1346
LETTERS to the EDITOR Didanosine for zidovudine-intolerant patients with HIV disease SIR,-We report here preliminary findings from the European/ Australian Alpha trial, coordinated by the UK Medical Research Council and the French Agence National de Recherche sur le SIDA. The Alpha trial compares the clinical efficacy and tolerance of didanosine (dideoxyinosine, ddl) in patients with symptomatic HIV disease intolerant of zidovudine. Patients were randomised to receive high dose (H) didanosine, 750 mg per day for patients weighing 60 kg or more, 500 mg for those weighing 40-59 kg, and 334 mg for lighter patients, or low (L) doses of 200, 134, or 90 mg, respectively. The drug was given as one sachet twice daily in a double-blind design. Although the original design also included a placebo-controlled option, this was stopped because of very slow recruitment, perhaps because of a perception among potential participants that didanosine might be effective and, despite potential toxicity, preferable to taking no medication. Recruitment to the dose-comparison option was expanded. It was hoped that the two doses-chosen, on the basis of phase 1/11 data, to be at the lower limit of efficacy as judged by surrogate markers and the upper limit of tolerance as judged by the occurrence of peripheral neuropathy-would differ sufficiently in efficacy and/or tolerance to demonstrate by implication the efficacy of the drug as well as selecting the optimal dose. A total of 1930 patients were recruited from France, the UK, Ireland, Australia, the Netherlands, Switzerland, Sweden, Denmark, Norway, and Luxembourg between May, 1990, and November, 1991. A preliminary analysis has been undertaken on data up to Sept 30, 1992, for the 1775 (907 H, 868 L) patients who started trial treatment. On admission 61% of the 1775 patients had AIDS, 65% had CD4 cell counts of less than 50/1 (50% less than 25), and 55% had received zidovudine for 12 months or more. The distribution of prognostic markers was very similar in the two groups. 86 patients, about 5% in each group, were lost from follow-up for 3 months or more, and the proportions who withdrew from trial sachets for personal reasons (but continued to be followed up) were similar, 23% of the H and 20% of the L groups. However, more patients in group H than in group L were reported to have stopped trial sachets because of adverse events (38% vs 26%). The proportion of total patient-time spent on sachets was 64% for the H group and 71 % for the L group. At the time of the analysis patients had been followed up for 10 to 28 months, the mean follow-up being 12 months because of the high death rate. There was no detectable difference between H and L in terms of survival, deaths per 100 person-years being 65 for H and 67 for L, with a median survival of 12-9 months (95% CI 12-0-14-1) and 12-4 months (95% CI 11 -5-13-5), respectively. The hazard ratio (H/L) was 0-98 (95% CI 0-87-1-10, log rank p=0-7). There was also no difference when the analysis was restricted to those deaths attributed to HIV-related causes. Subgroup analyses by baseline clinical disease staging or CD4 counts did not reveal any survival differences; nor did those by risk-group or sex.
The rate of progression to AIDS or death (in the 691 patients without AIDS on admission) was similar in the H and L groups, 51% (95% CI 46-56) compared with 56% (95% CI 50-61) being alive and AIDS-free at 1 year. Similarly, the rate of development of HIV encephalopathy in the two groups was comparable. Secondary evidence of a dose-related anti-HIV effect was seen in laboratory markers. There was a small (but highly significant) difference in the changes in CD4 count between the groups. The median count on admission was 26 cells/ill in the H group and 23 cells/ill in the L group. The median of the average change in count during the first 6 months (as measured by the area under the curve)
was -1 ’7 cells in L and + 2.5 in H, a difference of 4-2 (95% CI 1-8-6-7). Although an increase in CD4 cells was associated with improved survival in both groups, the impact of the difference in CD4 response in the two groups would be too small to be detected as a survival difference even in this large trial. There is no detectable difference between H and L dose didanosine in terms of survival or progression of disease in this population. The lack of difference cannot reasonably be attributed to chance; this study is powerful statistically because of the trial’s size and the large number of events observed. There is also no compelling evidence that the lack of difference is due to dilution of effect because of poor compliance or a large imbalance in the rates of trial drug discontinuation in the two groups. By contrast, there were clear differences in adverse events; 41 patients in group H and 5 in group L developed pancreatitis, of whom 7 and 1, respectively, died from it. A further 16 and 4 had possible pancreatitis and 197 and 100 were reported to have symptom-free rises in serum amylase or lipase or both. Half of the cases of pancreatitis occurred within 4 months of starting didanosine. Peripheral neuropathy, abnormal liver function, and dry mouth were also reported more often in group H, but diarrhoea, although a common adverse event, occurred with a similar frequency in both groups. Haematological abnormalities were similar in both groups and infrequent. Alpha has not answered the question as to whether didanosine is effective in zidovudine-intolerant patients with symptomatic (mostly advanced) HIV disease, partly because of the lack of sufficient recruitment to the placebo-controlled option and partly because there was no apparent difference in disease progression or survival between H and L groups. The lack of difference in survival may mean that, if either dose is effective, the two doses are at an approximate plateau of the dose-response curve. In view of the difference between the two dose levels in changes in CD4 count there remains some doubt whether the low dose is at the top of the
dose-response curve. Although the question of the drug’s efficacy is unresolved, it is anticipated that more information on this will be obtained from several ongoing trials including the Delta trial from our group and AIDS Clinical Trials Groups (ACTG) 116A, 118, and 175 in the US. The ACTG 116B/117 trial’ indicated that patients with generally less advanced disease than those in Alpha switching from zidovudine to didanosine at a dose of 500 or 750 mg per day had no significant benefit in terms of survival compared with continuing zidovudine but there appeared to be some benefit in terms of delay in the devlopment of a new AIDS-defining event. This effect was seen primarily in the patients with AIDS-related complex or symptomless infection on admission and in the 500 mg didanosine group, which was attributed by the authors in part to the increased dropout rate in the 750 mg group. However, in Alpha there was no difference between the 200 and 750 mg doses in terms of disease progression in the subgroup of patients who had not developed AIDS at entry, and in all patients the higher dose was associated with significantly more severe toxicity, especially pancreatitis, and this has a small but important mortality. Ultimately it is for individual clinicians to decide whether one of the two doses from Alpha, or the intermediate dose of 500 mg from ACTG 116B/ 117 that was selected for the Delta trial, is preferable. Data from ongoing trials may help with this decision, but on the basis of the preliminary Alpha results it would be prudent at this stage to offer patients in whom didanosine is clinically indicated a dose of less than 750 mg a day. A more detailed analysis of Alpha will be undertaken and a report prepared as soon as all data are complete. It was considered important to provide limited information from this preliminary analysis to aid clinicians and patients in their selection of an appropriate dose of didanosine.
1347
We acknowledge the contribution of Bristol-Myers Squibb to the costs of organising the trial.
Endobulln treatment - -I-
MRC HIV Clinical Trials Centre, Department of Clinical Epidemiology,
No Immunoglobulin Infusion
Royal Brompton National Heart and Lung Hospital, London SW3 6NP, UK
JANET H. DARBYSHIRE
JEAN-PIERRE ABOULKER, behalf of the MRC/ANRS International Coordinating Committee for the European/ Australian Alpha Trial
on
Unité de Recherches Statistiques,
INSERM Villejuif, France
1. Khan JO, Lagakos SW, Richman DD, et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. N Engl J Med 1992; 327: 581-87.
A1 B8DR3-associated
expansion in HIV infection SiR.—Dr Oksenhendler and colleagues (July 25, p 207) report 3 HIV-infected white patients characterised by pseudotumoural splenomegaly, polyclonal CD8-positive T-cell expansion, and sharing of the extended A1B8DR3 major histocompatibility complex haplotype. We report a similar case showing that T-cell expansion may not be restricted to lymphoid tissue. A 40-year-old Gambian man was referred to our institution because of acute renal failure (creatinine 1435 pmol/1) in the setting of nephrotic syndrome. He had major splenomegaly and hepatomegaly, peripheral lymphadenopathy, and parotid enlargement. A renal biopsy disclosed focal and segmental glomerulosclerosis and striking interstitial infiltration by numerous CD8-positive, CD25-negative, HLA class II-positive T cells. At the same time, the patient proved HIV-1positive by enzyme-linked immunosorbent assay and western blot. Serological tests for HIV-2, HTLV-1, and HTLV-2 were negative. No opportunistic infection was found. CD4-positive and CD8-positive T-cell counts were 228/ul and 1292/ul, respectively. Salivary gland biopsy showed a lymphocytic infiltrate compatible with a diagnosis of Sjogren’s syndrome. HLA typing was A1B8DR3. Treatment by zidovudine and methylprednisolone resulted in sustained improvement in renal function (creatinine 376 umot/1), and haemodialysis was stopped for 10 months. This report shows that the A1B8DR3-linked CD8-positive T-cell expansion described by Oksenhendler et al in HIV-1infected patients may not arise only in the spleen and that it can involve organs outside the lymphoid system. We suggest that this expansion might account for some visceral complications of HIV infection, such as interstitial nephritis. It may, in some cases, be amenable to antiretroviral and corticosteroid treatment. Service of Clinical Immunology, INSERM U25, and Laboratory of Anatomy and Renal
Pathology,
Hôpital Necker, 75743 Paris, France
Survival of AIDS patients after IVIG therapy.
CD8-positive T-cell
groups of patients were similar in age, weight, low number of CD4 cells, treatment, previous infections, and time between AIDS and entry to the study. All patients had been receiving antiretroviral therapy for 3 months or more at the beginning of study. Clinical evaluation was every month before every IVIG administration.
Laboratory tests (serum immunoglobulins, complement fractions, &bgr;2-microglobulin, transaminases, T-cell counts [CD2, CD3, CD4, or CD8 phenotype], and B-cell counts [CD19, CD20, or CD21 phenotype]) were done every 3 months. IVIG infusions were well tolerated in all patients. No high temperatures, headache, or nausea were observed and no modification of the infusion schedule was necessary in any patient at any time. Survival was significantly better in the IVIG-treated group than in the controls (figure, p < 0-01). 50% of IVIG patients survived 450 days, while less than 50% reached a 200-day survival among controls. After 12 months of follow-up, 9 patients in the IVIG group were alive compared with 3 controls. In addition, and as a possible explanation, the episodes of serious and moderate bacterial or viral infections were fewer in the IVIG-treated group. This study establishes that IVIG has some clinical benefit in adult patients with AIDS. The mechanism of this benefit and the selection of the most appropriate patients deserve further
investigations. Transplantation and Clinical Immunology Unit, Pavillion P, Hôpital Edouard Herriot, 69437 Lyon, France
T. SAINT-MARC J-L. TOURAINE
N. BERRA
1. Buckley RH, Schiff RI. The use of intravenous immune globulin in immunodeficiency disease. N Engl J Med 1991; 325: 110-17. 2. The National Institute of Child Health and Human Development Intravenous Immunoglobulin Study Group. Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection. N Engl J Med 1991; 325: 73-80.
JEAN-PAUL VIARD LAURE-HÉLÈNE NOËL DOMINIQUE DROZ JEAN-FRANÇOIS BACH
Beneficial effects of intravenous immunoglobulins in AIDS SiR,—With the introduction of intravenous formulations, the use of immunoglobulins, once limited to IgG replacement in severe humoral immunodeficiencies, has been extended to include the prevention or treatment of infections and immunological disorders.1 Controlled studies in children with HIV infection have shown that immunoglobulin reduces the frequency of bacterial infection and morbidity without changing mortality? We have evaluated the clinical and immunological effects of systematic and regular infusions of immunoglobulins in adults with severe deficiency of cell-mediated immunity and of antibody production because of HIV infection. Between January, 1990, and October, 1991, 24 AIDS patients were enrolled in a prospective trial. All patients were randomised to receive either no additional treatment (controls) or a monthly infusion of intravenous immunoglobulin (IVIG) (Endobulin, lmmunoFrance) at 200 mg/kg for at least 12 months. The two
Role of glucose and insulin resistance in development of type 2 diabetes mellitus SIR,-Dr Martin and colleagues’ study (Oct 17, p 925) of the predictive power of measures of insulin resistance (SD and insulin-independent glucose elimination (Sg) in the development of non-insulin dependent diabetes mellitus (NIDDM) is to be welcomed. This large prospective study of the offspring of parents with NIDDM in 6-25 years of follow-up predicted some 75% of cases of diabetes in subjects with the lowest quintiles of both S; and Sg, who had normal glycaemia at the outset of the study, and for at least 10 years before the onset of NIDDM. By contrast, no offspring in the highest quintile of Sj and Sg developed diabetes in this time. The technique used by Martin et al was the standard intravenous glucose tolerance test (IVGTT) with analysis by the minimum model teclmique.1 A feature of Martin’s study was the use of a higher dose of glucose (05g/kg) than that used by Bergman et aU This will have had the effect of increasing the endogenous insulin response, thus improving the success rate of the subsequent modelling.2 Martin et al successfully analysed 97% of cases. Our experience with this technique has been similar,3-S with an average 96%
success rate.
LETTERS to the EDITOR Didanosine for zidovudine-intolerant patients with HIV disease SIR,-We report here preliminary findings from the European/ Australian Alpha trial, coordinated by the UK Medical Research Council and the French Agence National de Recherche sur le SIDA. The Alpha trial compares the clinical efficacy and tolerance of didanosine (dideoxyinosine, ddl) in patients with symptomatic HIV disease intolerant of zidovudine. Patients were randomised to receive high dose (H) didanosine, 750 mg per day for patients weighing 60 kg or more, 500 mg for those weighing 40-59 kg, and 334 mg for lighter patients, or low (L) doses of 200, 134, or 90 mg, respectively. The drug was given as one sachet twice daily in a double-blind design. Although the original design also included a placebo-controlled option, this was stopped because of very slow recruitment, perhaps because of a perception among potential participants that didanosine might be effective and, despite potential toxicity, preferable to taking no medication. Recruitment to the dose-comparison option was expanded. It was hoped that the two doses-chosen, on the basis of phase 1/11 data, to be at the lower limit of efficacy as judged by surrogate markers and the upper limit of tolerance as judged by the occurrence of peripheral neuropathy-would differ sufficiently in efficacy and/or tolerance to demonstrate by implication the efficacy of the drug as well as selecting the optimal dose. A total of 1930 patients were recruited from France, the UK, Ireland, Australia, the Netherlands, Switzerland, Sweden, Denmark, Norway, and Luxembourg between May, 1990, and November, 1991. A preliminary analysis has been undertaken on data up to Sept 30, 1992, for the 1775 (907 H, 868 L) patients who started trial treatment. On admission 61% of the 1775 patients had AIDS, 65% had CD4 cell counts of less than 50/1 (50% less than 25), and 55% had received zidovudine for 12 months or more. The distribution of prognostic markers was very similar in the two groups. 86 patients, about 5% in each group, were lost from follow-up for 3 months or more, and the proportions who withdrew from trial sachets for personal reasons (but continued to be followed up) were similar, 23% of the H and 20% of the L groups. However, more patients in group H than in group L were reported to have stopped trial sachets because of adverse events (38% vs 26%). The proportion of total patient-time spent on sachets was 64% for the H group and 71 % for the L group. At the time of the analysis patients had been followed up for 10 to 28 months, the mean follow-up being 12 months because of the high death rate. There was no detectable difference between H and L in terms of survival, deaths per 100 person-years being 65 for H and 67 for L, with a median survival of 12-9 months (95% CI 12-0-14-1) and 12-4 months (95% CI 11 -5-13-5), respectively. The hazard ratio (H/L) was 0-98 (95% CI 0-87-1-10, log rank p=0-7). There was also no difference when the analysis was restricted to those deaths attributed to HIV-related causes. Subgroup analyses by baseline clinical disease staging or CD4 counts did not reveal any survival differences; nor did those by risk-group or sex.
The rate of progression to AIDS or death (in the 691 patients without AIDS on admission) was similar in the H and L groups, 51% (95% CI 46-56) compared with 56% (95% CI 50-61) being alive and AIDS-free at 1 year. Similarly, the rate of development of HIV encephalopathy in the two groups was comparable. Secondary evidence of a dose-related anti-HIV effect was seen in laboratory markers. There was a small (but highly significant) difference in the changes in CD4 count between the groups. The median count on admission was 26 cells/ill in the H group and 23 cells/ill in the L group. The median of the average change in count during the first 6 months (as measured by the area under the curve)
was -1 ’7 cells in L and + 2.5 in H, a difference of 4-2 (95% CI 1-8-6-7). Although an increase in CD4 cells was associated with improved survival in both groups, the impact of the difference in CD4 response in the two groups would be too small to be detected as a survival difference even in this large trial. There is no detectable difference between H and L dose didanosine in terms of survival or progression of disease in this population. The lack of difference cannot reasonably be attributed to chance; this study is powerful statistically because of the trial’s size and the large number of events observed. There is also no compelling evidence that the lack of difference is due to dilution of effect because of poor compliance or a large imbalance in the rates of trial drug discontinuation in the two groups. By contrast, there were clear differences in adverse events; 41 patients in group H and 5 in group L developed pancreatitis, of whom 7 and 1, respectively, died from it. A further 16 and 4 had possible pancreatitis and 197 and 100 were reported to have symptom-free rises in serum amylase or lipase or both. Half of the cases of pancreatitis occurred within 4 months of starting didanosine. Peripheral neuropathy, abnormal liver function, and dry mouth were also reported more often in group H, but diarrhoea, although a common adverse event, occurred with a similar frequency in both groups. Haematological abnormalities were similar in both groups and infrequent. Alpha has not answered the question as to whether didanosine is effective in zidovudine-intolerant patients with symptomatic (mostly advanced) HIV disease, partly because of the lack of sufficient recruitment to the placebo-controlled option and partly because there was no apparent difference in disease progression or survival between H and L groups. The lack of difference in survival may mean that, if either dose is effective, the two doses are at an approximate plateau of the dose-response curve. In view of the difference between the two dose levels in changes in CD4 count there remains some doubt whether the low dose is at the top of the
dose-response curve. Although the question of the drug’s efficacy is unresolved, it is anticipated that more information on this will be obtained from several ongoing trials including the Delta trial from our group and AIDS Clinical Trials Groups (ACTG) 116A, 118, and 175 in the US. The ACTG 116B/117 trial’ indicated that patients with generally less advanced disease than those in Alpha switching from zidovudine to didanosine at a dose of 500 or 750 mg per day had no significant benefit in terms of survival compared with continuing zidovudine but there appeared to be some benefit in terms of delay in the devlopment of a new AIDS-defining event. This effect was seen primarily in the patients with AIDS-related complex or symptomless infection on admission and in the 500 mg didanosine group, which was attributed by the authors in part to the increased dropout rate in the 750 mg group. However, in Alpha there was no difference between the 200 and 750 mg doses in terms of disease progression in the subgroup of patients who had not developed AIDS at entry, and in all patients the higher dose was associated with significantly more severe toxicity, especially pancreatitis, and this has a small but important mortality. Ultimately it is for individual clinicians to decide whether one of the two doses from Alpha, or the intermediate dose of 500 mg from ACTG 116B/ 117 that was selected for the Delta trial, is preferable. Data from ongoing trials may help with this decision, but on the basis of the preliminary Alpha results it would be prudent at this stage to offer patients in whom didanosine is clinically indicated a dose of less than 750 mg a day. A more detailed analysis of Alpha will be undertaken and a report prepared as soon as all data are complete. It was considered important to provide limited information from this preliminary analysis to aid clinicians and patients in their selection of an appropriate dose of didanosine.
1347
We acknowledge the contribution of Bristol-Myers Squibb to the costs of organising the trial.
Endobulln treatment - -I-
MRC HIV Clinical Trials Centre, Department of Clinical Epidemiology,
No Immunoglobulin Infusion
Royal Brompton National Heart and Lung Hospital, London SW3 6NP, UK
JANET H. DARBYSHIRE
JEAN-PIERRE ABOULKER, behalf of the MRC/ANRS International Coordinating Committee for the European/ Australian Alpha Trial
on
Unité de Recherches Statistiques,
INSERM Villejuif, France
1. Khan JO, Lagakos SW, Richman DD, et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. N Engl J Med 1992; 327: 581-87.
A1 B8DR3-associated
expansion in HIV infection SiR.—Dr Oksenhendler and colleagues (July 25, p 207) report 3 HIV-infected white patients characterised by pseudotumoural splenomegaly, polyclonal CD8-positive T-cell expansion, and sharing of the extended A1B8DR3 major histocompatibility complex haplotype. We report a similar case showing that T-cell expansion may not be restricted to lymphoid tissue. A 40-year-old Gambian man was referred to our institution because of acute renal failure (creatinine 1435 pmol/1) in the setting of nephrotic syndrome. He had major splenomegaly and hepatomegaly, peripheral lymphadenopathy, and parotid enlargement. A renal biopsy disclosed focal and segmental glomerulosclerosis and striking interstitial infiltration by numerous CD8-positive, CD25-negative, HLA class II-positive T cells. At the same time, the patient proved HIV-1positive by enzyme-linked immunosorbent assay and western blot. Serological tests for HIV-2, HTLV-1, and HTLV-2 were negative. No opportunistic infection was found. CD4-positive and CD8-positive T-cell counts were 228/ul and 1292/ul, respectively. Salivary gland biopsy showed a lymphocytic infiltrate compatible with a diagnosis of Sjogren’s syndrome. HLA typing was A1B8DR3. Treatment by zidovudine and methylprednisolone resulted in sustained improvement in renal function (creatinine 376 umot/1), and haemodialysis was stopped for 10 months. This report shows that the A1B8DR3-linked CD8-positive T-cell expansion described by Oksenhendler et al in HIV-1infected patients may not arise only in the spleen and that it can involve organs outside the lymphoid system. We suggest that this expansion might account for some visceral complications of HIV infection, such as interstitial nephritis. It may, in some cases, be amenable to antiretroviral and corticosteroid treatment. Service of Clinical Immunology, INSERM U25, and Laboratory of Anatomy and Renal
Pathology,
Hôpital Necker, 75743 Paris, France
Survival of AIDS patients after IVIG therapy.
CD8-positive T-cell
groups of patients were similar in age, weight, low number of CD4 cells, treatment, previous infections, and time between AIDS and entry to the study. All patients had been receiving antiretroviral therapy for 3 months or more at the beginning of study. Clinical evaluation was every month before every IVIG administration.
Laboratory tests (serum immunoglobulins, complement fractions, &bgr;2-microglobulin, transaminases, T-cell counts [CD2, CD3, CD4, or CD8 phenotype], and B-cell counts [CD19, CD20, or CD21 phenotype]) were done every 3 months. IVIG infusions were well tolerated in all patients. No high temperatures, headache, or nausea were observed and no modification of the infusion schedule was necessary in any patient at any time. Survival was significantly better in the IVIG-treated group than in the controls (figure, p < 0-01). 50% of IVIG patients survived 450 days, while less than 50% reached a 200-day survival among controls. After 12 months of follow-up, 9 patients in the IVIG group were alive compared with 3 controls. In addition, and as a possible explanation, the episodes of serious and moderate bacterial or viral infections were fewer in the IVIG-treated group. This study establishes that IVIG has some clinical benefit in adult patients with AIDS. The mechanism of this benefit and the selection of the most appropriate patients deserve further
investigations. Transplantation and Clinical Immunology Unit, Pavillion P, Hôpital Edouard Herriot, 69437 Lyon, France
T. SAINT-MARC J-L. TOURAINE
N. BERRA
1. Buckley RH, Schiff RI. The use of intravenous immune globulin in immunodeficiency disease. N Engl J Med 1991; 325: 110-17. 2. The National Institute of Child Health and Human Development Intravenous Immunoglobulin Study Group. Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection. N Engl J Med 1991; 325: 73-80.
JEAN-PAUL VIARD LAURE-HÉLÈNE NOËL DOMINIQUE DROZ JEAN-FRANÇOIS BACH
Beneficial effects of intravenous immunoglobulins in AIDS SiR,—With the introduction of intravenous formulations, the use of immunoglobulins, once limited to IgG replacement in severe humoral immunodeficiencies, has been extended to include the prevention or treatment of infections and immunological disorders.1 Controlled studies in children with HIV infection have shown that immunoglobulin reduces the frequency of bacterial infection and morbidity without changing mortality? We have evaluated the clinical and immunological effects of systematic and regular infusions of immunoglobulins in adults with severe deficiency of cell-mediated immunity and of antibody production because of HIV infection. Between January, 1990, and October, 1991, 24 AIDS patients were enrolled in a prospective trial. All patients were randomised to receive either no additional treatment (controls) or a monthly infusion of intravenous immunoglobulin (IVIG) (Endobulin, lmmunoFrance) at 200 mg/kg for at least 12 months. The two
Role of glucose and insulin resistance in development of type 2 diabetes mellitus SIR,-Dr Martin and colleagues’ study (Oct 17, p 925) of the predictive power of measures of insulin resistance (SD and insulin-independent glucose elimination (Sg) in the development of non-insulin dependent diabetes mellitus (NIDDM) is to be welcomed. This large prospective study of the offspring of parents with NIDDM in 6-25 years of follow-up predicted some 75% of cases of diabetes in subjects with the lowest quintiles of both S; and Sg, who had normal glycaemia at the outset of the study, and for at least 10 years before the onset of NIDDM. By contrast, no offspring in the highest quintile of Sj and Sg developed diabetes in this time. The technique used by Martin et al was the standard intravenous glucose tolerance test (IVGTT) with analysis by the minimum model teclmique.1 A feature of Martin’s study was the use of a higher dose of glucose (05g/kg) than that used by Bergman et aU This will have had the effect of increasing the endogenous insulin response, thus improving the success rate of the subsequent modelling.2 Martin et al successfully analysed 97% of cases. Our experience with this technique has been similar,3-S with an average 96%
success rate.
