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Drugs for Diabetes
Metabolic Syndrome and Prediabetes
Obesity has become a common problem in Western society, and it is a strong predictor of type 2 diabetes mellitus (T2DM). In the United States it is estimated that almost one-third of the population will develop T2DM in their lifetimes. T2DM, in turn, predisposes to cardiovascular abnormalities.
An increased waistline is one of the five criteria of the metabolic syndrome (MetSyn)—a prediabetic state—in addition to fasting hyperglycemia and blood pressure (BP) elevation, increased circulating triglycerides (TGs), and decreased circulating high-density lipoprotein (HDL) cholesterol (HDL-C) ( Fig. 4.1 ). Three of these are required for the diagnosis of the MetSyn ( Table 4.1 ). Abdominal girth, insulin resistance (IR), and insulin response are the three main factors that, each independently, increase the metabolic risk of cardiovascular disease (CVD). However, waist circumference is a better predictor of the risk of myocardial infarction (MI) than body mass index (BMI) is.
Table 4.1
Common Definitions for Metabolic Syndrome
From Floege J, et al.: Comprehensive clinical nephrology, ed 4, Philadelphia, 2010, Saunders.
| Criterion | NCEP ATP III (3 or more criteria) |
|---|---|
| Abdominal obesity | Waist circumference |
| Men | > 40 inches (> 102 cm) |
| Women | > 35 inches (> 88 cm) |
| Hypertriglyceridemia | > 150 mg/dl (≥ 1.7 mmol/L) |
| Low HDL | |
| Men | < 40 mg/dl (< 1.03 mmol/L) |
| Women | < 50 mg/dl (< 1.30 mmol/L) |
| Hypertension | ≥ 130/85 mm Hg or on antihypertensive medication |
| Impaired fasting glucose or diabetes | > 100 mg/dl (5.6 mmol/L) or taking insulin or hypoglycemic medication |
Abdominal adipose tissue is now recognized as a metabolically active organ and regarded as the basic abnormality in the MetSyn by the International Diabetes Federation. There are strong links between excessive abdominal fat leading to excessive circulating free fatty acids (FFAs) and cytokines, which contribute to the other four features of the MetSyn and help explain worsening IR ( Fig. 4.2 ). The MetSyn is of clinical importance in that it increases the risk of CVD and especially T2DM, driven almost entirely by the fasting glucose component. Currently an increasing number of patients with the MetSyn obesity or T2DM are being treated by cardiologists, often in close collaboration with primary care physicians and diabetologists.
Risks of Metabolic Syndrome
MetSyn comprises a group of cardiometabolic risk factors, each of which individually may be of only borderline significance, but when taken together indicate enhanced risk of development of overt T2DM or CVD. While a useful tool to communicate underlying pathophysiology and shared risk factors, influential authorities have questioned the independent predictive value of the MetSyn for the future development of T2DM and stress the role of one of the five components alone; glucose. For cardiologists, becoming alert to risk-factor clustering, including abdominal obesity, high TGs, low HDL-C, prehypertension, and hyperglycemia, is an important widening of vision. The risk of developing future CVD is proportional to the number of MetSyn features. With four or five features, the risk of T2DM was 25-fold greater than with no features and still much more than with only one feature. In an analysis of 172,573 persons in 37 studies, MetSyn had a relative risk of 1.78 for future cardiovascular events, and the association remained after adjusting for traditional cardiovascular risk factors (relative risk [RR], 1.54; confidence interval [CI], 1.32–1.79). The International Day for Evaluation of Abdominal Obesity study measured waistlines in 168,000 primary care patients spread worldwide to confirm an association between waist and CVD (RR 1.36) and more so with T2DM (RR 1.59 in men and 1.83 in women).
Insulin Resistance
IR leads to the MetSyn via increased circulating FFA ( Fig. 4.2 ) and elevated glucose production in the liver, which are the precursors of T2DM. There is a dose-response effect of elevated plasma FFA on insulin signaling. Importantly, early life dietary patterns strongly predispose to IR.
How is obesity related to IR? Already modestly elevated FFA often observed in obese persons, and in some increased FFA flux, inhibit insulin signaling and stimulate nuclear factor kappa B (NFκB) to promote IR (Figure 1 in Kim, 2012). NFκB in turn stimulates macrophages to provoke the chronic low-grade inflammatory response (Figure 2 in Kim, 2012) 16 with increased plasma levels of C-reactive protein, and inflammatory cytokines such as tumor necrosis factor–alpha, interleukin (IL) 6, monocyte chemotactic protein 1, and IL-8, and the multifunctional proteins leptin and osteopontin. The “Western” high-fat diet experimentally enhances such cytokine production, whereas exercise diminishes it. The overall sequence is:
Diabetes Prevention
Lifestyle Changes to Slow the Onset of Diabetes
The transition from MetSyn to full-blown T2DM can be significantly lessened by lifestyle intervention. Walking only approximately 19 km per week can be beneficial in treating MetSyn. However, more intense intervention is needed for more substantial change. Tuomilehto et al. studied a group of overweight subjects with impaired glucose tolerance who, on average, also had the features of the MetSyn. Dietary advice and exercise programs were individually tailored. The five aims were weight reduction, decreased fat intake, decreased saturated fat intake, increased fiber intake, and increased endurance exercise (at least 30 minutes daily). Of these, increased exercise was achieved in 86% of participants, and the other components less frequently. After a mean duration of 3.2 years, the relative risk for new T2DM in the lifestyle intervention group was 0.4 ( P < 0.001).
In the Diabetes Prevention Group, similar subjects were given lifestyle modification or metformin for a mean of 2.8 years. Lifestyle intervention was very intense with a 16-lesson curriculum covering diet, exercise, and behavior modification taught by case managers on a one-to-one basis during the first 24 weeks after enrollment. Lifestyle intervention was more effective than metformin in delaying the onset of T2DM, and both were more effective than placebo in preventing new T2DM.
However, while lifestyle intervention may significantly reduce the severity of DM, lifestyle changes seem to have little effect on the cardiovascular risk seen in T2DM. In the Look-AHEAD study, the National Institute of Health sponsored a randomized controlled trial, assessing if Intensive Lifestyle Intervention (ILI) or Diabetes Support and Education (DSE) would lead to cardiovascular benefits in overweight or obese T2DM patients. Look-AHEAD was stopped prematurely because of futility, as there was no difference in reduction of cardiovascular events between the two groups. For the ILI group, the cardiovascular event rate was 1.83 per 100 patient-years while the DSE group had a similar rate of 1.92 events for 100 patient-years (HR 0.95, 95% CI 0.83–1.09, P = 0.51). However, other aspects of DM morbidity were improved in the ILI group, such as glucose and lipid control biomarkers, sleep apnea, liver fat, depression, quality of life, knee pain, inflammation, sexual function, and kidney disease. Overall, these outcomes reduced health care costs of the ILI group.
Is the protection from DM found in the Diabetes Prevention Group study sustained? The postintervention 10-year follow-up says no, with an equal incidence of new T2DM in placebo, former lifestyle, and metformin groups. Yet the cumulative incidence of T2DM remained lowest in the lifestyle group. Thus, prevention or delay of T2DM with lifestyle intervention or metformin may persist for at least 10 years.
Blood Pressure and Lifestyle
Modest BP elevation, a component of the MetSyn, is often associated with overweight and obesity. Weight loss and exercise in the setting of intensive behavioral intervention in the MetSyn can reduce systolic blood pressure (SBP) in the range of 8 mmHg with small additional reductions if the Dietary Approaches to Stop Hypertension (DASH) diet is added. When added drugs are required, β-blockers and diuretics should be considered second-line agents and avoided except when there are compelling indications. There is now growing but controversial evidence that new T2DM may develop during the therapy of hypertension, more so with β-blockers and diuretics than with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) ( Fig. 4.3 ). There is a “weight of evidence against β-blockers” as first choice for obese patients with hypertension. A network meta-analysis linked diuretic and β-blocker therapy separately to new T2DM in hypertension ( Fig. 4.3 ). Thus, current European Hypertension Guidelines list MetSyn as a possible contradiction to the use of β-blockers and diuretics (thiazides/thiazide-like). In view of the potential increased risk of new T2DM, it seems prudent to give preference to antihypertensive therapy initially based on ACE inhibitors or ARBs, with low-dose diuretics (hydrochlorothiazide 12.5 to 25 mg) as needed (unless there are compelling indications for β-blocker–diuretic therapy).
Which Drugs Halt the Slide to Diabetes?
Metformin 850 mg twice daily when given in the Diabetes Prevention Study reduced future T2DM, albeit less than vigorous lifestyle changes.
Thiazolidinediones (TZDs) increase hepatic and peripheral insulin sensitivity by activation of peroxisome proliferator-activated receptor- γ (PPAR- γ ) receptors. In the ACT NOW trial (Actos Now for Prevention of Diabetes), pioglitazone, as compared to placebo, reduced the risk of conversion of impaired glucose tolerance to T2DM by 72%, but was associated with significant weight gain and edema.
Acarbose inhibits the intestinal absorption of glucose but is often poorly tolerated because of gastrointestinal symptoms. Findings from the Acarbose Cardiovascular Evaluation (ACE) trial, a randomized, double-blind, placebo-controlled phase IV ACE trial of 6522 Chinese adults, demonstrated a reduction of T2DM incidence by 18%. However, there was no significant reduction in the incidence of the composite, five-point major adverse cardiovascular events (MACE).
Because there have been no comparative studies between metformin, acarbose, and TZDs, it is difficult to say with certainty which would be most effective in preventing progression to new T2DM should lifestyle modifications prove inadequate. However, metformin and pioglitazone have convincing data. In light of this, the 2019 Standards of Medical Care of the American Diabetes Association (ADA) recommend metformin for high-risk individuals (patients with gestational diabetes mellitus history or BMI ≥ 35 kg/m 2 ) due to strong evidence, low cost, and safety profile.
What Can Be Achieved?
For lifestyle by itself to be effective in preventing transition to T2DM as well as reducing BP, major behavioral changes have to be affected, requiring intense input from professional personnel such as nutritionists and exercise physiologists. Although this intensive counseling may not be a cost-effective approach when applied to the general population, it is undeniable that the ideal strategy for the whole population is a broad behavior modification that avoids obesity. Drug therapy to prevent the transition to T2DM is both feasible and effective in selected patients, yet not widely applied.
Cardiovascular Disease Risk Assessment
The primary cause of morbidity and mortality of individuals with T2DM is atherosclerotic cardiovascular disease (ASCVD). While T2DM is clearly associated with risk, not all patients with T2DM are at the same risk. A meta-analysis of 45,108 patients in 13 trials showed that patients without T2DM but with a prior MI had a 43% higher coronary heart disease (CHD) risk than individuals with T2DM without previous CVD. This risk heterogeneity argues for the routine use of risk assessment in clinical practice.
Risk Calculators
Both major current DM guidelines, the 2019 guidelines by the American College of Cardiology and the American Heart Association (ACC/AHA) and the 2019 ADA/EASD Standards of Medical Care, recommend evaluating the 10-year risk of first atherosclerotic CVD (10-year ASCVD) using the race-and sex-specific pooled cohort equation (PCE). This risk model is used for patients with as well as without DM. The use of DM-specific risk calculators is questionable, as most studies have shown that risk factors modify CVD risk similarly, irrespective of whether or not the patient suffers from DM. However, when intermediate risk (7.5%–20%) is present, noninvasive imaging such as a coronary calcium score may be useful in decision making to follow, i.e., intensity of statin and aspirin therapy.
Risk Enhancing Factors
In addition to using risk calculators, both guidelines also recommend evaluating CVD risk by assessing each patient’s diabetes-specific cardiovascular risk factors ( Tables 4.2 and 4.3 ). The ADA Standards of Medical Care recommend the assessment of these risk factors at least annually. In clinical practice, it is best to assess any comorbid cardiometabolic risk factors (including presence of MetSyn), the duration of DM, and the age of onset.
Table 4.2
Risk-enhancing factors according to the 2019 ACC/AHA Guidelines on the primary prevention of cardiovascular disease
|
|
|
|
|
|
ABI , ankle brachial index; eGFR , estimated glomerular filtration flow.
Table 4.3
Risk-enhancing factors according to 2019 ADA guideline “Standard of Medical Care”
| Obesity |
| Hypertension |
| Chronic kidney disease |
| Smoking |
| Family history of premature coronary disease |
| Dyslipidemia |
| Presence of albuminuria |
Duration of Diabetes
Duration of DM is independently associated with cardiovascular events. Evidence shows that patients with > 10-year history of T2DM without history of CHD have similar risk of CHD as patients without DM but with prior CHD. By extension, individuals with less than 10 years of T2DM history are not considered CHD risk equivalents. The 2019 ACC/AHA guidelines of preventive CVD state that a T2DM duration of over 10 years is an independent cardiovascular risk enhancer.
Age of Onset
Age of T2DM diagnosis is an important prognostic factor for cardiovascular risk.
A study using data from the Swedish National Diabetes Registry showed that patients diagnosed with T2DM before the age of 40 had the highest excess relative risk for CVD-related mortality (HR 1.95 [1.68–2.25]), heart failure (HF) (HR 4.77 [3.86–5.89]), and CHD (HR 4.33 [3.82-4.91]) compared to controls. Controls were randomly selected individuals from the general population matched for age, sex, and county. The authors observed that all CVD risks diminished with each additional decade of diagnostic age. Survival of patients with T2DM diagnosed in adolescence was almost a decade less than controls, while patients diagnosed > 80 years had the same survival as controls.
Data from a cross-sectional survey of 222,773 T2DM patients showed that early-onset T2DM (mean diagnostic age 35 years) was associated with a higher risk of nonfatal CVD events compared to late-onset T2DM (mean diagnostic age 55 years) (OR, 1.91; 95% CI, 1.81–2.02). While the risk was diminished when adjusted for DM duration, it still remained significant (OR, 1.13; 95% CI 1.06–1.20). This study showed that while duration of T2DM and diagnostic age are associated, age of onset is an independent and significant risk factor for CVD.
The ADA 2019 Standards of Medical Care specifically point out that patients with youth-onset T2DM have a particularly high risk of suffering from DM complications. A cross-sectional study of 2733 patients showed that youth-onset T2DM is associated with microvascular as well as macrovascular risk burden. Further, β-cell function in patients with youth onset T2DM seems to deteriorate faster than that of βT2 cells of patients with adult-onset DM.
Coronary Artery Calcium Testing
The CHD and CVD risk variability of patients with T2DM is perhaps best measured by coronary artery calcium (CAC). The CAC score—resulting from a noncontrast cardiac-gated computed tomography scan of the heart—is a marker for atherosclerosis burden, in effect measuring the cumulative effect of a lifetime exposure of measured and unmeasured cardiovascular risk factors. Evidence suggests that CAC can improve risk discrimination of CHD and CVD events more effectively than traditional risk factors. Studies have also shown that the CAC score mirrors the variance in CVD risk of patients with T2DM. For instance, a study by Silverman et al. showed that most individuals with DM < 60 years have an extremely low risk at < 5 deaths per 1000 person years when CAC = 0. In contrast, CAC was detected in almost all patients with DM with prior CHD (92.5%) and CVD (82.5%) events.
The Diabetes Heart Study suggested that CAC scoring can reclassify risk of patients with T2DM with a heightened risk for CVD mortality. The study showed that CVD mortality risk increased proportionally to CAC score after adjusting for cardiovascular factors. The area under the curve (AUC) without CAC was 0.70 (0.67–0.73) while with CAC was 0.75 (0.72–0.78). After addition of the CAC, the model that classified participants into different risk categories reclassified 28% individuals with a net reclassification index (NRI) = 0.13 (0.07–0.19).
The Multi-Ethnic Study of Atherosclerosis (MESA) evaluated the use of CAC in long-term prognostication of incident CHD and ASVD among patients with T2DM. The addition of CAC to global risk assessment significantly improved risk stratification in individuals with T2DM. CAC was independently associated with CAC (HR 1.3 [1.19–1.43]), and the net reclassification improvement with CAC addition to traditional risk assessment was 0.23 (95% CI, 0.10–0.37). In light of this evidence, current DM guidelines endorse CAC testing for cardiovascular risk assessment for intermediate-risk (7.5%–20%) patients where risk and treatment decisions are uncertain.
Value of Improved Glycemic Control
Guideline Recommendations on Glycemic Control
The major adverse events of T2DM are microvascular and macrovascular complications. Both are affected by the intensity of glycemic control, typically assessed by levels of glycosylated hemoglobin A1c (HbA1c).
While it is established that effective management of all levels of gylcemia reduces microvascular complications, results from the large outcome trials (ACCORD, ADVANCE, VADT— Table 4.4 ) have not shown that more intensive glycemic control significantly reduces CVD outcomes. In response to this evidence, the 2019 ADA/EASD Standards of Medical Care acknowledge the complexity of adequate glycemic control and strongly endorse the importance of shared decision making to incorporate the individual characteristics and preferences of each patient to find optimal glycemic targets. A general target of < 7% HbA1c for nonpregnant adults is still recommended. However, in individuals just diagnosed with T2DM, without CVD, patients with long life expectancy or individuals treated with lifestyle therapy and metformin only, more aggressive glycemic management(< 6.5%) is reasonable and can prevent microvascular complications. For patients with short life expectancy who may not profit from the long-term benefits of more aggressive glycemic management, or suffer from serious comorbidities and poor self-management, an HbA1c up to 8% is more suitable. Where tight HbA1c levels cannot be achieved safely, higher HbA1c levels are acceptable. In order to personalize glycemic targets for each patient, the Standards of Medical Care recommend assessing seven categories to decide on the stringency of the glycemic target; risks of hypoglycemia/drug adverse effects, disease duration, life expectancy, comorbidities, established vascular complications, patient preference, and resources and support system.
Table 4.4
Rates of hypoglycemia in the ACCORD, ADVANCE, and VADT clinical trials
Modified from Connelly KA, Yan AT, Leiter LA, Bhatt DL, Verma S. Cardiovascular implications of hypoglycemia in diabetes mellitus. Circulation 2015;132(24):2345–2350.
| HbA1c target, % | Standard glucose control arm% | Intensive glucose control arm % | P value | |
|---|---|---|---|---|
| ACCORD | < 6 | 5.1 | 16.2 | < 0.001 |
| ADVANCE | < 6.5 | 1.5 | 2.7 | < 0.001 |
| VADT | If > 6, insulin added | 9.9 | 21.2 | < 0.001 |
Microvascular Complications
Multiple randomized controlled studies have repeatedly established that intensive glycemic control can reduce microvascular complications in T2DM. The Diabetes Control and Complications Trial (DCCT) reported that a 60% reduction of development of diabetic retinopathy, nephropathy, and neuropathy was achieved in the intensive treatment group (mean HbA1c of 7%) than in the standard group (HbA1c of 9%) in early-onset youths and younger adults with T1DM. The landmark trial, UK Prospective Diabetes Study (UKPDS), which included over 7600 subjects with T2DM and a median follow-up of 10 years, assessed the effects of intensive glycemic control on incidence of complications. One of the major conclusions drawn from the study showed that the microvascular complication rate was reduced by 25% more in the intensive treatment arm (median HbA1c of 7.0%) compared to the control treatment arm (median HbA1c of 7.9%).
Macrovascular Complications
However, the microvascular benefits of more aggressive glycemic management may be offset by the effects on cardiovascular outcomes. The current discussion of glycemic control on cardiovascular risk is shaped by recent major outcome studies including the ACCORD, ADVANCE, and VADT ( Table 4.4 ).
ACCORD
In patients with T2DM at high cardiovascular risk, perhaps similar to those that a cardiologist might see, the NID-supported Action to Control Cardiovascular Risk in Diabetes (ACCORD) study compared intense versus standard glycemic control. Mean HbA1c levels were 6.4% in the intense and 7.5% in the standard arms. ACCORD ended the glycemic control study early after results showing an increased mortality in individuals belonging to the very intense glycemic control arm, with an HbA1c target of < 6%, compared to the standard arm (1.41 versus 1.14% per year; 257 versus 203 deaths over a mean 3.5 years of follow-up; hazard ratio [HR] 1.22 [95% CI 1.01–1.46]). As a result, the ACCORD study researchers wrote, “Such a strategy cannot be recommended for high-risk patients with advanced T2D.” As a result of the ACCORD study, the subsequently published ADA Standards of Care in Diabetes 2013 guidelines only recommended intensive glycemic control in low 10-year ASCVD risk patients.
ADVANCE
The ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) was launched with a similar motivation to ACCORD: to evaluate more aggressive glycemic management on the risk of CVD in patients with T2DM. The primary outcome of ADVANCE combined macrovascular (MI, stroke, and cardiovascular death) and microvascular (nephropathy and retinopathy) events. While intensive glycemic control resulted in a significant reduction of this combined primary endpoint (18.1% intensive versus 20.0% conventional therapy—HR 0.90; 95% CI 0.82–0.98; P = 0.01), this decrease was mainly driven by the reduction of microvascular events (mainly albuminuria). There was no significant reduction in major macrovascular events (10.0% intensive versus 10.6% conventional therapy; HR 0.94; 95% CI 0.84–1.06; P = 0.32). Unlike ACCORD, ADVANCE did not observe an elevated risk in mortality for patients with intensive glucose control.
VADT
The Veterans Affairs Diabetes Trial (VADT), a prospective-randomized trial in patients with advanced T2DM, also failed to demonstrate a significant benefit in terms of overall or cardiovascular mortality, herein from lowering HbA1c to 6.9% in the intensive-therapy group versus 8.4% in the standard-therapy group. The VADT trial’s population included predominantly (98%) older men with poorly controlled T2DM (median entry HbA1c 9.4%). CVD risk factors such as BP, smoking cessation, aspirin therapy, and statin therapy were treated intensively. While the tight glycemic control group reduced HbA1C levels to 6.9% within the first year of the study, the primary outcome, time to first cardiovascular event, was not significantly reduced in the intensive group (HR 0.88 [95% CI 0.74–1.05], P = 0.12). The study also reported more CVD deaths in the intensive glycemic control group than in the standard control group (38 versus 29); however, this difference was not statistically significant. More recent analysis has demonstrated that VADT participants randomly assigned to intensive glycemic control over 5.6 years had fewer CVD events only during the prolonged period in which the glycated hemoglobin curves were separated.
Summary
Results from these outcome studies suggest that patients with a long history of T2DM, history of hypoglycemia, advanced atherosclerosis, and old age are less likely to benefit from tight glycemic control. In all three trials, significantly more hypoglycemic episodes occurred in tight glycemic control groups than in others. In response to ACCORD, VADT, and ADVANCE, the 2019 ADA/EASD Standards of Medical Care state that physicians should be cautious of intensive glucose control for patients with long history of T2DM and cardiovascular risk factors. The risks associated with intensive glycemic control might outweigh its benefits.
Importance of Large Cardiovascular Disease Outcome Trials
Until 2008, antidiabetic drugs were exclusively approved on the basis of lowering of HbA1c, as trials with intensive glycemic control demonstrated lower rates of microvascular complications. Most participants in trials evaluating effects of certain glycemic targets had no established ASCVD or very low cardiovascular risk and were generally drug naïve. This study design limited the ability to adequately assess cardiovascular effects of these drugs. Over time, a range of evidence demonstrated that some diabetic drugs might pose risks to cardiovascular safety ( Table 4.5 ).
Table 4.5
Cardiovascular data for selected type 2 diabetes mellitus drugs before guidance
Modified from Cecilia C, Low Wang M, Brendan M, et al. Cardiovascular safety trials for all new diabetes mellitus drugs? Ten years of FDA guidance requirements to evaluate cardiovascular risk. Circulation 2019;139:1741–1743.
| Class | Medication | Trial phase | Outcomes | Events | Subjects | Other outcomes |
|---|---|---|---|---|---|---|
| GLP-1 RA | Exenatide | Phase 2 and 3 | Cardiac disorders SAEs | 27 | 2371 | … |
| Liraglutide | Phase 3 | Custom MACE SMQ | 38 | 6638 | … | |
| DPP-4i | Saxagliptin | Phase 3 | Custom MACE SMQ | 40 | 4607 | … |
| Alogliptin | Phase 3 | Custom MACE SMQ | 18 | 4702 | … | |
| Sitagliptin | Pooled phase 3 | Cardiac disorders SAEs | 12 | 2342 | … |
DPP-4 , Dipeptidyl peptidase 4;
Perhaps the most famous trial that initiated the debate on cardiovascular safety of antidiabetic drugs was the study showing that rosiglitazone was associated with an elevated risk of MI and risk of death from cardiovascular causes. Ironically, later studies did not confirm the adverse cardiovascular effects of rosiglitazone, and the FDA since lifted safety regulations against this agent.
In response to the overall rosiglitazone trial data and other trials questioning cardiovascular safety of antidiabetic agents, in 2008 the US Food and Drug Administration (FDA) published guidance for industry recommending the inclusion of enough patients with high CVD risk in order for trials to adequately assess the cardiovascular risks of diabetic drugs. In order for novel drugs to demonstrate sufficient cardiovascular safety and win FDA approval, the agency mandated that a premarketing outcomes trial show that the upper bound of the two-sided 95% confidence interval of the estimated hazard ratio is less than 1.8 for composite three-point MACE (cardiovascular death, nonfatal MI, and nonfatal stroke) or four-point MACE (cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina). For approved drugs, the FDA also required a postmarketing safety trial that must demonstrate that the estimated risk ratio of the upper bound of the two-sided 95% confidence interval is less than 1.3 for the composite MACE outcome. To achieve this, most enrolled patients must have established CVD or high ASCVD risk.
Drug manufacturers quickly adapted to this new regulatory climate. While most trials were designed to only demonstrate the antidiabetic agent’s noninferiority to placebo, some drugs were powered to show superiority compared to standard treatment.
As a result, a multitude of large CVOTs for antidiabetic agents were published after 2008 ( Table 4.6 ). Categorically, the drugs tested demonstrated cardiovascular safety (noninferior cardiovascular outcomes compared to placebo). These post-2008 FDA mandated CVOTs led to a paradigm shift in T2DM treatment; therapies now are not primarily aimed at HbA1c reduction but are focused on other aspects of T2DM comorbidities as well, such as the effects on cardiovascular health. In addition, the information of these CVOTs led to great insights, such as the demanding issue of HF in older patients with T2DM and the effects of these agents on kidney function. In response to the outcome of these trials, the FDA for the first time approved label changes to drugs used to treat patients with diabetes for lower risk of MACE (liraglutide, canagliflozin ) and cardiovascular death (empagliflozin ).
Table 4.6
Cardiovascular data for selected type 2 diabetes mellitus drugs after guidance
Modified from Cecilia C, Low Wang M, Brendan M, et al. Cardiovascular Safety Trials for All New Diabetes Mellitus Drugs? Ten Years of FDA guidance requirements to evaluate cardiovascular risk. Circulation 2019;139:1741–1743.
| Class | Medication | Trial | Cardiovascular safety signals or MACE-three-Point CVD Risk, Hazard Ratio (95% CI) | Events | Subject | Other outcomes |
|---|---|---|---|---|---|---|
| GLP-1 RA | Lixisenatide | ELIXA a (2015) | 1.02 (0.89–1.17) b | 805 | 6068 | … |
| Liraglutide c | LEADER (2016) | 0.87 (0.78–0.97) D | 1302 | 9340 | … | |
| Semaglutide | SUSTAIN-6 (2016) | 0.74 (0.58–0.95) D | 254 | 3297 | Retinopathy 1.76 (1.11–2.78) D | |
| Exenatide | EXSCEL (2017) | 0.91 (0.83–1.00) | 1744 | 14752 | … | |
| Albiglutide | HARMONY OUTCOMES (2018) | 0.78 (0.68–0.90) D | 766 | 9463 | … | |
| Dulaglutide | REWIND (2019) | 0.88 (0.79–0.99) D | 1257 | 9901 | … | |
| Oral semaglutide | PIONEER-6 (2019) | 0.79 (0.57–1.11) D | 137 | 3183 | … | |
| SGLT-2i | Empagliflozin d | EMPA-REG (2015) | 0.86 (0.74–0.99) D | 772 | 7020 | … |
| Canagliflozin d | CANVAS program (2017) | 0.86 (0.75–0.97) D | 1011 | 10142 | Amputation 1.97 (1.41–2.75) D | |
| Dapagliflozin | DECLARE-TIMI 58 (2018) | 0.93 (0.84–1.03) | 1559 | 17160 | Diabetic ketoacidosis 2.18 (1.10–4.30) D | |
| Canagliflozin | CREDENCE (2019) | 0.80 (0.67-0.95) D | 486 | 4401 | … | |
| DPP-4i | Saxagliptin | SAVOR-TIMI 53 (2013) | 1.00 (0.89–1.12) | 1222 | 16492 | HF hospitalization 1.27 (1.07–1.51) D |
| Alogliptin | EXAMINE a (2013) | 0.96 (0.80–1.16) | 621 | 5380 | HF hospitalization 1.19 (0.90–1.58) | |
| Sitagliptin | TECOS (2015) | 0.98 (0.89–1.08) B | 1690 | 14671 | HF hospitalization 1.00 (0.83–1.20) | |
| Linagliptin | CARMELINA (2018) | 1.02 (0.89–1.17) | 854 | 6979 | HF hospitalization 0.90 (0.74–1.08) |
CANVAS , Canagliflozin cardiovascular assessment study; CARMELINA , Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus; CVD , cardiovascular disease; DECLARE-TIMI 58 , Dapagliflozin effect on cardiovascular events–thrombolysis in myocardial infarction 58; DPP-4 , Dipeptidyl peptidase 4; ELIXA , Evaluation of lixisenatide in acute coronary syndrome; EMPA-REG , Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes trial; EXAMINE , Cardiovascular outcomes study of alogliptin in patients with type 2 diabetes and acute coronary syndrome; EXSCEL , Exenatide study of cardiovascular event lowering trial; HARMONY OUTCOMES , Effect of albiglutide, when added to standard blood glucose lowering therapies on major cardiovascular events in subjects with type 2 diabetes mellitus; GLP-1 , glucagon-like peptide-1; HF , heart failure; LEADER , Liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results; MACE–3-point , major adverse cardiovascular event: myocardial infarction, stroke, or cardiovascular death; REWIND , Researching cardiovascular events with a weekly incretin in diabetes; SAVOR-TIMI 53 , Saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus–thrombolysis in myocardial infarction 53; SGLT , sodium glucose transporter; SMQ , Standardized medical query (of adverse event terms); SUSTAIN-6 , Trial to evaluate cardiovascular and other long-term outcomes with semaglutide in subjects with type 2 diabetes; TECOS , Trial evaluating cardiovascular outcomes with sitagliptin.
a Patient population with recent acute coronary syndrome
b MACE + hospitalization for unstable angina.
d Approved for reduction of cardiovascular mortality or MACE in established CVD.
After a decade under the 2008 guidance, in October 2018, the FDA Endocrinologic and Metabolic Drugs Advisory Committee discussed whether to provide updated guidance. Perhaps the most important critique about the past CVOTs is the lack of generality of the trial’s results. Most participants had high baseline CVD risk, and this limits how much the results can be extrapolated onto the entire population. Further, some point out that focusing new T2DM drugs on atherosclerotic cardiovascular safety is too limited. For instance, members of the committee emphasized the importance of drug development for outcomes such as HF, peripheral artery disease, and fatty liver disease, and these comorbidities are all important to individuals with T2DM. In addition, the high cost and rigor of these large outcome trials might deter the development of novel drugs by pharmaceutical companies.
The committee voted 10 to 9 to continue the 2008 guidance; the close decision demonstrates the complexity of the subject. While the new guidelines have not been finalized, a possible outcome of the committee’s discussion is that trials assessing new drugs should be more strict than before the implementation of the FDA 2008 guidance for industry, but more lenient than 2008 recommendations. For instance, there were discussions on modifying the approval procedure to a one-step process and altering the preapproval hazard ratios from 1.8 to < 1.5, while removing the 1.3 postapproval limit. If implemented by the FDA, this simplified approach to diabetes related CVOT trial design would allow more resources to be directed to development of drugs that show efficacy against outcomes like peripheral artery disease, HF, glycemic variability, quality of life, or kidney disease.
Drugs That Lower Cardiovascular Disease Risk
Metformin
Drug Class Overview
Singly or in combination, metformin is the standard of care to promote glycemic control and is the first-choice agent in international T2DM guidelines. Importantly, it also suppresses appetite, is associated with modest (2%–3%) weight reduction, appears to be devoid of cardiovascular harm, and may benefit when given to patients with T2DM and HF. In the prolonged UKPDS study, metformin was the only drug to reduce T2DM-related and all-cause mortality, although the number of events was low. Since then, it has been the first-line treatment in overweight patients with T2DM.
Mechanisms of Action
Most of the metabolic effect of metformin occurs in the liver wherein it reduces glucose production. Although the in vivo effects in patients with T2DM or at risk for T2DM remain unproven, in skeletal muscle, metformin phosphorylates, and activates 5' AMP-activated protein kinase (AMPK), which facilitates many of the observed cellular effects of metformin, such as inhibition of glucose and lipid synthesis. AMPK activation also leads to the glucose transporter-4 mediated glucose uptake ( Fig. 4.4 ). Overall, metformin leads to a higher systemic insulin sensitivity. Another putative mechanism of metformin relates to the impact on the intestinal microbiome.
Differences Among Drugs in Class
Metformin can be administered twice daily in the short-release form or once daily in the long-release form. Both forms are equally effective. However, the long release is associated with fewer gastrointestinal effects than the short-release form.
Data for Use
Overall, the initial treatment with metformin shows many benefits on clinical outcomes, such as less hypoglycemia and weight gain compared to insulin or sulfonylureas.
Glycemic control
Metformin is the first-choice agent for T2DM primarily because of its glycemic efficacy in the absence of side effects seen with other glucose-lowering agents. The United States Multicenter Metformin Study group showed that after 29 weeks, patients randomly assigned to metformin had a mean HbA1c concentration of 7.1% compared to 8.6% in the placebo group.
Weight loss
An additional advantage over other antidiabetics is the weight loss associated with metformin. In the Diabetes Prevention Program, study participants reduced their body weight by 2.06 ± 5.65% when taking metformin, compared to the 0.02 ± 5.52% weight loss of the placebo group ( P < 0.001). In a meta-analysis, when combined with insulin, metformin reduced HbA1c by 0.5% and weight gain by 1 kg, whereas the insulin dose fell by 5 U/day.
Cardiovascular outcomes
Trials on cardiovascular outcomes of metformin preceded the FDA guidance, and as a result there are no definitive CVOTs similar to those with SGLT-2 (sodium-glucose cotransporter-2) inhibitors, GLP-1 receptor agonists, and DPP-4 (dipeptidyl peptidase 4) inhibitors. Evidence on cardiovascular effect of metformin relies on a number of smaller studies that, even though controversial, overall point toward cardiovascular benefits. Evidence from a meta-analysis of 179 trials and 25 observational studies concluded that cardiovascular mortality was lower for metformin compared to sulfonylureas. For example, compared to sulfonylureas, metformin was associated with a lower all-cause mortality (HR 0.5–0.8), lower CVD mortality (HR 0.6–0.9), and lower CVD morbidity (HR 0.3–0.9), In a Danish retrospective national cohort study, Andersson et al. demonstrated that patients with T2DM with HF treated with metformin had a lower risk of mortality compared with sulfonylureas and/or insulin.
REMOVAL (Reducing with Metformin Vascular Adverse Lesions), the largest and longest double-blinded randomized control study assessing metformin, observed the progression of atherosclerosis in patients with T1DM. Atherosclerosis progression was measured by average maximal carotid intima-media thickness (CIMT). In the group treated with metformin, CIMT was significantly reduced (− 0.013 mm/year, − 0.024 to − 0.003; P = 0.0093), suggesting cardiovascular benefits. There is also evidence that metformin may protect against coronary atherosclerosis in prediabetes and early T2DM in men. This hypothesis is currently being examined in the study VA-IMPACT (Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular Outcomes), testing if metformin reduces mortality and cardiovascular morbidity in patients with prediabetes and established ASCVD compared to placebo.
Cancer incidence
In addition, observational studies have observed that metformin may lower cancer incidence.
Side Effects
The major side effects of metformin are gastrointestinal intolerances such as bloating or diarrhea. A very rare observed occurrence is lactic acidosis at very high circulating metformin levels if patients suffer from overdose, or acute renal failure. Consequently, metformin should be avoided in patients with a predisposition to lactic acidosis. Such factors include an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m 2 or severe illness with vomiting and dehydration. Additionally, metformin is potentially associated with Vitamin B12 deficiency. The 2019 ADA Standards of Medical Care state that Vitamin B levels should be routinely measured in patients treated with metformin, especially in patients with anemia or peripheral neuropathy (Level B recommendation).
Drug Interactions or Major Restriction
Metformin demonstrates synergistic effects when coadministered with SGLT-2 inhibitors. In comparison to the application of metformin alone, the combination of metformin and SGLT-2 inhibitors improved arterial stiffness in T1DM patients. Endothelial dysfunction is improved through the combination of metformin and saxagliptin in T2DM.
Metformin and kidney disease
Metformin is renally excreted. Bearing in mind that moderate to severe renal disease with eGFR < 60 mL/min occurs in 20%–30% of patients with T2DM, metformin dose reduction should be considered at an eGFR < 45 mL/min and at an eGFR < 30 mL/min, metformin should not be used. If eGFR is 30–60 mL/min, the 2019 ADA Standards of Medical Care additionally advise to pause metformin treatment before iodinated contrast imaging procedures.
SGLT-2 Inhibitors
Drug Class Overview
The 2019 ADA Standards of Medical Care state that if the HbA1c target is not achieved after 3 months of metformin and lifestyle intervention alone, metformin can be combined with additional drugs. For patients with ASCVD, HF, or CKD, the guidelines recommend the addition of SGLT-2 inhibitors or glucagon-like peptide 1 (GLP-1) receptor agonists.
Mechanisms of Action
SGLT-2 inhibitors work by decreasing glucose levels through urinary excretion ( Fig. 4.5 ). Their glucosuric effect, coupled with a diuretic-mediated antihypertensive effect and hemoconcentration, may explain their cardiovascular benefits. The inhibition of SGLT-2 receptors in the kidneys result in increased urinary excretion of glucose, which reduces postprandial glycemic excursions and leads to more effective glycaemic control and weight loss. The weight loss associated with SGLT-2 inhibitors, which was confirmed in a meta-analysis that compared SGLT-2 inhibitors with placebo showing that SGLT-2 inhibitors, were associated with a mean of 2.99 kg reduction in weight over 2 years (95% CI − 3.64 to − 2.34 ), may also contribute CVD risk reductions. These effects improve insulin sensitivity. The negative energy balance associated with glycosuria leads to ketone body metabolization by cardiac myocytes, which are a more efficient energy fuel. The osmotic diuresis contributes to the BP reduction associated with SGLT-2 inhibitors. For example, the CANTATA-M (Canagliflozin Treatment and Trial Analysis – Monotherapy) trial showed that SBP and diastolic blood pressure (DBP) values were reduced with 300 mg canagliflozin by − 5.4 mmHg and − 2 mmHg, respectively.
Differences Among Drugs in Class
While canagliflozin and empagliflozin have demonstrated cardiovascular and renal benefits, canagliflozin was associated with a higher risk of lower limb amputations and fractures. The ADA 2019 Standards of Medical Care state that for patients with established ASCVD, evidence for empagliflozin is the strongest. Dapagliflozin showed significant benefits for individuals with HF.
Data for Use
Multiple large FDA mandated CVOTs have since reported on the cardiovascular effects of SGLT-2 inhibitors ( Table 4.6 ). The two FDA-approved SGLT-2 inhibitors, empagliflozin and canagliflozin, showed significant reductions in cardiovascular events.
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