Diabetes Mellitus and Insulin Resistance
Todd T. Brown, M.D. and Joseph Cofrancesco, Jr., M.D., M.P.H.
- Diabetes incidence/prevalence in Zambian HIV+ pts likely to increase with time as pts living longer with HAART.
- Important to review diet of diabetics in Zambia to evaluate intake of refined sugars: drinking sodas, chewing sugarcane, adding large quantities of sugar to tea are all common habits.
- Rx in Zambia usually with metformin or sulfonylureas, as TZDs not generally available.
Zambia Information Author: David Riedel, M.D.
Insulin resistance (IR) common in PI-treated pts.
- Diabetes less common, but still 2-4x higher than in general population.
- IR also caused by fat accumulation (lipodystrophy). In general population (and presumably in HIV+ pts), IR increases risk for coronary artery disease.
- Risk factors for IR/DM: abdominal fat accumulation, peripheral fat wasting, family Hx of DM, obesity, age, HCV, low CD4 nadir, black/Hispanic race.
- Consider role of other medications: corticosteroids, growth hormone, megestrol acetate, immunosuppressants, atypical antipsychotics.
- PIs differ in effect on IR: IDV >> NFV, RTV, LPV/r > SQV, APV >> ATV.
- DM = "fasting" glucose >126 mg/dL confirmed with a repeat test, or Sx of DM and a random plasma glucose >200 mg/dL.
- Impaired fasting glucose (IFG) ="100-125" mg/dL, at risk for developing DM per American Diabetes Association (ADA) definition.
- If unclear, consider 2hr 75g oral glucose tolerance test (OGTT), more sensitive than fasting glucose: 140-199 = "impaired" glucose tolerance (IGT), >200 = "DM."
- IGT or IFG is considered pre-DM.
- Check fasting glucose at baseline, prior to and 3 & 6 mos after ART initiation, then yearly if normal.
- No accepted role for clinical use of insulin levels to assess IR.
- Balanced diet and regular exercise crucial. ADA diet consisting of 50% carbohydrates (higher-fiber, unrefined preferred), 30% fat (unsaturated preferred), and 20% protein recommended.
- Nutrition consultation recommended.
- Modest weight loss (10%) in those with BMI >25 reduces glucose intolerance and can prevent onset of DM in non-HIV infected population at risk. Lifestyle modification shown to improve metabolic parameters in HIV-infected patients.
- Aggressive risk factor modification for coronary disease: lipid control, HTN control (generally with ACE-I or ARB), smoking cessation, cocaine avoidance, aspirin therapy.
- First line treatment for DM: metformin or thiazolidinediones (TZDs) such as rosiglitazone or pioglitazone.
- Metformin: reduces hepatic IR. Associated with reduced visceral fat, BP, triglycerides (TG) (10-20%) in HIV+ subjects. Some studies have shown decrease limb fat with metformin; use with caution in pts with lipoatrophy. Serum creat >1.5 mg/dL an absolute contraindication due to lactic acidosis risk. Also enhanced theoretical risk with NRTIs, liver disease, and CHF. GI upset most common. Start at 500 mg qd, titrate 500 mg q wk to 2 g bid (max dose 850 tid).
- TZDs (pioglitazone and rosiglitazone): reduce peripheral IR as peroxisome proliferator-activated receptor (PPAR) gamma agonists. Effect on lipoatrophy controversial. Pioglitzaone may be better than rosiglitazone for lipoatrophy, but no head-to-head trials. Effect present only on those not on thymidine analogs. Some increase in TG with rosiglitazone but not pioglitazone. Rosiglitazone: Start at 2 mg qd, titrate up to 8 mg qd. Pioglitazone: start at 15 mg, titrate up to 45 mg/d. Max effect seen after several wks. Fluid retention common. Avoid with CHF, liver disease.
- Combination of metformin and TZDs not established in HIV+ pts, but synergy expected.
- Use sulfonylureas, meglitinides, exenatide, sitagliptin or acarbose as 2nd line therapies.
- No accepted role for pharmacologic interventions for those with IR or pre-diabetes, though data are emerging.
- Consider low dose (10-15 units) bedtime glargine or NPH insulin in combination with oral anti-diabetic agents if failing oral agents. Insulin effective for glucose control with individualized regimen.
- Consider referral to diabetes expert.
- Consider switching from PI to NNRTI-based regimen provided viral control not jeopardized.
- Although data limited, some PIs, especially ATV, may cause less insulin resistance.
|insulin ||Many different choices. Regimen needs to be individualized. If glucose >250 mg/dL and/or HgbA1c >10%, pt will likely need insulin, at least initially. Once glucose controlled, some pts can be transitioned to oral agents alone. There is also growing consensus to add insulin earlier, i.e. after failure or 1 or 2 orals.
|metformin ||Best drug for mild DM in setting of obesity. Nausea, diarrhea common initially; generally improves over time. Minimize by starting at a low dose and titrating upwards. Watch for lactic acidosis. Concerns about worsening lipoatrophy.
|pioglitazone ||Excellent drug. May have theoretical interactions with ART because of partial CYP3A4 metabolism. Better lipid profile than rosiglitazone. Used in largest TZD trial in HIV-infected patients with lipoatroph,y showing a beneficial result.
|rosiglitazone ||Mixed data in pts with lipoatrophy. Good DM drug. Triglycerides may increase.
|exenatide ||New DM drug. Works by increasing insulin secretion and decreasing glucagon. Also associated with modest weight loss. Given SC. No studies in HIV+ pts.
- Lifestyle changes only: self-monitored blood glucose q wk.
- Oral agents: monitor fasting glucose q am.
- Insulin: monitor glucose 2-4 x/d .
- Pts with pre-DM should be screened at 3-6 mo intervals. After Dx of DM, monitor HgbA1c q 3-6 mos, depending on control. Goal at least <7% or as close to 6% as possible without significant hypoglycemia per ADA.
- Monitoring for complications: dilated fundoscopic exam by ophthalmology, spot urine for microalbumin and foot exam with inspection, monofilament, and vibration testing at baseline and q 6-12 mos.