June 19, 2015
Worthy statisticians who tried to disentwine HIV from other variables as a diabetes risk factor have reached two conclusions on whether HIV alone can lead to diabetes: Yes, it can. And no, it can't. One problem in any such analysis, no matter how large or refined, is residual confounding -- the unassailable possibility that factors not melded into the covariate mix are swaying results one way or the other. And HIV populations typically shoulder a fugal array of diabetes risk factors. So it may be impossible to say whether HIV infection -- independently of other risk factors common to people with HIV -- propels them toward a diabetes diagnosis.
Certainly one can imagine a rationale for why HIV, by itself, makes diabetes more likely. NIH metabolic mavens Colleen Hadigan and Sarah Kattakuzhy note that HIV-induced inflammation riles chemokines that regulate insulin and so could explain why HIV abets diabetes development.2 As an example, they cite an AIDS Clinical Trials Group (ACTG) study that linked systemic inflammation after antiretroviral therapy (ART) began to new-onset diabetes.16 This case-control study compared 55 people diagnosed with diabetes within 48 weeks of starting their first antiretroviral regimen and 55 controls matched for baseline BMI and race/ethnicity who remained free of diabetes. After adjustment for 48-week BMI and CD4 count, baseline marker levels, and indinavir use, people with higher initial levels of inflammation signals hsCRP, sTNFR1, and sTNFR2 had higher odds of a diabetes diagnosis. After further adjustment for week-48 glucose, higher sTNFR1 remained an independent predictor of diabetes (highest versus lowest quartile aOR 23.2, 95% CI 1.28 to 423, P = 0.03).
A more recent analysis of 3695 antiretroviral-treated people in the SMART and ESPRIT studies buttressed these findings, discerning links between higher inflammatory marker levels and newly diagnosed diabetes.17 During an average 4.6 years of follow-up, diabetes developed in 137 people. A regression model adjusted for baseline diabetes- and HIV-related factors determined that every doubling of IL-6 or hsCRP, two inflammation markers, nudged up the risk of incident diabetes (aHR 1.29, 95% CI 1.08 to 1.55, P = 0.005; aHR 1.22, 95% CI 1.10 to 1.36, P < 0.001).
But a study of 214 antiretroviral-naive people in France found no significant links between these same inflammation markers and insulin resistance in an analysis adjusted for age, sex, geographic origin, BMI, and waist circumference.18 This French analysis differs from the ACTG and SMART/ESPRIT studies in focusing on antiretroviral-naive people and in choosing a softer endpoint -- insulin resistance rather than new-onset diabetes. But one would prefer concordant results in all three studies to nail down the HIV→inflammation →diabetes hypothesis.
And if you look at studies weighing the impact of HIV as an independent diabetes risk factor, results are all over the map: Some find HIV does boost diabetes risk,10,19 others find it does not,20-22 and others find a lower diabetes risk in antiretroviral-treated people with HIV than in comparison groups.19,21,23 Two studies reached two of these three conclusions, depending on the study period and antiretroviral use.19,21
Two big cohort studies -- one in Italy and one in Denmark -- tagged HIV infection as an independent diabetes risk factor in comparisons with general-population groups. A 2008 Italian study compared 4249 HIV-positive people attending a Milan infectious diseases clinic and 9148 healthy controls from 15 Italian regions (Table 1).10 About three quarters of both groups were men, median age was significantly younger in the HIV group (45.7 versus 46.6, P < 0.0001), and BMI was significantly lower (23.2 versus 25.3 kg/m2, P < 0.0001). Median triglycerides were higher in the HIV group (126 versus 100 mg/dL, P < 0.0001). Diabetes prevalence proved significantly greater in the HIV group (4.1% versus 2.5%, P < 0.0001). After statistical adjustment for age, gender, BMI, triglycerides, and total, HDL, and low-density lipoprotein (LDL) cholesterol, chances of prevalent diabetes were 55% higher in people with HIV (aOR 1.55, 95% CI 1.02 to 2.31, P = 0.035).
|Table 1. Independent Risk Factors for New-Onset or Prevalent Diabetes in People With HIV|
|Author||n, Year(s), Age||M/F, Race, BMI, ART||Risk Factors* (95% CI)|
|Yoon,25 New York City (case-control study)||49, 1991-2000, A 45.1||63/37, 39% black, 35% Hispanic, 27% white, M 28.5, 82% NRTI use, 10% NNRTI use, 71% PI use||BMI: OR 1.13/kg/m2 (1.03-1.23)|
Family history: OR 5.55 (1.41-21.85)
ALT: OR 1.16/10-unit higher (1.03-1.30) PI use, HCV not associated
|Rasmussen,19 Denmark (HIV+/HIV- matched-cohort comparison)||3540, 1996-2010, M 38.7||84/26, 97.5% white, 18% overweight or obese, 86% on ART||HIV+ vs HIV- in 1996-1998: IRR 2.83 (1.57-5.09)|
HIV+ vs HIV- in 1999-2010 before ART begins: IRR 0.45 (0.21-0.96)
Obese vs normal weight: IRR 9.25 (5.37-15.94) Age 60+ vs <30: IRR 8.16 (1.91-34.74)
Lipoatrophy: IRR 2.30 (1.39-3.80)
SQV use: IRR 1.53 (1.01-2.34)
d4T use: IRR 1.81 (1.19-2.75)
|De Wit,24 Europe, U.S., Australia, Argentina (DAD Study)||33,389, 1999-2005, M 38||74/26, 13% nonwhite, M 23.0, 73% on ART, 58% on PI|
A 33,389-person DAD Study analysis linked nevirapine use to lower risk of new diabetes.24
|d4T use: RR 1.13 (1.08-1.15)|
ZVD use: RR 1.05 (1.01-1.10)
ddI use: RR 1.06 (1.01-1.11)
RTV use: RR 0.90 (0.85-0.95)
NVP use: RR 0.92 (0.86-0.99)
HDL: RR 0.75/mmol/L higher (0.58-0.96)
Trig: RR 1.64/doubling (1.50-1.80)
Fat gain: RR 1.36 (1.09-1.68)
|Tien,20 U.S. (WIHS)||1524, 2000-2006, M 39.2||0/100, 56% black, 28% Hispanic, 16% white, M 26.8, 84% on ART||NRTIs >3 y: aRH 2.64 (1.11-6.32)|
3TC >1 y: aRH 2.81 (1.33-5.95) HIV, PIs not associated
|Galli,10 Milan||4299, 2008, M 45.7||76/24, race not reported, 29.6% overweight or obese, 91.5% on ART||HIV: aOR 1.55 (1.02-2.31)†|
Age >50 vs ≤50: aOR 3.77 (2.82-5.10)
BMI 25-29.9 vs <25: aOR 1.59 (1.12-2.29)
BMI ≥ 30 vs <25: aOR 4.03 (2.72-5.99)
HTN: aOR 1.34 (1.01-1.79)
|Petoumenos,9 Europe, U.S., Australia, Argentina (DAD Study)||16,632, 2000-2010, M 46.2||73/27, 7% nonwhite, M 23.0, 95% on ART||Age/5 y: IRR 1.16 (1.10-1.21)|
Glucose ≥141/100 nonfasting/fasting: IRR 12.89 (10.43-15.92)
Trig 150-200: IRR 1.87 (1.34-2.60)
Trig 200-500: IRR 2.91 (2.23-3.79)
Trig ≥ 500: IRR 5.91 (4.23-8.27)
BMI: IRR 1.10/kg/m2 (1.08-1.18)
Lipodystrophy: IRR 1.27 (1.02-1.56)
CD4 200-349 vs <200: IRR 0.52 (0.36-0.77)
CD4 ≥ 350 vs < 200: IRR 1.27 (1.02-1.56)
BP ≥ 130/85: IRR 1.37 (1.09-1.72)
|Ledergerber,26 Switzerland (Swiss HIV Cohort Study)||6513, 2000-2006, M38||69/31, 15.5% nonwhite, M 22.5, 73% on ART||Male: IRR 2.54 (1.53-4.21)|
40-49 vs < 40: IRR 1.93 (1.22-3.05)
50-59 vs < 40: IRR 2.29 (1.30-4.09)
≥ 60 vs < 40: IRR 4.32 (2.28-8.16)
Black vs white: IRR 2.10 (1.11-4.00)
Asian vs white: IRR 4.88 (2.17-10.9)
CDC stage C vs A/B: IRR 1.56 (1.04-2.35)
Central obesity: IRR 4.69 (3.14-7.00)
HCV, HTN not associated
|Tripathi,21 South Carolina (HIV+/HIV-matched-cohort comparison)||6816, 1994-2011, M 39||57/43, 79% nonwhite, 10% documented obese, 80% on ART||ART-treated vs HIV-neg: aHR 0.55 (0.46-0.65)|
ART-naive vs HIV-neg: aHR 0.82 (0.63-1.07, NS)
Cumulative PI: aHR 1.35 (1.03-1.78)
Female: aHR 1.32 (1.06-1.65)
Age: aHR 1.09/year (1.04-1.15)
HTN: aHR 2.01 (1.59-2.55)
Dyslipidemia: aHR 1.71 (1.29-2.26)
Obesity: aHR 1.57 (1.15-2.13)
HCV not associated (aHR 1.41, 0.98-2.03)
|Butt,23 U.S. (Veterans Aging Cohort Study)||3227, 2002-, A 49.6||97.5/2.5, 67% black, 10% Hispanic, 20% white, A 25.2, proportion on ART not reported||HIV: aOR 0.84 (0.72-0.97)†|
ART use: aOR 1.11 (1.05-1.17)
NRTI/y: aOR 1.06 (1.02-1.10)
NNRTI/y: aOR 1.09 (1.02-1.10)
Older age (increasing with stratum)
Black vs white: 1.65 (1.22-2.22)
Hispanic vs white: 1.55 (1.01-2.37)
Higher BMI (increasing with stratum)
HCV: aOR 1.36 (1.06-1.73)
* Only independently associated variables listed.
† Adjusted odds ratios for prevalent diabetes, not new-onset diabetes.
A, average (mean); aHR, adjusted hazard ratio; ALT, alanine aminotransferase; aOR, adjusted odds ratio; aRH, adjusted relative hazard; aRR, adjusted relative risk; BMI, body mass index; BP, blood pressure; d4T, stavudine; ddI, didanosine; HCV, hepatitis C virus; HDL, high-density lipoprotein cholesterol; HTN, hypertension; IRR, incidence rate ratio; M, median; M/F, proportion male/female; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NS, not significant; NVP, nevirapine; PI protease inhibitor; RR, relative rate; RTV, ritonavir; SQV, saquinavir; 3TC, lamivudine; Trig, triglycerides; WIHS, Women's Interagency HIV Study; ZVD, zidovudine.
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