. Our patient, while at low risk for renal disease, was placed on an agent that is usually quite safe. Yet we need to balance benefits versus risks every day in clinical practice.
Due to numerous studies, we now are using statins even more frequently than ACE inhibitors or ARBs. The 2007 Clinical Practice Recommendations from the American Diabetes Association note that for all individuals with diabetes >40 years, statin therapy should be used to reduce LDL cholesterol by 30–40% regarddless of baseline LDL level.2 While I try to get as many of my >40-year-old patients as possible on statins, some have side effects as—like all drugs—they are not totally benign. Similar comments can be made about aspirin therapy, also generally recommended for people with diabetes >40 years.2 Yet not all people can tolerate aspirin, statins, or certainly ACE inhibitors.
But our patient is a bit different in that, as opposed to the statin and aspirin recommendation, we have no randomized controlled trial for the prevention of diabetic renal disease with the use of the ACE inhibitor. The well-intentioned physician assumed it to be protective, but I'm not aware of any studies looking at normotensive patients with relatively good glucose control using any drug for the prevention of this complication. To my knowledge, there are no recommendations by any diabetes or kidney society for renal protection with ACE inhibitors for a normotensive patient. Yet, based on the strong data, physicians do this all the time for patients with renal disease or albuminuria.
My guess is, if a study were done with high-risk patients with poor glucose control, especially with a family history of hypertension, an ACE inhibitor or ARB prophylaxis would prove beneficial. But that is speculation. Without the data, all I know for sure is that the best way to prevent microvascular disease is with meticulous glucose control and certainly blood pressure control if hypertension develops.
In the meantime, all of us need to be cautious when starting a patient on
any pharmacological agent, particularly when data don't exist for its use. A
history and physical exam may well have discovered our patient's Addison's
disease before she became so ill. The good news is she is doing well now. But
it was an important lesson for me to recall what we were all taught in our
training: "First, do no harm." 
Footnotes
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References
2. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators: Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. Lancet 355:253–259, 2000.[Medline]
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