Protease inhibitor-associated hyperinsulinaemia

Field: Medicine (Health Sciences)

Protease inhibitors have proved to be powerful drugs capable of changing the natural history of HIV-1 infection. However, knowledge of the long-term safety profile of these drugs is limited because they were approved under an accelerated mechanism. Adverse effects such as hyperglycaemia and abnormal body-fat distribution in association with protease inhibitors have been recently reported [1–7], although their pathogenesis remains unknown. To determine whether protease inhibitor therapy is associated with metabolic effects and to avoid confounding factors biasing study results, we studied two groups of otherwise clinically stable (CD4 cells >300 × 106/l and plasma HIV-1 RNA <5000 copies/ml) non-obese (body mass index <25 kg/m2) HIV-1-infected patients with normal liver, kidney and exocrine pancreatic functions, with no previous individual or first-degree family history of diabetes or dyslipaemia, and without concurrent therapies affecting carbohydrate or lipid metabolism. One group included protease inhibitor-naive patients treated with two nucleoside reverse transcriptase inhibitors, whereas patients in the other group had been receiving short-term (3–6 months) combination therapy including a protease inhibitor. Ten consecutive patients for each group fulfilling the inclusion criteria were recruited from December 1997 to March 1998 from a population of nearly 1800 HIV-1-infected patients cared at our hospital. The distribution of protease inhibitors in the group of patients treated were as follows: indinavir (five patients), ritonavir (two patients), hard-gel saquinavir (two patients), ritonavir plus hard-gel saquinavir (one patient). None of the patients in either group was aware of changes in weight or fat distribution for the previous 6 months. Fasting plasma glucose, triglycerides, cholesterol, insulin (measured by insulin radioactive monoclonal antibody assay), C-peptide (measured by polyclonal radioimmunosassay) and cortisol were assessed for each patient. Baseline characteristics were compared using the student' t-test and χ2 test, and metabolic parameters were compared using the Mann-Whitney U-test. Baseline charactersitics were similar in both groups. However, higher values of plasma triglycerides, cholesterol and insulin distinguished patients treated with protease inhibitors from those not treated (Table 1). Although insulin production (measured by C-peptide concentration) tended to be increased in those patients treated with protease inhibitors compared with those not treated (P = 0.09), hyperinsulinaemia was mainly due to reduced insulin clearance (estimated by C-peptide to insulin ratio; P = 0.02). Hyperinsulinaemia in the protease inhibitor group reflected some degree of insulin resistance, as determined by the fasting insulin resistance index [8] (P = 0.06).Table 1: . Baseline characteristics and metabolic parameters of patients treated with and without protease inhibitors.Our data show an association between short-term therapy with protease inhibitors and certain metabolic abnormalities. The metabolic disturbances that we have seen in the group of patients with short-term protease inhibitor therapy had no obvious cause, and differed from those described in clinically stable HIV-1-infected patients before the advent of protease inhibitors [9] (normal or increased plasma triglycerides, decreased plasma cholesterol and increased rates of insulin clearance). We speculate that a decrease in insulin clearance may be the first event because it may be enough to cause insulin resistance [10]. The development of insulin resistance leads to mismanagement of lipid metabolism and is often associated with increased levels of triglycerides and cholesterol. Our patients were not symptomatic at the time of the study, but prospective follow-up will let us know whether any of them become glucose intolerant or develop fat redistribution in the future.