diabetes update AHRQ, and pioglitazone to prevent cardiovasc disease

the Agency for Healthcare Research and Quality (AHRQ)  just published an update on diabetes meds for adults with type 2 DM, looking at some of the newer studies on the meds (see https://www.effectivehealthcare.ahrq.gov/ehc/products/607/2215/diabetes-update-2016-report.pdf​ , also published in annals of internal medicine at doi:10.7326/M15-2650 ). they assessed 4 key questions (KQs). findings (which limited in many cases by lack of reasonable studies):

KQ1. comparative effectiveness of monotherapies for A1c, weight, systolic BP (SBP), and heart rate; and in particular for metformin-based combinations

--for reducing A1c:

    --metformin, thiazolidinediones (TZDs) and sulfonylureas (SU) were best. DPP-4 inhibitors less good

    --combos of metformin plus TZD, SU, SGLT-2 inhibitors and DPP-4 inhibitors were generally better in lowering A1c than metformin alone. (best were metformin plus SU or TZD). not enough data for GLP-1 receptor agonists

--for reducing weight:

    --metformin better than DPP4. GLP-1 better than SU. SU better than TZD

    --combos: metformin alone better than metformin with TZD, SU; metformin plus GLP-1 or SGLT2 were better than metformin alone; metformin plus SU was better than metformin plus premixed or basal insulin (-0.5 to -1.7 kg)

--for SBP and pulse:

    --SGLT-2 was best for reducing SBP (2.8 mmHg better than metformin); and a GLP-1 with metformin was better than metformin

    --metformin and GLP-1 increased heart rate equivalently. adding SGLT-2 to metformin had less increase

KQ2. comparative effectiveness of monotherapies for all-cause mortality, cardiovascular and cerebrovascular morbidity/mortality, and microvascular morbidity (retinopathy, nephropathy, neuropathy); and in particular for metformin-based combinations 

--only one comparison had moderate strength-of-evidence for these outcomes

    --SU (vs metformin)  was associated with a 50-70% higher relative risk of cardiovascular mortality; data on all-cause mortality also favored metformin, but less consistent studies. no comment on cerebrovascular morbidity/mortality

KQ3. comparative safety of monotherapies for liver injury, lactic acidosis, pancreatitis, hypoglyemcia, heart failure, cancer, severe allergic reactions, macular edema/decreased vision, GI side-effects; and in particular for metformin-based combinations

--hypoglycemia

    --SU alone or in combo with metformin had higher risk; SU had higher risk than GLP-1; metformin plus GLP-1 had less than metformin plus SU or metformin plus insulin. SU had more risks of severe hypoglycemia vs TZD

--GI

    --metformin and GLP-1 had the most (mostly nausea, vomiting, diarrhea); metformin plus GLP-1 had more diarrhea than metformin plus DPP-4 or metformin plus TZD. TZDs were similar to SUs

--heart failure

    --more HF with TZDs (though low strength of evidence) vs metformin or SU; insufficient evidence for DPP-4.

--cancer

    --not great data. low strength of evidence that metformin plus SU was better than metformin plus DPP-4

--specific to SGLT-2:

    --UTIs, genital mycotic infections, renal function impairment, fractures, volume depletion. (apparently not enough data about DKA)
--other outcomes

    --not enough data about liver injury, pancreatitis, lactic acidosis, severe allergic reactions, macular edema/decreased vision

KQ​4. do the comparative safety and effectiveness of thse treatments vary by age, sex, race/ethnicity, BMI

--little evidence for any of this

so, a few points from this analysis:

--again, these comparative effectiveness reports highlight more about the inadequacy of what we really know than reveal unexpected or novel clinical conclusions. 

--as per most of my blogs on diabetes, there is no question to me that metformin is the best drug, that we should do whatever we can to convince patients to take it (including being lenient on the renal failure prohibitions as per blogs below, and even using very small doses, such as 250mg taken with food, in those with significant GI toxicity). my personal approach is to start new diabetics on metformin 500mg once a day (to minimize adverse effects), and the vast majority of time, that is a sufficient dose. 

--and, very unfortunately, drug companies were able to dumb-down the required studies for the FDA for new diabetes meds so that A1C was an FDA-acceptable endpoint (and we know that all drugs that lower A1C are not necessarily good for you: eg rosiglitazone, see below). so, there is little drug company investment in looking for longer-term (and more important) outcomes, such as mortality or heart disease (70-80% of diabetics die from ASCVD). so, again, i am still reluctant to use many of the newer drugs given the overall lack of important clinical outcomes, though, as mentioned in prior blogs, i do use a fair amount of the GLP-1 agonists (they are physiologically appealing in that they restore the normal incretin effect (they stimulate insulin release only when there is food in the stomach), they decrease weight, and they do not cause hypoglycemia. and i do use some pioglitazone, as segue to the next study....

relevant prior blogs:

http://gmodestmedblogs.blogspot.com/2015/06/metformin-ckd-and-death.html  and http://gmodestmedblogs.blogspot.com/2015/01/metformin-in-renal-failure.html look at using metformin in patients with renal dysfunction.

http://gmodestmedblogs.blogspot.com/2019/04/new-diabetes-guidelines-from-ada.html  for the 2016 ADA guidelines, which clearly situate metformin as the primary drug to use

2. a recent article found benefit for pioglitazone in patients with insulin resistance who had a transient ischemic attack (TIA) or an ischemic stroke (see stroke tia prevention with pioglitazone nejm2016 in dropbox, or N Engl J Med 2016;374:1321). they chose pioglitazone since it is a potent insulin sensitizer, with insulin resistance being a significant risk factor for cerebrovascular disease. details:

--3876 patients with a recent ischemic stroke or TIA were randomized to pioglitazone up to 45mg/d vs placebo

--all patients had insulin resistance by the hometostasis model assessment of insulin resistance (HOMA-IR), with a score >3.0. Followed 4.8 years​

--mean age 64, 65% male, 12% Black/4% Hispanic, 88% had recent stroke, 72% hypertensive, 12% CAD, 7% atrial fib, BMI 30, BP 134/79, HOMA-IR=4.7, A1c=5.8, LDL 88/HDL47, 83% on statin, 92% antiplatelet drug/55% ACE-I or ARB.

--funded by National Institute of Neurological Disorders and Stroke

--primary outcome: fatal or nonfatal stroke or MI

--results:

    --primary outcome in 175 (9.0%) in the pioglitazone group and 228 (11.8%) in the placebo group, a 34% decrease: HR 0.76 (0.62-0.93), p=0.007

    --diabetes developed in 73 (3.8%) in pioglitazone and 149 (7.7%) in placebo, a 52% decrease; HR 0.48 (0.33-0.69, p<0.001

    --no diff in all-cause mortality or in heart failure, but there was more weight gain with pioglitazone (52.2% vs 33.7% gained >4.5 kg), edema (35.6% vs 24.9%) and bone fracture requiring surgery or hospitalization (5.1% vs 3.2%)

so, a few points:

--HOMA-IR index is a pretty simple (?simplistic) calculation used in many studies as a proxy for insulin resistance, calculated by: fasting glucose (in mmol/L) x fasting insulin (in microunits/ml) x 22.5

--pioglitazone is one of the PPAR-g agonists (peroxisome proliferator-activated receptor) and causes partial activation of PPAR-a, and in combination leads to improved insulin sensitivity, fat distribution, lipid and protein metabolism, vascular endothelial function, and inflammation. its cousin, rosiglitazone, is a bad actor associated with increased cardiac events. but pioglitazone has positive effects on lipids (vs rosiglitazone) as well as CRP levels, and an older study (the PROactive study, see dm pioglit PROACTIVE study lancet 2005 in dropbox, or Lancet 2005; 366: 1279) found a significant decrease in the secondary endpoint of the composite of all-cause mortality, non-fatal MI, stroke.

--not surprisingly, pioglitazone does seem to decrease (or delay) the progression from insulin resistance/glucose intolerance to frank diabetes. And by a pretty whopping 50%

--i do not use much pioglitazone, and do so pretty much only in patients who adamantly refuse injection therapies but have miserable glucose control on metformin with glipizide (the SU of choice). i do think that this study adds to the PROACTIVE study in showing that there are significant macrovascular benefits, though i don't like the fact that pioglitazone affects a really important and pervasive enzyme system in the body (ie, not even close to being a targeted therapy/silver bullet, which unnerves me a tad about unforeseen longterm issues), and causes so much weight gain (combo of increased adipose tissue and fluid accumulation).