P&T News: June 1997

Use of Ace Inhibitors in Prevention of Renal Disease: Focus on Diabetic Nephropathy

Jane C. Chandramouli, Pharm.D. and John B. Stokes, M.D.
Internally Peer Reviewed by Lawrence G. Hunsicker, M.D. and William I. Sivitz, Associate Professor

Diabetes is the leading underlying cause of end-stage renal disease (ESRD) in the United States.¹ Patients with diabetes or hypertension account for more than 60% of new cases of ESRD.² About 20 to 40% of insulin dependent diabetics (Type I DM) will develop ESRD and 10 to 20% of non-insulin dependent diabetic patients (Type II DM) will develop ESRD.³ Recent studies have demonstrated that the onset and course of diabetic renal disease can be ameliorated to a very significant degree by several interventions.¹ The published clinical guidelines on diabetic renal disease recommend strict glucose control, treatment of hypertension primarily with angiotensin converting enzyme (ACE) inhibitors, smoking cessation, and the management of hyperlipidemia.¹

The cost of providing dialysis for uremic diabetic patients in the U.S. exceeded $2 billion in 1990.⁴ These costs are only going to increase, as the incidence of diabetic ESRD increases between 13 to 18% per year and hypertensive ESRD increases between 10 to 23% per year.² Preventing or delaying the sequelae from diabetes could lead to significant health care cost savings. While the ACE inhibitors are fairly expensive, their cost may be offset by a delay or prevention of dialysis treatment and a delay of diabetic complications.

The purpose of this review is to discuss the clinical application and importance of ACE inhibitor use in patients with renal disease and to review the recommended guidelines for screening, monitoring, and treating patients with diabetic nephropathy.

Diabetic Nephropathy

Diabetic nephropathy, the most common form of renal disease in diabetics, is defined as the appearance of proteinuria, elevated arterial blood pressure, and diminished glomerular filtration rate (GFR).^5,6 In Type I DM the appearance of clinically detectable microalbuminuria (>30 mg/day) signals the onset of the progression of diabetic nephropathy. The usual course of diabetic nephropathy progresses from microalbuminuria (urinary albumin excretion rate 30 to 300 mg/day) to proteinuria (urinary protein excretion > 300 mg/day) to nephrotic syndrome (>2.5 grams/day) to ESRD (urinary protein excretion rate declining because of decreased number of functioning nephrons).⁷ It is important to note that once a patient reaches overt diabetic nephropathy intervention can slow - but not reverse - the progression to renal failure. Table 1 reviews the different stages of diabetic renal disease in insulin dependent diabetes.

The clinical course of diabetic nephropathy in patients with Type II DM is less predictable than for patients with Type I DM. This variability reflects differing degrees of severity as well as an often insidious onset. Whereas the onset of Type I DM is usually dramatic with polyuria, polydipsia, and often ketosis, patients with Type II DM might be hyperglycemic for years with minimal symptoms. Greater than 30% of newly diagnosed Type II DM patients will have microalbuminuria, and 6% will have clinical proteinuria.⁸

Table 1. Stages of Renal Disease in Type I Diabetes Mellitus Patients9
Stage	Characteristics	Primary Structural Changes	Glomerular Filtration Rate	Urinary Albumin Excretion	Blood Pressure
I and II	Glomerular hyperfiltration; normal urinary albumin excretion	Glomerular hypertrophy (increasing basal membrane thickness)	Hyperfiltration 150 to 200 ml/min	Normal	Normal
III	Raised urinary albumin excretion (microalbuminuria)	Urinary albumin excretion correlated to structural damage	Normal to slightly elevated 130 to 150 ml/min	30 to 300 mg/day	Raised compared to stages I and II
IV	Urinary albumin excretion >300 mg/day (overt nephropathy)	Advanced structural damage	Usually reduced < 100 ml/min	> 300 mg/day	Hypertension (increase by ~ 5% yearly)
V	Uremia and ESRD	Extensive fibrosis	Very Low ~ 10 ml/min	Decreasing albuminuria	Often high, related to volume expansion

Pathogenesis and Risk Factors

Currently, it is believed that hyperglycemia, systemic hypertension, altered renal hemodynamics, and genetic predisposition play important roles in the pathogenesis of diabetic nephropathy.¹⁰

Persistent hyperglycemia causes intraglomerular hypertension and renal hyperperfusion.¹¹ An increased responsiveness to the vasoconstrictor effects of angiotensin II also increases glomerular capillary pressure.¹² Glomerular hyperfiltration results primarily from increased renal plasma flow and increased glomerular capillary pressure secondary to decreased afferent arteriolar resistance, increased efferent arteriolar resistance, and loss of renal autoregulation.^5,13 The hemodynamic changes together with the continued effects of elevated glucose produce changes which alter the permeability of glomerular capillaries to protein resulting in proteinuria and ultimately causing mesangial matrix expansion and thickening of the glomerular basement membrane (glomerulosclerosis).⁵ As the number of functioning nephrons decrease, compensatory afferent arteriolar vasodilation occurs in the remaining nephrons.

The Diabetes Complications and Control Trial demonstrated that optimizing glycemic control reduced the progression of diabetic nephropathy.¹⁴ Intensively-treated Type I diabetics (mean HgA1c 7.1%) had over the interval of the trial a 50% reduction in progression to diabetic nephropathy (defined as the appearance of microalbuminuria) compared with those who had less strict glycemic control (mean HgA1c 9.1%).¹⁴ Although many practitioners believe that similar risk reductions will be achieved in Type II DM patients, there are little supporting data.

Hypertension also contributes to the progression of diabetic nephropathy. Laffel et al found that the rate of decline in renal function is proportional to the level of blood pressure in patients with diabetes and proteinuria.¹⁵ Usually an increase in blood pressure appears before a major decline in GFR, but it may not precede the onset of albuminuria. Renal vasodilation allows for greater transmission of systemic elevations in pressure to the glomerulus and may further exaggerate the glomerular capillary hypertension. Pharmacologic measures to prevent diabetic nephropathy should focus on controlling systemic BP and intraglomerular pressure. The fifth report of the Joint National Commission on Detection, Evaluation, and Treatment of High Blood Pressure states that blood pressure for patients with diabetes should be no more than 130/85 mmHg.

Appropriate antihypertensive intervention can significantly increase the median life expectancy in Type I DM patients, with a reduction in mortality from 94% to 45%, and the reduction in the need for dialysis from 73% to 31%, 16 years after the development of overt nephropathy.¹

Because not all patients with diabetes develop nephropathy, it is suggested familial or genetic factors also play a role.10 Factors providing evidence that there is a genetic susceptibility for the development of diabetic nephropathy include: 1) familial clustering of nephropathy; 2) the association between nephropathy and a family history of hypertension; and 3) the similarity of renal lesions in diabetics siblings. Furthermore, certain ethnic groups, particularly African Americans, Hispanics, and Americans Indians seem predisposed to renal disease as a complication of diabetes.

Clinical Experience with ACE Inhibitors in Diabetic Nephropathy

ACE inhibitors affect many of the components involved in the evolution of diabetic nephropathy. These agents control systemic hypertension leading to a lowered pressure in the afferent arteriole and a concomitant reduction in hyperperfusion. Furthermore, they dilate the efferent arteriole leading to a reduction in intraglomerular pressure and thus hyperfiltration. The reduction of hyperfiltration seen with ACE inhibitors in diabetic nephropathy is not only a result of their effect on systemic hypertension. In studies using hypertension patients, an additional reduction in proteinuria is evident with ACE inhibitors compared with other antihypertensive agents where equal BP lowering was achieved.^5,13 ACE inhibition has also been shown to attenuate mesangial matrix expansion. Angiotensin II, along with other cytokines, acts as a modulator of cell proliferation and size; inhibition of angiotensin II production by ACE inhibitors in experimental renal disease decreases proteinuria, reduces histologic evidence of renal damage, and slows the progression of renal failure.^16-19

Studies in both Type I DM and Type II DM patients demonstrate that ACE inhibitors reduce or stabilize microalbuminuria, reduce proteinuria, and slow the progression of nephropathy.^9,21-24 Data for use of ACE inhibitors in patients with overt nephropathy and declining GFR are somewhat more compelling than for ACE inhibitor use in patients with microalbuminuria. The relatively weaker case for ACE inhibitor therapy at this earlier stage derives largely from the need to use more indirect markers of efficacy, such as progression of microalbuminuria rather than declining GFR. This is because GFR has usually not begun to fall at this stage. However, ACE inhibitor use in patients with microalbuminuria does reduce albumin excretion rate and blunt the risk of progression to greater levels of albuminuria.

The Collaborative Study Group compared captopril 25 mg three times daily with placebo in a randomized trial of 409 patients with insulin-dependent diabetes and proteinuria in excess of 500 mg daily.²³ The median follow-up was three years and the primary end-point was doubling of baseline serum creatinine. Mean rate of decline in creatinine clearance (CrCl) was 11% per year in the captopril group versus 17% in the placebo group (p=0.03). Captopril delayed time to doubling of serum creatinine concentration, and therapy was associated with a 50% reduction in the risk of combined end-points of death, dialysis, and kidney transplantation. 

Ravid et al evaluated the long-term stabilizing effect of ACE inhibition on plasma creatinine and on proteinuria in normotensive Type II DM patients.²⁴ Ninety-four normotensive patients with microalbuminuria and normal renal function (serum creatinine <1.4 mg/dl) were randomized to receive enalapril 10 mg daily or placebo and were followed for seven years. In the enalapril treated group, albuminuria and serum creatinine remained stable while the placebo group had an increase in albuminuria and a decline in renal function. Overall, treatment with enalapril resulted in an absolute risk reduction of 42% (p<0.001) for nephropathy to develop during these seven years. 

Table 2 summarizes the use of ACE inhibitors in diabetic renal disease. The results of the above trials, taken together with other clinical and experimental data, suggest that all Type I DM patients with microalbuminuria should be treated with an ACE inhibitor even if they are normotensive. Because of the high prevalence of hypertension, potentially contributed to by insulin resistance, and the greater coexistence of atherosclerotic vascular disease and renal disease in Type II DM patients, treatment of hypertension may be more difficult compared to Type I DM patients.3,10 However, it appears reasonable to use ACE inhibitors as first line antihypertensive agents in these patients as the benefits demonstrated in Type I DM seem likely to accrue in this population also.³ 

ACE Inhibitor Use in Other Types of Renal Disease 

In addition to the studies evaluating the use of ACE inhibitors in patients with renal disease due to diabetes mellitus, a series of reports has described similar findings with ACE inhibitors in patients with various forms of renal disease.^37-40 

A recent study demonstrated that benazepril protected against the progression of renal insufficiency in patients with various renal diseases, including glomerulopathies, interstitial nephritis, nephrosclerosis, and diabetic nephropathy. Maschio et al evaluated whether benazepril was effective in slowing the progression of renal dysfunction in patients with mild to moderate renal insufficiency.²² In this double-blind study, 583 patients were randomized to receive benazepril or placebo. The primary end-point was a doubling of the base-line serum creatinine concentration or the need for dialysis. At three years, 31 patients in the benazepril group and 57 in the placebo group had reached the primary endpoint (p<0.001). The overall risk reduction was 53% (71% in patients with mild chronic renal insufficiency and 46% with moderate renal insufficiency). However, beneficial effects were not observed in patients with polycystic kidney disease. Again, only a portion of the benefit could be explained by the drug's antihypertensive action, suggesting that the blockade of the renin-angiotensin system per se is largely responsible for renoprotection in these patients. Patients with substantial proteinuria received the greatest benefit, as was similarly reported with captopril and enalapril. Table 3 summarizes the use of ACE inhibitors in other renal diseases.

Table 2. ACE Inhibitor Trials in Diabetic Patients
Study	Duration (months)	N	Blood Pressure	Treatment	Mean GFR		Mean Urinary Albumin Excretion		Comments
					Initial ml/min/1.73m	Change ml/min/1.73m2	Initial mg/day	Therapy mg/day
Type I Diabetes Mellitus
Björk et al25	28	40	hypertensive	Enalapril	46	2ml/min/yr	1600	600	Urinary albumin excretion (UAE) was 60% lower during treatment with enalapril than metoprolol.
				Metoprolol	48	5.6ml/min/yr	1400	1500
Parving et al26	27	31	hypertensive	Captopril	98	5.8ml/min/yr	1410	560
				Placebo	96	10ml/min/yr	1350	1970
Mathiesen et al27	48	44	normotensive	Captopril	126 ml/min	1.4ml/min/yr	82	57	7 pts in control group progressed to DN versus 0 in captopril group,P<.05
				Placebo	129 ml/min	0.6ml/min/yr	105	166
Viberti et al28	24	92	normotensive	Captopril	124	no change	75	59	12 pts in placebo and 4 in captopril group had UAE > 30% from baseline (p=0.05). Probability of progression reduced by captopril (p=0.03).
				Placebo	136		75	109
Laffel et al29	24	143	normotensive	Captopril	80	0.9ml/min/yr	80	17.9%
				Placebo	80	4.9ml/min/yr	89	11.8%
Lewis et al23	36	409	75% hypertensive	Captopril	84 ml/mm	11%/yr	2500		UAE decreased in treated groups compared to placebo (p=0.001); 50% risk reduction for death, dialysis, transplantation.
				Placebo	79 ml/mm	17%/yr	3000
Type I and II Diabetes Mellitus
Marre et al30	12	20	normotensive	Enalapril	131	124	<300		UAE decreased in treated group compared to placebo (p<0.001).
				Placebo	129	109	<300
Bauer et al31	18	33	22/33 pts hypertensive	Enalapril	61	51	2.8g/g creatinine/day	1.4g/g creatinine/ day	61% in enalapril group and 66% in placebo had a decrease in GFR. UAE was reduced by 33% in enalapril group whereas placebo had no effect (p<0.05).
				Placebo	64	58	2.1	1.77
deJong et al 32	3	18	hypertensive	Lisinopril	29 ml/min	23 ml/min	4200	2300
Keilani et al33	3	26	hypertensive	Fosinopril	55ml/min	2.4 ml/min	5600	4280	Study showed decrease in UAE, total cholesterol, LDL-cholesterol, and lipoprotein a levels p<0.05.
				Placebo	66 ml/min	3.6ml/min	5110	4820
Type II Diabetes Mellitus
Valvo et al34	6	12	hypertensive	Captopril	57	51	4500	3400
Lacourciere et al35	36	74	19/74 hypertensive	Captopril	99**	93	86	30	UAE reduced at 3 years only in captopril group with microalbuminuria (p<0.05); no change in either group in pts without microalbuminuria (**data shown for pts with microalbuminuria only).
				Metoprolol	87	86	66	78
Nielson et al 36	12	35	hypertensive	Lisinopril	75	64	961	414	UAE reduced 45% with lisinopril vs. 12% with atenolol (p<0.05); GFR declined identically between groups.
				Atenolol	74	63	1578	1507
Ravid et al24	84	94	normotensive	Enalapril		no change	143	140	42% risk reduction to develop DN in treated group. (p<0.001).
				Placebo		13% at 5 years; 16% at 7 years	123	310
N = Number of patients DN = diabetic nephropathy pts = patients

Table 3. Studies Using ACE Inhibitors in Non-Diabetic Renal Disease
Reference	Drugs	Nature of Trial	Duration (months)	# of Pts	Proteinuria	Blood Pressure	Comments
Maschio et al22	Benazepril 10 mg/d	double-blind, placebo controlled, randomized	36	88	reduced	hypertensive	57 pts in placebo group and 31 pts in benazepril group had doubling of serum creatinine (p<0.001).
Ihle et al37	Enalapril 5 mg/d	double-blind, placebo controlled, randomized	24	31	reduced	hypertensive	Enalapril reduced rate of decline of GFR (p=0.038), reciprocal plasma creatinine (p=0.017), or CrCl (p=0.031).
Hannedouche38	Enalapril 5 to 10 mg/d or beta blocker	open, randomized	36	100	reduced for first year only	hypertensive pts had chronic renal failure	19% in enalapril group and 35% in other treatment group progressed to ESRD (p<0.05).
Kamper39	Enalapril, (mean 6.9 mg/d)	open, randomized	24	70	reduced	mixed	Progression from nephropathy to uremia was slower in enalapril group.
Bedogna et al40	Benazepril 10 mg/d	randomized, placebo-controlled	3	10	reduced	normotensive	Degree of reduced urinary albumin excretion was not consistent.

Caveats to ACE Inhibitor Use

Despite the proven importance of ACE inhibitor therapy, several important clinical issues remain. These include use in patients with renal dysfunction and borderline hypotension, management of hyperkalemia, and ACE inhibitor-induced cough.

Renal Dysfunction
Worsening of baseline renal function is often a frequent concern when initiating ACE inhibitor therapy. ACE inhibitor-induced increases in serum creatinine is usually a reversible phenomenon; serum creatinine will return to baseline once the drug is discontinued. If the serum creatinine at baseline is 3.0 mg/dl or greater, the current recommendation is to titrate the ACE inhibitor slowly to one-half the usual recommended maintenance dose. The studies by Ihle,³⁷ Maschio²², and Lewis²³ demonstrate the beneficial effects of ACE inhibitors in patients that already have increased serum creatinine. The concern of worsening baseline renal function should be weighed against the benefits in preserving renal function with ACE inhibitors.

Circumstances in which the patient would be at risk for developing acute renal failure if started on an ACE inhibitor include bilateral renal artery stenosis, congestive heart failure, or moderate to severe intravascular volume depletion (e.g., diuretics). In these situations, glomerular filtration is maintained by efferent arteriolar vasoconstriction which is disrupted by ACE inhibitors.⁴¹ 

Hyperkalemia
Suppression of adrenal aldosterone release caused by ACE inhibitors may lead to hyperkalemia. This adverse effect rarely occurs in patients with normal renal function. Risk factors for development of hyperkalemia include renal dysfunction, concomitant use of potassium supplements, potassium sparing diuretics, nonsteroidal anti-inflammatory drugs, or salt substitutes.^42,43 In patients with renal dysfunction, close monitoring of serum potassium levels is warranted. ACE inhibitors should not be instituted when the serum potassium is 5.5 mEq/L or greater.

Cough
The most common adverse effect associated with ACE inhibitors is a persistent nonproductive cough. Although various manufacturers report the incidence of cough to be low, the incidence reported in clinical studies varies between 5% and 20%, and some investigators report rates of up to 33%.⁴⁴ Most studies have found the same frequency of cough among the various ACE inhibitors, with no clear relationship between dose and response. A few anecdotal reports have suggested that cough disappears after switching to another ACE inhibitor.^45,46 However, this practice has not been adequately studied. The cough can develop within days, have a delayed onset of up to 20 months, disappear within 3 to 4 days after the drug is stopped, or take up to 12 weeks to resolve completely. Because of the beneficial effects of ACE inhibitors, some authors are recommending cough prophylaxis with cromolyn sodium.⁴⁷ However, more controlled studies are needed to support this practice.

While Angiotensin II receptor blockers such as losartan or valsartan have not been studied yet for their effect in protecting renal function in diabetic patients, it is reasonable to try these agents in patients who cannot tolerate an ACE inhibitor because of cough.

Management Guidelines for Diabetic Nephropathy

Measures to prevent diabetic nephropathy are focused on the metabolic and hemodynamic abnormalities that contribute to the progression of kidney damage. Table 4 describes the American Diabetes Association recommendations for the management of diabetic nephropathy. Appropriate screening of diabetic patients for diabetic nephropathy is also important as many patients are clinically asymptomatic in early stages of diabetic nephropathy. Currently, the American Diabetes Association and the National Kidney Foundation recommend that screening for microalbuminuria be initiated in patients who have had Type I DM for at least five years and are greater than 14 years old. Because of the difficulty in determining the precise onset of Type II DM, screening for these patients should begin at the time of diagnosis. Follow-up screening for each group should be done annually.

Table 4. Management of Diabetic Nephropathy1,48 Intensive diabetes management with the goal of achieving normoglycemia; goal of preprandial glucose concentrations to be < 120 mg/dl and postprandial concentrations to be < 180 mg/dl; Lowering blood pressure in hypertensive individuals to < 130/85 mmHg; Use of ACE inhibitors in patients with microalbuminuria or clinical albuminuria; Smoking cessation; Yearly screening for urine albumin in all postpubertal patients who have had Type I DM for at least 5 years and in all patients with Type II DM; Institution of protein restriction to 0.8 gm/kg/day with the onset of overt nephropathy; and Management of hyperlipidemia.

Summary

Because of their efficacy as antihypertensive agents and since clinical studies have demonstrated their benefit in retarding the progression of diabetic nephropathy, ACE inhibitors are recommended as the primary treatment of all hypertensive diabetic patients with microalbuminuria. In normotensive Type I DM patients, the optimal time to initiate an ACE inhibitor is not clear, although an argument can be made for initiating therapy when microalbuminuria is evident. There is little argument regarding the benefits in patients with overt albuminuria and or diabetic nephropathy. The benefits of treating Type II DM patients with ACE inhibitors is not completely established. However, based on the results in patients with Type I DM and the results in patients with other types of chronic renal insufficiency, ACE inhibitor therapy in patients with Type II DM is reasonable.

No compelling evidence suggests that any particular ACE inhibitor is better than another in retarding diabetic nephropathy. The effect of ACE inhibitors appears to be a class effect, so choice of agent may depend more on cost and compliance issues, rather than therapeutic outcome. Also, ACE inhibitors as a class perform better than other agents, even with similar lowering of arterial pressure.

Overall efforts to maintain euglycemia, lower blood pressure to < 130/85 mmHg, use ACE inhibitors in patients with microalbuminuria, manage hyperlipidemia, and stop smoking are most likely to be rewarded by prevention or slowing the progression of diabetic nephropathy, and should reduce extra renal vascular injury as well.

References

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2. Am J Kid Dis 1997;29:368-75.

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7. Ann Pharmacotherapy 1993;27:344-50.

8. Diabetologia. 1993;36:1007-16.

9. Br Heart J 1994;72(Suppl):S38-45.

10. Rosenberg M, Correa-Rotter R. Pathogenesis and Risk Factors for Diabetic Nephropathy. In: Jacobson et al. Principles and Practice of Nephrology. St Louis: Mosby; 1997: 330-51.

11. N Engl J Med. 1995; 332:1210-7.

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18. J Clin Invest 1986;77:1925-30.

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21. Ann Pharmacotherapy 1996;30:791-801.

22. N Engl J Med 1996;334:939-45

23. N Engl J Med 1993;329:1456-62.

24. Ann Intern Med 1993; 118:577-81.

25. Br Med J 1992; 300:904-7.

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32. Nephron 1990; 55(Suppl 1):43-8.

33. Ann Intern Med 1993;118:246-54.

34. Am J Med 1988;85:344-8.

35. Hypertension 1993;21:786-93.

36. Diabetes 1994;43:1108-13.

37. Am J Kid Dis 1996;27:489-95.

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39. Am J Hypertens 1992; 5:423-30.

40. Kidney Int 1990;38:101-7.

41. Ann Pharmacother 1993;27:205-10.

42. Drug Safety 1995;12:334-47.

43. Clin Pharmacokinet 1993;25:20-58.

44. Eur Heart J 1994; 15(Suppl C): 52-6.

45. Am J Cardiol 1993;72(Suppl H):45-8.

46. Ann Pharmacother 1994;28:720-1.

47. Ann Pharmacother 1997;31:773-5

48. Diabetes Care 1997; 20(Suppl 1):S5-13.

The manufacturer of lamotrigine (Lamictal®-Glaxo Wellcome) has issued a "Dear Doctor" letter warning healthcare professionals of severe, potentially life-threatening reactions.

These new warnings concern reports of severe, potentially life-threatening rash, including Stevens-Johnson syndrome, and rarely, toxic epidermal necrolysis, reported in association with the use of lamotrigine. Clinical trials have shown that the rate of developing a potentially life-threatening rash in pediatric patients is 1 in 50 to 1 in 100 pediatric patients, compared to 1 in 1000 adult patients. The revised labeling includes a boxed warning emphasizing that lamotrigine is not indicated for use in patients less than 16 years of age.

Most cases of life-threatening rashes associated with lamotrigine therapy have occurred within two to eight weeks of initiation of therapy. However, isolated cases have been reported after prolonged treatment (e.g., 6 months). Benign rashes can also occur, but it is not possible to predict reliably which rashes will become life-threatening. Lamotrigine therapy should be discontinued at the first sign of rash. Unfortunately, stopping lamotrigine therapy may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring.

Hypersensitivity reactions have also occurred with lamotrigine therapy; some reactions have been fatal or life-threatening. These reactions have included clinical features of multiorgan dysfunction such as hepatic abnormalities and evidence of disseminated intravascular coagulation. Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may present even without a rash. If such signs and symptoms are present, the patient should be evaluated and lamotrigine therapy discontinued if an alternative etiology for the signs and symptoms cannot be established.

Prior to initiating therapy with lamotrigine, the patient should be instructed to report any signs or symptoms of rash or hypersensitivity (e.g., fever, lymphadenopathy) to their physician immediately.

Source: Glaxo Wellcome
March 1997

Protease Inhibitor-Induced Diabetes Mellitus and Hyperglycemia

The FDA has received reports that protease inhibitors [e.g., indinavir (Crixivan®-Merck), saquinavir (Invirase®-Roche), ritonavir (Norvir®-Abbott), and nelfinavir (Viracept®-Agouron) ] may be infrequently associated with increases in blood glucose and even diabetes in HIV patients.

The FDA has received 83 reported cases of diabetes mellitus or hyperglycemia in patients receiving protease inhibitor therapy as of May 12, 1997. Twenty-seven of the 83 cases required hospitalization. Fourteen patients were known diabetics who had a loss of glucose control. The average time to onset was approximately 76 days after initiating therapy with a protease inhibitor, but loss of glucose control occurred as early as four days after starting therapy. Five cases of diabetic ketoacidosis have occurred, including patients not reported to have diabetes at baseline.

Some patients have required initiation or adjustment of their insulin or oral hypoglycemic agents for the treatment of increased blood glucose. While many patients who discontinued protease inhibitor therapy saw a reduction in their symptoms, a clear causal relationship between the drugs and the onset of hyperglycemia or diabetes has not been established.

HIV patients on protease inhibitor therapy should be counseled on the warning signs of hyperglycemia and diabetes: increased thirst and hunger, unexplained weight loss, increased urination, fatigue, and dry, itchy skin. Patients should also be instructed not to stop protease inhibitor therapy without consulting with a healthcare professional. 

Source: FDA Public Health Advisory
June 11, 1997

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