Weighing down the kidney
At least three out of ten diabetic patients will have nephropathy
In a short time people's reactions toward warnings could degenerate from serious fear to polite curiosity to utter apathy. Desensitization could set in too easily that sometimes even the most serious of issues would only be met with blasé expressions, if not altogether ignored.
Consider the usual warnings about diabetes mellitus: that the so-called life-style diseases have taken over infectious diseases in terms of incidence; that since lifestyle diseases easily hook up with one another the resultant complications can get exponentially more serious; that once diabetes sets in reversal is downright impossible.
Information that warrants serious attention, true, but how to make people feel it? And to those who have heard it over and over, how to make them feel it again? Doctors, researchers, and other health advocates may very well be modern-day Cassandras: their predictions are often disregarded, until they are proved right.
Now if people don't consider it as mere medical apocalypticism, the view that diabetes and its attendant complications, particularly diabetic nephropathy, are now a "world pandemic" would hopefully generate rightful attention. Dr. Robert Charles Atkins, president of the International Society of Nephrology, spoke about this at the 14th Asian Colloquium of Nephrology hosted November last year by the Philippine Society of Nephrology.
Atkins said that in the next seven years, the number of type 2 diabetics all over the world could easily jump to 221 million-twice the 1995 figure of 110 million. A recent epidemiological study conducted in Australia called AusDiab showed 7.5 percent of adults-half of whom are undiagnosed-are diabetics. The study also yielded data that are likely to influence future trends in diabetes: 16 percent of Australians have impaired glucose tolerance, 60 percent are overweight, 29 percent are hypertensive. "Thus, one in [every] four Australian adults had impaired glucose metabolism and at risk [of] diabetic nephropathy," he explained. "This would be representative of other developed countries…[but] the greatest rise in prevalence over the next decade will be in developing countries."
Diabetologist Rima Tan of the Far Eastern University cited in a press conference in February that a study pointed to a diabetes prevalence of nine percent among Singaporeans, with Singaporean Indians being the hardest hit (15.8 percent) and Singaporean Chinese with the lowest pre-valence (eight percent). 11.3 percent of Singaporean Malays have diabetes. This fact may give people a rough idea of the diabetes situation in the country, although a 1998 study conducted by the Philippine Society of Hypertension, Philippine Lipid Society, and the Food and Nutrition Research Institute points to a 2.8 million prevalence, or only about four percent.
These are huge numbers, but what do they mean? The World Health Organization projects that the global diabetes situation will more than double in the next 30 years. If the growth of Philippine population continues the trend it exhibited between 1995 and 2000-2.36 percent annually-the Commission on Population projects that there may be 150 million Filipinos by 2030. If the Philippine situation mirrors the expected diabetes situation in 2030, there will be between 12 million and 33 million Filipino diabetics. These are the populations of medium-sized countries.
Atkins said that 30 to 50 percent of diabetics develop microalbuminuria within 10 years and overt diabetic nephropathy in 20 years. Given that proteinuria among DM patients has a significant bearing on patient survival as well as their risk of cardiovascular disease, uncontrolled microalbuminuria leads inexorably to outright diabetic nephropathy and then to end-stage renal disease (ESRD)-if they don't die first of cardiovascular complications. Says Atkins: "If you double your proteinuria, you double your risk of progressing to ESRD. Similarly, if you halve your proteinuria, you halve [that] risk." The decline in renal function becomes even more staggering if uncontrolled microalbuminuria is coupled with such manageable factors as poor glucose and blood pressure control and smoking. And once microalbuminuria progresses to proteinuria, there is almost no hope of reversing the decline.
The above shows the necessity of preventing the appearance of early signs of nephropathy by controlling the diabetes itself. It has been proved that the le-vels at which blood sugar is controlled significantly contribute to the diminution of the appearance of microalbuminuria. In other words, consistently keeping blood sugar at normal or near-normal levels means a decreased possibility of suffering from nephropathy, not to mention ESRD. This is especially true among type 1 diabetics, as shown by the landmark Diabetes Control and Complications Trial, although recent data show that the same benefits could be seen among type 2 diabetics.
Aside from blood sugar control, blood pressure control has also shown to be a very effective way in preventing end points, including death. The United Kingdom Prospective Diabetes Study (UKPDS), one of the most important diabetes studies to be conducted, showed that maintaining blood pressure at normal levels significantly reduces the development of microvascular and ma-crovascular complications. In fact, blood pressure control has greater benefits than glycemic control. These findings, together with the results of other studies showing the same benefits, prompted the American Diabetes Association to say that blood pressure lowering should be on the first line of diabetes management.
Cardiologist Eugene Reyes of the University of the Philippines-Philippine General Hospital, in a press conference in February, said that cardiologists should "consider diabetic patients as heart di-sease patients." Tan agreed, adding that since 80 percent of diabetics die of either a myocardial infarction or stroke, diabetes should be seen as a vascular disease.
Although different blood pressure-lowering agents have shown efficacy in the prevention of complications especially nephropathy among diabetics, the agents that have received considerable attention in recent years are the angiotensin-II-receptor blockers. This relatively new class of drugs selectively keeps angiotensin II from binding to angiotensin II receptors located in different areas, such as the kidney and blood vessels. Since angiotensin II is a vasoconstrictor, blocking it will result in the dilation of blood vessels and thus lower blood pressure.
Delaying the Game
Among the recent wide-scale studies to investigate the effects of blood pressure-lowering with the use of ARBs in diabetic nephropathy is the PRogram for Irbesartan Mortality and morbidity Evaluation (PRIME), the results of which were initially unveiled at the 16th scientific meeting of the American Society of Hypertension (ASH) in San Francisco in May 2001, and subsequently published by the New England Journal of Medicine in September of the same year. PRIME investigated the effect of the ARB irbesartan in two stages of diabetic nephropathy-one in early diabetic nephropathy/microalbuminuria (IRbesartan MicroAlbuminuria type II diabetes mellitus in hypertensive patients, or IRMA II) and another in late diabetic nephropathy (Irbesartan Diabetic Nephropathy Trial, or IDNT).
In IRMA II, a total of 590 hypertensive patients with type 2 diabetes and persistent microalbuminuria were randomly assigned to irbesartan 150mg daily, irbesartan 300mg daily, or placebo groups. Over a period of two years, the progression of microalbuminuria to outright nephropathy was observed, and it turned out that patients on irbesartan had reduced albumin excretion-a 38-percent reduction among those on irbesartan 300mg, 24-percent reduction among those on irbesartan 150 mg, and a two-percent reduction among those on placebo. This became apparent in the third month of follow-up, and the divergence became wider as the study progressed.
The return of albumin levels to normal (urinary excretion of less than 20µg per minute) was also observed to happen in the irbesartan 300mg group (34 percent) compared with irbesartan 150mg and placebo (24 percent and 21 percent, respectively). It also came out that the renoprotective benefits of irbesartan were quite independent of its blood pressure-lowering capacity, since the blood pressure of the participants hardly differed. Dr. Hans-Henrik Par-ving of Denmark's Steno Diabetes Center, principal investigator, said before the participants of the ASH meeting: "IRMA II was specifically designed to assess the preventive role of irbesartan in hypertensive patients with microalbuminuria and the trial results clearly demonstrate that it could significantly benefit the patient population, since a 70-percent reduction in diabetic nephropathy was [observed]."
Parving said the results meant that "by treating just ten patients in two years, you can avoid diabetic kidney di-sease in one-and the effects get better with time."
Meanwhile, IDNT randomly divided 1,715 type 2 diabetic patients with hypertension and proteinuria into three groups: irbesartan 300mg; the calcium channel blocker amlodipine 10 mg; and placebo. Patients followed up for a mean period of 2.6 years.
It turned out that the primary composite end points (progression of doubling of baseline serum creatinine, ESRD, or all-cause mortality) were prevented by 20 percent compared with placebo (p=0.02) and 23 percent compared with amlodipine (p=0.006). Proteinuria was significantly reduced in the irbesartan group, with the serum creatinine concentration increasing 24-percent more slowly than placebo and 21-percent more slowly than amlodipine. As for the degeneration of renal function and the necessity of submitting to dialysis or transplantation, those on irbesartan had 26-percent risk reduction compared with placebo and 34 percent compared with amlodipine. Dr. Edmund Lewis of Chicago's Rush-Presbyterian-St. Luke's Medical Center, principal investigator, said: "Since irbesartan can prevent or delay the progression of kidney disease, dialysis, or kidney transplantation, treating patients with this therapy can save lives and improve quality of life. It can also lead to an enormous reduction in health-care costs."
Also presented at the same meeting-and published in the same issue of the New England Journal of Medicine-were the results of a study on the renoprotective benefits of losartan, another ARB. The study known as RENAAL (Reduction of End points in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan) randomized a total of 1,513 patients from 29 countries into two groups: the losartan group (50mg or 100mg daily) and placebo group. Both groups continued to receive the appropriate conventional blood pressure me-dication (except an ACE inhibitor or another ARB). The study was initially set to run for more than four years, but the steering committee, who are unaware of the treatment assignments, voted to stop it in February 2001, or 13 months ahead of schedule, because of "new evidence [from other sources] suggesting that angiotensin-I-converting enzyme inhibitors…may be effective in reducing the incidence of cardiovascular events in patients with renal impairment including those with diabetes."
It was shown that losartan with conventional blood pressure medication reduces the risk of primary end points (ESRD, doubling of baseline creatinine concentration, death) by 16 percent, with its benefits arising quite independently from its blood pressure-lowering ability. The risk of progression to ESRD was reduced by 28 percent (p=0.002), just as the progression of proteinuria was significantly reduced by 35 percent (p=0.0001). The risk of doubling of serum creatinine concentration was also reduced by 25 percent (p=0.006) in the losartan group, and this became apparent as early as the first year, and more notable in the 18th month. The risk of death had no significant difference in the two groups.
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