The Sweet Spot
Why type 2 diabetes patients continue to fall through the cracks
Last updated: February 2026
Case Examples
Patient A
49 year old male with Type 2 diabetes mellitus (T2DM) and CAD with a previous stent to the LAD presents for routine endocrinology visit to discuss his diabetes management.
His A1C is 7.5% and stable compared to last year. He is on metformin and glimepiride.
He asks about new medications he saw on television which may be good for his heart.
He is advised that he is doing great, with his A1C right in the "sweet spot".
Years ago, his doctor attended a lecture at a national conference where they discussed studies showing that overaggressive management of blood sugar, with an A1C less than 7%, was associated with an increase in adverse cardiac events. Similarly, undertreatment of blood sugar, with an A1C greater than 8% showed an increase in adverse outcome.
With his A1C of 7.5% right in the "sweet spot" he is encouraged to continue his present management.
Patient B
A 42 year old female with Type 2 diabetes mellitus and obesity with BMI 31kg/m2 presents for a primary care visit to discuss her cholesterol management.
Her LDL-C is 77 mg/dL, HDL-C 37 mg/dL, TG 213 mg/dL.
She is informed that her LDL-C numbers are outstanding and at her age, she does not need to start taking a statin.
However, her TGs are a little high and she was encouraged to work harder on a low carb diet.
Patient C
A 57 year old male with T2DM and a recent heart attack (STEMI) treated with a stent to the LAD 6 months ago, presents to his cardiologist to review his progress. He has finished cardiac rehab, has been adhering to a Mediterranean diet and been faithfully taking the maximum dose of rosuvastatin at 40 mg daily, which was initiated in the hospital, without any side effects.
Labs from 1 week prior to the visit reveal an LDL-C is 68 mg/dL, TG 216 mg/dL, HDL-C 40 mg/dL.
He is told no additional treatments are needed for his lipids since his LDL-C is below the recommended goal of 70 mg/dL.
Patient D
A 57 year old female with T2DM, Heart Failure with a Preserved Ejection Fraction (HFpEF) and obesity with BMI 31 kg/m2, presents to her cardiologist following a recent stay in the hospital for 4 days for heart failure, characterized by shortness of breath with fluid in her lungs (pulmonary vascular congestion) and legs (edema).
She was placed on furosemide and instructed to follow up with her cardiologist.
Since then she has lost 8 lbs and feels much better.
On exam, her cardiologist notes that her lungs are clear and the lower extremity edema has resolved.
She is congratulated on the weight loss and her furosemide is reduced to once daily. She is advised to avoid salt and weigh herself daily, while keeping track in a diary.
She asks about newer diabetes drugs she heard about on TV that reduce risk for heart failure hospitalization, such as Farxiga, Jardiance, Invokana and others that reduce cardiovascular risk and help with weight loss such as Ozempic.
Her cardiologist informs her that the drugs are expensive but she can talk to her primary care doctor or endocrinologist about them, since those are not drugs that cardiologists prescribe.
"Flying Under the Radar"
The cases above represent some of the most frequent lapses and missed opportunities in the cardiometabolic care of the diabetic patient:
Patient A:
Missing the point of landmark clinical trials
It's about how you get to euglycemia
The failure of previous therapies employed to achieve intense glucose lowering is not a free pass to undertreat. An A1C of 7.5% is not desirable.
Taking the easy way out by persisting with outdated, yet inexpensive (and therefore easier to prescribe) sulfonylurea drugs that have been relegated below several other proven therapies in just about every guideline.
Yes, new branded medications can be expensive and may require labor intensive prior authorizations, but the patient needs to be informed.
Help is on the way with Federal initiative to make branded diabetes drugs cheaper. Farxiga (dapagliflozin) now has a generic.
It's not always about the sugar anymore.
Several clinical trials have now shown that glycemic control has little impact on major cardiovascular events.
Thankfully, we now have many therapies that, independent of glycemic improvement, also improve cardiovascular endpoints.
Patient B:
Lack of awareness of guideline recommendations
Reliance on suboptimal metrics — in this case, LDL-C is less accurate and underestimates risk compared with nonHDL-C when TGs are elevated (see Atherogenic Triad).
Failure to appreciate high lifetime risk and implementing early prevention — another example of undertreating cardiovascular risk in the female (diabetic) patient.
Patient C:
Applying outdated and more conservative guidelines to our highest risk patients — LDL-C needs to be much lower.
Failing to appropriately inform patients of potentially life saving therapies they may be eligible for.
Even if some practitioners feel there is controversy with the REDUCE-IT Trial (see Something Smells Fishy — The Controversy with Fish Oil), patients ought to be informed of icosapent ethyl (Vascepa) when they fit the indications for it. That's part of shared decision making.
Patient D:
Passing the buck — assuming some other specialist will take care of it.
We are in an interesting time in medicine, where multiple classes of diabetes medications now have separate indications for improving cardiovascular disease risk — independent of glycemic control.
"I don't treat diabetes"
It's not acceptable for a cardiologist to fail to treat the underlying cardiovascular risk in a high risk heart failure patient recently hospitalized, simply out of misplaced fear about a "diabetes" drug.
To put it bluntly, the diabetic patient is left behind due to a lack of cohesiveness across medical disciplines. The PCP, already burdened with everything else, is left holding the bag when the specialists (cardiologists, endocrinologists and nephrologists) assume that the other is going to act. So, nobody acts, and the diabetic patient is exposed to unnecessary "residual risk" when there are potentially effective treatments available. Far too often the patient is left in the dark and never finds out about these therapies.
Instead of fostering mutual trust and building a multidisciplinary community that agrees to take advantage of every opportunity to attack this risk, at every encounter, the opposite often occurs. The cardiologist doesn't want to step on the endocrinologist's toes and vice versa. The PCP may yield to the specialist, assuming they had a reason not to act, rather than seeing it as a missed opportunity.
This is why some are trying to create a "cardiometabolic" subspecialty in its own right. Someone needs to put it all together. And in 2025, someone may have. Dr. Milton Packer's "Adipokine Hypothesis of HFpEF" (JACC 2025) argues that the cardiometabolic diseases we see clustering in our diabetic patients — HFpEF, hypertension, CKD, atrial fibrillation, MASLD — are not independent comorbidities acting in concert. They are all downstream consequences of one common upstream driver: dysfunctional visceral adipose tissue (adiposopathy, or "pissed off fat") secreting a toxic mix of inflammatory adipokines. Insulin resistance itself may be a biomarker of this adipokine dysregulation rather than an independent cause. This framework explains why SGLT2 inhibitors and GLP-1 receptor agonists — drugs that shrink visceral fat and restore healthy adipokine biology — show benefits across diabetes, heart failure, kidney disease, and liver disease simultaneously. They aren't just glucose-lowering drugs that happen to help the heart. They are anti-adiposopathy drugs that fix the fat — and the downstream organs follow.
Read more in Deep Dive below.
CardioAdvocate Checklist
Cholesterol Management
Check ApoB
May be used as the preferred biomarker for all patients with high TG, diabetes, obesity, metabolic syndrome or "very low LDL-C" for screening, diagnosis, risk management (Ia ESC/EAS)
T2DM at very high risk → LDL-C ≥ 50% reduction, and LDL-C < 55 mg/dL
T2DM at high risk → LDL-C ≥ 50% reduction, and LDL-C < 70 mg/dL
If goal LDL-C not achieved with statin, combination with ezetimibe should be used (ECS/EAS IIa)
Combination therapy with lower dose statin, ezetimibe and/or PCSK9i in a patient centered discussion regarding safety, efficacy and cost may be considered (Expert Opinion — many experts prefer a combination approach but recognize the high cost of newer non-statin therapies such as PCSK9i mAb, siRNA, ACL inhibitors)
DM deemed to be at higher risk: Age 50–75 or multiple risk factors → High intensity statin to reduce LDL-C ≥ 50%
All DM age 40–75 regardless of 10 year risk → Moderate-intensity statin (2018 ACC/AHA Cholesterol Guidelines)
DM 20–39 with risk enhancers — start statin:
Type 2 DM ≥ 10 years | Type 1 DM ≥ 20 years
Albuminuria ≥ 30 mcg albumin/mg creatinine
Triglycerides are rarely normal in those with dysglycemia.
TG > 150–499 mg/dL: In the presence of "max tolerated statin," those with established CVD or T2DM, Vascepa (icosapent ethyl) may be indicated to reduce CV risk (25% reduction in MACE in the REDUCE-IT Trial).
See Atherogenic Triad for more information.
Cardiovascular Risk Reduction
We have arrived at a new era in the management of Type 2 diabetes — don't get left behind.
Two new classes of treatments for T2DM have produced CV benefits: SGLT2 inhibitors and GLP-1 agonists.
GLP-1 agonists have shown a reduction in CV risk. Ozempic (semaglutide) presently is the only agent in this class with indications to reduce CV risk.
Heart Failure: SGLT2i
Consider options for SGLT2i, which reduce CV risk independent of their impact on glycemic control.
Reduces Heart Failure hospitalization
Reduces Heart Failure death
Farxiga (dapagliflozin) | Jardiance (empagliflozin) | Invokana (canagliflozin)
Chronic Kidney Disease: SGLT2i
Check your kidney function — typically measured with BUN and Cre. Look for the calculated eGFR. Simple blood test panel called a BMP (Basic Metabolic Panel).
Farxiga (dapagliflozin) | Jardiance (empagliflozin) | Invokana (canagliflozin)
Deep Dive
Patient A
The #1 killer in diabetic patients is heart disease, particularly coronary artery disease and heart failure.
So, what has been the primary objective in treating diabetes? Controlling blood sugar, right?
One would think that if you optimally control blood sugar then you should see benefits in its worst outcome — cardiovascular disease, right? Wrong.
Intense Glucose Lowering
The UKPDS Trial (The UK Prospective Diabetes Study: clinical and therapeutic implications for type 2 diabetes) failed to show reduction in cardiovascular events in those treated to reduce an A1C from 8.0% to 7.0% (although, a subset of patients treated with metformin had lower event rates.)
Too many practitioners remain under the outdated impression that they dare not treat type 2 diabetics too aggressively, as this leads to an increase in mortality.
This notion is born out of older randomized controlled trials, such as the ACCORD Trial (Effects of Intensive Glucose Lowering in Type 2 Diabetes | NEJM), showing that the "intensive" therapy arm in diabetes did worse than the "standard" treatment arm, and the ADVANCE Trial (Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes | NEJM) which showed no significant difference in major cardiovascular events but did show a difference in microvascular outcomes (nephropathy) when randomized to an "intensive" therapy of sulfonylurea plus other medications as needed to achieve an A1C of 6.5% or less.
A breakdown of these two trials is well summarized in this editorial: Intensive Glycemic Control in the ACCORD and ADVANCE Trials | NEJM.
In brief, the ACCORD trial randomized ~10,000 type 2 diabetics with A1C of 8.1% at baseline to an "intensive" treatment arm aimed at achieving an A1C < 6.0%. The "standard" therapy arm aimed to achieve A1C 7.0–7.9%. At 1 year, the intense arm achieved an A1C of 6.4%, the standard arm 7.5% (sweet spot!). However, at 3.5 years the intensive arm was stopped due to an increase in total mortality. The differences in MACE (cardiovascular events) were not statistically different, however total mortality was statistically significant. In the intense arm there was more frequent hypoglycemia requiring intervention and significant weight gain (average 3.5 kg), with 28% experiencing > 10 kg (22 lbs)!
The ADVANCE trial required all patients in the intensive arm to receive a sulfonylurea, whereas the ACCORD trial held no restrictions, thus more use of a combination of thiazolidinediones (TZDs — insulin sensitizers) — in particular rosiglitazone (Avandia), sulfonylureas and insulin utilization.
The ADVANCE trial also combined macrovascular and microvascular endpoints, which was a peculiar decision when trying to establish if glycemia plays a role in major cardiovascular events.
Cardiovascular Risk
Initially it was felt that hypoglycemia was the culprit for the increase in events, but it was already known that:
• Insulin causes weight gain
• Rosiglitazone, in a meta-analysis, was associated with an increase in myocardial infarction and other cardiovascular events: Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes | NEJM
Nonetheless, many practitioners conflated the hazardous mechanisms of the drugs used in the trials with the notion that "treating" a type 2 diabetic to a lower A1C% (<7.0%) might somehow place that individual at increased risk of an adverse event. This is short sighted thinking.
Hypoglycemia most definitely is not a good thing and the body will react violently to this very primitive need to maintain adequate blood glucose levels. Therapies that frequently provoke hypoglycemia are associated with a plethora of bad outcomes to include heart attack etc, but the adverse events in the "intensive" treatment arm were not entirely explained by hypoglycemic events. Other mechanisms with adverse off-target effects from insulin, drugs that promote the release of, or sensitivity to, insulin in higher risk patients were likely at play.
It's one thing to conclude that the therapies employed in these clinical trials did not demonstrate favorable benefits, but it's quite another to conclude that all attempts at achieving euglycemia (normal blood sugar regulation) should be abandoned. Or that therapies that promote euglycemia might also have favorable off-target or "pleiotropic" cardiovascular benefits that have little to do with blood sugar regulation.
About 10 years ago at the American College of Cardiology Annual meeting a lecture titled "The Sweet Spot" attempted to make sense of these trials and thread the needle between overtreatment and undertreatment of blood sugar in diabetics.
It turns out, it depends on how you get there.
This meta-analysis published in 2015 (Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials) suggests that agents that seemed to promote weight gain, such as PPAR agonists (highest) and DPP-4 inhibitors (intermediate) to achieve lower blood sugars were associated with worsening heart failure. Whereas, agents that promote weight loss were not associated with heart failure.
Despite newer therapies and updated guidelines demoting sulfonylureas (like glimepiride) way down on the list of medications to choose from to treat diabetes, they continue to be frequently prescribed as the next agent following metformin (second-line) or sometimes first-line in the real world.
Sulfonylureas (like glimepiride)
Sulfonylureas are insulin secretagogues, which promote the release of endogenous insulin from pancreatic beta islet cells. They have the propensity to promote hypoglycemia, weight gain and fluid retention — all of which are cardiovascular risk factors (Sulfonylureas and the Risks of Cardiovascular Events and Death | Diabetes Care).
Thiazolidinediones (TZDs — like rosiglitazone)
TZDs are peroxisome proliferator-activated receptors (PPARs) that work by increasing insulin sensitivity by acting on muscle, adipose and liver to better utilize glucose and reduce glucose production.
In November 2007, the FDA issued a black box warning for rosiglitazone (Avandia) due to an increased risk of heart attack. It was removed from the market in early 2010.
Not all TZDs are the same, however. Pioglitazone remains a helpful medication for many patients with diabetes.
The story of rosiglitazone (Avandia) underscores many important lessons in science and medicine:
• The better we adhere to evidence based medicine through randomized controlled trials (RCT) and meta-analysis, the better off we are.
• While not every clinical question can or ever will be answered by an RCT, when it can, we should.
• Not everything that sounds right, is right.
• Often, only large trials can detect harmful off-target effects of certain drugs.
Cardiovascular Benefit — What We've All Been Waiting For
Fortunately, we now live in a world where we have several treatments that can be employed against diabetes and reduce cardiovascular events! Finally, right?!
In 2015, the EMPA-REG Outcomes Trial was published showing that empagliflozin (Jardiance), an SGLT2 inhibitor, when used on top of standard care, reduced the "primary composite cardiovascular outcome and of death from any cause."
Since that publication, these and other therapies have exploded:
• Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes | NEJM
• Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes | NEJM
But even still — see how long this takes? EMPA-REG was published in 2015…
There are pluses and minuses regarding this delay: It takes a while for the entirety of the peer-review process to take place, for journal publication, for FDA label indication updates, for replication with other drugs in this class and for general acceptance in the cardiometabolic community and then the broader general medical community.
Another axiom of medicine is — "you don't want to be the first to try something new, but you don't want to be the last either."
In between the time from when positive outcomes from a large scale randomized controlled trial are accepted as the new standard of care — and the time until it is widely implemented in real world medicine, many lives would have been saved or improved. This represents an example of where we can do better.
SGLT2 Inhibitors (Sodium-Glucose Transport Proteins 2)
SGLT2 inhibitors lower blood sugar by inhibiting glucose reabsorption through the sodium-glucose transport protein in the kidneys. Glucose is therefore excreted in the urine. This causes a mild diuretic effect, which can help with fluid retention, blood pressure and promote some weight loss.
However, since the urine is a little sweeter, it can increase the risk of urogenital infections like a rash or urinary tract infection. Bacteria and yeast like sugar too. Good urogenital hygiene can prevent this.
Drugs in this class:
• Farxiga (dapagliflozin)
• Jardiance (empagliflozin)
• Invokana (canagliflozin)
• Steglatro (ertugliflozin)
• BRENZAVVY (bexagliflozin)
These drugs are currently branded (expensive and may require prior authorization), though dapagliflozin (Farxiga) has now been released as a generic.
Given the history with intense glucose lowering and rosiglitazone, the FDA mandated cardiovascular safety trials. Any new diabetes drugs were required to at least prove they didn't promote cardiovascular risk.
Most of the SGLT2i now have multiple indications other than improving blood sugar control in type 2 diabetes. Separate indications include:
• Type 2 Diabetes
• Type 2 Diabetes with established cardiovascular disease (CVD) to reduce CV death
• Heart Failure (HF) — reduce the risk of HF death and HF hospitalization
• Chronic Kidney Disease (CKD) — reduce risk of sustained decline in eGFR, End Stage Kidney Disease, CV death and hospitalization
The Discovery of a New Treatment for Heart Failure
Somewhat surprisingly, SGLT2i were found to improve cardiovascular risk, mostly with regards to heart failure and heart failure hospitalizations.
While they proved to be a nice addition to several therapies already available for HFrEF (Heart Failure with Reduced Ejection Fraction — due to a weak pump: Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction | NEJM, Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure | NEJM), of particular value, was the benefit to the enigmatic subgroup of heart failure patients called "HFpEF" — the so-called "diastolic heart failure" due to a stiff left ventricle, with difficulty relaxing between beats. Previous treatments for HFpEF centered around treating the underlying causes, but no specific therapies for HFpEF — until now:
• Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction | NEJM
• Empagliflozin in Heart Failure with a Preserved Ejection Fraction | NEJM
Chronic Kidney Disease
Since then we have now seen separate indications for chronic kidney disease as well:
• Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy | NEJM
• Dapagliflozin in Patients with Chronic Kidney Disease | NEJM
• Empagliflozin in Patients with Chronic Kidney Disease | NEJM
GLP-1 Agonists (Glucagon-like Peptide-1)
Drugs in this class:
• Semaglutide subcutaneous injection (Ozempic), oral tablet (Rybelsus)
• Dulaglutide (Trulicity)
• Tirzepatide (Mounjaro)
Ozempic and Trulicity are both indicated by the FDA to reduce risk of major adverse cardiac events (MACE) in those with T2DM and established CV disease.
Semaglutide demonstrated ~25% reduction in cardiovascular death, nonfatal myocardial infarction and nonfatal stroke (collectively called MACE): Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes | NEJM
Dulaglutide also demonstrated CV risk reduction, with a 12% reduction in MACE in diabetics on top of standard therapy, regardless of preexisting cardiovascular disease and in a broad range of glycemic control — thus presumably a lower risk patient population: Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND) | The Lancet
2026 Update — The Incretin Revolution Accelerates: SURPASS-CVOT and the Pipeline
The landscape of incretin-based therapies for T2DM and cardiovascular risk has shifted dramatically. In late 2025, the SURPASS-CVOT trial was published, and a wave of next-generation agents is approaching FDA approval — transforming how we think about treating the diabetic patient with established cardiovascular disease.
The SURPASS-CVOT Trial
The SURPASS-CVOT trial (Nicholls et al., NEJM 2025) is a landmark — the first active-comparator cardiovascular outcomes trial in the GLP-1/GIP space. Rather than comparing tirzepatide (Mounjaro) to placebo, it was tested head-to-head against dulaglutide (Trulicity), an agent with established CV benefit. At a median of 4 years, tirzepatide met noninferiority for the primary MACE endpoint (cardiovascular death, MI, or stroke: 12.2% vs. 13.1%). But the secondary endpoints told a broader story — tirzepatide demonstrated a 16% reduction in all-cause mortality, superior weight loss, better glycemic control, and preservation of kidney function. Clinical decisions in T2DM with ASCVD may now hinge on the magnitude of weight loss, glycemic efficacy, and tolerability rather than cardiovascular outcome differences alone.
The SELECT Trial
Meanwhile, the SELECT trial (Lincoff et al., NEJM 2023) expanded the cardiovascular reach of GLP-1 agonists beyond diabetes entirely. In over 17,000 overweight or obese adults with established CVD but without diabetes, semaglutide 2.4 mg reduced the primary MACE endpoint by 20% (HR 0.80) — establishing that the cardiovascular benefits of GLP-1 agonists extend to the non-diabetic population with obesity and ASCVD.
Pipeline: What's Coming
What's on the horizon: Eli Lilly's orforglipron, an oral small-molecule GLP-1 receptor agonist, has an FDA decision expected by March 2026. The ATTAIN-2 trial (Lancet 2026) showed meaningful weight loss and A1C reduction without the injection requirement — a potential game-changer for patient adherence. Further out, retatrutide — a triple agonist targeting GLP-1, GIP, and glucagon receptors simultaneously — showed up to 24% weight loss in phase 2 (Jastreboff et al., NEJM 2023), with a projected 2028 launch timeline. Morgan Stanley projects the cardiometabolic market will reach $150 billion by 2035.
Updated Guidelines
The 2026 ADA Standards of Care in Diabetes now recommend GLP-1 receptor agonists and SGLT2 inhibitors with proven cardiovascular benefit as part of the treatment algorithm for adults with T2DM and established or high-risk ASCVD — independent of glycemic targets. Tirzepatide is recognized for its dual GIP/GLP-1 mechanism with favorable weight and glycemic profiles. The days of reserving these agents until after metformin and sulfonylureas have "failed" are numbered.
I have diabetes and heart disease. Am I on a GLP-1 agonist or SGLT2 inhibitor that has been proven to reduce my cardiovascular risk? If not — why not?
Patient B
This case illustrates a few missed opportunities:
Standards of Care in Diabetes — 2023 Guidelines recommends "high-intensity statin therapy in individuals with diabetes aged 40–75 years at higher risk, including those with one or more atherosclerotic cardiovascular disease risk factors, to reduce the LDL cholesterol by >50% of baseline and to target an LDL cholesterol goal of <70 mg/dL."
Looking closer at the lipid panel (TC and nonHDL-C intentionally not provided), one sees that the TG are elevated (> 150 mg/dL) and the HDL-C is low (< 50 mg/dL). This should alert the clinician that the LDL-C is being underestimated. Looking at nonHDL-C, which is all too frequently not listed in the lipid panel but can be calculated by using math (ugh!) by subtracting HDL-C from TC. Using ApoB is even better. This is perhaps one of the biggest reasons for "residual risk" and "flying under the radar" in the diabetic patient.
Young female diabetic patients are often undertreated for their risk. While a CAC CT score to assess for early plaque development by way of coronary calcification has been shown to "de-risk" many patients, including diabetics, a score of "0" really only tells us her "short term risk." Lifetime risk remains high. The common phrase "Even lower is even better, for even longer" applies to this patient.
Patient C
There are several points to be made here:
This patient is lucky to be alive. 50% of such heart attack victims die at home.
The European Society of Cardiology (ESC) and the American Endocrine Societies (AACE) would characterize this patient as "very high risk" and "extreme risk," respectively, with goal LDL-C < 55 mg/dL and nonHDL-C < 80 mg/dL.
The Standards of Care in Diabetes — 2023 recommend high intensity statins be used in diabetics with established ASCVD to achieve > 50% LDL-C reduction and a goal LDL-C < 55 mg/dL. Ezetimibe or PCSK9 inhibitor should be added if goals are not achieved.
If it's the 2nd vascular event for this patient, the ESC would shoot for LDL-C < 40 mg/dL. After suffering a near death experience with a STEMI, many would not want to wait around for the next one before taking such measures.
One thing is for sure, < 70 mg/dL as a goal LDL-C in a post STEMI patient, is simply not getting the job done.
Here is where it is helpful to point out the elevated TGs.
In this patient, getting a complete lipid panel (rather than just the ApoB that the savvy clinician may prefer), reveals the elevated TGs that now become (like it or not) a prerequisite for additional potentially life saving therapies.
In the REDUCE-IT Trial, those with established cardiovascular disease or diabetes with residually elevated TGs of 135–499 mg/dL despite maximum tolerated statin therapy achieved a 25% further reduction in cardiovascular events (MACE) when treated with icosapent ethyl (highly purified eicosapentaenoic acid, or EPA, under the trade name Vascepa) 2 grams twice daily on top of statins.
Interestingly, the risk benefit was independent of TG lowering, leading many to believe that high TGs merely identify a very high risk patient population, benefitting not necessarily from the TG lowering itself, but rather some other mechanism (see Something Smells Fishy — The Controversy with Fish Oil).
The benefit also was seen proportionate to the percent saturation of red blood cells (RBCs) with EPA, meaning, those who absorbed more, fared better.
Patient D
This case is perhaps the most emblematic of the struggles in treating the cardiometabolic risk of the diabetic patient.
No single discipline wants to "own," or take responsibility for treating the cardiovascular risk of the diabetic.
Not the endocrinologist (aside from those who specialize in lipids). Why? Several reasons:
They're not accustomed to it. Endocrinologists who treat diabetes tend to focus on glycemic control and have not had to consider the cardiovascular risk — because until recently, glycemic therapies had never shown any positive cardiovascular impact (negative in some cases).
One would think that if the leading cause of death and demise in the diabetic patient is ASCVD, then surely improving dysglycemia, the main derangement in the diabetic, would result in improvement of its most common bad outcome, right? Nope.
Quite the opposite. As touched on in Patient A, the more aggressive treatment arms for diabetes in clinical trials showed cardiovascular harm.
When another promising agent, rosiglitazone (Avandia) was removed from the market due to its association with worsening heart failure — that was it — The Institute of Medicine and the FDA had had it. From then on, any new drugs for diabetes would need to prove that they at least didn't worsen cardiovascular health.
But nobody expected that the diabetes drug pipeline would bring therapies that actually improved cardiovascular health — and seemingly independent of glycemic control!
Endocrinologists are getting on board — perhaps faster than cardiologists.
The Standards of Care in Diabetes — 2023 calls for the "addition of specific SGLT2 inhibitors or GLP-1 receptor agonists that have demonstrated CVD benefit is recommended in patients with established CVD, chronic kidney disease, and heart failure."
The American Association of Clinical Endocrinology Consensus Statement: Comprehensive Type 2 Diabetes Management Algorithm — 2023 Update has easy to follow algorithms for all cardiometabolic diseases associated with diabetes. The "glycemic control" algorithm recommends SGLT2i and GLP-1 receptor agonists for those with known ASCVD, high ASCVD risk, Heart Failure, Stroke/TIA and CKD. This is "independent of glycemic target and other T2D therapies."
But far too many are either stuck in their ways, or can't be bothered with the prior authorizations.
It's easier and far cheaper to prescribe inferior sulfonylureas and TZDs, than the more expensive and branded drugs that have been shown to reduce cardiovascular risk.
Not the cardiologists either. If it has to do with diabetes management, it's icky, complicated and foreign to them.
For cardiologists, that part of Internal Medicine is quickly disposed of upon entering fellowship training — as it was for this author — when the attending interventional cardiologist asked "why are you prescribing metformin? You're a cardiologist — you don't treat diabetes anymore."
That was not necessarily true then — and it certainly isn't true anymore.
Cardiologists do not want to concern themselves with a heart failure medicine that may require them to alter any of their other diabetes medications, such as lowering or discontinuing their sulfonylurea (glimepiride). Diuretics? Sure, no problem. But not blood sugar medications. Too messy.
They don't want to be responsible for educating their patients about urogenital hygiene when using SGLT2i (makes the urine sweeter, which may increase chances for bacterial or yeast infection down below), for instance. Nor the issues of delayed gastric emptying with GLP-1 agonists such as nausea, diarrhea or constipation.
They can't be bothered with prior authorizations so they punt back to endocrinology or their PCP.
But there is hope…most cardiologists will aim to follow cardiology guidelines.
These therapies are all over the guidelines now and have received Class I recommendations for the treatment of patients with type 2 diabetes with established CVD or high cardiovascular risk to prevent heart failure hospitalization…and for the treatment of those with HFrEF; Class 2a for HFmrEF and HFpEF — independent of whether diabetes is present or not (2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure).
Cardiologists are beginning to toe the line, but opportunities continue to be missed.
2026 Update — Diabetes Physically Reshapes the Heart: The Molecular Evidence
Throughout this article, we've discussed the clinical consequences of diabetes on the heart — the heart failure, the missed opportunities, the therapies that finally work. But a landmark 2025 study from the University of Sydney, published in EMBO Molecular Medicine, now provides the first comprehensive molecular map of how diabetes and ischemic heart disease interact to physically reshape the heart at its most fundamental level.
Led by Associate Professor Sean Lal and Dr. Benjamin Hunter, the team performed multi-omic analyses — examining proteins, lipids, and RNA simultaneously — on donated human heart tissue from transplant patients with and without diabetes. What they found was striking: diabetes doesn't merely coexist with heart disease. It fundamentally alters cardiac biology through distinct molecular pathways.
What the Study Revealed
The researchers identified a unique molecular signature present only in hearts with both diabetes and ischemic cardiomyopathy — a signature not seen in hearts with either condition alone. Think of it this way: if ischemic heart disease is damage from a blocked pipe, diabetes rewires the entire plumbing system.
Key Molecular Findings
Mitochondrial Dysfunction — The heart's power plants are broken. Mitochondrial complex I protein subunits — the first step in the energy production chain — were significantly more downregulated in diabetic ischemic hearts compared to all other heart failure groups. The heart cells can't make enough energy to keep pumping effectively. This aligns with what we know about why SGLT2 inhibitors like empagliflozin improve cardiac energy status — they may directly address this mitochondrial deficit.
Impaired Contractile Proteins — The proteins responsible for heart muscle contraction (like ATP2A2 and ALDOA) were found to be both disorganized and produced at lower levels. Calcium regulation — the precise electrical signaling that tells each heart cell when and how hard to squeeze — is disrupted. The heart literally can't contract as efficiently.
Fibrosis (Scarring) — Genes responsible for extracellular matrix remodeling (COL1A2 and AEBP1) were upregulated specifically in diabetic ischemic hearts. The heart muscle is being replaced by fibrous, scar-like tissue — making it stiffer, less compliant, and harder to fill between beats. This is the molecular basis for the diastolic dysfunction so common in diabetic patients.
Disrupted Energy Metabolism — Fatty acid transport and oxidation proteins were the most downregulated pathway. Fifteen medium-to-very-long-chain acylcarnitines — molecules that shuttle fatty acids into mitochondria for fuel — were found to be depleted only in the diabetic ischemic group. The heart is starving for fuel even when nutrients are available.
Synergistic Damage — Critically, these changes were worse when diabetes and ischemic heart disease occurred together than when either existed alone. Diabetes amplifies ischemic injury at every level — energy production, structural integrity, and tissue architecture.
As Associate Professor Lal stated: "Now that we've linked diabetes and heart disease at the molecular level, we can begin to explore new treatment avenues." This is exactly the kind of mechanistic understanding that transforms how we approach therapy.
Diabetic Cardiomyopathy: A Disease That Progresses in Stages
The molecular findings above don't exist in a vacuum — they map directly onto the clinical progression of diabetic cardiomyopathy, a condition where diabetes itself damages the heart muscle independent of coronary artery blockages. Understanding the stages helps explain why early intervention matters so much, and why waiting for symptoms means you're already behind.
| Stage | What's Happening | Molecular Drivers | What You'd Notice |
|---|---|---|---|
|
Stage 1 Subclinical |
Early myocardial fibrosis begins. The heart muscle starts getting stiffer. Early diastolic dysfunction — the heart has trouble relaxing between beats to fill properly. | Mitochondrial stress, oxidative damage, AGE accumulation, early collagen deposition | Often nothing. Most patients feel fine. This is why it flies under the radar. May be detectable with advanced echo techniques like global longitudinal strain (GLS). |
|
Stage 2 Established |
Left ventricular hypertrophy develops. Diastolic dysfunction advances. This is when HFpEF — heart failure with a preserved ejection fraction — emerges. The pump squeezes fine, but can't fill properly. | Worsening calcium handling abnormalities, progressive fibrosis, RAAS activation, inflammation (NF-κB, NLRP3 inflammasome) | Shortness of breath with exertion, fatigue, exercise intolerance. Fluid retention in some. Echo shows diastolic dysfunction but EF looks "normal." |
|
Stage 3 Advanced |
Now both diastolic and systolic dysfunction are present. The heart can't fill properly or squeeze properly. This is the transition to HFrEF — reduced ejection fraction. | Contractile protein disorganization (ATP2A2, ALDOA — as shown in the Hunter/Lal study), cardiomyocyte apoptosis, microvascular dysfunction | Worsening symptoms at rest and with minimal activity. Fluid overload. Frequent hospital admissions. EF now measurably reduced. |
|
Stage 4 End-Stage |
Irreversible cardiac remodeling. Infarction and extensive fibrosis. Clinical heart failure refractory to standard therapy. Consideration for advanced therapies including transplant or mechanical support. | Global mitochondrial failure, extensive ECM replacement, irreversible cardiomyocyte loss — the full molecular picture described by Hunter et al. in end-stage transplant tissue | Severe limitation. Recurrent hospitalizations. Consideration for LVAD or transplant. This is where the University of Sydney tissue samples came from. |
Adapted from Jia et al., Circulation Research (AHA) and the Hunter/Lal EMBO Molecular Medicine study. Up to 75% of individuals with type 2 diabetes display diastolic or systolic LV dysfunction, often before symptoms appear.
What makes this progression particularly insidious is that it typically moves from diastolic to systolic dysfunction — the reverse of what happens in ischemic heart failure from coronary artery disease. This explains why HFpEF is so disproportionately common in diabetic patients, and why it was historically so difficult to treat. The heart "looks fine" on a standard echocardiogram for far too long.
Why This Matters: Connecting the Dots to Treatment
Here's where it all comes together. Earlier in this article, we discussed how SGLT2 inhibitors (Jardiance, Farxiga, Invokana) have shown remarkable benefits in heart failure — benefits that appear independent of their glucose-lowering effects. That always seemed a bit mysterious. Why would a "diabetes drug" that makes you urinate sugar also protect the heart?
The University of Sydney molecular data may finally explain why. Look at the pathways diabetes damages: mitochondrial energy production, contractile protein function, and fibrosis. Now look at what SGLT2 inhibitors do at the molecular level:
SGLT2 Inhibitors: Targeting the Molecular Damage
Restoring Mitochondrial Energy — Empagliflozin has been shown to significantly increase mitochondrial ATP production in diabetic hearts. It appears to enter cardiac mitochondria directly and improve energy output — addressing the very Complex I dysfunction identified by the Sydney group.
Fixing Ion Handling — SGLT2 inhibitors reduce sodium and calcium overload inside cardiac cells by inhibiting the sodium-hydrogen exchanger (NHE). This helps normalize the calcium signaling that controls heart muscle contraction — directly relevant to the impaired contractile proteins and calcium regulation found in the study. A Nature Reviews Cardiology analysis describes this as "protective reprogramming" of cardiac nutrient transport.
Anti-Fibrotic Effects — SGLT2 inhibitors have been shown to attenuate cardiac fibroblast activation and reduce the endothelial-to-mesenchymal transition that drives fibrosis — the same fibrous tissue accumulation driving stiffness in diabetic hearts.
Promoting Cellular Cleanup — Through activation of AMPK and enhanced autophagy (the cell's recycling system), SGLT2 inhibitors help clear damaged mitochondria and restore cellular homeostasis. They also promote ketone body utilization — an efficient alternative fuel source for the energy-starved diabetic heart.
Remarkably, these cardioprotective effects occur even in hearts without SGLT2 receptors. As noted in a JACC review of the enigma of SGLT2 inhibitor cardioprotection, empagliflozin reduced infarct size even in transgenic mice lacking the SGLT2 receptor entirely — confirming these are "off-target" effects unrelated to glucose transport. The drugs appear to work through direct mitochondrial and ion channel effects.
This is why the molecular findings matter clinically. They validate what we've seen in the DAPA-HF and EMPEROR-Reduced trials: SGLT2 inhibitors aren't just diabetes drugs that happen to help the heart. They are heart drugs that also happen to lower blood sugar. And for the diabetic patient with heart failure, they may be targeting the exact molecular pathways that diabetes has damaged.
The Bigger Picture: Glucose Control Alone Is Not Enough
The University of Sydney findings reinforce the central message of this article — and it bears repeating: glucose control alone does not prevent the cardiac damage caused by diabetes. The molecular damage involves distinct pathways beyond hyperglycemia: mitochondrial dysfunction, structural protein disorganization, and extracellular matrix remodeling. These pathways operate even when blood sugar is "controlled."
This is precisely why the ACCORD and ADVANCE trials failed to show cardiovascular benefit from intensive glucose lowering — they were using the wrong drugs to hit the wrong target. The heart damage from diabetes is not just about sugar in the blood. It's about what's happening inside the cardiac cells themselves.
Modern 2026 ADA Standards of Care recognize this. SGLT2 inhibitors and GLP-1 receptor agonists are now recommended for their cardiovascular and renal benefits independent of glycemic targets. The molecular evidence tells us why: these agents address the fundamental biology of how diabetes damages the heart, not just the blood sugar number on a lab report.
Future therapies may go further — targeting specific pathways like the NF-κB and NLRP3 inflammasome inflammatory cascades, the FoxO1 transcription factor, or adiponectin signaling pathways. The University of Sydney study has given us the molecular roadmap. The next decade of diabetic cardiomyopathy therapeutics will be built on this foundation.
Additional References
Here is an interesting take on insulin resistance, described by Dr. Jason Fung during his interview with Dr. Peter Attia on his podcast: Jason Fung, M.D.: Fasting as a potent antidote to obesity, insulin resistance, type 2 diabetes, and the many symptoms of metabolic illness — Peter Attia
Landmark Trials — Incretin Therapies
SURPASS-CVOT Trial (NEJM 2025) — Tirzepatide vs. dulaglutide in T2DM with ASCVD
SELECT Trial (NEJM 2023) — Semaglutide and cardiovascular outcomes in obesity without diabetes
ATTAIN-2 Trial (Lancet 2026) — Orforglipron oral GLP-1 agonist phase 3 results
Retatrutide Phase 2 (NEJM 2023) — Triple-hormone-receptor agonist for obesity
2026 ADA Standards of Care — Pharmacologic Approaches to Glycemic Treatment
Diabetic Ischemic Cardiomyopathy — Molecular Profiling
Hunter B, Zhang Y, Harney D, et al. Left ventricular myocardial molecular profile of human diabetic ischaemic cardiomyopathy. EMBO Mol Med. 2025. EMBO Molecular Medicine
Diabetic Cardiomyopathy — Mechanisms and Staging
Jia G, Hill MA, Sowers JR. Diabetic Cardiomyopathy. Circ Res. 2018. Circulation Research (AHA)
Bellemare S, et al. Mechanisms of diabetic cardiomyopathy: Focus on inflammation. Diabetes Obes Metab. 2025. Diabetes, Obesity and Metabolism
Lee MMY, et al. Early diagnostic biomarkers and therapeutic interventions in diabetic cardiomyopathy. Cell Death Discovery. 2023. Cell Death Discovery (Nature)
SGLT2 Inhibitors — Mitochondrial and Cardioprotective Mechanisms
Shiraki A, et al. SGLT2 inhibitor empagliflozin improves cardiac energy status via mitochondrial ATP production. Commun Biol. 2023. Communications Biology (Nature)
Lopaschuk GD, Verma S. SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport. Nat Rev Cardiol. 2023. Nature Reviews Cardiology
Packer M. The Enigmata of Cardioprotection With SGLT2 Inhibition. JACC Basic Transl Sci. 2024. JACC
Pandey A, et al. SGLT2 inhibitors attenuate cardiac fibroblast activation. Sci Rep. 2024. Scientific Reports (Nature)
Kolijn D, et al. SGLT2 Inhibitors and Mitochondrial Function in Heart Failure. Front Cardiovasc Med. 2020. Frontiers in Cardiovascular Medicine
Zheng Y, et al. SGLT2 inhibitor treatment of diabetic cardiomyopathy: focus on the mechanisms. Cardiovasc Diabetol. 2023. Cardiovascular Diabetology
Echocardiographic Diagnosis
Zoroddu S, et al. Echocardiography in Diagnosis and Prognosis of Diabetic Cardiomyopathy. Diagnostics. 2025. MDPI Diagnostics
CardioAdvocate — Bridging the 17-year implementation gap
This article is for educational purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider.
