Inflammation in Diabetes: What Role for Glucose-lowering Drugs?

May 8, 2015

Some key classes of antidiabetes agents could play a dual physiologic role. Find out which ones hold most promise in this at-a-glance summary.

Evidence is mounting that supports an integral role for inflammation and activation of the innate immune system in the evolution of the metabolic syndrome, type 2 diabetes (T2DM), cardiovascular disease (CVD), and microvascular diabetic complications.1 Specific anti-inflammatory agents are now marketed to help quell this so-called "silent" inflammation. There are studies, too, that suggest anti-inflammatory properties among glucose-lowering agents, potentially giving these drugs a dual role. Most of this research has been performed with the insulin sensitizers metformin and the thiazolidinedione (TZD) class. Insulin-secreting agents (sulphonylureas, glinides) have shown less impact.

Following are highlights of the evidence for anti-inflammatory properties among the key classes of antihyperglycemics.

Insulin Sensitizers: Metformin and Thiazolidinediones

► Comparative data and head-to-head trials suggest greater anti-inflammatory effects for insulin sensitizers (metformin, TZD) vs. insulin-secreting agents (sulphonylureas, glinides)

► Metformin: Activates AMP kinase, leading to antiatherosclerotic effects and inhibition of proinflammatory responses that may act independently of anti-hyperglycemic effect. BUT:

     ♦Human trials: Metformin slightly reduced CRP levels in patients with glucose intolerance2

► TZDs: Activate PPAR-γ receptors, a possible molecular pathway in insulin resistance, T2DM, and atherosclerosis

    ♦TZDs are the only anti-hyperglycemics for which a wide range of evidence suggests broad anti-inflammatory effects on visceral adipose tissue, liver, atherosclerosis, and serum markers of inflammation
     ♦Clinical use limited by adverse effects

► Head-to-head trials suggest metformin has greater anti-inflammatory activity than TZDs

Insulin-Secreting Agents: Sulphonylureas, Glinides

► Insulin secreting agents close K(ATP) channels in beta cells; K(ATP) channels promote inflammation through MAPK/NF-ĸB pathways in macrophages

► Sulphonylureas: Head-to-head trials suggest less anti-inflammatory effects on CRP levels, lipid profiles, atherosclerosis, and low-grade inflammation than various comparators  (pioglitazone, exenatide, metformin)

► Glinides: Some human trials suggest modest anti-inflammatory activity, but less effective at lowering inflammatory markers than metformin; little or no effect on CRP levels or the development of diabetes


Other Oral Agents: Alpha-glucosidase inhibitors, DPP-4 inhibitors, SGLT2-inhibitors

► Alpha-glucosidase inhibitors: Reduce postprandial glucose peaks, which play a major role in post-meal inflammation and related endothelial damage

     ♦Human trials suggest modest, if any, effects on inflammatory markers, no reduction in CV events

► DPP-4 inhibitors: Consistent data suggest positive effect on reducing cardiovascular risk factors and inflammatory markers

     ♦Sitaglipitin: Most extensively studied, potent and rapid anti-inflammatory activity in T2DM3

► SGLT-2 Inhibitors:  May indirectly reduce inflammation through improved glycemia

     ♦No human data available yet
     ♦Studies in rats and mice have suggested SGLT2Is inhibit inflammation and oxidative stress involved in liver fibrosis, obesity, and nephropathy4-6

Injectables, table of comparisons, and take-home points, next page.

Injectables: GLP-1 Receptor Agonists, Insulin

► Insulin: May have long-term anti-inflammatory effects by controlling hyperglycemia and modulating key inflammatory mediators

     ♦Limited, poor quality clinical and observational studies reveal unconvincing data on decreases in hs-CRP
     ♦Complex effect on atherosclerosis; ORIGIN trial suggested neutral effect for glargine on CV outcomes over six years7

► GLP-1 receptor agonists: Potent anti-inflammatory effect through direct modulation of innate immune-mediated inflammation; associated with significant decreases in inflammatory markers

     ♦Studies suggest these drugs reverse the progression of nonalcoholic fatty liver disease through improved metabolic parameters, as well as a direct effect on hepatocyte lipid metabolism and liver inflammation

 

Table: Anti-Inflammatory Effects of Anti-Hyperglycemics

Drug classMode of actionAnti-inflammatory effects
BiguanidesAMPK activationModerate
SulphonylureasClose K(ATP) channelsModest (if any)
GlinidesClose K(ATP) channelsModest (if any)
α-glucosidase inhibitorsα-glucosidase inhibitionMinimal (if any)
ThiazolidinedionesPPARʎ agonistImportant (beyond glucose control)
DPP-4 inhibitorsDPP-4 inhibitionModerate (to be confirmed)
SGLT2 inhibitorsSGLT2 inhibitionUnknown (may be indirect)
GLP-1 receptor agonistsMimic GLP-1Moderate (to be confirmed)
Exogenous insulinInsulin receptor agonistModerate (no good evidence)

Important distinction to keep in mind: It is important to distinguish anti-inflammatory effects resulting from improved glycemia vs anti-inflammatory effects related to intrinsic action of the drug class.

 

Take Home Points

►  Overall, the anti-inflammatory activity of antihyperglycemics is modest except for TZD and, to a lesser extent, metformin

►  Insulin sensitizers (metformin, TZD) have greater anti-inflammatory effects than insulin-secreting agents (sulphonylureas, glinides)

►  Alpha-glucosidase inhibitors have modest, if any, effects on inflammatory markers

►  SGLT-2 Inhibitors may indirectly reduce inflammation through improved glycemia; no human data available yet

►  Limited, poor quality studies suggest insulin has a limited effect on lowering hs-CRP, complex relationship with CV outcomes

►  Incretin-based therapies (DPP-4 inhibitors, GLP-1 agonists) have a more promising, potent anti-inflammatory effect; further research is needed

References:

1. Scheen AJ, Esser N, Paquot N.  Antidiabetic agents: Potential anti-inflammatory activity beyond glucose control. Diabetes Metab. 2015 Mar 17. pii: S1262-3636(15)00027-0. doi: 10.1016/j.diabet.2015.02.003. [Epub ahead of print]

2. Haffner S, Temprosa M, Crandall J,et al. Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes. 2005; 54:1566-72.

3. Wolk R, Bertolet M, Brooks MM, et al. Differential effects of insulin sensitization and insulin provision treatment strategies on concentrations of circulating adipokines in patients with diabetes and coronary artery disease in the BARI 2D trial. Eur J Prev Cardiol. 2014 Jul 29. pii: 2047487314544046. [Epub ahead of print]

4. Terami N, Ogawa D, Tachibana H, et al. Long-term treatment with the sodium glucose cotransporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. PLoS One. 2014;9:e100777. doi: 10.1371/journal.pone.0100777. eCollection 2014.

5. Gembardt F, Bartaun C, Jarzebska N, et al. The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. Am J Physiol Renal Physiol. 2014;307:F317-25. doi: 10.1152/ajprenal.00145.2014. Epub 2014 Jun 18.

6. Tahara A, Kurosaki E, Yokono M, et al. Effects of sodium-glucose cotransporter 2 selective inhibitor ipragliflozin on hyperglycaemia, oxidative stress, inflammation and liver injury in streptozotocin-induced type 1 diabetic rats. J Pharm Pharmacol. 2014;66:975-87. doi: 10.1111/jphp.12223. Epub 2014 Feb 17.

7. ORIGIN Trial Investigators, Gerstein HC et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2015;367:319-328. doi: 10.1056/NEJMoa1203858. Epub 2012 Jun 11.