what does triglycerides have to do with high blood glucose
Curr Diab Rep. Author manuscript; bachelor in PMC 2019 Jul thirty.
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PMCID: PMC6664805
NIHMSID: NIHMS1042726
Triglycerides: Emerging Targets in Diabetes Intendance? Review of Moderate Hypertriglyceridemia in Diabetes
Anastasia-Stefania Alexopoulos
1Department of Medicine, Sectionalization of Endocrinology, Knuckles Academy Medical Center, Durham, NC, The states
2Section of Medicine, Division of Endocrinology, Durham VA Medical Centre, Durham, NC, USA
Ali Qamar
1Department of Medicine, Segmentation of Endocrinology, Duke University Medical Center, Durham, NC, USA
2Department of Medicine, Division of Endocrinology, Durham VA Medical Middle, Durham, NC, United states
Kathryn Hutchins
1Department of Medicine, Partitioning of Endocrinology, Duke University Medical Center, Durham, NC, The states
twoDepartment of Medicine, Division of Endocrinology, Durham VA Medical Heart, Durham, NC, U.s.a.
Matthew J. Crowley
1Section of Medicine, Division of Endocrinology, Knuckles University Medical Center, Durham, NC, United states
twoDepartment of Medicine, Partition of Endocrinology, Durham VA Medical Middle, Durham, NC, USA
Bryan C. Batch
oneDepartment of Medicine, Division of Endocrinology, Duke University Medical Center, Durham, NC, Us
2Department of Medicine, Partitioning of Endocrinology, Durham VA Medical Center, Durham, NC, USA
John R. Guyton
oneDepartment of Medicine, Division of Endocrinology, Duke Academy Medical Center, Durham, NC, USA
Abstruse
Purpose of Review
Moderate hypertriglyceridemia is exceedingly common in diabetes, and there is growing show that information technology contributes to residual cardiovascular risk in statin-optimized patients. Major fibrate trials yielded inconclusive results regarding the cardiovascular benefit of lowering triglycerides, although in that location was a point for improvement among patients with high triglycerides and low high-density lipoprotein (HDL)—the "diabetic dyslipidemia" phenotype. Until recently, no trials have examined a priori the impact of triglyceride lowering in patients with diabetic dyslipidemia, who are probable among the highest cardiovascular-risk patients.
Recent Findings
In the recent REDUCE IT trial, omega-3 fatty acid icosapent ethyl demonstrated efficacy in lowering cardio-vascular events in patients with high triglycerides, depression HDL, and statin-optimized low-density lipoprotein (LDL). The ongoing PROMINENT trial is examining the impact of pemafibrate in a like patient population.
Summary
Emerging bear witness suggests that lowering triglycerides may reduce residual cardiovascular risk, especially in high-gamble patients with diabetic dyslipidemia.
Keywords: Hypertriglyceridemia, Blazon 2 diabetes, Diabetic dyslipidemia, Medications
Introduction
Compared to patients without diabetes, individuals with diabetes are at 2–four times the adventure of stroke and death from heart disease [1]. Elevated triglyceride levels are common in patients with blazon 2 diabetes. Discussions regarding the cardio-vascular risk associated with moderate hypertriglyceridemia are escalating. While low-density lipoprotein (LDL) is a well-established hazard factor in diabetes, and statins remain first-line therapy for cardiovascular risk reduction, it has get credible that "residue hazard" exists for cardiovascular affliction, despite attainment of at-goal LDL-C levels [two••].
In the PROVE IT-TIMI 22 trial, on-statin triglycerides of ≥ 150 mg/dL were independently associated with increased take chances of recurrent coronary heart disease [3]. However, in 2010, Accord Lipid demonstrated no significant cardiovascular benefit with the use of fenofibrate to target triglycerides in statin-treated patients [4]. While major fibrate trials have yielded conflicting results regarding the cardiovascular do good of lowering triglycerides [4–ten], a systematic review and meta-assay of these trials suggests benefit in patients with a blueprint of high triglycerides and low high-density lipopro-tein (HDL) [11]—a classic lipid phenotype in diabetes referred to as "diabetic dyslipidemia" or "atherogenic dyslipidemia." In addition to clinical and epidemiologic studies [12–14], genetic [xv–xix] and Mendelian randomization studies [20–22] take more recently highlighted triglycerides every bit a modifiable risk factor in cardiovascular disease. Therefore, there is renewed interest in targeting triglycerides to reduce "residual" cardiovascular risk, particularly in patients with diabetes who exhibit a high-risk lipid phenotype and are at baseline heightened risk of cardiovascular events. Hither, we review moderate hypertriglyceridemia in diabetes, including a proposed approach to management based on updated evidence.
Triglyceride Metabolism and Diabetic Dyslipidemia
Fatty acids and glucose both have major roles in supplying free energy to body tissues during cycles of feeding and fasting. In addition to energy storage within adipocytes and other cells, triglycerides provide majority send of esterified fatty acids in circulating chylomicrons, very low-density lipoproteins (VLDL), and their remnants. Collectively, these are called triglyceride-rich lipoproteins (TRL). See Fig. 1 for a schematic of TRL metabolism, specifically how plasma TRL interact with organ systems and other lipoprotein particles.
Triglyceride-rich lipoprotein metabolism. TRL, triglyceride-rich lipoproteins; VLDL, very low-density lipoprotein; FA, fatty acids; LPL, lipoprotein lipase; TG, triglycerides; CE, cholesterol esters; CETP, cholesteryl ester transfer protein; LDL, depression-density lipoprotein; HDL, high-density lipoprotein; NEFA, nonesterified fatty acids; HSL, hormone sensitive lipase; ATL, adipocyte triglyceride lipase
Fatty acids from the diet are largely incorporated into triglycerides in intestinal mucosal cells and secreted in chylomicrons, which bypass the liver and enter the systemic circulation via abdominal lymph through the thoracic duct.
Chylomicrons then evangelize dietary fatty acids to peripheral tissues through the action of lipoprotein lipase (LPL), which hydrolyzes chylomicron triglyceride to release free fatty acids, generating chylomicron remnants in the process.
The liver receives some fat acids from boosted lipolysis and uptake of remnant lipoproteins. Other important sources of hepatic fatty acids are (1) de novo hepatic lipogenesis and (2) uptake of nonesterified fatty acids (NEFA) which circulate in plasma bound to albumin. NEFA are released by adipocytes through the activeness of hormone sensitive lipase (HSL) and adipocyte triglyceride lipase. Access of these intracellular enzymes to adipocyte triglyceride is suppressed by insulin and activated when insulin levels are very low [23]. Excessive release of NEFA by adipocytes under conditions of insulin resistance and/or deficiency appears to exist a major driver of dyslipidemia in diabetes, equally well as in insulin-resistant states such every bit obesity [24].
Circulating VLDL undergo progressive lipolysis past LPL in peripheral tissues, delivering fat acids for energy use by muscle and other tissues, and for energy storage as triglyceride in adipocytes. LPL activity as well produces VLDL remnant particles, chosen intermediate-density lipoproteins (IDL). IDL return to the liver, where they are partly internalized and partly processed at the prison cell surface past hepatic lipase to become LDL. Insulin also stimulates the function of LPL, then insulin resistance contributes suboptimal metabolism of VLDL particles.
Hypertriglyceridemic states can arise from excess VLDL production and/or inefficient lipolysis. In either case, TRL participate in heteroexchange of neutral lipids (triglycerides and cholesteryl esters) with LDL and HDL via cholesteryl ester transfer poly peptide, which in turn leads to triglyceride en-richment of LDL and HDL particles. Through subsequent action of hepatic lipase, LDL particles go small, dumbo, and more atherogenic. With similar lipolysis, HDL particles lose some of their apolipoproteins which desorb from the shrinking HDL surface and undergo catabolism in the kidney. Overall, this leads to the archetype triad of elevated triglyceride, depression HDL, and small dense LDL that characterizes the dyslip-idemia associated with diabetes and insulin resistance [24], known every bit diabetic dyslipidemia.
Secondary Causes of Hypertriglyceridemia
Prior to starting pharmacotherapy, it is important to consider and accost secondary causes of hypertriglyceridemia. While not an exhaustive list, Table 1 includes several secondary, nongenetic causes of hypertriglyceridemia. Efforts should be made to optimize lifestyle habits and medical conditions as a ways of lowering triglycerides, and if possible, culprit medications should exist discontinued.
Table ane
Secondary causes of hypertriglyceridemia
| Lifestyle |
| Loftier glycemic alphabetize nutrition |
| Loftier fructose or sucrose intake |
| Concrete inactivity |
| Excess alcohol intake |
| Tobacco abuse |
| Medical weather condition |
| Type two diabetes |
| Obesity or overweight status |
| Hypothyroidism |
| Nephrotic syndrome |
| Polycystic ovarian syndrome |
| Cushing's syndrome |
| Human immunodeficiency virus (HIV) |
| Lipodystrophy |
| Acromegaly |
| Pregnancy |
| Medications |
| Oral estrogens |
| Steroids |
| Tamoxifen |
| Atypical antipsychotics |
| Antiretroviral therapy |
| Bile acid sequestrants |
| Thiazides |
| Beta-blockers |
| Cyclosporine |
| Sirolimus |
| Retinoic acrid derivatives |
Diabetes is a mutual and important contributor to dyslipidemia. Poorly controlled diabetes can stand for a medical emergency requiring urgent insulin therapy when it leads to farthermost hypertriglyceridemia and risk of pancreatitis. Notwithstanding, when one moves from modest to tight glycemic control, say, from hemoglobin A1c of 8.5 to 6.five%, the dyslipidemic triad tends to persist. Dietary measures such as emptying of sugar-sweetened or naturally sweet beverages should be a priority in any patient with hypertriglyceridemia.
Glucose-Lowering Medications and Triglycerides
Glucose-lowering medications accept varying effects on tri-glycerides. Equally mentioned above, insulin lowers circulating triglycerides by a number of mechanisms, including consecration of LPL and suppression of HSL. Metformin is a small-scale insulin sensitizer that can lower triglycerides, an upshot that appears independent of its effects on weight and glycemic control [25, 26•, 27, 28•, 29]. A systematic review of 37 studies revealed a decrease in serum triglycerides averaging xi.five mg/dL with metformin use, although higher doses (> 1700 mg per day) are required to achieve this [25].
Pioglitazone is a peroxisome proliferator-activated receptor-ϒ (PPAR-ϒ) agonist; a strong insulin sensitizer with strong effect on triglycerides. Pioglitazone tin can reduce triglycerides past up to 50 mg/dL and raise HDL cholesterol (HDL-C) by 5 mg/dL [26•, 27, 28•, 29], although LDL cholesterol (LDL-C) also rises. Notwithstanding, it is important to note that a rising in LDL-C does not necessarily impart higher cardiovascular risk. In fact, LDL particle number (LDL-P) better captures the exceptional atherogenicity of modest, dense LDL particles which comport less cholesterol than large, buoyant LDL [30, 31]. Pioglitazone reduces dumbo atherogenic LDL particles [32]; therefore, information technology is plausible that this observed rise in LDL-C reflects an increment in LDL particle size rather than particle number (LDL-P). Dissimilar pioglitazone, rosiglitazone is a PPAR-ϒ agonist with less favorable touch on lipids, as some studies report a neutral result, while others annotation increment in triglycerides [26•, 27, 28•, 29].
Sulfonylureas, which human action by augmenting beta prison cell insulin release, have not demonstrated a consistent issue on lipids [29, 33].
Newer glucose-lowering agents take demonstrated benefit in their ability to ameliorate triglycerides. Glucagon-like peptide-one (GLP-1) receptor agonists improve both fasting and postprandial hypertriglyceridemia with a mean reduction upward to 27 mg/dL, merely with no consistent effect on HDL levels [26•, 28•, 34, 35••, 36]. Unlike GLP-i receptor agonists which provide supraphysiological levels of circulating GLP-1, dipeptidyl peptidase 4 (DPP4) inhibitors increment endogenous GLP-ane levels. Thus, DPP-four inhibitors by and large exert a more than minor effect on triglycerides [26•, 29], although mean triglyceride reductions as high equally 26 mg/dL accept been reported [28•]. For unclear reasons saxagliptin is an exception to the typical DPP-4 inhibitor effect, equally it consistently appears lipid-neutral [26•, 29]. Aside from weight loss (GLP-1 receptor agonists only) and glycemic control, incretin-based therapies may lower triglycerides by promoting GLP-1-mediated delay in gastric emptying, reduction of intestinal triglyceride assimilation, and subsequent decrease in chylomicron synthesis [37]. Additional mechanisms probable mediate the furnishings of GLP-1 on lipid metabolism, though they have nonetheless to be fully elucidated.
Sodium glucose cotransporter-2 (SGLT2) inhibitors increase HDL and lead to a 10% reduction in triglycerides, just as well heighten LDL-C [26•, 28•]. Despite the business of increasing LDL-C, SGLT2 inhibitors have cardioprotective furnishings in type 2 diabetes [38•], and similar to pioglitazone, they reduce small, dense LDL particles with a consequent shift towards big, buoyant, less atherogenic LDL [39•].
Established Methods of Lowering Triglycerides
Diet and Lifestyle
Lifestyle modification remains the mainstay of therapy for hypertriglyceridemia. Combining dietary regulation, do, and moderation of booze intake can reduce triglycerides by upwards to threescore% [forty]. In addition, weight loss of v–x% of initial trunk weight reduces triglycerides by 25% and increases HDL-C by 8% [40]. A number of dietary approaches may be effective in reducing triglycerides; however, a central theme is abstention of high glycemic alphabetize foods, which is equally important from a diabetes standpoint. A very low fatty nutrition becomes important merely when LPL activity is severely dumb, such as in patients with familial chylomicronemia syndrome, or just when triglycerides are very elevated (e.grand., > 1000 mg/dL). When LPL is severely deficient or functionally dumb, there can be rapid accumulation of TRL with contribution of dietary fat [41•], hence the rationale for reducing fatty intake. Still, for patients with functioning LPL and less than severe hypertriglyceridemia (< 1000 mg/dL), weight loss and low glycemic diet are more effective at lowering triglycerides than low fat diet [42], via reductions of circulating NEFA and of de novo hepatic lipogenesis [43].
Statins
Statins are the cornerstone of treatment for LDL and cardiovascular take chances reduction in diabetes. Patients with baseline hypertriglyceridemia feel a 22–45% reduction in levels with statin therapy [44]; however, hypertriglyceridemia may persist. Other available medication classes for the direction of hypertriglyceridemia include fibrates, niacin, and omega-iii fat acids.
Fibrates
Fibrates are often considered first-line adjuncts to manage hypertriglyceridemia if lifestyle modifications and statin therapy fail to achieve goals. Fibrates work past activating PPAR-a, which in turn enhances expression of LPL and other lipid-modifying genes [45]. Currently in that location are ii fibrates approved in the U.s.a.: fenofibrate and gemfibrozil. Fibrates are potent triglyceride-lowering agents, reducing plasma levels by 30–fifty% [46]. Fibrates are generally well tolerated, although take a chance of muscle toxicity increases when combined with statin therapy. One should avoid gemfibrozil in statin-treated patients for this reason, but fenofibrate can exist used safely with some caution [47].
There are mixed data concerning fibrates and cardiovascular outcomes. In the Helsinki Heart Report, gemfibrozil reduced the charge per unit of incident coronary heart disease by 32% [5]. Similarly, VA Hit (Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group) plant that gemfibrozil reduced the combined outcome of death from coronary eye disease, nonfatal myocardial infarction, and stroke by 24% compared to placebo [8]. Subsequently, the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study specifically examined patients with type 2 diabetes (of which in that location was poor representation in previous studies) and failed to demonstrate a decrease in their composite cardiovascular event, although fewer nonfatal myocardial infarctions and revascularizations occurred in the fenofibrate-treated group [6]. High statin initiation in the placebo arm and driblet outs in the intervention arm render FIELD a hard report to translate, as benefits of fenofibrate may have been masked past these occurrences. ACCORD (Activity to Control Cardiovascular Risk in Diabetes) Lipid was the outset report to examine the cardiovascular benefit of fibrates as improver therapy to statins [4]. This written report did non demonstrate cardiovascular benefit with fenofibrate beyond that already conferred by statins; however, subgroup analysis suggested that patients with loftier triglycerides (≥ 204 mg/dL) and low HDL-C (≤ 34 mg/dL) may have been the most likely to derive benefit [iv]. Additional studies are ongoing to evaluate the impact of fibrates on cardiovascular outcomes in high-risk patients. PROMINENT (Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes) is a multicenter phase Three trial which will examine major cardiovascular outcomes with pemafibrate versus placebo in ten,000 patients with diabetes and dyslipidemia (clinicaltrials.gov identifier: ). In short-term trials, pemafibrate has shown good lipid efficacy and superior tolerability compared to fenofibrate [48••, 49••].
Dual PPAR-a/ϒ agonists were developed with the expectation that they could lower triglycerides similarly to fibrates (PPAR-a activity), and improve insulin sensitivity similarly to thiazolidinediones (PPAR-ϒ action). While these agents produce favorable lipid and glycemic changes [50], robust evidence of cardiovascular benefit is lacking, and safety concerns have express their use [51]. For case, aleglitazar is a dual PPAR-a/ϒ agonist that did not demonstrate do good in cardiovascular outcomes, and also caused a significant increase in gastrointestinal bleeding and renal dysfunction [51]. New PPAR agonists are nether investigation for dyslipidemia [52], and elafibrinor is a dual PPAR-a/δ agonist which is likewise in phase III trials for not-alcoholic fatty liver illness (clinicaltrials.gov identifier: ).
Omega-iii Fatty Acids
Omega-iii fatty acrid preparations containing eicosapentaenoic acid (EPA) and/or docosahexaenoic acrid (DHA) reduce fasting and postprandial triglycerides through suppression of hepatic VLDL production [53–55]. Omega-iii fatty acids are typically used as an adjunct to diet and other therapies. Over the counter preparations take variable proportions of EPA and DHA, so prescribed capsules are preferable for triglyceride reduction as their omega-iii fat acrid content is consistently ≥ 85%. Doses of 3–4 g per twenty-four hour period of EPA ± DHA are required to reduce triglycerides past up to 45% [56, 57]. Available preparations in the USA include combination EPA/DHA in varying proportions (Epanova, Lovaza) [58, 59], and ≥ 95% icosapent ethyl (Vascepa) [60], an ethyl ester of EPA [58–61]. EPA/DHA and icosapent ethyl are equally effective in reducing triglycerides, though the EPA/DHA formulation Lovaza may heighten LDL-C modestly, and icosapent ethyl (Vascepa) has no significant consequence on LDL-C [56, 57]. Epanova is the virtually recent EPA/DHA preparation approved by the Food and Drug Administration (2014), and it may too increase LDL-C by up to 19% [62]. The clinical relevance of this LDL-C ascent with EPA/DHA formulations is unclear, and it is non accompanied by a rise in non-HDL or ApoB, which are better indicators of cardiovascular run a risk [63].
Outcomes trials yielded mixed results for cardiovascular do good with the employ of omega-3 fat acids [64–66]. However, doses used in initial studies were much lower than currently recommended for hypertriglyceridemia (i m instead of 3–iv g), and these low doses were examined on background statin therapy [64, 65]. Additionally, patients with hypertriglyceridemia were not targeted, and mean baseline triglyceride levels were ≤ 150 mg/dL among participants [64, 65]. A subsequent landmark study in Japan utilized a moderate dose of EPA ethyl esters (ane.eight k) in conjunction with low-dose statin therapy versus statin therapy lonely, and observed a nineteen% reduction in major coronary events in those receiving EPA [67]. Furthermore, the REDUCE It trial (Reduction of Cardiovascular Events with Icosapent Ethyl Intervention Trial) recently demonstrated a meaning 25% reduction in major adverse cardiovascular events in patients receiving iv g of icosapent ethyl daily with statin therapy versus statin solitary [68••]. Information technology is worth noting that (1) most patients in REDUCE Information technology had diabetes (> 57%); (2) mean baseline triglycerides were 216 mg/dL; (3) mean baseline LDL-C levels were low at 74–76 mg/dL; and (four) reduction in the primary endpoint was most prominent in patients with atherogenic dyslipidemia; a pattern of loftier triglycerides (≥ 200 mg/dL) and low HDL-C (≤ 35 mg/dL) [68••]. REDUCE Information technology therefore supports the concept that while treating all patients with moderate hypertriglyceridemia may non be useful, targeting high-hazard patients with diabetic dyslipidemia despite statin-optimized LDL may be of benefit.
It is important to go on in mind that cardiovascular do good of omega-3 fat acids may not only be mediated past triglyceride reduction, simply also by their anti-inflammatory, antioxidant, and antiarrhythmic properties [69]. It remains to be determined whether other methods of triglyceride lowering will have a like touch on cardiovascular outcomes, and the results of PROMINENT volition be specially informative in this regard.
Additional ongoing trials are investigating the effects of moderate- and high-dose omega-three fatty acids on cardiovascular outcomes. These studies include RESPECT-EPA (Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy—statin and EPA; clinical trials registry no. UMIN000012069), a secondary prevention trial in Japan exploring the combination of statin and EPA (one.eight g daily), and EVAPORATE (Effect of Vascepa on Improving Coronary Atherosclerosis in People with High Triglycerides Taking Statin Therapy; clinicalTrials.gov number, ) which will be investigating the effects of Icosapent ethyl (Vascepa), four g daily, on coronary atherosclerosis in patients with hypertriglyceridemia on-statin therapy. STRENGTH (Outcomes study to appraise STatin Residue risk reduction with EpaNova in high cardiovascular risk patienTs with Hypertriglyceridemia) is a trial that will be exploring residual cardiovascular risk reduction with 4 g daily of EPA/DHA (Epanova) and statin therapy, versus corn oil with statin therapy (clinicalTrials.gov number, ). Finally, icosabutate is a synthetic omega-three fat acid under evolution, and emerging show suggests that in addition to lowering triglycerides, it has antifibrotic properties which may prove benign in nonalcoholic steatohepatitis [70•, 71•].
Niacin
Niacin, or nicotinic acid, reduces triglyceride levels and increases HDL by upwardly to 30% when doses of 1.five–3 g daily are used [72]. Niacin can lead to a 15% reduction in LDL-C and 25% reduction in lipoprotein(a) levels [72, 73]. Fibrates are utilized more ofttimes than niacin to lower triglycerides as they are more stiff and are better tolerated. Concerns have been raised regarding niacin'south trend to worsen glycemic control [74–76], although patients with diabetes who have moderate-to-good glycemic control can use niacin safely at moderate dosages [77, 78]. Other agin furnishings which may deter employ of niacin include flushing and less ofttimes eczema-like skin rash, acanthosis nigricans, and gastrointestinal distress.
Considering it lowers triglycerides, raises HDL, and decreases lipoprotein(a), which is an independent risk factor for atherosclerosis not impacted by statins [79], niacin might be expected to improve patient outcomes. In older niacin trials of secondary cardiovascular prevention before the appearance of statin therapy, accented mortality reductions of 6.2 and vii.8% were demonstrated, compared to the best absolute mortality reduction of 3.5% with a statin in the Scandinavian Simvastatin Survival Study [fourscore]. Yet, bear witness does not suggest improved outcomes with niacin for patients on background statin therapy. The AIM-HIGH trial did not demonstrate incremental cardiovascular benefit of niacin therapy (1.5–two g) for patients already on simvastatin ± ezetimibe. Yet, interpretation of this written report is difficult, as it was terminated early and HDL levels in the "placebo" arm (who all the same received 100–200 mg niacin daily) increased more than initially anticipated, which may accept masked a true benefit from niacin therapy [81]. The subsequent HPS2-THRIVE (Middle Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) report of 25,673 patients was too conducted on background simvastatin ± ezetimibe therapy, and the trial examined the impact of niacin two g daily plus laropiprant (to reduce flushing), versus double placebo [76]. After a median follow-up of 3.nine years, the primary endpoint of start major vascular consequence was non significantly lower in niacin-treated patients. Patients on niacin experienced more serious agin events including myopathy, gastrointestinal effect, rash, and an increase in infections and bleeding. This study also demonstrated unfavorable glycemic effects, with an increment in both new cases of diabetes and meaning worsening of glycemic control in patients with established diabetes [76].
A possible pharmacophysiologic flaw in both AIM-HIGH and HPS2-THRIVE was bedtime niacin assistants, as bedtime dosing may lead to a catecholamine surge (plausibly increasing cardiovascular run a risk). This possibility was circumvented past mealtime dosing utilized in earlier trials [80]. Nevertheless, these studies argue against niacin equally a first-line offshoot to lower triglycerides in patients already on-statin therapy. They practice not answer the question of whether niacin may improve outcomes in nonstatin-treated patients (e.thou., in the case of statin intolerance).
Approach to Moderate Hypertriglyceridemia in Diabetes
Guidelines
According to the National Wellness and Nutrition Examination Survey (NHANES), fasting triglycerides of > 150, > 200, and > 500 mg/dL are seen in 31%, sixteen.2%, and 1.ane% of United states adults, respectively [82]. Many organizations have published guidelines for the diagnosis and categorization of hypertriglyceridemia, including the American Association of Clinical Endocrinologists (AACE) [83•]; the National Lipid Association (NLA) [84, 85•]; the National Cholesterol Education Programme Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP) [86]; and the Endocrine Club (TES) [87]. These organizations concur that normal fasting triglycerides should be defined as < 150 mg/dl. Tabular array 2 summarizes the categorization of triglyceride levels across lipid guidelines.
Table 2
Categorization of triglyceride levels past lipid guidelines
| Categorization | AACE | NLA | NCEP | TES |
|---|---|---|---|---|
| Normal | < 150 | < 150 | < 150 | < 150 |
| Deadline high (TES: Mild) | 150–199 | 150–199 | 150–199 | 150–199 |
| Loftier (TES: Moderate) | 200–499 | 200–499 | 200–499 | 200–999 |
| Very high (TES: severe) | ≥500 | ≥500 | ≥500 | 1000–1999 |
| Very severe | N/A | Due north/A | Northward/A | ≥2000 |
All guidelines recommend screening adults for hypertriglyceridemia as part of a complete lipid panel at least every five years [83•, 84, 85•, 86, 87], and AACE further advises annual screening for dyslipidemia in patients with type 1 or 2 diabetes [83•]. Information technology is generally accustomed that patients with very high/severe hypertriglyceridemia warrant both lifestyle modifications and pharmacotherapy due to the likelihood of unrecognized increases in triglycerides and associated pancreatitis risk [83•, 84, 85•, 86, 87]. While recent guidelines recognize heightened cardiovascular risk with moderate triglyceride elevations (typically considered 200–499 mg/dL) [85•], there remains a gap in guidance regarding approaches to modifying this run a risk in patients with diabetes who have sustained moderate hypertriglyceridemia despite appropriate lifestyle modifications and statin-optimized LDL. Based on recent evidence, Fig. 2 proposes an approach to managing patients with diabetes in this scenario.
Proposed approach to management of triglycerides in diabetic dyslipidemia. LDL, low-density lipoprotein; HDL, loftier-density lipoprotein
Triglyceride-Lowering Therapies in Evolution
In improver to pemafibrate, dual PPAR agonists and icosabutate mentioned above, a number of other triglyceride-lowering agents are nether investigation.
Apolipoprotein CIII Inhibitors
Apolipoprotein (apo) CIII increases triglyceride levels past inhibiting LPL and reducing hepatic uptake of remnant lipoproteins [88]. Mendelian randomization studies demonstrate that variants with loss of apoCIII have lower triglyceride levels, higher HDL, and a forty% risk reduction of coronary heart disease [17, 19]. Antisense oligonucleotides, such as volanesorsen, have been developed to decrease apoCIII expression. In phase 2 trials of patients with type 2 diabetes and baseline hypertriglyceridemia (triglycerides 201–499 mg/dL), volanesorsen reduced apoCIII levels by 88%, triglycerides by 69%, and raised HDL past 42% compared to placebo. Volanesorsen besides improved insulin sensitivity as measured past the insulin sensitivity index, and reduced glycated albumin (− 1.7%), glycated hemoglobin (− 0.44%), and fructosamine (− 38.7 μmol/L) [89•]. The ability of volanesorsen to target both dyslipidemia and insulin resistance renders it a promising agent for diabetic dyslipidemia, but thrombocytopenia and serious bleeding are concerning side effects which have and then far prevented its approval by the Food and Drug Administration [ninety•].
Angiopoietin-Like 3 Protein Inhibitors
Angiopoietin-similar 3 protein (ANGPTL3) is an endogenous inhibitor of LPL. Like to apoCIII, loss-of-function variants have lower triglyceride and LDL levels. Evinacumab is a monoclonal antibiotic confronting ANGPTL3 which can lower fasting triglyceride levels by upward to 76% and LDL past 23% in a dose-dependent manner [91•]. An antisense oligonucleotide against ANGPTL3 has likewise demonstrated similar results in phase I trials [92•]. So far, ANGPTL3 appears to exist a promising therapeutic target, although boosted phase 2 and III data are needed to push button these therapies frontwards.
Conclusion
Hypertriglyceridemia is exceedingly mutual amidst patients with diabetes, and at that place is growing testify that moderate triglyceride elevations are a modifiable chance factor for cardiovascular disease. While addressing glycemic control, diet, and other secondary causes of hypertriglyceridemia are central steps in management, there is sufficient testify to back up the addition of triglyceride-lowering therapies (peculiarly omega-three fatty acids) in patients with persistently elevated triglycerides (> 200 mg/dL) and low HDL despite statin therapy. Still, it is important to consider that patients with diabetes are at risk of polypharmacy, so the benefit of initiating new medications should be weighed against the risk of declining adherence to existing regimens. Ongoing studies may determine the value of lowering triglycerides and improving diabetic dyslipidemia using various pharmacotherapies, and futurity studies will continue to inform our approach to moderate hypertriglyceridemia in this high-hazard population.
Funding Information
MJC is supported past a Career Development Accolade from VHA Health Services Enquiry & Development (CDA 13–261) and acknowledges support from the Middle of Innovation to Accelerate Discovery and Do Transformation (CIN thirteen–410). Additionally, enquiry reported in this publication was supported by the National Institutes of Wellness under Award No. T32DK007012 (ASA).
Footnotes
This article is part of the Topical Collection on Macrovascular Complications in Diabetes
Conflict of Interest John R. Guyton has received research back up from Sanofi, Regeneron Pharmaceuticals, and Amarin Pharmaceuticals.
Anastasia-Stefania Alexopoulos, Ali Qamar, Kathryn Hutchins, Matthew J. Crowley, Bryan C. Batch, and John R. Guyton declare that they have no conflict of interest.
Man and Brute Rights and Informed Consent This commodity does not contain any studies with homo or animal subjects performed past whatsoever of the authors.
Publisher'south Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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