Module 5: Hypertension and Microvascular Disease in Diabetes

Physiologically, it is a reasonable approach but not yet approved by the FDA. Several studies show a modest benefit on A1c and weight, but this should still be considered “off label” use until we know more.

There is no known cause and effect. However, patients with autonomic neuropathy are prone to postural hypotension, and the abnormality can be greatly aggravated and augmented by beta blockers due to their negative effects on cardiac rate, cardiac contractility, cardiac output, and peripheral vasoconstriction.

Insulin requirements decrease often in patients with advancing renal disease, with the degree of decrease being variable. The decreased requirement is in part due to decreased clearance of insulin by the diseased kidney. The adjustment in insulin dosages must be individualized, because in some patients the daily requirement decreases to near zero, while in others a minor decrease in requirement is observed.

The decrease in renal function associated by the rise in creatinine due to mild to moderate dehydration (short of acute tubular necrosis) is considered reversible. Hence, the return of the creatinine and eGFR to normal levels signifies recovery. Metformin can be re-instituted.

The clinical definition of diabetes is based on the level of fasting or 2-hour postprandial blood glucose level, or Hgb A1c >6.5%. Based on this, the patient may be said to have no diabetes. However, based on pathophysiological considerations, it is worth remembering that at the time of diagnosis, the patient had lost >50% of his maximal beta-cell function, and there is no known experimental evidence that beta cells make a recovery. What he has accomplished by the healthy lifestyle, exercise, and weight loss is increased insulin sensitivity and decreased requirement for insulin. Under these conditions, his insulin secretion is now adequate for his metabolism. This issue has been studied to some extent in patients with weight loss secondary to bariatric surgery and apparent “cure” of T2DM. Here, the evidence suggests that there is no improvement or recovery of beta-cell function. Whether this is always true is unknown, and it is possible that some recovery of beta-cell function may occur during the early stages of the disease (soon after diagnosis). In keeping with this possibility is the recent finding that patients with relatively short duration of T2DM (less than 4 years) placed on a markedly hypocaloric diet (600 kcal/day) showed a remarkable recovery of beta-cell function to normal levels within 8 weeks. In summary, and on the positive side, what the above patient has accomplished is a delay in the recurrence of the clinical disease.

1. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009 Apr;58(4):773-95.
2. Schernthaner G, Brix JM, Kopp HP, Schernthaner GH. Cure of type 2 diabetes by metabolic surgery? A critical analysis of the evidence in 2010. Diabetes Care. 2011 May;34 Suppl 2:S355-60.
3. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia. 2011 Jun 9. [Epub ahead of print]

There are no definitive data to inform us on this question, nor is there solid data for the age. Given that the BP is on the low side, I would use lower doses of ACE inhibitors to decrease the possibility of clinically significant hypotension.

It is becoming increasingly evident that microalbuminuria is not a very strong predictor of diabetic nephropathy, but it is a risk factor for CVD and retinopathy. Some patients have microalbuminuria that reverts to normal levels over time. Other patients with diabetes and advancing renal disease do not have, and may have never had, albuminuria. In fact, there is a growing trend that the prevalence of diabetic nephropathy manifested by decreased eGFR without microalbuminuria is increasing in the United States. Based on current information, attention to trends in albuminuria as well as changes in eGFR is most prudent.

de Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss NS, Himmelfarb J. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA. 2011 Jun 22;305(24):2532-9.

There are no good uniform treatments for this disorder, and there is no solid data for efficacy of anticonvulsants. Frequent small portions and avoidance of high-fiber foods is helpful. Oral medications such as metoclopramide and erythromycin (to stimulate gastric muscles and hasten gastric emptying) are effective in some patients. Other agents and modes of therapy under study include antiemetics, mirtazapine (antidepressant), and gastric bypass surgery.

1. Gastroparesis. National Institute of Diabetes and Digestive and Kidney Diseases. http://digestive.niddk.nih.gov/ddiseases/pubs/gastroparesis/index.aspx
2. Fox J, Foxx-Orenstein A. Gastroparesis. The American College of Gastroenterology. http://www.acg.gi.org/patients/gihealth/gastroparesis.asp.
3. Waseem S, Moshiree B, Draganov PV. Gastroparesis: current diagnostic challenges and management considerations. World J Gastroenterol. 2009 Jan 7;15(1):25-37. Review.

The evidence is strong for control of BP in reducing CVD risk, but the evidence is less strong in favor of any particular class of medications. ARB medications could be considered. The ALLHAT trial reported that a thiazide diuretic (chlorthalidone) was superior to amlodipine, lisinopril, and doxazosin in prevention of CVD outcomes.

1. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 Dec 18;288(23):2981-97. Erratum in: JAMA. 2004 May 12;291(18):2196.
2. Cushman WC, Ford CE, Cutler JA, Margolis KL, Davis BR, Grimm RH, Black HR, Hamilton BP, Holland J, Nwachuku C, Papademetriou V, Probstfield J, Wright JT Jr, Alderman MH, Weiss RJ, Piller L, Bettencourt J, Walsh SM; ALLHAT Collaborative Research Group. Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens (Greenwich). 2002 Nov-Dec;4(6):393-404.

The established therapeutic approach to slow the progression of renal failure in diabetic patients with early renal disease is to control hypertension. Among the available medications, ACE inhibitors appear to be somewhat more effective. In the absence of hyperkalemia or other side effects, a higher dose of lisinopril (or addition of other antihypertension medications) for better BP control is advisable.

There are no definitive studies detailing the dose-response for use of ACE inhibitors for the prevention of renal disease in patients with diabetes. In the presence of hypertension and normal renal function, relatively higher doses may be used. In contrast, in the absence of hypertension or presence of diabetic nephropathy, more moderate or lower doses should be considered. Higher doses could be considered if albuminuria is present, even in the absence of hypertension.

Erythromycin is a macrolide antibiotic that is also a motilin receptor agonist. The oral dose is 125-250 mg 3 or 4 times daily to treat gastroparesis. Adverse effects at higher doses include nausea, vomiting, and abdominal pain. Erythromycin has limited data for use in gastroparesis. There was no significant difference in mean symptoms scores or any individual symptom in a randomized, double-blind, placebo-controlled trial of 12 patients.

Maganti K, Onyemere K, Jones MP. Oral erythromycin and symptomatic relief of gastroparesis: a systematic review. Am J Gastroenterol. 2003 eb;98(2):259-63. Review.