By Dr. Geoffrey Modest
The Am Assn of Clinical Endocrinologists and the Am College of Endocrinology just came out with their 2016 updated diabetes management algorithms (see https://www.aace.com/sites/all/files/diabetes-algorithm-executive-summary.pdf ). Note: this is different from the annual Am Diabetes Assn diabetes care summary, which I cannot access now (website down) but will review at some point.
- Lifestyle optimization is the cornerstone of diabetes therapy:
- Optimal weight, regular activity (at least 150 min/week of moderate-intensity activity such as brisk walking plus strength training), sufficient amount of sleep (6-9 hours/night is associated with improved cardiometabolic risk factors), tobacco avoidance, behavioral support including groups for emotional support, motivation, and specific support around issues such as weight loss and exercise.
- They also support the 8 FDA-approved drugs for weight loss in overweight or obese patients, and bariatric surgery if BMI>35.
- The importance to individualize A1C targets: though an A1c<=6.5 is optimal “if it can be achieved in a safe and affordable manner”. But “minimizing both severe and non-severe hypoglycemia is a priority”.
- Glycemic control targets include fasting and postprandial blood sugars, as per self-monitoring of blood glucose (SMBG)
- Minimizing weight gain is a priority
- The choice of meds should be individualized, looking at the array of risk/benefits (see MEDS below)
- The drug algorithm stratifies drug choices by initial A1C levels
- Comprehensive therapy includes lipid and blood pressure therapy [though I would add smoking cessation, and decreasing alcohol when applicable]
- Until patient is stable, then should be seen at least every 3 months to review SMBG, check A1c, check comorbidites (g. blood pressure, lipids), psychosocial issues [again, would add smoking, alcohol]. When stable, can have less frequent monitoring
- Prediabetes: primary goal is weight loss when indicated, and they emphasize [appropriately] that these patients have a higher atherosclerotic risk and should have more aggressive risk factor management. There may also be a role for metformin, acarbose, TZDs, and GLP-1 agonists (espliraglutide3mg) in preventing diabetes, as shown in clinical trials
MEDS:
- Low risk of hypoglycemia, promotes weight loss, “has good antihyperglycemic efficacy at doses of 2,000 to 2,500 mg/d”, and has “robust cardiovascular safety relative to sulfonylureas”. They do upgrade the creatinine/GFR limitations, commenting that some authorities recommend stopping metformin only when the GFR<30 (see blog: https://stg-blogs.bmj.com/bmjebmspotlight/2015/01/23/primary-care-corner-with-geoffrey-modest-md-metformin-in-renal-failure/). And they comment on vitamin b12 deficiency in up to 16% of users, and advocating monitoring levels and treating [see below on my comments on metformin dosing]
- GLP-1 agonists. Low risk of hypoglycemia, robust A1C lowering, reduce blood sugar fluctuations in both fasting and postprandial states. Do not use exenatide if creat clearance <30, hx of pancreatitis (though no studies showing it can cause pancreatitis), and theycan cause delayed gastric emptying [which may be part of the weight loss, but can be a problem in patients with gastroparesis]
- Sodium glucose cotransporter 2 (SGLT-2) inhibitors: cause glycosuria, decrease A1c, decrease weight. They recommend, despite the increased risk of mycotic genital infections, severe DKA though infrequent, increases in bone fractures in some studies. limited efficacy if GFR <45
- Dipeptidyl peptidase 4 (DPP-4) inhibitors: enhances GLP-1 by blocking its breakdown, modest A1C effect, weight neutral, low risk of hypoglycemia,
- Thiazolidinediones (TZD): directly reduce insulin resistance, relatively potent A1C effects, low risk of hypoglycemia. And pioglitazone may confer cardiovasc disease benefit. Adverse effects include weight gain, increased bone fracture risk, and increased risk of edema/heart failure. Decreased adverse effects if use <=30mg/d of pioglitazone. [Appropriately, they do not even mention rosiglitazone]
- Alpha-glucosidase inhibitors (AGIs): modest A1C lowering, low risk of hypoglycemia, and some data finding lower cardiovasc Adverse effects of bloating, flatulence, diarrhea.
- Sulfonylureas (SFUs): relatively potent hypoglycemic effect (though lower durability than others), risk of weight gain and hypoglycemia. Glinides have lower effect on A1C, have shorter half-life, and lower risk of hypoglycemia
- Colesevelam: bile-acid sequestrant which lowers A1C modestly, no hypoglycemia, decreases LDL levels, though 10% have GI intolerance. can also increase triglycerides
- Bromocriptine: slight A1C lowering, no hypoglycemia, and may be associated with decreased cardiovascular events
- Insulin: most potent glucose-lowering agent. Consider especially in patient on 2 oral agents and A1C>8%. Usually start with single daily dose of basal insulin. Dosage can be adjusted by the patient, with clear instructions, based on SMBG readings. If on basal insulin and inadequate control, consider adding GLP-1, SGLT-2 or DPP-4 active drugs [I personally advocate the GLP-1 ones, as below]. May need to decrease insulin dose when adding these drugs. Can also add mealtime rapid insulin bolus to cover the meals. Problems with insulin include weight gain (1-3 kg more than those on other agents) and hypoglycemia (7-15% have at least 1 episode/yr). [I also have some concern about potential cardiovascular effects of the commonly associated hyperinsulinemia, as per prior blogs]
- In new onset diabetics with A1C<7.5, lifestyle plus metformin. But can use pretty much anything (GLP-1, SGLT-2 inhib, DPP-4 inhib, TZDs, AGIs, SFUs or glinides)
- If A1C>7.5, use metformin withanother drug. [See below. I think this is too aggressive and potentially dangerous]
- A1C>9 who are symptomatic might benefit from insulin. Asymptomatic, can use insulin or “may initiate therapy with maximum doses of 2 other medications” [See below. I think this is too aggressive and potentially dangerous]
COMORBIDITIES
- Blood pressure: target <130/80 [lower than JNC-8 suggests]. Less stringent in elderly [and I would add my usual caveats: check orthostatics regularly anyway, since I have seen many patients with systolics of 150 range which fall rapidly to 110 on standing; and even 130+ may be associated with cognitive decline]. In younger patients, a goal of <120/80 is reasonable if achieved safely, which seems to have a protective effect against strokes in a few studies. Lifestyle therapy is also important here (weight loss, Na restriction, alcohol restriction [though they comment on the benefits of moderate drinking, which I have challenged in several recent blogs, such as https://stg-blogs.bmj.com/bmjebmspotlight/2015/11/13/primary-care-corner-with-geoffrey-modest-md-prescribing-alcohol-to-diabetics/], and exercise. They also suggest starting with 2 agents if BP>150/100 [which I still think is too aggressive/potentially dangerous, and has appropriately been abandoned by JNC-8]
- Lipids: all diabetic patients should be classified as high or very high ASCVD risk, even those <40 yo. They recommend treating-to-goal (unlike the AHA recommendations) with LDL targets of <100 or <70 depending on their ASCVD risk. Lifestyle changes as above. They do bring up using ezetimibe to achieve further LDL reduction [though I am hesitant to endorse this; see https://stg-blogs.bmj.com/bmjebmspotlight/2015/06/23/primary-care-corner-with-geoffrey-modest-md-improve-it-trial-ezetimibe/ ] and the PCSK9 inhibitors. They also mention colesevelam and fibrates as potential add-ons, and even high-dose niacin. Also, high dose of fish or omega-3 fish oil. In those with triglycerides>500, consider low-fat and low carbohydrate diet, fibrates, omega-3-fatty acid and/or niacin (though these combos are unproven in clinical trials)
So,
- They do acknowledge the importance of life style optimization. In my experience, treating diabetes is the hardest issue in primary care, since achieving optimal (or even marginal) control is contingent on motivating the patient to optimize their lifestyle issues: exercise is often difficult for patients (g., for medical reasons such as knee arthritis or underlying depression/other psych issues, etc; or for practical reasons such as unsafe neighborhoods to walk around for personal safety issues or specific neighborhood issues such as poorly maintained sidewalks, unsafe crosswalks, etc), and diet is often difficult for a variety of reasons (lack of access to healthy foods, traditional diets high in carbs, psych issues, just trouble breaking the habit of eating unhealthy and very tasty foods for a long time, etc). and if someone does not eat a reasonably consistent diabetic die, blood sugars may range from 45-450 mg/dl, and simply cranking up the diabetic meds is potentially dangerous no matter what their A1C is (ie, lowering the 45 even further).
- As noted in many of my blogs on diabetes meds, there are precious few studies looking at important clinical outcomes. The FDA many years ago allowed drug companies to use the A1C as a surrogate marker for advances in diabetic meds. I will certainly grant that there are enough older studies that have shown consistently that lowering the A1C does lower the risk for microvascular disease, and I do not want to understate the importance of that. BUT, diabetic patients, by far, die from macrovascular disease (heart disease, strokes…), on the order of 80% of their deaths. And, though studies suggest that lowering the A1c can be beneficial for that outcome, it really depends on the drug (g., rosaglitazone was pretty effective in lowering A1C levels, but was associated in several studies with increased cardiac outcomes). The DPP-4 drugs have also been associated with adverse cardiovascular events in some studies (see https://stg-blogs.bmj.com/bmjebmspotlight/2015/06/24/primary-care-corner-with-geoffrey-modest-md-dpp-4-inhibitors-and-cardiovascular-outcomes/. And there are other significant adverse outcomes which may override the benefits of lowering the A1C: the FDA just supplemented their warning on SGLT-2 inhibitors, which are also pretty good for lowering A1c, but are associated with severe urosepsis and ketoacidosis (for prior blog, see https://stg-blogs.bmj.com/bmjebmspotlight/2015/05/27/primary-care-corner-with-geoffrey-modest-md-sglt2-inhibitors-for-diabetes-may-cause-ketoacidosis/ )
- So, my general approach to drugs (again, always continuing to work on the lifestyle issues) is:
- Metformin is generally very well-tolerated. I have seen dramatic effects of low dose metformin, with my typical starting dose of 500mg once a day, and only raise the dose as needed. There is decreased marginal effectiveness with increasing doses, similar to statins, where the majority of effectiveness is with the lowest dose. Also, metformin is better tolerated from a GI perspective when taken with meals. I think metformin is the single most useful agent for diabetic control. also, see the curious/interesting blog on metformin and the intestinal microbiome, suggesting that much of its effect may be from positive changes in the microbiome (see: https://stg-blogs.bmj.com/bmjebmspotlight/2015/01/28/primary-care-corner-with-geoffrey-modest-md-heart-failure-microbiome/). I am concerned with the above recommendations which advocate using pretty much any drug as a single agent, as opposed to other guidelines which make metformin #1, then adding others.
- I really disagree with their aggressive approach to patients with new onset diabetes. Many have A1C in the 13-19 range. I think this is mostly due to slowly progressive increases over time, which in part is from glucotoxicity (that is: as the sugar increases, the endogenous insulin works less well with documented decreases in insulin-mediated glucose uptake, leading to higher blood sugars), and this progresses until the patient becomes very symptomatic. Physiologically, my approach, as with very high but not hypertension emergency, is to see the increased sugar or blood pressure typically as a slowly progressive, with some physiologic adaptation by the body, and that it is safer to lower the blood sugar or pressure more slowly with frequent follow-up (I have seen too many patients treated aggressively, leading to electrolyte disturbances in diabetics and strokes in hypertensives). In terms of new onset diabetes with initial A1C >15%: my experience with at least 25 newly diagnosed diabetics, 100% do very well and for a long time with just metformin (which often is initially augmented with insulin, which can be tapered off over weeks to months). And this is typically with just 500-1000 mg metformin/day.
- Lately, I have been using more GLP-1 agonists if metformin needs a boost. They work really well, are mostly very well tolerated, do not cause hyperglycemia, to me seem to be pretty targeted and physiologic agents (they restore the “incretin effect”, which is blunted in diabetics). I also prescribe older drugs with more of a track record and known adverse effects (g., insulin, sulfonylureas). Though I often do add them to metformin, there is not much support for their macrovascular efficacy. Pioglitazone, especially in the 15-30mg range, works well and seems to be cardioprotective, per the PROACTIVE study (Lancet2005; 366: 1279)
- For the newer drugs, I really focus on those with the best efficacy/adverse effect ratio, and also those that have the least ubiquitous effects (g., the DPP4 inhibitors poison a prevalent enzyme system in the body, so I am hesitant to use them because their efficacy is not so great in lowering A1C levels, and their potential for longterm adverse events is high given the abundance of potential non-diabetic effects). These issues have become more concerning as the FDA is pushing through approvals more quickly, often with the intention of requiring post-marketing surveillance which the drug companies mostly do not do (see blogs below). And, of note, 19 of the 20 members of the committee developing these recommendations have drug company ties….
See:
https://stg-blogs.bmj.com/bmjebmspotlight/2015/12/21/primary-care-corner-with-geoffrey-modest-md-empaglifozin-the-good-and-the-bad/ which critques the study on the SGLT2 inhibitor empaglifozin which purportedly shows cardiac benefit, though the FDA came out with an advisory about it causing severe urosepsis and ketoacidosis
But, as noted in prior blog https://stg-blogs.bmj.com/bmjebmspotlight/2015/08/31/primary-care-corner-with-geoffrey-modest-md-regulation-of-medical-devices/ , <20% of required postmarketing studies for medical devices were done within 3 years of the FDA requiring them, and no fines have been issued for noncompliance with the FDA mandates.
https://stg-blogs.bmj.com/bmjebmspotlight/2015/12/26/primary-care-corner-with-geoffrey-modest-md-the-drug-co-shenanigans-reach-new-heights/ which goes through some of the drug company malfeasance in nonreporting of severe drug adverse effects, lack of follow-up on postmarketing studies, and the poor enforcement by the FDA.
https://stg-blogs.bmj.com/bmjebmspotlight/2015/12/11/primary-care-corner-with-geoffrey-modest-md-fructose-restriction-and-cardiometabolic-and-weight-improvement/ promoting fructose restriction in diabetes management
https://stg-blogs.bmj.com/bmjebmspotlight/2015/11/13/primary-care-corner-with-geoffrey-modest-md-prescribing-alcohol-to-diabetics/ which questions advocating alcohol for diabetics
https://stg-blogs.bmj.com/bmjebmspotlight/2015/09/02/primary-care-corner-with-geoffrey-modest-md-dpp-4-inhibitors-in-diabetics-and-severe-joint-pain/ with FDA warning about DPP-4 inhibitors and joint pain
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