Gus Cairns spoke to a patient, George, about the complexities of managing diabetes and HIV.
George’s introduction to diabetes was rougher than most.
“In 2000 I started taking a combination therapy regime containing ddI. I was fine for four weeks then started suffering agonising abdominal pain. I stopped my HIV drugs and two days later the pain went away. But by that time the damage had been done.”
The blood tests made it clear he’d had pancreatitis (inflammation of the pancreas). As he subsequently found, the ddI in his regimen had turned someone with a family history of diabetes into someone with the condition, and a quite severe form at that. It’s resulted in a long struggle to find an HIV therapy that doesn’t make things worse.
What is diabetes?
The pancreas, a long organ sitting in the middle of your body, performs two vital tasks. Most of its cells secrete enzymes such as amylase that help to digest food, especially fats.
Scattered amongst these cells are different cells that secrete several important hormones into the bloodstream. Among these is insulin, a hormone that performs a vital role in regulating the amount of sugar in the blood.
Lack of insulin or a lack of ability to respond to it cause, respectively, type 1 and type 2 diabetes.
Diabetes is common, and getting more so. About 17 million people worldwide suffer from it or 2.8% of the population.1 This figure is expected to double by 2030, largely due to the adoption of western diets by people in Asia and Africa. Tony Wierzbicki (see below) estimates that 5 to 10% of the population of the UK is at risk of developing diabetes.
Type 1 diabetes is caused by a partial or complete loss of the insulin-producing cells. Its most common cause is when the body’s own immune system stops recognising the insulin-producing cells and starts killing them off. As there is no or little insulin circulating its treatment usually requires insulin injections
Type 2 diabetes is caused when the body stops being able to respond to its own insulin. In its mild stages this is called insulin resistance.Exactly how this happens is still unclear,2 but type 2 diabetes is strongly associated with obesity and especially with accumulation of fat inside the abdomen (‘lipohypertrophy’ or Visceral Adipose Tissue – VAT).3
A third type of diabetes exists caused by toxic damage to the pancreas. Although the most common cause is heavy alcohol use, it can also be caused by some drugs, including HIV drugs, which is what happened to George.
The definition of diabetes is the same in all cases: more than 7mmols/l (millimols per litre) of glucose in the blood 8 to 12 hours after food. The symptoms are the same too. People may first notice fatigue, weakness and muscle aches then, as glucose levels rise, the production of large amounts of dilute urine and a corresponding thirst. A life-threatening condition called ketoacidosis which involves an acute worsening of these symptoms can occur, but often the symptoms of type 2 diabetes are initially mild or absent – so easy to ignore.
They should not be ignored, however, as high glucose levels produce chronic symptoms that affect many organs in the body. Glucose damages the cells in many organs. This causes poor wound healing, and damage to blood vessels in the eye can cause blindness. Nerves get damaged too, leading to the pain and numbness of neuropathy. Overworked kidneys can fail and muscles deprived of energy at the right time can waste, including the heart muscles.
Diabetes is the most common cause of amputations, blindness and kidney failure in the developed world.4 Tony Wierzbicki says: “80% of people with type 2 diabetes will get a heart attack or stroke compared with 35% of the general population”.
George received a different reaction to his pancreatitis from his HIV doctor and a diabetologist he subsequently saw. “My HIV doctor said ‘your amylase levels were up 25% and we normally only start worrying if they’re up 50%’. The diabetologist said ‘It’s a good job you stopped the ddI when you did or you’d have ended up dead’.”
He feels HIV physicians are overly focused on HIV and have minimised and failed to treat his diabetes. Repeated requests to be referred to a diabetes specialist have been met with delay and reluctance. “I found out about the diabetic team at my former hospital via my GP,” he says.
The pancreatitis had scared George off from taking HIV drugs and he went on a treatment break for 18 months. His diabetes at that time was manageable with diet and exercise. When he restarted, at a CD4 count of 150, he went on AZT/3TC (Combivir) and nevirapine –chosen with diabetes in mind5 – and did well for another 18 months. Then unfortunately in 2003 he became resistant to the nevirapine.
After some chopping and changing he was eventually kept on the Combivir and switched to a boosted protease inhibitor – indinavir plus ritonavir. His glucose levels suddenly doubled to 12 mmols/l. Indinavir, as it turns out, may have been exactly the wrong thing to put him on.
HIV drugs and diabetes
“Insulin resistance appears to be triggered by some antiretrovirals,” says Dr Graeme Moyle of London’s Chelsea and Westminster Hospital. “Initially we suspected protease inhibitors (PIs),6 but found an association last year with d4T and AZT and, rather unexpectedly, not with PIs.7 I suspect that of the PIs only indinavir and full-dose ritonavir are implicated in insulin resistance and they damaged the reputation of the class.8
“HIV may itself cause diabetes. We haven’t much direct data, though one US study9 did find more diabetes in patients with HIV in California than age- and sex-matched people in the general population. So when people start HIV therapy any diabetic effects of therapy may be masked by an improvement of the effects of HIV."10
Another phenomenon, Moyle comments, is so-called ‘re-feeding’. This was first noticed in World War II prisoners and later in anorexics.11 “If thin people start eating again and put fat on quickly, it doesn’t get deposited evenly. They accumulate fat in the abdomen (Visceral Adipose Tissue or VAT) instead of under the skin. And VAT is exactly what we see in some people on HIV treatment.”
In addition, he adds, as patients with HIV both age and more resemble the typical population, he’s seeing more obesity in patients with HIV and therefore more insulin resistance and type 2 diabetes. “It’s partly caused by demographic shift. Africans and South Asians have a greater genetic susceptibility to diabetes."12
Moyle refers all his patients with raised blood glucose to the diabetologist. “I may put them on diabetic treatment straight away if they have very high glucose levels, but a diabetologist can manage them better. They can decide to put them on medications like blood-pressure drugs to help their kidneys, do proper retinal exams for blindness, and can draw up tailor-made diets. After that I’d recommend they get managed by their GP, because GPs see a lot of diabetics. About 30% of my patients have raised blood lipids (fats) and so I’m experienced at managing them, but only 3 to 4% have diabetes.”
“I felt really unwell,” continues George. “With high glucose, you feel kind of speedy. I got very bad tempered and emotional, alternated between feeling hyper and exhausted.”
When George’s glucose levels shot up, he went back to his HIV doctor. “She said, ‘It can’t be the meds, it must be your diet,’ and didn’t propose any diabetes medications. I don’t understand this; they give you statins for cholesterol as soon as your levels go over the limit.”
In desperation he stopped his HIV meds again. “I had 250 CD4 cells and felt I had some time.” He stayed off for four years, till June 2008.
“By this time my CD4s were down to 29. I went to a different hospital and basically blackmailed them. I said: ‘I’m not going back on my meds till I speak to someone from the diabetic team’. I did see the diabetologist there; that’s the very first time someone actually told me my diabetes was due to drug-induced pancreatitis.”
George was put on the anti-diabetes drug metformin and for his HIV was put on a novel regimen of Truvada, the protease inhibitor atazanavir and the integrase inhibitor raltegravir.
“Unfortunately my sugar levels went up the wall again, this time to 18 mmols/l.” Oddly enough it seems to have been not the atazanavir but the new integrase inhibitor that was to blame. “We stopped the raltegravir and so far things seem to be OK. I’m virally undetectable and my CD4s have gone up 50, though they’re a bit worried that’s on the low side.”
George says: “If someone had listened to me in the first place, some of this could have been avoided. But I’ve had to fight for the right treatment because there’s this attitude among HIV doctors these days that ‘one size fits all’ when it comes to HIV drugs. At the hospital, the HIV doctors don’t know enough about diabetes and the diabeticians don’t know enough about HIV – even though they’re one floor away from each other.”
Tony Wierzbicki is a lipid and cardiovascular risk specialist at St Thomas’s Hospital in London. He expects to see a lot more type 2 diabetes in people with HIV in the future.
“When people had AIDS-defining illnesses they lost a lot of weight, which protected them. But we’re now seeing increasing levels of diabetes. We see ddI-induced pancreatitis like George’s and d4T-caused insulin resistance, but anyone with VAT is pushed up the diabetes risk scale.”
The best form of diabetes treatment is prevention. “You can reduce your risk of type 2 diabetes by two-thirds if you work on being fit and not being overweight, and 50% of people with early diabetes can reverse it back to a pre-diabetic stage.13,14 Smoking contributes to insulin resistance,15 so give that up. Dietary trials have usually been about reducing saturated fat, but the modern diet problem is now too much sugar rather than too much fat.
“Unfortunately however there is a point of no return after which type 2 diabetes will continue to progress. After this point we can use drugs to control glucose levels. These can help control the condition for decades before we have to start using insulin.
“The drugs either reduce the amount of glucose released into the blood (e.g. metformin), boost insulin production (e.g. gliclazide) or make body cells more sensitive to insulin (e.g. rosiglitazone).16
“Metformin is the number one strategy for management. Unfortunately it also causes both diarrhoea and constipation.17 It also induces fat loss, so if you have lipoatrophy it could make that look worse.”
The second-line therapies are the sulphonylurea drugs like gliclazide. These boost insulin production but can cause weight gain and hypoglycaemia (‘hypos’, a condition familiar to insulin users, in which blood sugar falls drastically, causing fatigue, anxiety and eventually coma).
Dr Wierzbicki says, “Both metformin and sulphonylureas have long-term evidence of benefit.”18
The third-line drugs are the thiazolidinedione (TZD) or ‘glitazone’ drugs, which induce the sluggish cells to be more sensitive to insulin. However they may be associated with weight gain, fluid retention, possibly heart disease, and fractures.19
“There are a few new classes. One class is the DPP-4 antagonists which also increase insulin production.20 The first one, sitagliptin, was licensed in 2007.21 They reduce blood glucose in diabetics but only a handful of people with HIV have tried them. And there’s a new injectable agent called exenatide,22 which amplifies the action of any remaining insulin you have. Unfortunately it can also cause pancreatitis and I’ve seen ten cases of it being tried in people with HIV.”
Generally, Wierzbicki comments, “It feels like the early days of awareness of increased heart attack risk in people with HIV. Diabetes takes longer to develop, so we’re only just beginning to recognise that diabetes may be a big problem in the coming years.
“That is slowly changing, but the average diabetologist knows nothing about HIV and I think HIV doctors need better training to try and manage patients with pre-diabetes in their units. We have a cardiovascular risk clinic in the HIV clinic here now, as do some of the other large London clinics. With complex cases, however, HIV clinicians will still have to know when to bail out and seek expert help.”
Grinspoon S et al. Mechanisms and strategies for insulin resistance in acquired immune deficiency syndrome Clin Infect Dis. 37, Suppl 2:S85-90, 2003.
See for instance Gabriely I et al. Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process? Diabetes 51:2951-2958, 2002; Grunfeld C et al. Association of upper trunk and visceral adipose tissue volume with insulin resistance in control and HIV-infected subjects in the FRAM study JAIDS 46:283-290, 2007.
See for instance www.nfb.org/Images/nfb/Publications/vod/vod215/vodwin0701.htm
Domingo P et al. Switching to nevirapine decreases insulin levels but does not improve subcutaneous adipocyte apotosis in patients with highly active antiretroviral therapy-associated lipodystrophy Journal of Infectious Diseases 184:1197-1201, 2001.
Justman JE et al. Protease inhibitor use and the incidence of diabetes mellitus in a large cohort of HIV-infected women JAIDS 32: 298-302, 2003.
De Wit S et al. Relationship between use of stavudine and diabetes mellitus 8th International Congress on Drug Therapy in HIV Infection, Glasgow, Abstract PL9.5, 2006.
Schwartz J-M et al. Indinavir increases glucose production in healthy HIv-negative men AIDS, 18:1852-854, September 3, 2004.
Currier JS et al. Diabetes mellitus in HIV-infected individuals 9th CROI Seattle, abstract 677, 2002.
Koeppe J and Kosmiski L Apparent resolution of type 2 diabetes mellitus after initiation of potent antiretroviral therapy in a man from African with HIV infection Clin infect Dis 42: e79-e81, 2006.
Zamboni M et al. Body fat distribution before and after weight gain in anorexia nervosa International Journal of Obesity 21: 33-36, 1997.
Chandalia M et al. Ethnic differences in the frequency of ENPP1/PC1 121Q genetic variant in the Dallas Heart Study cohortJ Diabetes Complications. 21:143-8, 2007; Chowdhury TA. Br J Diabetes Vasc Dis. Type 2 diabetes in people of South Asian origin: potential strategies for prevention 7:279-82, 2007.
Lindstrom J et al. The Finnish Diabetes Prevention Study (DPS): Lifestyle intervention and 3-year results on diet and physical activity Diabetes Care 26:3230-6, 2003.
Knowler WC et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin N Engl J Med 346:393-403, 2002.
Eliasson B et al. The insulin resistance syndrome in smokers is related to smoking habits Arteriosclerosis and Thrombosis 14:1946-50, 1994.
Bolen S et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus Ann Intern Med 147:386-99. 2007.
Mulligan K et al. Effects of metformin and rosiglitazone in HIV-infected patients with hyperinsulinemia and elevated waist/hip ratio AIDS 21(1):47-57, January 2, 2007.
Holman RR et al. 10-year follow-up of intensive glucose control in type 2 diabetes and Long-term follow-up after tight control of blood pressure in type 2 diabetes N Engl J Med 359:1565-76 and 1577-89, 2008.
Singh S et al. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis JAMA 2298:1189-95, 2007.
Bailey CJ Drugs on the horizon for diabesity Current Diabetes Reports 5:353-9, 2005.
Aschner P. Diabetes 55 (Suppl. 1): A462, 2006.
- Buse JB et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes Diabetes Care 27:2628-35, 2004.